EA046076B1 - CSF1R INHIBITORS FOR CANCER TREATMENT - Google Patents

Description

Cross reference to related applications

This application claims priority to US Patent Application No. 62/786105, filed December 28, 2018, US Patent Application No. 62/926341, filed October 25, 2019, and US Patent Application No. 62/933830, filed November 11 2019, the contents of which are incorporated herein by reference in their entirety.

State of the art

Colony-stimulating factor 1 receptor (CSF1R) and its ligand, colony-stimulating factor 1 (CSF1), together form a linear pathway for the development and differentiation from monocytes of normal macrophages. Tumor associated macrophages (TAMs) themselves are dependent on the kinase activity of CSF1R (also known as FMS) to mediate proliferation and maintain their differentiated state and immunosuppressive phenotype. The role of TAMs in promoting the formation of an invasive and immunosuppressive tumor microenvironment is well established. TAM mediates tumor growth, angiogenesis, invasiveness, metastasis, and immunosuppression through the secretion of and response to a variety of cytokines or other soluble factors. TAMs are trained in tumors to evade immune surveillance by attenuating the immune response mediated by cytotoxic T cells, thereby protecting the tumor from T cell killing. For example, TAMs express PD-L1, a known immunosuppressive checkpoint that induces tolerance in T cells.

Several inhibitors targeting CSF1R have gained prominence in clinical practice as direct antitumor therapies and potential immunotherapies. Many of these drugs also inhibit closely related type III receptor tyrosine kinases (KIT, PDGFRa/β, and FLT3), which may limit their utility due to off-target toxicity. Antibodies targeting CSF1R are much more specific but, among other disadvantages, result in a more than 10,000-fold increase in plasma levels of CSF1, the CSF1R ligand, due to blockade of CSF1 clearance.

Tenosynovial giant cell tumor (TGCT) is a proliferative and inflammatory disease that includes elements formerly known as pigmented villonodular synovitis (PVNS) and giant cell tumor of the tendon sheath (GCTTS), either intra-articular or extra-articular. It is a rare neoplastic disease of the joints or tendon sheaths with a destructive proliferation of mononuclear cells similar to synovial cells mixed with multinucleated giant cells, foam cells, siderophages and inflammatory cells. There are two types of TGCT: the localized or nodular form (where the tumor affects the tendons that support the joint or is in one area of the joint) and the diffuse form (where the entire lining of the joint is affected). Treatment consists of surgically cutting out the tumor. However, in cases of diffuse TGCT, marginal resection is often difficult, leading to a high recurrence rate. It may be characterized by overexpression of CSF1.

There is a need for selective small molecule inhibitors of CSF1R that are useful for the treatment of disorders associated with TAM proliferation, including solid tumors in various cancers, and the treatment of mesenchymal tumors, including TGCT and diffuse type tenosynovial giant cell tumor (DTGCT).

Short description

In particular, the present invention provides methods for treating disorders such as tenosynovial giant cell tumors and/or cancers in a patient in need thereof, comprising orally administering to the patient a therapeutically effective amount of a compound that is 2-(isopropylamino)-3-methyl- 5-(6-methyl-5-((2-(1-methyl-III-pyrazol-4-yl)pyridin-4yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one or a pharmaceutically acceptable compound thereof salt.

For example, the present invention describes a method of treating cancer selected from the group consisting of solid tumors, acute myeloid leukemia, myelodysplastic syndrome, acute lymphocytic leukemia and chronic lymphocytic leukemia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound representing is 2-(isopropylamino)-3-methyl-5-(6-methyl-5-((2-(1-methyl-III-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2yl)pyrimidine -4(3H)-one or a pharmaceutically acceptable salt thereof, wherein administration comprises: administration of a loading dose of the compound daily for a first period of time and administration of a maintenance dose of the compound once per week, twice per week (also described as twice per week), or three times a week for the second period of time.

The present invention also provides a method of treating tumors, such as GCTTS, PVNS, TGCT or DTGCT, comprising administering to a patient a therapeutically effective amount of a compound that is 2-(isopropylamino)-3-methyl-5-(6-methyl-5-((2- (1-methyl-N-pyrazol-4yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof, wherein administration involves administering a loading dose of the compound daily for the first period of time; and administering a maintenance dose of the compound once a week, twice a week, or

- 1 046076 three times a week for the second period of time.

A method of inhibiting the proliferation of a cell known to express a receptor that is colony stimulating factor 1 receptor (CSF1R) or its ligands, colony stimulating factor 1 (CSF1) or interleukin (IL) 34 in a patient in need thereof is also discussed in of this invention, the method comprising administering to a patient a therapeutically effective amount of a compound which is 2-(isopropylamino)-3methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl )pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof, wherein administration comprises: administering a loading dose of the compound daily for a first period of time; and administering a maintenance dose of the compound once a week, twice a week, or three times a week for a second period of time.

Brief description of graphic materials

In fig. 1 depicts dose-dependent changes in the number of CD11b+/F4/80+ macrophages within the tumor in mice treated with Compound 1.

In fig. 2 depicts the change in the number of intratumor CD11b+/F4/80+ macrophages in mice treated with Compound 1 compared to vehicle control or isotype control.

In fig. 3 is a graphical representation demonstrating depletion of CSF1R-expressing monocytes in peripheral blood obtained from patients treated with Compound 1.

In fig. 4 is a graphical representation showing the increase in CSF1 levels in plasma obtained from patients treated with Compound 1.

In fig. 5 depicts the plasma concentration of Compound 1 as a function of time on Day 1 of Cycle 2 for subjects in each of Cohorts 1-7 described in Example 3.

In fig. 6 depicts (A) plasma CSF1 concentrations in subjects in each of cohorts 1-7 described in Example 3 at various times during certain cycles (day 1 of cycle 1, day 15 of cycle 1, and day 1 of cycle 2); (B) plasma concentrations of IL-34 in subjects in each of cohorts 1-7 described in Example 3 at different times during certain cycles (day 1 of cycle 1, day 15 of cycle 1, and day 1 of cycle 2); and (C) the percentage change in CD16+ monocyte population size in subjects in each of cohorts 1-7 described in Example 3 at different time points of certain cycles (day 1 of cycle 1, day 15 of cycle 1, and day 1 of cycle 2).

In fig. 7 depicts (A) percentage change in CD163+ macrophage numbers in patients in selected cohorts determined by maintenance dose in Example 3; and (B) illustrative tumor biopsies at baseline and day 15 of cycle 2 in patients with pancreatic cancer or colon cancer.

In fig. 8A, 8B, and 8C depict the percentage reduction in size of diffuse-type tenosynovial giant cell tumor in Patient 1 (A), Patient 2 (B), and Patient 3 (C) in additional studies of the DTGCT cases described in Example 4 of this invention at several time points some cycles defined according to RECIST version 1.1.

In fig. 9 and 10 depict MRI images of tumor sites in exemplary DTGCT patients 1 and 2, respectively, described in Example 4 of the present invention.

In fig. 11 depicts (A) plasma CSF1 concentrations in subjects in each of cohorts 1-7 described in Example 3 at various times during certain cycles (day 1 of cycle 1, day 15 of cycle 1, and day 1 of cycle 2) along with associated data for patients 1, 2 and 3 from the DTGCT case studies described in Example 4; (B) Plasma concentrations of IL-34 in subjects in each of Cohorts 1-7 described in Example 3 at different times during certain cycles (day 1 of cycle 1, day 15 of cycle 1, and day 1 of cycle 2) along with relevant data for patients 1, 2 and 3 from the DTGCT case studies described in Example 4; and (C) the percentage change in CD16+ monocyte population size in subjects in each of cohorts 1-7 described in Example 3 at different time points of certain cycles (day 1 of cycle 1, day 15 of cycle 1, and day 1 of cycle 2) along with relevant data for patients 2 and 3 from the DTGCT case studies described in Example 4.

In fig. 12 depicts exemplary IC ₅₀ values of Compound 1 or pexidartinib for inhibition of M-NFS-60 cell proliferation in the presence of varying levels of the CSF1R ligand, CSF1.

In fig. 13 depicts exemplary total steady-state plasma concentrations of Compound 1 and its active metabolite in patients on Day 1 of Cycle 2 of the study described in Example 8 and exemplary GLP-compliant toxicity studies on Week 13 in rats and dogs.

In fig. 14 depicts illustrative results of a steady-state plasma concentration study of pexidartinib in rats and humans.

In fig. 15 is an exemplary graphical representation showing the depletion of CD16+ monocytes in peripheral blood obtained from patients treated with Compound 1.

- 2 046076

In fig. 16 is an exemplary graphical representation showing increases in CSF1 and IL-34 levels in plasma obtained from patients treated with Compound 1.

In fig. 17 depicts exemplary simulated administered dose values for Compound 1. The plot plots simulated dosing concentrations of Compound 1 for 3 different dosing schedules: (1) 10 mg QD, (2) 5 days of 30 mg QD loading dose followed by maintenance dose. 30 mg twice weekly and (3) 3 days of a loading dose of 30 mg QD followed by a maintenance dose of 10 mg QD. Pharmacokinetic modeling is based on preliminary nonparametric fitting using data from cohorts 1–7 obtained from patients for whom pharmacokinetic parameters were available at the time of analysis.

Detailed description

Definitions.

As used herein, the abbreviation DTGCT refers to diffuse type tenosynovial giant cell tumor.

The terms individual, patient or subject are used interchangeably in this invention and include any animal, including mammals, including mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, and humans. The compounds described in this invention can be administered to a mammal, such as a human, but can also be administered to other mammals, such as an animal in need of veterinary care, such as pets (eg, dogs, cats, etc.), farm animals ( e.g. cows, sheep, pigs, horses, etc.) and laboratory animals (e.g. rats, mice, guinea pigs, etc.). The mammal treated in the methods described in this invention is preferably a mammal in need of treatment of the disorder described in this invention, such as a human.

The term pharmaceutically acceptable salt(s) as used in this invention refers to salts formed by acidic or basic groups that may be present in the compounds used in these compositions. The compounds contained in these compositions, which are basic in nature, are capable of forming a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable acid addition salts from such basic compounds are acids that form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions, including, without limitation, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate salts, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e. 1,1'methylene-bis(2 -hydroxy-3-naphthoate)).

As used herein, the abbreviation TAM refers to tumor associated macrophages.

As used herein, the abbreviation TGCT refers to tenosynovial giant cell tumor.

As used herein, the abbreviation DTGCT refers to diffuse tenosynovial giant cell tumor.

As used herein, the abbreviation GCTTS refers to giant cell tumor of the tendon sheath.

As used herein, the abbreviation PVNS refers to pigmented villonodular synovitis.

As used herein, the term treatment includes any effect, such as reduction, reduction, modulation, or elimination, that results in an improvement in a condition, disease, disorder, or the like.

The expression "therapeutically effective amount" refers to an amount of a test compound that produces a biological or medical response in a tissue, system, animal, or human that is expected by the investigator, veterinarian, physician, or other medical personnel. A compound described herein, eg Compound 1, is administered in therapeutically effective amounts to treat a condition, eg TGCT or DTGCT. Alternatively, a therapeutically effective amount of a compound is the amount required to achieve the desired therapeutic and/or prophylactic effect, such as an amount that results in preventing the development of a condition or reducing the intensity of symptoms associated with the condition.

The compound described in this invention, for example compound 1, can be formulated as a pharmaceutical composition using a pharmaceutically acceptable carrier and can be administered through a variety of routes. In some embodiments, such compositions are for oral administration. In some embodiments, such compositions

- 3 046076 are intended for parenteral (by injection) administration (for example, a composition formulated for local injection into a tumor site, for example a diffuse type giant cell tumor). In some embodiments, such compositions are intended for transdermal administration. In some embodiments, such compositions are for intravenous (IV) administration. In some embodiments, such compositions are intended for intramuscular (IM) administration. Such pharmaceutical compositions and methods for their preparation are widely known in the art. See, for example, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro et al., eds., 19th ed., Mack Publishing Co., 1995).

Throughout this disclosure, various patents, patent applications, and publications are incorporated by reference. The disclosures of such patents, patent applications and publications are incorporated herein by reference in their entirety to more fully describe the state of the art known to those skilled in the art as of the date of this disclosure. This disclosure will govern if there is any inconsistency between patents, patent applications and publications and this disclosure.

ChemDraw version 10 or 12 (CambridgeSoft Corporation, Cambridge, MA) was used to name the structures of intermediates and illustrative compounds.

Methods of application.

This invention discloses selective CSF1R inhibitors including 2-(isopropylamino)-3methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy )pyridin-2-yl)pyrimidin-4(3H)-one (ie compound 1) and pharmaceutically acceptable salts thereof. Compound 1 can be represented as follows.

Connection 1

A compound described herein, e.g. Compound 1, can be used to inhibit TAM proliferation, promote TAM depletion, repolarize pro-tumor M2 TAMs to form anti-tumor M1 type macrophages, and treat related disorders in patients such as the disorders disclosed herein. for example diffuse type tenosynovial giant cell tumor (DTGCT), where treatment with Compound 1 depletes the mesenchymal type tumor of macrophages. In some embodiments, Compound 1 provides potent inhibition of CSF1R-mediated signaling. In some embodiments, Compound 1 blocks macrophage-mediated tumor cell migration. In some embodiments, Compound 1 blocks osteoclast differentiation. In some embodiments, Compound 1 blocks proliferation of a CSF1R-dependent cell line. In some embodiments, Compound 1 provides potent inhibition of CSF1R-mediated signaling in cell-based assays, and also blocks macrophage-mediated tumor cell migration, osteoclast differentiation, and CSF1R-dependent cell line proliferation. In some embodiments, the compound is selective for CSF1R, inhibiting it to a greater extent than one or more of the FLT3, KIT, PDGFRa, PDGFRe, and VEGFR2 kinases. In some embodiments, the compound is selective for CSF1R, inhibiting it 100-fold more strongly than FLT3, KIT, PDGFRa, PDGFRe, and VEGFR2 kinases.

In one embodiment, there is provided a method of treating a tenosynovial giant cell tumor in a patient in need thereof, comprising orally administering to the patient (e.g., a human patient) a therapeutically effective amount of a compound that is 2-(isopropylamino)-3-methyl-5-(6- methyl 5-((2-(1-methyl-N-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2yl)pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof. In some embodiments, such a tenosynovial giant cell tumor may be localized, for example, as a single well-defined nodule. In some embodiments, such a tenosynovial giant cell tumor may be a diffuse type tenosynovial giant cell tumor, such as a benign tumor. In some embodiments, such a tenosynovial giant cell tumor may be a diffuse type tenosynovial giant cell tumor, eg, with multiple nodules that are more aggressive. The method may include administering from about 2 mg to about 60 mg of a compound (eg, Compound 1) every day, once a week, twice a week, or three times a week. For example, a disclosed method, such as a method for treating tenosynovial gigantocle

- 4 046076 precise tumor may involve administering from about 10 mg to about 90 mg of the disclosed compound every day, twice a week or three times a week to a patient in need thereof. In some embodiments, a method of treating tenosynovial giant cell tumor may include administering from about 5 mg to about 70 mg of a disclosed compound every day, twice a week, or three times a week to a patient in need thereof. In some embodiments, a method of treating tenosynovial giant cell tumor may include administering from about 5 mg to about 50 mg of a disclosed compound every day, twice a week, or three times a week to a patient in need thereof. In some embodiments, a method of treating tenosynovial giant cell tumor may include administering from about 5 mg to about 30 mg of a disclosed compound every day, twice a week, or three times a week to a patient in need thereof. In some embodiments, a method of treating tenosynovial giant cell tumor may include administering from about 6 mg to about 25 mg of a disclosed compound every day, twice a week, or three times a week to a patient in need thereof. In some embodiments, a method of treating tenosynovial giant cell tumor may include administering from about 6 mg to about 20 mg of a disclosed compound every day, twice a week, or three times a week to a patient in need thereof. In some embodiments, a method of treating tenosynovial giant cell tumor may include administering about 20 mg to about 50 mg of a disclosed compound every day, twice a week, or three times a week to a patient in need thereof.

Such a disclosed method, in one embodiment, may include administering a loading dose of the compound daily for a first period of time and administering a maintenance dose of the compound every day, once a week, twice a week, or three times a week for a second period of time. For example, the loading dose may be from about 10 mg/day to about 80 mg/day, or from about 20 mg/day to about 60 mg/day. In some embodiments, the loading dose is about 20 mg/day, about 30 mg/day, about 40 mg/day, about 50 mg/day, or about 60 mg/day. In some embodiments, the maintenance dose of the compound is approximately 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27 , 28, 29 or 30 mg/day.

Administration of a maintenance dose may involve administering to the patient from about 10 mg to about 60 mg of the compound, such as about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, or about 50 mg, each of which can be administered one at a time. two or three times a week. In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 40 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 30 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 20 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 40 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 30 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 20 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 40 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 30 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 20 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 40 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 30 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 20 mg of the compound once per week. In some embodiments, the maintenance dose may include administering approximately 3 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 5 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 6 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 8 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 10 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include

- 5 046076 administer approximately 11 mg of the compound to the patient once a week. In some embodiments, the maintenance dose may include administering approximately 12 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 13 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 14 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 15 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 16 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 17 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 18 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 19 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 20 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 22 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 24 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 26 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 28 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 30 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 32 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 34 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 36 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 38 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 40 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 42 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 44 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 46 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 48 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 50 mg of the compound to the patient once per week.

In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 40 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 30 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 20 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 40 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 30 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 20 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 40 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 30 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 20 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 40 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 30 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 20 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering approximately 3 mg to the patient

- 6 046076 connections twice a week. In some embodiments, the maintenance dose may include administering approximately 5 mg of the compound twice per week to the patient. In some embodiments, the maintenance dose may include administering approximately 6 mg of the compound twice per week to the patient. In some embodiments, the maintenance dose may include administering approximately 8 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 10 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 11 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 12 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 13 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 14 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 15 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 16 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 17 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 18 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 19 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 20 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 22 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 24 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 26 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 28 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 30 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 32 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 34 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 36 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 38 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 40 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 42 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 44 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 46 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 48 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 50 mg of the compound twice per week to the patient.

In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 40 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 30 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 20 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 40 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 30 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 20 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 40 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 30 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 20 mg

- 7 046076 connections three times a week. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 40 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 30 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 20 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering approximately 3 mg of the compound three times per week to the patient. In some embodiments, the maintenance dose may include administering approximately 5 mg of the compound three times per week to the patient. In some embodiments, the maintenance dose may include administering approximately 6 mg of the compound three times per week to the patient. In some embodiments, the maintenance dose may include administering approximately 8 mg of the compound three times per week to the patient. In some embodiments, the maintenance dose may include administering approximately 10 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 11 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 12 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 13 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 14 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 15 mg of the compound three times per week to the patient. In some embodiments, the maintenance dose may include administering approximately 16 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 17 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 18 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 19 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 20 mg of the compound three times per week to the patient. In some embodiments, the maintenance dose may include administering approximately 22 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 24 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 26 mg of the compound three times per week to the patient. In some embodiments, the maintenance dose may include administering approximately 28 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 30 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 32 mg of the compound three times per week to the patient. In some embodiments, the maintenance dose may include administering approximately 34 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 36 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 38 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 40 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 42 mg of the compound three times per week to the patient. In some embodiments, the maintenance dose may include administering approximately 44 mg of the compound three times per week to the patient. In some embodiments, the maintenance dose may include administering approximately 46 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 48 mg of the compound three times per week to the patient. In some embodiments, the maintenance dose may include administering approximately 50 mg of the compound three times per week to the patient.

The maintenance dose can also be administered once daily. For example, a maintenance dose may involve administering approximately 2 mg of the compound to the patient once daily. In some embodiments, maintenance therapy may include administering to the patient from about 2 mg to about 40 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient from about 2 mg to about 30 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient from about 2 mg to about 20 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient from about 5 mg to about 40 mg of the compound

- 8 046076 once a day. In some embodiments, maintenance therapy may include administering to the patient from about 5 mg to about 30 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient from about 5 mg to about 20 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient from about 6 mg to about 40 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient from about 6 mg to about 30 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient from about 6 mg to about 20 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient from about 10 mg to about 40 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient from about 10 mg to about 30 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient from about 10 mg to about 20 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 3 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 5 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 6 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 8 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 10 mg of the compound once daily. In some embodiments, maintenance therapy may include administering approximately 11 mg of the compound to the patient once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 12 mg of the compound once daily. In some embodiments, maintenance therapy may include administering approximately 13 mg of the compound to the patient once daily. In some embodiments, maintenance therapy may include administering approximately 14 mg of the compound to the patient once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 15 mg of the compound once daily. In some embodiments, maintenance therapy may include administering approximately 16 mg of the compound to the patient once daily. In some embodiments, maintenance therapy may include administering approximately 17 mg of the compound to the patient once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 18 mg of the compound once daily. In some embodiments, maintenance therapy may include administering approximately 19 mg of the compound to the patient once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 20 mg of the compound once daily. In some embodiments, maintenance therapy may include administering approximately 22 mg of the compound to the patient once daily. In some embodiments, maintenance therapy may include administering approximately 24 mg of the compound to the patient once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 26 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 28 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 30 mg of the compound once daily. In some embodiments, the maintenance dose may include administering approximately 32 mg of the compound to the patient once daily. In some embodiments, the maintenance dose may include administering approximately 34 mg of the compound to the patient once daily. In some embodiments, the maintenance dose may include administering approximately 36 mg of the compound to the patient once daily. In some embodiments, the maintenance dose may include administering approximately 38 mg of the compound to the patient once daily. In some embodiments, the maintenance dose may include administering approximately 40 mg of the compound to the patient once daily. In some embodiments, the maintenance dose may include administering approximately 42 mg of the compound to the patient once daily. In some embodiments, the maintenance dose may include administering approximately 44 mg of the compound to the patient once daily. In some embodiments, the maintenance dose may include administering approximately 46 mg of the compound to the patient once daily. In some embodiments, the maintenance dose may include administering approximately 48 mg of the compound to the patient once daily. In some embodiments, the maintenance dose may include administering approximately 50 mg of the compound to the patient once daily.

- 9 046076

In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 40 mg of the compound every other day. In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 30 mg of the compound every other day. In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 20 mg of the compound every other day. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 40 mg of the compound every other day. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 30 mg of the compound every other day. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 20 mg of the compound every other day. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 40 mg of the compound every other day. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 30 mg of the compound every other day. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 20 mg of the compound every other day. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 40 mg of the compound every other day. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 30 mg of the compound every other day. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 20 mg of the compound every other day. In some embodiments, the maintenance dose may include administering approximately 3 mg of the compound every other day to the patient. In some embodiments, the maintenance dose may include administering approximately 5 mg of the compound every other day to the patient. In some embodiments, the maintenance dose may include administering approximately 6 mg of the compound every other day to the patient. In some embodiments, the maintenance dose may include administering approximately 8 mg of the compound every other day to the patient. In some embodiments, the maintenance dose may include administering approximately 10 mg of the compound every other day to the patient. In some embodiments, the maintenance dose may include administering approximately 11 mg of the compound to the patient every other day. In some embodiments, the maintenance dose may include administering approximately 12 mg of the compound to the patient every other day. In some embodiments, the maintenance dose may include administering approximately 13 mg of the compound to the patient every other day. In some embodiments, the maintenance dose may include administering approximately 14 mg of the compound to the patient every other day. In some embodiments, the maintenance dose may include administering approximately 15 mg of the compound to the patient every other day. In some embodiments, the maintenance dose may include administering approximately 16 mg of the compound to the patient every two days. In some embodiments, the maintenance dose may include administering approximately 17 mg of the compound every other day to the patient. In some embodiments, the maintenance dose may include administering approximately 18 mg of the compound to the patient every two days. In some embodiments, the maintenance dose may include administering approximately 19 mg of the compound to the patient every two days. In some embodiments, the maintenance dose may include administering approximately 20 mg of the compound to the patient every two days. In some embodiments, the maintenance dose may include administering approximately 22 mg of the compound to the patient every two days. In some embodiments, the maintenance dose may include administering approximately 24 mg of the compound to the patient every two days. In some embodiments, the maintenance dose may include administering approximately 26 mg of the compound to the patient every two days. In some embodiments, the maintenance dose may involve administering approximately 28 mg of the compound to the patient every two days. In some embodiments, the maintenance dose may include administering approximately 30 mg of the compound to the patient every two days. In some embodiments, the maintenance dose may include administering approximately 32 mg of the compound to the patient every two days. In some embodiments, the maintenance dose may include administering approximately 34 mg of the compound to the patient every two days. In some embodiments, the maintenance dose may include administering approximately 36 mg of the compound every other day to the patient. In some embodiments, the maintenance dose may include administering approximately 38 mg of the compound to the patient every two days. In some embodiments, the maintenance dose may include administering approximately 40 mg of the compound every other day to the patient. In some embodiments, the maintenance dose may include administering approximately 42 mg of the compound every other day to the patient. In some embodiments, the maintenance dose may include administering approximately 44 mg of the compound every other day to the patient. In some embodiments

- 10 046076 maintenance dose may involve administering approximately 46 mg of the compound every two days to the patient. In some embodiments, the maintenance dose may include administering approximately 48 mg of the compound every other day to the patient. In some embodiments, the maintenance dose may include administering approximately 50 mg of the compound every other day to the patient. In some embodiments, the duration of the first period of time, for example, during which the loading dose is administered (for example, every day or every other day, or twice a day) is approximately one or two weeks, or one to three weeks, for example, the duration of such first the time period may be about 4 days, about 5 days, about 6 days, or about 10 days. In some embodiments, the duration of the first time period is approximately one to six days. In some embodiments, the duration of the first period of time is approximately one to five days. In some embodiments, the duration of the first period of time is approximately one to four days. In some embodiments, the duration of the first period of time is approximately one to three days. In some embodiments, the duration of the first period of time is approximately one to two days. In some embodiments, the duration of the first time period is approximately one to five weeks. In some embodiments, the duration of the first time period is approximately one to four weeks. In some embodiments, the duration of the first time period is approximately one to three weeks. In some embodiments, the duration of the first period of time is approximately one to two weeks.

In some embodiments, the loading dose is from about 2 mg to about 100 mg of compound. In some embodiments, the loading dose is from about 5 mg to about 90 mg of compound. In some embodiments, the loading dose is from about 10 mg to about 80 mg of compound. In some embodiments, the loading dose is from about 10 mg to about 70 mg of compound. In some embodiments, the loading dose is from about 10 mg to about 60 mg of compound. In some embodiments, the loading dose is from about 10 mg to about 50 mg of compound. In some embodiments, the loading dose is from about 10 mg to about 40 mg of compound. In some embodiments, the loading dose is from about 10 mg to about 30 mg of compound. In some embodiments, the loading dose is from about 10 mg to about 20 mg of compound. In some embodiments, the loading dose is approximately 2 mg of the compound. In some embodiments, the loading dose is approximately 3 mg of the compound. In some embodiments, the loading dose is approximately 4 mg of compound. In some embodiments, the loading dose is approximately 5 mg of the compound. In some embodiments, the loading dose is approximately 10 mg of the compound. In some embodiments, the loading dose is approximately 11 mg of compound. In some embodiments, the loading dose is approximately 12 mg of the compound. In some embodiments, the loading dose is approximately 13 mg of compound. In some embodiments, the loading dose is approximately 14 mg of compound. In some embodiments, the loading dose is approximately 15 mg of the compound. In some embodiments, the loading dose is approximately 16 mg of the compound. In some embodiments, the loading dose is approximately 17 mg of compound. In some embodiments, the loading dose is approximately 18 mg of compound. In some embodiments, the loading dose is approximately 19 mg of compound. In some embodiments, the loading dose is approximately 20 mg of the compound. In some embodiments, the loading dose is approximately 22 mg of the compound. In some embodiments, the loading dose is approximately 24 mg of the compound. In some embodiments, the loading dose is approximately 26 mg of the compound. In some embodiments, the loading dose is approximately 28 mg of the compound. In some embodiments, the loading dose is approximately 30 mg of the compound. In some embodiments, the loading dose is approximately 32 mg of the compound. In some embodiments, the loading dose is approximately 34 mg of compound. In some embodiments, the loading dose is approximately 36 mg of the compound. In some embodiments, the loading dose is approximately 38 mg of the compound. In some embodiments, the loading dose is approximately 40 mg of the compound. In some embodiments, the loading dose is approximately 42 mg of the compound. In some embodiments, the loading dose is approximately 44 mg of the compound. In some embodiments, the loading dose is approximately 40 mg of the compound. In some embodiments, the loading dose is approximately 46 mg of the compound. In some embodiments, the loading dose is

- 11 046076 approximately 48 mg of compound. In some embodiments, the loading dose is approximately 50 mg of the compound.

In some embodiments, the loading dose is from about 2 mg to about 100 mg of the compound once daily. In some embodiments, the loading dose is from about 2 mg to about 100 mg of the compound once daily. In some embodiments, the loading dose is from about 5 mg to about 90 mg of the compound once daily. In some embodiments, the loading dose is from about 10 mg to about 80 mg of the compound once daily. In some embodiments, the loading dose is from about 10 mg to about 70 mg of the compound once daily. In some embodiments, the loading dose is from about 10 mg to about 60 mg of the compound once daily. In some embodiments, the loading dose is from about 10 mg to about 50 mg of the compound once daily. In some embodiments, the loading dose is from about 10 mg to about 40 mg of the compound once daily. In some embodiments, the loading dose is from about 10 mg to about 30 mg of the compound once daily. In some embodiments, the loading dose is from about 10 mg to about 20 mg of the compound once daily. In some embodiments, the loading dose is approximately 2 mg of the compound once daily. In some embodiments, the loading dose is approximately 3 mg of the compound once daily. In some embodiments, the loading dose is approximately 4 mg of the compound once daily. In some embodiments, the loading dose is approximately 5 mg of the compound once daily. In some embodiments, the loading dose is approximately 10 mg of the compound once daily. In some embodiments, the loading dose is approximately 11 mg of the compound once daily. In some embodiments, the loading dose is approximately 12 mg of the compound once daily. In some embodiments, the loading dose is approximately 13 mg of the compound once daily. In some embodiments, the loading dose is approximately 14 mg of the compound once daily. In some embodiments, the loading dose is approximately 15 mg of the compound once daily. In some embodiments, the loading dose is approximately 16 mg of the compound once daily. In some embodiments, the loading dose is approximately 17 mg of the compound once daily. In some embodiments, the loading dose is approximately 18 mg of the compound once daily. In some embodiments, the loading dose is approximately 19 mg of the compound once daily. In some embodiments, the loading dose is approximately 20 mg of the compound once daily. In some embodiments, the loading dose is approximately 22 mg of the compound once daily. In some embodiments, the loading dose is approximately 24 mg of the compound once daily. In some embodiments, the loading dose is approximately 26 mg of the compound once daily. In some embodiments, the loading dose is approximately 28 mg of the compound once daily. In some embodiments, the loading dose is approximately 30 mg of the compound once daily. In some embodiments, the loading dose is approximately 32 mg of the compound once daily. In some embodiments, the loading dose is approximately 34 mg of the compound once daily. In some embodiments, the loading dose is approximately 36 mg of the compound once daily. In some embodiments, the loading dose is approximately 38 mg of the compound once daily. In some embodiments, the loading dose is approximately 40 mg of the compound once daily. In some embodiments, the loading dose is approximately 42 mg of the compound once daily. In some embodiments, the loading dose is approximately 44 mg of the compound once daily. In some embodiments, the loading dose is approximately 40 mg of the compound once daily. In some embodiments, the loading dose is approximately 46 mg of the compound once daily. In some embodiments, the loading dose is approximately 48 mg of the compound once daily. In some embodiments, the loading dose is approximately 50 mg of the compound once daily.

In some embodiments, the loading dose is from about 2 mg to about 100 mg of the compound once per week. In some embodiments, the loading dose is from about 2 mg to about 100 mg of the compound once per week. In some embodiments, the loading dose is from about 5 mg to about 90 mg of the compound once per week. In some embodiments, the loading dose is from about 10 mg to about 80 mg of the compound once per week. In some embodiments, the loading dose is from about 10 mg to about 70 mg of the compound once per week. In some embodiments, the loading dose is from about 10 mg to about 60 mg of the compound once per week. In some variants

- 12 046076 in each implementation, the loading dose is from about 10 mg to about 50 mg of the compound once a week. In some embodiments, the loading dose is from about 10 mg to about 40 mg of the compound once per week. In some embodiments, the loading dose is from about 10 mg to about 30 mg of the compound once per week. In some embodiments, the loading dose is from about 10 mg to about 20 mg of the compound once per week. In some embodiments, the loading dose is approximately 2 mg of the compound once per week. In some embodiments, the loading dose is approximately 3 mg of the compound once per week. In some embodiments, the loading dose is approximately 4 mg of the compound once per week. In some embodiments, the loading dose is approximately 5 mg of the compound once per week. In some embodiments, the loading dose is approximately 10 mg of the compound once per week. In some embodiments, the loading dose is approximately 11 mg of the compound once per week. In some embodiments, the loading dose is approximately 12 mg of the compound once per week. In some embodiments, the loading dose is approximately 13 mg of the compound once per week. In some embodiments, the loading dose is approximately 14 mg of the compound once per week. In some embodiments, the loading dose is approximately 15 mg of the compound once per week. In some embodiments, the loading dose is approximately 16 mg of the compound once per week. In some embodiments, the loading dose is approximately 17 mg of the compound once per week. In some embodiments, the loading dose is approximately 18 mg of the compound once per week. In some embodiments, the loading dose is approximately 19 mg of the compound once per week. In some embodiments, the loading dose is approximately 20 mg of the compound once per week. In some embodiments, the loading dose is approximately 22 mg of the compound once per week. In some embodiments, the loading dose is approximately 24 mg of the compound once per week. In some embodiments, the loading dose is approximately 26 mg of the compound once per week. In some embodiments, the loading dose is approximately 28 mg of the compound once per week. In some embodiments, the loading dose is approximately 30 mg of the compound once per week. In some embodiments, the loading dose is approximately 32 mg of the compound once per week. In some embodiments, the loading dose is approximately 34 mg of the compound once per week. In some embodiments, the loading dose is approximately 36 mg of the compound once per week. In some embodiments, the loading dose is approximately 38 mg of the compound once per week. In some embodiments, the loading dose is approximately 40 mg of the compound once per week. In some embodiments, the loading dose is approximately 42 mg of the compound once per week. In some embodiments, the loading dose is approximately 44 mg of the compound once per week. In some embodiments, the loading dose is approximately 40 mg of the compound once per week. In some embodiments, the loading dose is approximately 46 mg of the compound once per week. In some embodiments, the loading dose is approximately 48 mg of the compound once per week. In some embodiments, the loading dose is approximately 50 mg of the compound once per week.

In some embodiments, the loading dose is from about 2 mg to about 100 mg of the compound twice per week. In some embodiments, the loading dose is from about 2 mg to about 100 mg of the compound twice per week. In some embodiments, the loading dose is from about 5 mg to about 90 mg of the compound twice per week. In some embodiments, the loading dose is from about 10 mg to about 80 mg of the compound twice per week. In some embodiments, the loading dose is from about 10 mg to about 70 mg of the compound twice per week. In some embodiments, the loading dose is from about 10 mg to about 60 mg of the compound twice per week. In some embodiments, the loading dose is from about 10 mg to about 50 mg of the compound twice per week. In some embodiments, the loading dose is from about 10 mg to about 40 mg of the compound twice per week. In some embodiments, the loading dose is from about 10 mg to about 30 mg of the compound twice per week. In some embodiments, the loading dose is from about 10 mg to about 20 mg of the compound twice per week. In some embodiments, the loading dose is approximately 2 mg of the compound twice per week. In some embodiments, the loading dose is approximately 3 mg of the compound twice per week. In some embodiments, the loading dose is approximately 4 mg of the compound twice per week. In some embodiments, the loading dose is approximately 5 mg of the compound

- 13 046076 twice a week. In some embodiments, the loading dose is approximately 10 mg of the compound twice per week. In some embodiments, the loading dose is approximately 11 mg of the compound twice per week. In some embodiments, the loading dose is approximately 12 mg of the compound twice per week. In some embodiments, the loading dose is approximately 13 mg of the compound twice per week. In some embodiments, the loading dose is approximately 14 mg of the compound twice per week. In some embodiments, the loading dose is approximately 15 mg of the compound twice per week. In some embodiments, the loading dose is approximately 16 mg of the compound twice per week. In some embodiments, the loading dose is approximately 17 mg of the compound twice per week. In some embodiments, the loading dose is approximately 18 mg of the compound twice per week. In some embodiments, the loading dose is approximately 19 mg of the compound twice per week. In some embodiments, the loading dose is approximately 20 mg of the compound twice per week. In some embodiments, the loading dose is approximately 22 mg of the compound twice per week. In some embodiments, the loading dose is approximately 24 mg of the compound twice per week. In some embodiments, the loading dose is approximately 26 mg of the compound twice per week. In some embodiments, the loading dose is approximately 28 mg of the compound twice per week. In some embodiments, the loading dose is approximately 30 mg of the compound twice per week. In some embodiments, the loading dose is approximately 32 mg of the compound twice per week. In some embodiments, the loading dose is approximately 34 mg of the compound twice per week. In some embodiments, the loading dose is approximately 36 mg of the compound twice per week. In some embodiments, the loading dose is approximately 38 mg of the compound twice per week. In some embodiments, the loading dose is approximately 40 mg of the compound twice per week. In some embodiments, the loading dose is approximately 42 mg of the compound twice per week. In some embodiments, the loading dose is approximately 44 mg of the compound twice per week. In some embodiments, the loading dose is approximately 40 mg of the compound twice per week. In some embodiments, the loading dose is approximately 46 mg of the compound twice per week. In some embodiments, the loading dose is approximately 48 mg of the compound twice per week. In some embodiments, the loading dose is approximately 50 mg of the compound twice per week.

The duration of the second period of time, during which, for example, the maintenance dose is administered, may be at least about one week or more, such as about one month or more (for example, from about 1 month to about 2 months, from about 1 month to about 3 months, from about 1 month to about 4 months, from about 1 month to about 5 months, from about 1 month to about 6 months, from about 1 month to about 9 months, from 1 month to about 12 months or more).

The method includes administering a loading dose every day for a first period of time and administering a maintenance dose every day for a second period of time. In some embodiments, the duration of the first period of time is from one day to 6 days, and the duration of the second period is from one to 35 days. In some embodiments, the duration of the first period of time is from one day to 6 days, and the duration of the second period is from one to 30 days. In some embodiments, the duration of the first period of time is from one day to 6 days, and the duration of the second period is from one to 25 days. In some embodiments, the duration of the first period of time is from one day to 6 days, and the duration of the second period is from one to 22 days. In some embodiments, the duration of the first period of time is from one day to 6 days, and the duration of the second period is from one to 20 days. In some embodiments, the duration of the first period of time is from one day to 5 days, and the duration of the second period is from one day to 35 days. In some embodiments, the duration of the first period of time is from one day to 5 days, and the duration of the second period is from one to 30 days. In some embodiments, the duration of the first period of time is from one day to 5 days, and the duration of the second period is from one day to 25 days. In some embodiments, the duration of the first period of time is from one day to 5 days, and the duration of the second period is from one day to 22 days. In some embodiments, the duration of the first period of time is from 1 to 5 days, and the duration of the second period is from 1 to 20 days. In some embodiments, the duration of the first period of time is from one day to 4 days, and the duration

- 14 046076 of the second period is from one day to 35 days. In some embodiments, the duration of the first period of time is from one day to 4 days, and the duration of the second period is from one to 30 days. In some embodiments, the duration of the first period of time is from one day to 4 days, and the duration of the second period is from one day to 25 days. In some embodiments, the duration of the first period of time is from one day to 4 days, and the duration of the second period is from one day to 22 days. In some embodiments, the duration of the first period of time is from one day to 4 days, and the duration of the second period is from one day to 20 days. In some embodiments, the duration of the first period of time is from one day to 3 days, and the duration of the second period is from one day to 35 days. In some embodiments, the duration of the first period of time is from one day to 3 days, and the duration of the second period is from one to 30 days. In some embodiments, the duration of the first period of time is from one day to 3 days, and the duration of the second period is from one day to 25 days. In some embodiments, the duration of the first period of time is from one day to 3 days, and the duration of the second period is from one day to 22 days. In some embodiments, the duration of the first period of time is from one day to 3 days, and the duration of the second period is from one day to 20 days. In some embodiments, the duration of the first period of time is from one day to 2 days, and the duration of the second period is from one day to 35 days. In some embodiments, the duration of the first period of time is from one day to 2 days, and the duration of the second period is from one to 30 days. In some embodiments, the duration of the first period of time is from one day to 2 days, and the duration of the second period is from one day to 25 days. In some embodiments, the duration of the first period of time is from one day to 2 days, and the duration of the second period is from one day to 22 days. In some embodiments, the duration of the first period of time is from one day to 2 days, and the duration of the second period is from one day to 20 days. In other embodiments, the duration of the first time period and the second time period together is 20 days. In some embodiments, the duration of the first time period and the second time period together is 21 days. In some embodiments, the duration of the first time period and the second time period together is 22 days. In some embodiments, the duration of the first time period and the second time period together is 23 days. In some embodiments, the duration of the first time period and the second time period together is 24 days. In some embodiments, the duration of the first time period and the second time period together is 25 days. In some embodiments, the duration of the first time period and the second time period together is 26 days. In some embodiments, the duration of the first time period and the second time period together is 27 days. In some embodiments, the duration of the first time period and the second time period together is 28 days. In some embodiments, the duration of the first time period and the second time period together is 29 days. In some embodiments, the duration of the first time period and the second time period together is 30 days. In some embodiments, the duration of the first time period and the second time period together is 31 days. In some embodiments, the duration of the first time period and the second time period together is 32 days. In some embodiments, the duration of the first time period and the second time period together is 33 days. In some embodiments, the duration of the first time period and the second time period together is 34 days. In some embodiments, the duration of the first time period and the second time period together is 35 days. In the disclosed methods, administration may occur over a cycle comprising a first time period and a second time period. In some embodiments, the cycle includes 20 days. In some embodiments, the cycle includes 21 days. In some embodiments, the cycle includes 22 days. In some embodiments, the cycle includes 23 days. In some embodiments, the cycle is 24 days. In some embodiments, the cycle includes 25 days. In some embodiments, the cycle includes 26 days. In some embodiments, the cycle includes 27 days. In some embodiments, the cycle includes 28 days. In some embodiments, the cycle includes 29 days. In some embodiments, the cycle includes 30 days. In some embodiments, the cycle includes 31 days. In some embodiments, the cycle includes 32 days. In some embodiments, the cycle includes 33 days. In some embodiments, the cycle is 34 days. In some embodiments, the cycle includes 35 days. In other embodiments, this method may administer administration over one to 1200 cycles. In some embodiments of this method, the introduction of

- 15 046076 can be carried out within 10-1000 cycles. In some embodiments of this method, administration may occur over 50-800 cycles. In some embodiments of this method, administration may occur over 70-700 cycles. In some embodiments of this method, administration may occur over 100-500 cycles.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 7 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 10 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 7 days, followed by administration of a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 10 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 7 days, followed by administration of a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each

- 16 046076 day for 10 days, followed by a maintenance dose of 10 mg of the compound every day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method comprises administering a loading dose of 10 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method comprises administering a loading dose of 10 mg of the compound each day for 7 days, followed by administration of a maintenance dose of 10 mg of the compound each day. In some embodiments, the method comprises administering a loading dose of 10 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 10 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 7 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 10 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 7 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 10 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method

- 17 046076 involves the administration of a loading dose of 5 mg of the compound every day for 4 days, followed by the administration of a maintenance dose of 10 mg of the compound every two days. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 5 days, followed by administration of a maintenance dose of 10 mg of the compound once

- 18 046076 in two days. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 4 days, followed by administration of a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 5 days, followed by administration of a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 6 days, followed by administration of a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 7 days with

- 19 046076 followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 9 days, followed by administration of a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 8 days, followed by administration of a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 7 days, followed by administration of a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 8 days, followed by administration of a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 5 days, followed by administration of a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 8 days, followed by administration of a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg compound, every day for 9 days, followed by a maintenance dose of 10 mg of the compound, twice

- 21 046076 per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method

- 22 046076 involves the administration of a loading dose of 12 mg of the compound every day for 3 days, followed by the administration of a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 7 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg

- 23 046076 compound, every day for 4 days, followed by a maintenance dose of 10 mg of the compound, three times a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 7 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 10 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 7 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 7 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 10 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 5 days after

- 24 046076 by administering a maintenance dose of 10 mg of the compound three times a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 7 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 10 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 7 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 10 days, followed by a maintenance dose of 10 mg of the compound three times per week.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 10 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg

- 25 046076 compound, every day for 6 days, followed by a maintenance dose of 20 mg of the compound every day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 10 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 10 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method comprises administering a loading dose of 20 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 10 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments

- 26 046076 method includes administering a loading dose of 12 mg of the compound every day for 8 days, followed by administration of a maintenance dose of 20 mg of the compound every day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 10 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 10 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 20 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg with

- 27 046076 unity, once every two days. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 10 days, followed by

- 28 046076 a maintenance dose of 20 mg of the compound every two days. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 3 days, followed by administration of a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 4 days, followed by administration of a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound once a week. In some variants

- 29 046076 This method involves administering a loading dose of 8 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 4 days, followed by administration of a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes introducing

- 30 046076 giving a loading dose of 15 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each

- 31 046076 day for 6 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method comprises administering a loading dose of 15 mg of the compound each day for 7 days after

- 32 046076 by administering a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 10 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 10 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg with

- 33 046076 unity, three times a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 10 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 10 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some va

- 34 046076 embodiments, the method involves administering a loading dose of 15 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound three times a week.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 4 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 4 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 4 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg with

- 35 046076 unity, every day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 4 days, followed by administration of a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 4 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 4 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 4 days with

- 36 046076 followed by a maintenance dose of 30 mg of the compound every two days. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose, the composition

- 37 046076 giving 10 mg of the compound, every day for 6 days, followed by a maintenance dose of 30 mg of the compound every two days. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 5 days, followed by administration of a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 7 days, followed by administration of a maintenance dose of 30 mg of the compound once a week. IN

- 38 046076 In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 8 days, followed by administration of a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 7 days, followed by administration of a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 4 days, followed by administration of a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound once per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes

- 39 046076 administration of a loading dose of 10 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose, the composition

- 40 046076 giving 5 mg of the compound, every day for 10 days, followed by a maintenance dose of 30 mg of the compound, twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 3 days with

- 41 046076 followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 4 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 4 days, followed by administration of a maintenance dose, the composition

- 42 046076 giving 30 mg of the compound, three times a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 4 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 4 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 4 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound three times per week. In neko

- 43 046076 In other embodiments, the method comprises administering a loading dose of 12 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound three times a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 4 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound three times per week.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 3 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 4 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 5 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 6 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 7 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 8 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 9 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 10 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 3 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 4 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 5 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 6 days, followed by administration of a maintenance dose, the composition

- 44 046076 giving 40 mg of the compound, every day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 7 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 8 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 9 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 40 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 3 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 4 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 5 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 6 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 7 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 8 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 9 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 10 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 3 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 4 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 5 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 6 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 7 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 8 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 9 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 10 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 3 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 4 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 5 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 6 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 7 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 8

- 45 046076 days followed by a maintenance dose of 40 mg of the compound every day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 9 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 40 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 3 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 4 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 5 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 6 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 7 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 8 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 9 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 10 days, followed by a maintenance dose of 40 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 3 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 4 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 5 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 6 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 7 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 8 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 9 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 10 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 3 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 4 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 5 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 6 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 7 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 8 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 9 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes introducing a load

- 46 046076 a dose of 7 mg of the compound every day for 10 days, followed by a maintenance dose of 40 mg of the compound every two days. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 3 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 4 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 5 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 6 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 7 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 8 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 9 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 10 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 3 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 4 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 5 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 6 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 7 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 8 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 9 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 10 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 3 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 4 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 5 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 6 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 7 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 8 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 9 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 10 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 3 days, followed by a maintenance dose of 40 mg of the compound every other day. In some

- 47 046076 embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 4 days, followed by administration of a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 5 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 6 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 7 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 8 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 9 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 10 days, followed by a maintenance dose of 40 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 3 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 4 days, followed by administration of a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 5 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 6 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 7 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 8 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 9 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 10 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 3 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 4 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 5 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 6 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 7 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 8 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 9 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 10 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 3 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 4 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound

- 48 046076 neniya, every day for 5 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 6 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 7 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 8 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 9 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 10 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 3 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 4 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 5 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 6 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 7 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 8 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 9 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 40 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 3 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 4 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 5 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 6 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 7 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 8 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 9 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 10 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 3 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 4 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 5 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 6 days with

- 49 046076 followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 7 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 8 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 9 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 10 days, followed by a maintenance dose of 40 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 3 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 4 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 5 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 6 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 7 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 8 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 9 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 10 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 3 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 4 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 5 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 6 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 7 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 8 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 9 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 10 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 3 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 4 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 5 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 6 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 7 days, followed by administration of a maintenance dose, the composition

- 50 046076 giving 40 mg of the compound, twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 8 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 9 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 10 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 3 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 4 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 5 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 6 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 7 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 8 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 9 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 10 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 3 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 4 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 5 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 6 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 7 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 8 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 9 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 10 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 3 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 4 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 5 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 6 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 7 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 8 days, followed by a maintenance dose of 40 mg of the compound twice a week. IN

- 51 046076 In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 9 days, followed by administration of a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 10 days, followed by a maintenance dose of 40 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 3 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 4 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 5 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 6 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 7 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 8 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 9 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 10 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 3 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 4 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 5 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 6 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 7 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 8 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 9 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 10 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 3 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 4 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 5 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 6 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 7 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 8 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 9 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering

- 52 046076 a loading dose of 8 mg of the compound every day for 10 days, followed by a maintenance dose of 40 mg of the compound three times a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 3 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 4 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 5 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 6 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 7 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 8 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 9 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 10 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 3 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 4 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 5 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 6 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 7 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 8 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 9 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 10 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 3 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 4 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 5 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 6 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 7 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 8 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 9 days, followed by a maintenance dose of 40 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 10 days, followed by a maintenance dose of 40 mg of the compound three times per week.

In some embodiments, the loading dose is administered over a period of 1 to 20 days and under

- 53 046076 the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 3 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 4 days, followed by administration of a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 5 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 6 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 7 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 8 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 9 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 10 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 3 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 4 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 5 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 6 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 7 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 8 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 9 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 40 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 3 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 4 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 5 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 6 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 7 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 8 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 9 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 10 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 3 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for

- 54 046076 for 4 days, followed by a maintenance dose of 50 mg of the compound every day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 5 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 6 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 7 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 8 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 9 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 10 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 3 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 4 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 5 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 6 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 7 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 8 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 9 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 40 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 3 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 4 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 5 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 6 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 7 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 8 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 9 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 10 days, followed by a maintenance dose of 50 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 3 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 4 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 5 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering

- 55 046076 a loading dose of 5 mg of the compound every day for 6 days, followed by a maintenance dose of 50 mg of the compound every two days. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 7 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 8 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 9 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 10 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 3 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 4 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 5 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 6 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 7 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 8 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 9 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 10 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 3 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 4 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 5 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 6 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 7 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 8 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 9 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 10 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 3 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 4 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 5 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 6 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 7 days, followed by a maintenance dose of 50 mg of the compound every other day. In neko

- 56 046076 In other embodiments, the method comprises administering a loading dose of 10 mg of the compound every day for 8 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 9 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 10 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 3 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 4 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 5 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 6 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 7 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 8 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 9 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 10 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 3 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 4 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 5 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 6 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 7 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 8 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 9 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 10 days, followed by a maintenance dose of 50 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 3 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 4 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 5 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 6 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 7 days, followed by administration of a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 8 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 9 days thereafter.

- 57 046076 by administering a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 10 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 3 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 4 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 5 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 6 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 7 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 8 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 9 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 10 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 3 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 4 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 5 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 6 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 7 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 8 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 9 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 10 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 3 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 4 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 5 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 6 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 7 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 8 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 9 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 40 days followed by administration of a maintenance dose, the composition

- 58 046076 giving 10 mg of the compound, once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 3 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 4 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 5 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 6 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 7 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 8 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 9 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 10 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 3 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 4 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 5 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 6 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 7 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 8 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 9 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 10 days, followed by a maintenance dose of 50 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 3 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 4 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 5 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 6 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 7 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 8 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 9 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 10 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 3 days, followed by a maintenance dose of 50 mg of the compound twice a week. IN

- 59 046076 In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 4 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 5 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 6 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 7 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 8 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 9 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound every day for 10 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 3 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 4 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 5 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 6 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 7 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 8 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 9 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 10 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 3 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 4 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 5 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 6 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 7 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 8 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 9 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound every day for 10 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 3 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 4 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes

- 60 046076 administration of a loading dose of 12 mg of the compound every day for 5 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 6 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 7 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 8 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 9 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound every day for 10 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 3 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 4 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 5 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 6 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 7 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 8 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 9 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 10 days, followed by a maintenance dose of 50 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 3 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 4 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 5 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 6 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 7 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 8 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound each day for 9 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 5 mg of the compound every day for 10 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 3 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 4 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 5 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound

- 61 046076 neniya, every day for 6 days, followed by a maintenance dose of 50 mg of the compound three times a week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 7 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 8 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 9 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 7 mg of the compound each day for 10 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 3 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 4 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 5 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 6 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 7 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 8 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound each day for 9 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 8 mg of the compound every day for 10 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 3 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 4 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 5 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 6 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 7 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 8 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 9 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 10 mg of the compound each day for 10 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 3 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 4 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 5 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 6 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 7 days, followed by

- 62 046076 by administering a maintenance dose of 50 mg of the compound three times a week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 8 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 9 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 12 mg of the compound each day for 10 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 3 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 4 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 5 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 6 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 7 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 8 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound each day for 9 days, followed by a maintenance dose of 50 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 15 mg of the compound every day for 10 days, followed by a maintenance dose of 50 mg of the compound three times per week.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 3 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 4 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 5 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 6 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 7 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 8 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 9 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 10 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 3 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 4 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 5 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 6 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 7 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound, each

- 63 046076 day for 8 days, followed by a maintenance dose of 6 mg of the compound every day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 9 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 10 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 3 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 4 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 5 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 6 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 7 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 8 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 9 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 10 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 3 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 4 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 5 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 6 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 7 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 8 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 9 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 10 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 3 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 4 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 5 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 6 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 7 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 8 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 9 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose,

- 64 046076 containing 60 mg of the compound, every day for 10 days, followed by a maintenance dose of 6 mg of the compound every day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 3 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 4 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 5 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 6 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 7 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 8 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 9 days, followed by a maintenance dose of 6 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 10 days, followed by a maintenance dose of 6 mg of the compound each day.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 3 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 4 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 5 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 6 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 7 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 8 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 9 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 10 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 3 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 4 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 5 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 6 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 7 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 8 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 9 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 10 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg

- 65 046076 compound, every day for 3 days, followed by a maintenance dose of 8 mg of the compound every day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 4 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 5 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 6 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 7 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 8 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 9 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 10 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 3 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 4 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 5 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 6 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 7 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 8 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 9 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 10 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 3 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 4 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 5 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 6 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 7 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 8 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 9 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 10 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 3 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 4 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes introducing

- 66 046076 administration of a loading dose of 70 mg of the compound every day for 5 days, followed by a maintenance dose of 8 mg of the compound every day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 6 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 7 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 8 days, followed by a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 9 days, followed by administration of a maintenance dose of 8 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 10 days, followed by a maintenance dose of 8 mg of the compound each day.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 7 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 10 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method comprises administering a loading dose of 30 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 7 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 10 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes

- 67 046076 administration of a loading dose of 40 mg of the compound every day for 6 days, followed by administration of a maintenance dose of 10 mg of the compound every day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 7 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 10 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 7 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 10 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 7 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 10 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 7 days, followed by a maintenance dose of 10 mg of the compound.

- 68 046076 niya, every day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 10 days, followed by a maintenance dose of 10 mg of the compound each day.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method comprises administering a loading dose of 25 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 7 days, followed by administration of a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 10 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 10 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 8 days followed by

- 69 046076 maintenance dose of 20 mg of the compound every day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 10 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 10 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 10 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70

- 70 046076 mg of the compound, every day for 10 days, followed by a maintenance dose of 20 mg of the compound every day.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method comprises administering a loading dose of 25 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 4 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method comprises administering a loading dose of 30 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 4 days, followed by administration of a maintenance dose of 30 mg of the compound each day. In some embodiments, the method comprises administering a loading dose of 30 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method comprises administering a loading dose of 30 mg of the compound each day for 6 days, followed by administration of a maintenance dose of 30 mg of the compound each day. In some embodiments, the method comprises administering a loading dose of 30 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 8 days, followed by administration of a maintenance dose of 30 mg of the compound each day. In some embodiments, the method comprises administering a loading dose of 30 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 4 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 8 days, followed by administration of a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method

- 71 046076 involves administering a loading dose of 50 mg of a compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound every day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 4 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 4 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 4 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound each day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound each day.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 3 days, followed by a maintenance dose of 6 mg of the compound every other day. In neko

- 72 046076 In other embodiments, the method comprises administering a loading dose of 20 mg of the compound every day for 4 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 5 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 6 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 7 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 8 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 9 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 10 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 3 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 4 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 5 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 6 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 7 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 8 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 9 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 10 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 3 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 4 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 5 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every other day for 6 days, followed by a maintenance dose of 6 mg of the compound every day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every other day for 7 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 8 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 9 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 10 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 3 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 4 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 5 days followed by administration of a maintenance dose, the composition

- 73 046076 administering 6 mg of the compound, once every two days. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 6 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 7 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 8 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 9 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 10 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 3 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 4 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 5 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 6 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 7 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 8 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 9 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 10 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 3 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 4 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 5 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 6 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 7 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 8 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 9 days, followed by a maintenance dose of 6 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 10 days, followed by a maintenance dose of 6 mg of the compound every other day.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 3 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 4 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 5 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound, each

- 74 046076 day for 6 days, followed by a maintenance dose of 8 mg of the compound every two days. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 7 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 8 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 9 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 10 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 3 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 4 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 5 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 6 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 7 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 8 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 9 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 10 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 3 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 4 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 5 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 6 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 7 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 8 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 9 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 10 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 3 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 4 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 5 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 6 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 7 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments,

- 75 046076 sob includes the administration of a loading dose of 50 mg of the compound every day for 8 days, followed by the administration of a maintenance dose of 8 mg of the compound every two days. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 9 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 10 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 3 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 4 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 5 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 6 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 7 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 8 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 9 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 10 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 3 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 4 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 5 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 6 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 7 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 8 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 9 days, followed by a maintenance dose of 8 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 10 days, followed by a maintenance dose of 8 mg of the compound every other day.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound every other day.

- 76 046076 days. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 10 days, followed by

- 77 046076 with a maintenance dose of 10 mg of the compound every two days. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound every other day.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound,

- 78 046076 every day for 3 days, followed by a maintenance dose of 20 mg of the compound every two days. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments

- 79 046076 the method involves administering a loading dose of 60 mg of the compound every day for 5 days, followed by administration of a maintenance dose of 20 mg of the compound every two days. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound every other day.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 5 days, followed by administration of a maintenance dose of 30 mg of the compound once

- 80 046076 in two days. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 7 days from

- 81 046076 by administering a maintenance dose of 30 mg of the compound every two days. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound every other day. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound every other day.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 3 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 4 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 5 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 6 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 7 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 8 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 9 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 10 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 3 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 4 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 5 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 6 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 7 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes

- 82 046076 administration of a loading dose of 30 mg of the compound every day for 8 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 9 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 10 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 3 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 4 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 5 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 6 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 7 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 8 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 9 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 10 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 3 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 4 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 5 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 6 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 7 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 8 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 9 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 10 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 3 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 4 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 5 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 6 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 7 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 8 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound,

- 83 046076 every day for 9 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 10 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 3 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 4 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 5 days, followed by administration of a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 6 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 7 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 8 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 9 days, followed by a maintenance dose of 6 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 10 days, followed by a maintenance dose of 6 mg of the compound once a week.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 3 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 4 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 5 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 6 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 7 days, followed by administration of a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 8 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 9 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 10 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 3 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 4 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 5 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 6 days, followed by administration of a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 7 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 8 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 9 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 10 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 3 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 4 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 5 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 6 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 7 days, followed by administration of a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 8 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 9 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 10 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 3 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 4 days, followed by administration of a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 5 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 6 days, followed by administration of a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 7 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 8 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 9 days, followed by administration of a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 10 days, followed by a maintenance dose of 8 mg of the compound once per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 3 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 4 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 5 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 6 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 7 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 8 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 9 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 10 days, followed by administration of a maintenance dose of 8 mg of the compound once per week. In some embodiments

- 85 046076 implementation of the method includes the administration of a loading dose of 70 mg of the compound every day for 3 days, followed by the administration of a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 4 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 5 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 6 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 7 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 8 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 9 days, followed by a maintenance dose of 8 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 10 days, followed by a maintenance dose of 8 mg of the compound once a week.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg with

- 86 046076 compound, every day for 3 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 3 days, followed by administration of a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 4 days, followed by administration of a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 7 days, followed by administration of a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 9 days, followed by administration of a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method comprises administering a loading dose of 70 mg of the compound each day for 4 days after

- 87 046076 by administering a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound once a week.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 9 days, followed by administration of a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound once a week. In some

- 88 046076 embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 5 days, followed by administration of a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound once per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes introducing

- 89 046076 giving a loading dose of 70 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound once a week.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 6 days, followed by administration of a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound once per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 6 days followed by

- 90 046076 maintenance dose of 30 mg of the compound, once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 9 days, followed by administration of a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg.

- 91 046076 connections, once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound once a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound once a week.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 3 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 4 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 5 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 6 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 7 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 8 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 9 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 10 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 3 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 4 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 5 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 6 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 7 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 8 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 9 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 10 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 3 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 4 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 5 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 6 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 7 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of

- 92 046076 mg of the compound, every day for 8 days, followed by a maintenance dose of 6 mg of the compound, twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 9 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 10 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 3 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 4 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 5 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 6 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 7 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 8 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 9 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 10 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 3 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 4 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 5 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 6 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 7 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 8 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 9 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 10 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 3 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 4 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 5 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 6 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 7 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 8 days, followed by a maintenance dose of 6 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 9 days followed by

- 93 046076 maintenance dose of 6 mg of the compound, twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 10 days, followed by a maintenance dose of 6 mg of the compound twice a week.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 3 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 4 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 5 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 6 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 7 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 8 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 9 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound every day for 10 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 3 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 4 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 5 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 6 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 7 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 8 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 9 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 10 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 3 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 4 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 5 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 6 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 7 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 8 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 9 days, followed by a maintenance dose of 8 mg of the compound twice a week. In neko

- 94 046076 In other embodiments, the method comprises administering a loading dose of 40 mg of the compound every day for 10 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 3 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 4 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 5 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 6 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 7 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 8 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 9 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 10 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 3 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 4 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 5 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 6 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 7 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 8 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 9 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 10 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 3 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 4 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 5 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 6 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 7 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 8 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 9 days, followed by a maintenance dose of 8 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 10 days, followed by a maintenance dose of 8 mg of the compound twice a week.

- 95 046076

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for

- 96 046076 3 days followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 5 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 8 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 3 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 4 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 6 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 9 days, followed by a maintenance dose of 10 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound twice a week.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound twice a week. IN

- 97 046076 In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 4 days, followed by administration of a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method

- 98 046076 involves administering a loading dose of 50 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 8 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 3 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 7 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 9 days, followed by a maintenance dose of 20 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 10 days, followed by a maintenance dose of 20 mg of the compound twice a week.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 5 days after

- 99 046076 by administering a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 6 days followed by administration of a maintenance dose, the composition

- 100 046076 giving 30 mg of the compound, twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 3 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 6 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 7 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 8 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 9 days, followed by a maintenance dose of 30 mg of the compound twice a week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound twice a week.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 3 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 4 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 5 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 6 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes introducing

- 101 046076 administration of a loading dose of 20 mg of the compound every day for 7 days, followed by a maintenance dose of 6 mg of the compound three times a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 8 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 9 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 10 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 3 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 4 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 5 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 6 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 7 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 8 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 9 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 10 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 3 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 4 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 5 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 6 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 7 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 8 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 9 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 10 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 3 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 4 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 5 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 6 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 7 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day

- 102 046076 for 8 days followed by a maintenance dose of 6 mg of the compound three times a week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 9 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 10 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 3 days, followed by a maintenance dose of 6 mg of the compound three times a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 4 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 5 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 6 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 7 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 8 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 9 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 10 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 3 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 4 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 5 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 6 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 7 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 8 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 9 days, followed by a maintenance dose of 6 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 10 days, followed by a maintenance dose of 6 mg of the compound three times per week.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 3 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 4 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 5 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 6 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 7 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 8 days, followed by administration of a maintenance dose of 8 mg

- 103 046076 connections, three times a week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 9 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 20 mg of the compound each day for 10 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 3 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 4 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 5 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 6 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 7 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 8 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 9 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 10 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 3 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 4 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 5 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 6 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 7 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 8 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 9 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 10 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 3 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 4 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 5 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 6 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 7 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 8 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 9 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments

- 104 046076 method includes administering a loading dose of 50 mg of the compound every day for 10 days, followed by administration of a maintenance dose of 8 mg of the compound three times a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 3 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 4 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 5 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 6 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 7 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 8 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 9 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 10 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 3 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 4 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 5 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 6 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 7 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 8 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 9 days, followed by a maintenance dose of 8 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 10 days, followed by a maintenance dose of 8 mg of the compound three times per week.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 7 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound, each

- 105 046076 day for 10 days, followed by a maintenance dose of 10 mg of the compound three times a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 7 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 7 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 10 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 7 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 10 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 3 days, followed by

- 106 046076 maintenance dose of 10 mg of the compound, three times a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 7 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 10 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 3 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 4 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 5 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 6 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 7 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 8 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 9 days, followed by a maintenance dose of 10 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound every day for 10 days, followed by a maintenance dose of 10 mg of the compound three times per week.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 10 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments it is possible to

- 107 046076 The method involves administering a loading dose of 30 mg of the compound every day for 4 days, followed by a maintenance dose of 20 mg of the compound three times a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 10 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 5 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 10 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound every day for 6 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 10 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose,

- 108 046076 containing 60 mg of the compound, every day for 5 days, followed by a maintenance dose of 20 mg of the compound, three times a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 10 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 3 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 4 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 5 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 6 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 7 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 8 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 9 days, followed by a maintenance dose of 20 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 10 days, followed by a maintenance dose of 20 mg of the compound three times per week.

In some embodiments, the loading dose is administered for 1 to 20 days and the maintenance dose is administered for 20 to 37,000 days. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 4 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 25 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 4 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 5 days followed by maintenance

- 109 046076 a dose of 30 mg of the compound, three times a week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 30 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 4 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 40 mg of the compound every day for 10 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 4 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 50 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 4 days, followed by a maintenance dose of 30 mg of the compound for a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 5 days, followed by a maintenance dose of 30 mg of the compound for a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound three times per week. IN

- 110 046076 In some embodiments, the method includes administering a loading dose of 60 mg of the compound every day for 7 days, followed by administration of a maintenance dose of 30 mg of the compound three times a week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 60 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 3 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 4 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 5 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 6 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 7 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 8 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 9 days, followed by a maintenance dose of 30 mg of the compound three times per week. In some embodiments, the method includes administering a loading dose of 70 mg of the compound each day for 10 days, followed by a maintenance dose of 30 mg of the compound three times per week.

In some embodiments, such a disclosed method may further include administering an additional loading dose over a third period of time (eg, after a period of time of the initial loading and maintenance doses).

The disclosed method may further include administering an additional maintenance dose over a fourth period of time (eg, as part of another dosing cycle after the time of the initial loading and initial maintenance doses). In some embodiments, the third and/or fourth time periods follow the first and second time periods.

In such disclosed methods, after 1 month or more of administration, the patient may experience improved tumor response as measured by ultrasound, CT, MRI, and/or PET scans using either RECIST 1.1 and/or volumetric assessment. In some embodiments, after 7 days, after 10 days, after 15 days, after 20 days, after 25 days or more of administration of the compound, the patient has an improvement in range of motion and other disease-related symptoms, such as patient-reported symptoms. In some embodiments, after 1 month, after 2 months or more of administration of the compound, the patient has improvement in range of motion and other disease-related symptoms, such as patient-reported symptoms. In some embodiments, after 1 month or more of administration of a compound to a patient, the patient may experience a decrease in the level of macrophage infiltration in the injured joint and/or the amount of circulating chemokines/cytokines associated with inflammation compared to these values before administration. In some embodiments, the tenosynovial giant cell tumor, such as DTGCT, is reduced in size by 99-1%, such as 90-10%, such as 85-20%, such as 80-25%, such as 75-25%, such as 70-30%, such as 65- 35%, for example 60-40%, for example 55-45%, for example 80-60%, of its size before the introduction of the compound.

In some embodiments, administration of Compound 1 or a pharmaceutically acceptable salt thereof is a continuous administration without interruption of drug administration. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered continuously over a period of time ranging from 1 day to 100 years. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof is administered while the drug is being taken. In some embodiments, administration of Compound 1 or a pharmaceutically acceptable salt thereof is continuous for a period of 1 day to 5 years, followed by a dosing period of 1 month to 5 years, followed by continuous administration of Compound 1 or a pharmaceutically acceptable salt thereof. over a period lasting from 1 day to 100 years. In some embodiments, the implementation

- 111 046076 administration of compound 1 or its pharmaceutically acceptable salt is continuous for a period of 1 month to 5 years, followed by a break in taking the drug for a duration of 1 month to 5 years, followed by continuous administration of compound 1 or its pharmaceutically acceptable salt for period lasting from 1 day to 100 years. In some embodiments, administration of Compound 1 or a pharmaceutically acceptable salt thereof is continuous over a period of 3 months to 5 years, followed by a dosing period of 1 month to 5 years, followed by continuous administration of Compound 1 or a pharmaceutically acceptable salt thereof into over a period lasting from 1 day to 100 years. In some embodiments, administration of Compound 1 or a pharmaceutically acceptable salt thereof is continuous over a period of 6 months to 5 years, followed by a dosing period of 1 month to 5 years, followed by continuous administration of Compound 1 or a pharmaceutically acceptable salt thereof into over a period lasting from 1 day to 100 years. In some embodiments, administration of Compound 1 or a pharmaceutically acceptable salt thereof is continuous over a period of 1 year to 5 years, followed by a dosing period of 1 month to 5 years, followed by continuous administration of Compound 1 or a pharmaceutically acceptable salt thereof. over a period lasting from 1 day to 100 years. In some embodiments, the administration of Compound 1 or a pharmaceutically acceptable salt thereof is continuous for a period of 2 years to 5 years, followed by a dosing period of 1 month to 5 years, followed by continuous administration of Compound 1 or a pharmaceutically acceptable salt thereof in over a period lasting from 1 day to 100 years. In some embodiments, administration of Compound 1 or a pharmaceutically acceptable salt thereof is continuous for a period of 3 to 5 years, followed by a dosing period of 1 month to 5 years, followed by continuous administration of Compound 1 or a pharmaceutically acceptable salt thereof for period lasting from 1 day to 100 years.

The present invention contemplates the administration of Compound 1 or a pharmaceutically acceptable salt to a patient in need thereof before (neoadjuvant) or after (adjuvant) surgery (eg, TGCT surgery). In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered as an adjuvant. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered as a neoadjuvant. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered as a neoadjuvant and adjuvant. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered to a patient in need thereof as a neoadjuvant for a period of 1 month to 6 months, followed by administration of Compound 1 or a pharmaceutically acceptable salt as an adjuvant for a period of 1 day to 100 years. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered to a patient in need thereof as a neoadjuvant for a period of 1 month to 6 months, followed by administration of Compound 1 or a pharmaceutically acceptable salt as an adjuvant for a period of 1 day. up to 5 years. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered to a patient in need thereof as a neoadjuvant for a period of 3 months to 6 months, followed by administration of Compound 1 or a pharmaceutically acceptable salt as an adjuvant for a period of 1 day. up to 5 years. In some embodiments, administration of Compound 1 or a pharmaceutically acceptable salt is not administered until after surgery. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered as an adjuvant for a period ranging from 1 day to 100 years. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered as an adjuvant for a period ranging from 1 day to 5 years.

The present invention also provides a method of treating tumors, such as GCTTS, PVNS, TGCT or DTGCT, comprising administering to a patient a therapeutically effective amount of a compound that is 2-(isopropylamino)-3-methyl-5-(6-methyl-5-((2 -(1-methyl-N-pyrazol4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3N)-one or a pharmaceutically acceptable salt thereof, before surgery. In some embodiments, administration involves administering a loading dose of the compound daily for a first period of time and administering a maintenance dose of the compound once a week, twice a week, or three times a week for a second period of time.

The present invention also provides a method for treating cancer, such as cancers selected from the group consisting of solid tumors, acute myeloid leukemia, myelodysplastic syndrome, acute lymphocytic leukemia, and chronic lymphocytic leukemia, in a patient in need thereof (e.g., a human patient suffering from cancer) comprising administering to the patient a therapeutically effective amount of a compound that is 2-(isopropylamino)-3

- 112 046076 methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H )-he or a pharmaceutically acceptable salt thereof, wherein administration involves administering a loading dose of the compound daily for a first period of time and administering a maintenance dose of the compound every day, twice a week, or three times a week for a second period of time. In some embodiments, the patient may suffer from a solid tumor, such as a solid tumor of the breast, cervix, pancreas, bladder, prostate, stomach, ovary, melanoma, glioma, glioblastoma multiforme, osteosarcoma, osteolytic cancers, chondrosarcoma, histiocytosis or lung cancer. In some embodiments, the breast cancer is ductal carcinoma in situ (DCIS). In some embodiments, the breast cancer is an invasive (or infiltrating) breast cancer (ILC or IDC). In some embodiments, the breast cancer is invasive ductal carcinoma. In some embodiments, the breast cancer is invasive lobular carcinoma. In some embodiments, the pancreatic cancer is exocrine pancreatic cancer. In some embodiments, the exocrine pancreatic cancer is a pancreatic adenocarcinoma. In some embodiments, the exocrine pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the pancreatic cancer is pancreatic adenocarcinoma. In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the pancreatic cancer is a pancreatic neuroendocrine tumor (PanNET).

Precursors or stem cells of myeloid cells or white blood cells can differentiate into blood monocytes and tissue macrophages. Macrophages can further differentiate into hepatic Kupffer cells, alveolar macrophages, osteoclasts, and bone histiocytes. Histiocytoses are a group of diseases that occur when there is an increase in the production of white blood cells known as histiocytes, which leads to organ damage and tumor formation. Histiocytoses include a wide range of conditions that can affect both children and adults. There are several groups of histiocytoses, distinguished based on the types of histiocyte cells involved. In some embodiments, histiocytosis is a disorder of dendritic cells. In some embodiments, the dendritic cell disorder is Langerhans cell histiocytosis. In some embodiments, the dendritic cell disorder is juvenile xanthogranuloma. In some embodiments, the dendritic cell disorder is Erdheim-Chester disease. In some embodiments, histiocytosis is a disorder of macrophage cells. In some embodiments, the macrophage cell disorder is hemophagocytic lymphohistiocytosis (HLH). In some embodiments, the macrophage cell disorder is Rosai-Dorfman disease. In some embodiments, the histiocytosis is a malignant histiocytosis. In some embodiments, malignant histiocytosis is some type of leukemia or malignancy. Recently, a relapsing disease has been described that is caused by activating mutations in receptor tyrosine kinases such as CSF1R (essential for the development of monocytes and macrophages). Inhibition of the therapeutic target CSF1R in histiocytosis may be possible, as demonstrated in preclinical models where CSF1R-activating changes sensitized cells to the CSF1R-specific small molecule inhibitors pexidartinib and BLZ945.

Expression of CSF1R and its ligand CSF1 has been demonstrated in the human chondrosarcoma cell line SW1353 (Am. J. Cancer. Res., 2017, 7(4):801-815). This cell line expresses both CSF1R receptors and CSF1 ligand, suggesting autocrine activation of this chondrosarcoma cell line. Additionally, silencing of CSF1R receptor kinase by shRNA in this cell line resulted in a significant reduction in tumor volume in a murine xenograft model in vivo. In contrast, a genetic modification that overexpressed CSF1R in this sarcoma cell line resulted in enhanced tumor growth in vivo. Overexpression of CSF1R significantly enhanced migration, invasion, and epithelial-mesenchymal transition (EMT) levels of SW1353 cells, while silencing of CSF1R inhibited these processes. These results indicate that some human chondrosarcomas that express CSF1R can be treated with CSF1R inhibitors to suppress tumor growth and/or inhibit invasion and metastasis.

For example, a disclosed method, such as a method for treating cancer, may involve administering from about 10 mg to about 90 mg of a disclosed compound every day, twice a week, or three times a week to a patient in need thereof. In some embodiments, a method of treating cancer may include administering from about 5 mg to about 70 mg of a disclosed compound

- 113 046076 every day, twice a week or three times a week for a patient in need. In some embodiments, a method of treating cancer may include administering from about 5 mg to about 50 mg of a disclosed compound every day, twice a week, or three times a week to a patient in need thereof. In some embodiments, a method of treating cancer may include administering from about 5 mg to about 30 mg of a disclosed compound every day, twice a week, or three times a week to a patient in need thereof. In some embodiments, a method of treating cancer may include administering from about 6 mg to about 25 mg of a disclosed compound every day, twice a week, or three times a week to a patient in need thereof. In some embodiments, a method of treating cancer may include administering from about 6 mg to about 20 mg of a disclosed compound every day, twice a week, or three times a week to a patient in need thereof. In some embodiments, a method of treating cancer may include administering from about 20 mg to about 50 mg of a disclosed compound every day, twice a week, or three times a week to a patient in need thereof.

Such a disclosed method, in one embodiment, may include administering a loading dose of the compound daily for a first period of time and administering a maintenance dose of the compound every day, once a week, twice a week, or three times a week for a second period of time. For example, the loading dose may be from about 10 mg/day to about 80 mg/day, or from about 20 mg/day to about 60 mg/day. In some embodiments, the loading dose is about 20 mg/day, about 30 mg/day, about 40 mg/day, about 50 mg/day, or about 60 mg/day. In some embodiments, the maintenance dose of the compound is approximately 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27 , 28, 29 or 30 mg/day.

Administration of a maintenance dose may involve administering to the patient from about 10 mg to about 60 mg of the compound, such as about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, or about 50 mg, each of which can be administered one at a time. two or three times a week.

In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 40 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 30 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 20 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 40 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 30 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 20 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 40 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 30 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 20 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 40 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 30 mg of the compound once per week. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 20 mg of the compound once per week. In some embodiments, the maintenance dose may include administering approximately 3 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 5 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 6 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 8 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 10 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 11 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 12 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 13 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 14 mg of the compound to the patient once per week. In some

- 114 046076 embodiments, the maintenance dose may involve administering approximately 15 mg of the compound to the patient once a week. In some embodiments, the maintenance dose may include administering approximately 16 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 17 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 18 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 19 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 20 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 22 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 24 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 26 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 28 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 30 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 32 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 34 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 36 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 38 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 40 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 42 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 44 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 46 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 48 mg of the compound to the patient once per week. In some embodiments, the maintenance dose may include administering approximately 50 mg of the compound to the patient once per week.

In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 40 mg of the compound twice per week. In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 30 mg of the compound twice per week. In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 20 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 40 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 30 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 20 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 40 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 30 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 20 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 40 mg of the compound twice per week. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 30 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 20 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering approximately 3 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 5 mg of the compound twice per week to the patient. In some embodiments, the maintenance dose may include administering approximately 6 mg of the compound twice per week to the patient. In some embodiments, the maintenance dose may include administering approximately 8 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may involve administering to the patient approximately

- 115 046076 approximately 10 mg of the compound twice a week. In some embodiments, the maintenance dose may include administering approximately 11 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 12 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 13 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 14 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 15 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 16 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 17 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 18 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 19 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 20 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 22 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 24 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 26 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 28 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 30 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 32 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 34 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 36 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 38 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 40 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 42 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 44 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 46 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 48 mg of the compound to the patient twice per week. In some embodiments, the maintenance dose may include administering approximately 50 mg of the compound to the patient twice per week.

In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 40 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 30 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 20 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 40 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 30 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 20 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 40 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 30 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 20 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 40 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 30 mg of the compound three times per week. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 20 mg of the compound three times per week. In some variants

- 116 046076 implementation of the maintenance dose may involve administering to the patient approximately 3 mg of the compound three times a week. In some embodiments, the maintenance dose may include administering approximately 5 mg of the compound three times per week to the patient. In some embodiments, the maintenance dose may include administering approximately 6 mg of the compound three times per week to the patient. In some embodiments, the maintenance dose may include administering approximately 8 mg of the compound three times per week to the patient. In some embodiments, the maintenance dose may include administering approximately 10 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 11 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 12 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 13 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 14 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 15 mg of the compound three times per week to the patient. In some embodiments, the maintenance dose may include administering approximately 16 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 17 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 18 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 19 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 20 mg of the compound three times per week to the patient. In some embodiments, the maintenance dose may include administering approximately 22 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 24 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 26 mg of the compound three times per week to the patient. In some embodiments, the maintenance dose may include administering approximately 28 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 30 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 32 mg of the compound three times per week to the patient. In some embodiments, the maintenance dose may include administering approximately 34 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 36 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 38 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 40 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 42 mg of the compound three times per week to the patient. In some embodiments, the maintenance dose may include administering approximately 44 mg of the compound three times per week to the patient. In some embodiments, the maintenance dose may include administering approximately 46 mg of the compound to the patient three times per week. In some embodiments, the maintenance dose may include administering approximately 48 mg of the compound three times per week to the patient. In some embodiments, the maintenance dose may include administering approximately 50 mg of the compound to the patient three times per week.

The maintenance dose can also be administered once daily. For example, a maintenance dose may involve administering approximately 2 mg of the compound to the patient once daily. In some embodiments, maintenance therapy may include administering to the patient from about 2 mg to about 40 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient from about 2 mg to about 30 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient from about 2 mg to about 20 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient from about 5 mg to about 40 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient from about 5 mg to about 30 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient from about 5 mg to about 20 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient from about 6 mg to about 40 mg of the compound once daily. In some embodiments

- 117 046076 maintenance therapy may involve administering to the patient from about 6 mg to about 30 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient from about 6 mg to about 20 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient from about 10 mg to about 40 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient from about 10 mg to about 30 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient from about 10 mg to about 20 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 3 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 5 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 6 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 8 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 10 mg of the compound once daily. In some embodiments, maintenance therapy may include administering approximately 11 mg of the compound to the patient once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 12 mg of the compound once daily. In some embodiments, maintenance therapy may include administering approximately 13 mg of the compound to the patient once daily. In some embodiments, maintenance therapy may include administering approximately 14 mg of the compound to the patient once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 15 mg of the compound once daily. In some embodiments, maintenance therapy may include administering approximately 16 mg of the compound to the patient once daily. In some embodiments, maintenance therapy may include administering approximately 17 mg of the compound to the patient once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 18 mg of the compound once daily. In some embodiments, maintenance therapy may include administering approximately 19 mg of the compound to the patient once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 20 mg of the compound once daily. In some embodiments, maintenance therapy may include administering approximately 22 mg of the compound to the patient once daily. In some embodiments, maintenance therapy may include administering approximately 24 mg of the compound to the patient once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 26 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 28 mg of the compound once daily. In some embodiments, maintenance therapy may include administering to the patient approximately 30 mg of the compound once daily. In some embodiments, the maintenance dose may include administering approximately 32 mg of the compound to the patient once daily. In some embodiments, the maintenance dose may include administering approximately 34 mg of the compound to the patient once daily. In some embodiments, the maintenance dose may include administering approximately 36 mg of the compound to the patient once daily. In some embodiments, the maintenance dose may include administering approximately 38 mg of the compound to the patient once daily. In some embodiments, the maintenance dose may include administering approximately 40 mg of the compound to the patient once daily. In some embodiments, the maintenance dose may include administering approximately 42 mg of the compound to the patient once daily. In some embodiments, the maintenance dose may include administering approximately 44 mg of the compound to the patient once daily. In some embodiments, the maintenance dose may include administering approximately 46 mg of the compound to the patient once daily. In some embodiments, the maintenance dose may include administering approximately 48 mg of the compound to the patient once daily. In some embodiments, the maintenance dose may include administering approximately 50 mg of the compound to the patient once daily.

In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 40 mg of the compound every other day. In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 30 mg of the compound every other day. In some embodiments, the maintenance dose may include administering to the patient from about 2 mg to about 20 mg of the compound every other day. In some embodiments, the maintenance dose may

- 118 046076 provide for the administration of about 5 mg to about 40 mg of the compound to the patient every two days. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 30 mg of the compound every other day. In some embodiments, the maintenance dose may include administering to the patient from about 5 mg to about 20 mg of the compound every other day. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 40 mg of the compound every other day. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 30 mg of the compound every other day. In some embodiments, the maintenance dose may include administering to the patient from about 6 mg to about 20 mg of the compound every other day. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 40 mg of the compound every other day. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 30 mg of the compound every other day. In some embodiments, the maintenance dose may include administering to the patient from about 10 mg to about 20 mg of the compound every other day. In some embodiments, the maintenance dose may include administering approximately 3 mg of the compound every other day to the patient. In some embodiments, the maintenance dose may include administering approximately 5 mg of the compound every other day to the patient. In some embodiments, the maintenance dose may include administering approximately 6 mg of the compound every other day to the patient. In some embodiments, the maintenance dose may include administering approximately 8 mg of the compound every other day to the patient. In some embodiments, the maintenance dose may include administering approximately 10 mg of the compound every other day to the patient. In some embodiments, the maintenance dose may include administering approximately 11 mg of the compound to the patient every other day. In some embodiments, the maintenance dose may include administering approximately 12 mg of the compound to the patient every other day. In some embodiments, the maintenance dose may include administering approximately 13 mg of the compound to the patient every other day. In some embodiments, the maintenance dose may include administering approximately 14 mg of the compound to the patient every other day. In some embodiments, the maintenance dose may include administering approximately 15 mg of the compound to the patient every other day. In some embodiments, the maintenance dose may include administering approximately 16 mg of the compound to the patient every other day. In some embodiments, the maintenance dose may include administering approximately 17 mg of the compound every other day to the patient. In some embodiments, the maintenance dose may include administering approximately 18 mg of the compound to the patient every other day. In some embodiments, the maintenance dose may include administering approximately 19 mg of the compound to the patient every other day. In some embodiments, the maintenance dose may include administering approximately 20 mg of the compound to the patient every two days. In some embodiments, the maintenance dose may include administering approximately 22 mg of the compound to the patient every other day. In some embodiments, the maintenance dose may include administering approximately 24 mg of the compound to the patient every two days. In some embodiments, the maintenance dose may include administering approximately 26 mg of the compound to the patient every two days. In some embodiments, the maintenance dose may involve administering approximately 28 mg of the compound to the patient every two days. In some embodiments, the maintenance dose may include administering approximately 30 mg of the compound to the patient every other day. In some embodiments, the maintenance dose may include administering approximately 32 mg of the compound to the patient every other day. In some embodiments, the maintenance dose may include administering approximately 34 mg of the compound to the patient every other day. In some embodiments, the maintenance dose may include administering approximately 36 mg of the compound to the patient every other day. In some embodiments, the maintenance dose may include administering approximately 38 mg of the compound every other day to the patient. In some embodiments, the maintenance dose may include administering approximately 40 mg of the compound every two days to the patient. In some embodiments, the maintenance dose may include administering approximately 42 mg of the compound every other day to the patient. In some embodiments, the maintenance dose may include administering approximately 44 mg of the compound to the patient every other day. In some embodiments, the maintenance dose may include administering approximately 46 mg of the compound to the patient every other day. In some embodiments, the maintenance dose may include administering approximately 48 mg of the compound every other day to the patient. In some embodiments, the maintenance dose may include administering approximately 50 mg of the compound every other day to the patient.

In some embodiments, the duration of the first period of time, e.g.

- 119 046076 the duration of which the loading dose is administered (for example, every day or every two days, or twice a day) is approximately one or two weeks, or one to three weeks, for example the duration of such first period of time may be approximately 4 days, approximately 5 days, approximately 6 days or approximately 10 days. In some embodiments, the duration of the first time period is approximately one to six days. In some embodiments, the duration of the first period of time is approximately one to five days. In some embodiments, the duration of the first period of time is approximately one to four days. In some embodiments, the duration of the first period of time is approximately one to three days. In some embodiments, the duration of the first period of time is approximately one to two days. In some embodiments, the duration of the first time period is approximately one to five weeks. In some embodiments, the duration of the first time period is approximately one to four weeks. In some embodiments, the duration of the first period of time is approximately one to three weeks. In some embodiments, the duration of the first period of time is approximately one to two weeks.

In some embodiments, the loading dose is from about 2 mg to about 100 mg of compound. In some embodiments, the loading dose is from about 5 mg to about 90 mg of compound. In some embodiments, the loading dose is from about 10 mg to about 80 mg of compound. In some embodiments, the loading dose is from about 10 mg to about 70 mg of compound. In some embodiments, the loading dose is from about 10 mg to about 60 mg of compound. In some embodiments, the loading dose is from about 10 mg to about 50 mg of compound. In some embodiments, the loading dose is from about 10 mg to about 40 mg of compound. In some embodiments, the loading dose is from about 10 mg to about 30 mg of compound. In some embodiments, the loading dose is from about 10 mg to about 20 mg of compound. In some embodiments, the loading dose is approximately 2 mg of the compound. In some embodiments, the loading dose is approximately 3 mg of the compound. In some embodiments, the loading dose is approximately 4 mg of compound. In some embodiments, the loading dose is approximately 5 mg of the compound. In some embodiments, the loading dose is approximately 10 mg of the compound. In some embodiments, the loading dose is approximately 11 mg of compound. In some embodiments, the loading dose is approximately 12 mg of the compound. In some embodiments, the loading dose is approximately 13 mg of compound. In some embodiments, the loading dose is approximately 14 mg of compound. In some embodiments, the loading dose is approximately 15 mg of the compound. In some embodiments, the loading dose is approximately 16 mg of the compound. In some embodiments, the loading dose is approximately 17 mg of compound. In some embodiments, the loading dose is approximately 18 mg of compound. In some embodiments, the loading dose is approximately 19 mg of compound. In some embodiments, the loading dose is approximately 20 mg of the compound. In some embodiments, the loading dose is approximately 22 mg of the compound. In some embodiments, the loading dose is approximately 24 mg of the compound. In some embodiments, the loading dose is approximately 26 mg of the compound. In some embodiments, the loading dose is approximately 28 mg of the compound. In some embodiments, the loading dose is approximately 30 mg of the compound. In some embodiments, the loading dose is approximately 32 mg of the compound. In some embodiments, the loading dose is approximately 34 mg of compound. In some embodiments, the loading dose is approximately 36 mg of the compound. In some embodiments, the loading dose is approximately 38 mg of the compound. In some embodiments, the loading dose is approximately 40 mg of the compound. In some embodiments, the loading dose is approximately 42 mg of the compound. In some embodiments, the loading dose is approximately 44 mg of the compound. In some embodiments, the loading dose is approximately 40 mg of the compound. In some embodiments, the loading dose is approximately 46 mg of the compound. In some embodiments, the loading dose is approximately 48 mg of the compound. In some embodiments, the loading dose is approximately 50 mg of the compound.

In some embodiments, the loading dose is from about 2 mg to about 100 mg of the compound once daily. In some embodiments, the loading dose is from about 2 mg to about 100 mg of the compound once daily. In some embodiments, the loading dose is from about 5 mg to about

- 120 046076 mg of the compound once a day. In some embodiments, the loading dose is from about 10 mg to about 80 mg of the compound once daily. In some embodiments, the loading dose is from about 10 mg to about 70 mg of the compound once daily. In some embodiments, the loading dose is from about 10 mg to about 60 mg of the compound once daily. In some embodiments, the loading dose is from about 10 mg to about 50 mg of the compound once daily. In some embodiments, the loading dose is from about 10 mg to about 40 mg of the compound once daily. In some embodiments, the loading dose is from about 10 mg to about 30 mg of the compound once daily. In some embodiments, the loading dose is from about 10 mg to about 20 mg of the compound once daily. In some embodiments, the loading dose is approximately 2 mg of the compound once daily. In some embodiments, the loading dose is approximately 3 mg of the compound once daily. In some embodiments, the loading dose is approximately 4 mg of the compound once daily. In some embodiments, the loading dose is approximately 5 mg of the compound once daily. In some embodiments, the loading dose is approximately 10 mg of the compound once daily. In some embodiments, the loading dose is approximately 11 mg of the compound once daily. In some embodiments, the loading dose is approximately 12 mg of the compound once daily. In some embodiments, the loading dose is approximately 13 mg of the compound once daily. In some embodiments, the loading dose is approximately 14 mg of the compound once daily. In some embodiments, the loading dose is approximately 15 mg of the compound once daily. In some embodiments, the loading dose is approximately 16 mg of the compound once daily. In some embodiments, the loading dose is approximately 17 mg of the compound once daily. In some embodiments, the loading dose is approximately 18 mg of the compound once daily. In some embodiments, the loading dose is approximately 19 mg of the compound once daily. In some embodiments, the loading dose is approximately 20 mg of the compound once daily. In some embodiments, the loading dose is approximately 22 mg of the compound once daily. In some embodiments, the loading dose is approximately 24 mg of the compound once daily. In some embodiments, the loading dose is approximately 26 mg of the compound once daily. In some embodiments, the loading dose is approximately 28 mg of the compound once daily. In some embodiments, the loading dose is approximately 30 mg of the compound once daily. In some embodiments, the loading dose is approximately 32 mg of the compound once daily. In some embodiments, the loading dose is approximately 34 mg of the compound once daily. In some embodiments, the loading dose is approximately 36 mg of the compound once daily. In some embodiments, the loading dose is approximately 38 mg of the compound once daily. In some embodiments, the loading dose is approximately 40 mg of the compound once daily. In some embodiments, the loading dose is approximately 42 mg of the compound once daily. In some embodiments, the loading dose is approximately 44 mg of the compound once daily. In some embodiments, the loading dose is approximately 40 mg of the compound once daily. In some embodiments, the loading dose is approximately 46 mg of the compound once daily. In some embodiments, the loading dose is approximately 48 mg of the compound once daily. In some embodiments, the loading dose is approximately 50 mg of the compound once daily.

In some embodiments, the loading dose is from about 2 mg to about 100 mg of the compound once per week. In some embodiments, the loading dose is from about 2 mg to about 100 mg of the compound once per week. In some embodiments, the loading dose is from about 5 mg to about 90 mg of the compound once per week. In some embodiments, the loading dose is from about 10 mg to about 80 mg of the compound once per week. In some embodiments, the loading dose is from about 10 mg to about 70 mg of the compound once per week. In some embodiments, the loading dose is from about 10 mg to about 60 mg of the compound once per week. In some embodiments, the loading dose is from about 10 mg to about 50 mg of the compound once per week. In some embodiments, the loading dose is from about 10 mg to about 40 mg of the compound once per week. In some embodiments, the loading dose is from about 10 mg to about 30 mg of the compound once per week. In some embodiments, the loading dose is from about 10 mg to about 20 mg of the compound once per week. In some embodiments, implementation

- 121 046076 leniya loading dose is approximately 2 mg of the compound once a week. In some embodiments, the loading dose is approximately 3 mg of the compound once per week. In some embodiments, the loading dose is approximately 4 mg of the compound once per week. In some embodiments, the loading dose is approximately 5 mg of the compound once per week. In some embodiments, the loading dose is approximately 10 mg of the compound once per week. In some embodiments, the loading dose is approximately 11 mg of the compound once per week. In some embodiments, the loading dose is approximately 12 mg of the compound once per week. In some embodiments, the loading dose is approximately 13 mg of the compound once per week. In some embodiments, the loading dose is approximately 14 mg of the compound once per week. In some embodiments, the loading dose is approximately 15 mg of the compound once per week. In some embodiments, the loading dose is approximately 16 mg of the compound once per week. In some embodiments, the loading dose is approximately 17 mg of the compound once per week. In some embodiments, the loading dose is approximately 18 mg of the compound once per week. In some embodiments, the loading dose is approximately 19 mg of the compound once per week. In some embodiments, the loading dose is approximately 20 mg of the compound once per week. In some embodiments, the loading dose is approximately 22 mg of the compound once per week. In some embodiments, the loading dose is approximately 24 mg of the compound once per week. In some embodiments, the loading dose is approximately 26 mg of the compound once per week. In some embodiments, the loading dose is approximately 28 mg of the compound once per week. In some embodiments, the loading dose is approximately 30 mg of the compound once per week. In some embodiments, the loading dose is approximately 32 mg of the compound once per week. In some embodiments, the loading dose is approximately 34 mg of the compound once per week. In some embodiments, the loading dose is approximately 36 mg of the compound once per week. In some embodiments, the loading dose is approximately 38 mg of the compound once per week. In some embodiments, the loading dose is approximately 40 mg of the compound once per week. In some embodiments, the loading dose is approximately 42 mg of the compound once per week. In some embodiments, the loading dose is approximately 44 mg of the compound once per week. In some embodiments, the loading dose is approximately 40 mg of the compound once per week. In some embodiments, the loading dose is approximately 46 mg of the compound once per week. In some embodiments, the loading dose is approximately 48 mg of the compound once per week. In some embodiments, the loading dose is approximately 50 mg of the compound once per week.

In some embodiments, the loading dose is from about 2 mg to about 100 mg of the compound twice per week. In some embodiments, the loading dose is from about 2 mg to about 100 mg of the compound twice per week. In some embodiments, the loading dose is from about 5 mg to about 90 mg of the compound twice per week. In some embodiments, the loading dose is from about 10 mg to about 80 mg of the compound twice per week. In some embodiments, the loading dose is from about 10 mg to about 70 mg of the compound twice per week. In some embodiments, the loading dose is from about 10 mg to about 60 mg of the compound twice per week. In some embodiments, the loading dose is from about 10 mg to about 50 mg of the compound twice per week. In some embodiments, the loading dose is from about 10 mg to about 40 mg of the compound twice per week. In some embodiments, the loading dose is from about 10 mg to about 30 mg of the compound twice per week. In some embodiments, the loading dose is from about 10 mg to about 20 mg of the compound twice per week. In some embodiments, the loading dose is approximately 2 mg of the compound twice per week. In some embodiments, the loading dose is approximately 3 mg of the compound twice per week. In some embodiments, the loading dose is approximately 4 mg of the compound twice per week. In some embodiments, the loading dose is approximately 5 mg of the compound twice per week. In some embodiments, the loading dose is approximately 10 mg of the compound twice per week. In some embodiments, the loading dose is approximately 11 mg of the compound twice per week. In some embodiments, the loading dose is approximately 12 mg of the compound twice per week. In some embodiments, the loading dose is approximately 13 mg of the compound twice per week. In some embodiments, the loading dose is approximately 14 mg of compound two

- 122 046076 times a week. In some embodiments, the loading dose is approximately 15 mg of the compound twice per week. In some embodiments, the loading dose is approximately 16 mg of the compound twice per week. In some embodiments, the loading dose is approximately 17 mg of the compound twice per week. In some embodiments, the loading dose is approximately 18 mg of the compound twice per week. In some embodiments, the loading dose is approximately 19 mg of the compound twice per week. In some embodiments, the loading dose is approximately 20 mg of the compound twice per week. In some embodiments, the loading dose is approximately 22 mg of the compound twice per week. In some embodiments, the loading dose is approximately 24 mg of the compound twice per week. In some embodiments, the loading dose is approximately 26 mg of the compound twice per week. In some embodiments, the loading dose is approximately 28 mg of the compound twice per week. In some embodiments, the loading dose is approximately 30 mg of the compound twice per week. In some embodiments, the loading dose is approximately 32 mg of the compound twice per week. In some embodiments, the loading dose is approximately 34 mg of the compound twice per week. In some embodiments, the loading dose is approximately 36 mg of the compound twice per week. In some embodiments, the loading dose is approximately 38 mg of the compound twice per week. In some embodiments, the loading dose is approximately 40 mg of the compound twice per week. In some embodiments, the loading dose is approximately 42 mg of the compound twice per week. In some embodiments, the loading dose is approximately 44 mg of the compound twice per week. In some embodiments, the loading dose is approximately 40 mg of the compound twice per week. In some embodiments, the loading dose is approximately 46 mg of the compound twice per week. In some embodiments, the loading dose is approximately 48 mg of the compound twice per week. In some embodiments, the loading dose is approximately 50 mg of the compound twice per week.

The duration of the second period of time, during which, for example, the maintenance dose is administered, may be at least about one week or more, such as about one month or more (for example, from about 1 month to about 6 months, to about 12 months or more ).

The method includes administering a loading dose every day for a first period of time and administering a maintenance dose every day for a second period of time. In some embodiments, the duration of the first period of time is from 1 to 6 days and the duration of the second period is from 1 to 35 days. In some embodiments, the duration of the first period of time is from 1 to 6 days and the duration of the second period is from 1 to 30 days. In some embodiments, the duration of the first period of time is from 1 to 6 days and the duration of the second period is from 1 to 25 days. In some embodiments, the duration of the first period of time is from 1 to 6 days and the duration of the second period is from 1 to 22 days. In some embodiments, the duration of the first period of time is from 1 to 6 days and the duration of the second period is from 1 to 20 days. In some embodiments, the duration of the first period of time is from 1 to 5 days and the duration of the second period is from 1 to 35 days. In some embodiments, the duration of the first period of time is from 1 to 5 days and the duration of the second period is from 1 to 30 days. In some embodiments, the duration of the first period of time is from 1 to 5 days and the duration of the second period is from 1 to 25 days. In some embodiments, the duration of the first period of time is from 1 to 5 days and the duration of the second period is from 1 to 22 days. In some embodiments, the duration of the first period of time is from 1 to 5 days and the duration of the second period is from 1 to 20 days. In some embodiments, the duration of the first period of time is from 1 to 4 days and the duration of the second period is from 1 to 35 days. In some embodiments, the duration of the first period of time is from 1 to 4 days and the duration of the second period is from 1 to 30 days. In some embodiments, the duration of the first period of time is from 1 to 4 days and the duration of the second period is from 1 to 25 days. In some embodiments, the duration of the first period of time is from 1 to 4 days and the duration of the second period is from 1 to 22 days. In some embodiments, the duration of the first period of time is from 1 to 4 days and the duration of the second period is from 1 to 20 days. In some embodiments, the duration of the first period of time is from 1 to 3 days and the duration of the second period is from 1 to 35 days. In some embodiments, the duration of the first period of time is from 1 to 3 days and the duration of the second period is from 1 to 30 days. In some variants

- 123 046076 implementation, the duration of the first period of time is from 1 to 3 days and the duration of the second period is from 1 to 25 days. In some embodiments, the duration of the first period of time is from 1 to 3 days and the duration of the second period is from 1 to 22 days. In some embodiments, the duration of the first period of time is from 1 to 3 days and the duration of the second period is from 1 to 20 days. In some embodiments, the duration of the first period of time is from 1 to 2 days and the duration of the second period is from 1 to 35 days. In some embodiments, the duration of the first period of time is from 1 to 2 days and the duration of the second period is from 1 to 30 days. In some embodiments, the duration of the first period of time is from 1 to 2 days and the duration of the second period is from 1 to 25 days. In some embodiments, the duration of the first period of time is from 1 to 2 days and the duration of the second period is from 1 to 22 days. In some embodiments, the duration of the first period of time is from 1 to 2 days and the duration of the second period is from 1 to 20 days. In other embodiments, the duration of the first time period and the second time period together is 20 days. In some embodiments, the duration of the first time period and the second time period together is 21 days. In some embodiments, the duration of the first time period and the second time period together is 22 days. In some embodiments, the duration of the first time period and the second time period together is 23 days. In some embodiments, the duration of the first time period and the second time period together is 24 days. In some embodiments, the duration of the first time period and the second time period together is 25 days. In some embodiments, the duration of the first time period and the second time period together is 26 days. In some embodiments, the duration of the first time period and the second time period together is 27 days. In some embodiments, the duration of the first time period and the second time period together is 28 days. In some embodiments, the duration of the first time period and the second time period together is 29 days. In some embodiments, the duration of the first time period and the second time period together is 30 days. In some embodiments, the duration of the first time period and the second time period together is 31 days. In some embodiments, the duration of the first time period and the second time period together is 32 days. In some embodiments, the duration of the first time period and the second time period together is 33 days. In some embodiments, the duration of the first time period and the second time period together is 34 days. In some embodiments, the duration of the first time period and the second time period together is 35 days. In the disclosed methods, administration may occur over a cycle comprising a first time period and a second time period. In some embodiments, the cycle includes 20 days. In some embodiments, the cycle includes 21 days. In some embodiments, the cycle includes 22 days. In some embodiments, the cycle includes 23 days. In some embodiments, the cycle is 24 days. In some embodiments, the cycle includes 25 days. In some embodiments, the cycle includes 26 days. In some embodiments, the cycle includes 27 days. In some embodiments, the cycle includes 28 days. In some embodiments, the cycle includes 29 days. In some embodiments, the cycle includes 30 days. In some embodiments, the cycle includes 31 days. In some embodiments, the cycle includes 32 days. In some embodiments, the cycle includes 33 days. In some embodiments, the cycle is 34 days. In some embodiments, the cycle includes 35 days. In other embodiments, this method may administer administration over one to 1200 cycles. In some embodiments of this method, administration may occur over 10-1000 cycles. In some embodiments of this method, administration may occur over 50-800 cycles. In some embodiments of this method, administration may occur over 70-700 cycles. In some embodiments of this method, administration may occur over 100-500 cycles.

Contemplated methods may include treating patients suffering from solid tumors that have progressed following previous administration of a different type of cancer therapy (eg, an advanced tumor). For example, the present invention contemplates the treatment of a solid tumor, such as metastatic breast or prostate cancer with bone disease. In some embodiments, the solid tumor is gastric, ovarian, or non-small cell lung cancer that is characterized by the presence of malignancy-associated ascites or effusion(s).

Contemplated tumors that can be treated using the disclosed methods include tumors that express one or more of CSF1R or its ligands, CSF1 and IL-34. For example,

- 124 046076 the method in question may further include identifying whether CSF1R, CSF1 and/or IL-34 are expressed in the tumor.

The disclosed methods may include administering a loading dose of the compound daily for a first period of time and administering a maintenance dose of the compound every day, once a week, twice a week, or three times a week for a second period of time (or every other day), for example , where the maintenance dose is lower than or equal to each loading dose. A contemplated loading dose is from about 10 mg/day to about 80 mg/day, or from about 10 mg to about 80 mg every day. In some embodiments, the loading dose is from about 20 mg/day to about 60 mg/day, such as about 20 mg/day, about 30 mg/day, about 40 mg/day, about 50 mg/day, or about 60 mg/day . In some embodiments, the maintenance dose is from about 2 mg to about 60 mg. In some embodiments, the maintenance dose is about 2 mg, about 10 mg, about 20 mg, about 25 mg, about 30 mg, about 40 mg, or about 50 mg, administered every day, twice a week, or three times a week. week. In some embodiments, the duration of the first period of time, where the loading dose is, for example, administered every day, is approximately one or two weeks. The duration of exemplary first periods of time may be about 4 days, about 5 days, about 6 days, or about 10 days. In some embodiments, the duration of the second period of time (eg, where the maintenance dose is administered every day, twice a week, or three times a week) is one week or from one month to about six months or more. In some embodiments, the subject methods further include administering an additional loading dose over a third period of time. In some embodiments, the method further includes administering an additional maintenance dose for a fourth period of time. In some embodiments, the third and/or fourth time periods follow the first and second time periods.

After 1 or 3 months or more of administration, a patient treated with the disclosed method may experience improved tumor response as measured by RECIST. In some embodiments, after 1 week or 1 month or more of administration, the patient may have one of the following: decreased levels of specific monocyte populations (such as CD16+ or CSF1R+ monocytes) in the blood as determined by flow cytometry, increased levels of CSF1 in the blood plasma, decreased levels of markers of bone turnover, where the markers of remodeling may include collagen fragments, - C-terminal fragment of collagen in blood serum and N-terminal fragment of collagen in urine, and reduced macrophage content and/or repolarization of pro-tumor M2 macrophages with the formation of anti-tumor macrophages of the M1 phenotype in tumor or fluids associated with tumor ascites/effusions compared with the associated level before administration.

The present invention also provides a method for treating cancer, such as cancers selected from the group consisting of solid tumors, acute myeloid leukemia, myelodysplastic syndrome, acute lymphocytic leukemia, and chronic lymphocytic leukemia, in a patient in need thereof (e.g., a human patient suffering from cancer) comprising administering to the patient a therapeutically effective amount of a compound that is 2-(isopropylamino)-3methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl) pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof, and at least one other therapeutic agent. In some embodiments, the patient may suffer from a solid tumor, such as a solid tumor of the breast, cervix, pancreas, bladder, prostate, stomach, ovary, melanoma, glioma, glioblastoma multiforme, osteosarcoma, osteolytic cancers, chondrosarcoma, histiocytosis or lung cancer. In some embodiments, the breast cancer is ductal carcinoma in situ (DCIS). In some embodiments, the breast cancer is an invasive (or infiltrating) breast cancer (ILC or IDC). In some embodiments, the breast cancer is invasive ductal carcinoma. In some embodiments, the breast cancer is invasive lobular carcinoma. In some embodiments, the pancreatic cancer is exocrine pancreatic cancer. In some embodiments, the exocrine pancreatic cancer is a pancreatic adenocarcinoma. In some embodiments, the exocrine pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the pancreatic cancer is pancreatic adenocarcinoma. In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the pancreatic cancer is a pancreatic neuroendocrine tumor (PanNET).

The present invention contemplates the administration of Compound 1 or a pharmaceutically acceptable

- 125 046076 my salt to a patient in need of it, before (neoadjuvant) or after (adjuvant) surgery (eg, surgery for a solid tumor). In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered as an adjuvant. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered as a neoadjuvant. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered as a neoadjuvant and adjuvant. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered to a patient in need thereof as a neoadjuvant for a period of 1 to 6 months, followed by administration of Compound 1 or a pharmaceutically acceptable salt as an adjuvant for a period of 1 to 100 days. years. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered to a patient in need thereof as a neoadjuvant for a period of 1 to 6 months, followed by administration of Compound 1 or a pharmaceutically acceptable salt as an adjuvant for a period of 1 day to 5 years. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered to a patient in need thereof as a neoadjuvant for a period of 3 to 6 months, followed by administration of Compound 1 or a pharmaceutically acceptable salt as an adjuvant for a period of 1 day to 5 years. In some embodiments, administration of Compound 1 or a pharmaceutically acceptable salt is not administered until after surgery. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered as an adjuvant for a period ranging from 1 day to 100 years. In some embodiments, Compound 1 or a pharmaceutically acceptable salt is administered as an adjuvant for a period ranging from 1 day to 5 years.

Contemplated methods may further include administration of another immunomodulatory therapy. In some embodiments, such immunomodulatory therapy is an anti-PD-1 antibody therapy, an anti-PD-L1 antibody therapy, a CD40 agonist therapy, an anti-CD47 antibody therapy, an anti-CD47 antibody therapy. anti-LAG3, an anti-CD20 antibody therapy, an anti-CD38 antibody therapy, and/or an anti-TIM3 antibody therapy. The disclosed method may, for example, further include administering a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from the group consisting of paclitaxel, eribulin, docetaxel, gemcitabine, vemurafenib, dabrafenib, trametinib, cobimetinib, and binimetinib. In some embodiments, the method further includes administering an immunomodulatory therapy and another chemotherapeutic agent.

In one aspect, the present invention describes a method of treating tumors known to express a receptor that is colony stimulating factor 1 receptor (CSF1R) and/or its ligand(s), colony stimulating factor 1 (CSF1) or interleukin (IL). ) 34, to a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound that is 2-(isopropylamino)-3-methyl-5-(6-methyl-5-((2(1-methyl-1H-pyrazole -4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof, wherein administration comprises: administering a loading dose of the compound daily for a first period of time and administering a maintenance dose doses of the compound every day, twice a week, or three times a week for a second period of time. Such a disclosed method may include determining whether a tumor or its microenvironment expresses CSF1R, CSF-1, or IL-34 based on isolated patient tumor samples. In some embodiments, the disclosed method includes determining whether a tumor or its microenvironment expresses CSF1R, CSF1, or IL-34 based on isolated samples of the patient's tumor or extracellular fluid from the patient, for example, the extracellular fluid is the patient's blood plasma.

In some embodiments, a compound described herein, eg Compound 1, is administered in increasing doses, eg one or both of a loading or maintenance dose may be increased. In some embodiments, the escalating doses include at least a first dose level and a second dose level. In some embodiments, the escalating doses include at least a first dose level, a second dose level, and a third dose level. In some embodiments, the escalating doses further provide a fourth dose level. In some embodiments, the escalating doses include a first dose level, a second dose level, a third dose level, a fourth dose level, and a fifth dose level. In some embodiments, six, seven, eight, nine, and ten dose levels are contemplated.

In some embodiments, each dose level is no more than 60% of the dose level immediately following it. In some embodiments, each dose level is no more than 50% of the dose level immediately following it. In some embodiments, each dose level is no more than 40% of the dose level immediately following it. In some embodiments, each dose level is no more than 33% of

- 126 046076 dose level immediately following it. In some embodiments, each dose level is no more than 20% of the dose level immediately following it. In some embodiments, dose levels are separated by ½ log unit. In some embodiments, the dose levels are separated by 1 log unit.

In some embodiments, the first, second, third, and fourth dosage levels are administered to the subject over a period of from about 2 days to about 6 months. In some embodiments, the first, second, third and fourth dosage levels are administered to the subject over a period of from about 7 days to about 35 days. In some embodiments, the first, second, third and/or fourth dose levels are administered to the subject over a period of about 2 weeks to about 4 weeks. In some embodiments, the first, second, third and/or fourth dosage levels are administered to the subject over a period of approximately 4 weeks. In some embodiments, the first, second, and/or third dose levels are administered to the subject over a period of about 2 days to about 40 days, and the fourth dose level is administered to the subject over a period of about 2 days to about 6 months.

In some embodiments, the first dose level is from about 5 mg/day to about 30 mg/day. In some embodiments, the second dose level is from about 20 mg/day to about 50 mg/day. In some embodiments, the third dose level is from about 30 mg/day to about 60 mg/day. In some embodiments, the fourth dose level is from about 40 mg/day to about 75 mg/day. In some embodiments, the fifth dose level is from about 50 mg/day to about 75 mg/day.

In some embodiments, the first dose level is from about 10 mg/day to about 30 mg/day (eg, when administered every day for the first period of time). In some embodiments, the second dose level is from about 5 mg/day to about 30 mg/day (eg, when administered once every two days; twice a week or three times a week). In some embodiments, the third dose level is from about 10 mg/day to about 50 mg/day. In some embodiments, the fourth dose level is from about 20 mg/day to about 60 mg/day. In some embodiments, the fifth dose level is from about 30 mg/day to about 75 mg/day.

In some embodiments, the first dose level is from about 10 to about 80 mg/day for about 1 week or more and the second dose level is from about 10 mg/day to about 40 mg/day (every day, twice a week, or three times a day). once a week, for example 2 weeks or more).

In some embodiments, the first dose level is from about 30 to 60 mg/day. In some embodiments, the second dose level is from about 10 to 30 mg/day.

In some embodiments, the methods include administering five or more escalating doses to a subject. In some embodiments, the first dose level is 10 mg/day, the second dose level is 20 mg/day, the third dose level is 30 mg/day, the fourth dose level is 40 mg/day, and the fifth dose level is 50 mg/day or greater .

In some embodiments, each dose level is administered to a subject over a period of from 2 days to 104 weeks. In some embodiments, each dose level is administered to a subject over a period of 2 days to 26 weeks. In some embodiments, each dose level is administered to a subject over a period of from about 1 week to about 26 weeks. In some embodiments, each dose level is administered to a subject over a period of from about 1 week to about 12 weeks. In some embodiments, each dose level is administered to a subject over a period of 1 to 5 weeks. In some embodiments, the loading dose level is administered to the subject over a period of 1 to 4 weeks, or about 1 to 2 weeks, or about 5 to 7 days. In some embodiments, a maintenance dose level is administered to the subject for from about 14 days to about 60 days or more. In some embodiments, the loading dose level is administered to the subject over a period of about 3 weeks, 1 month, 2 months, or more.

In some embodiments, the first dose level is administered to the subject over 1 week, the second dose level is administered to the subject over 4 weeks or more.

In some embodiments, the first dose level is administered to the subject over a period of about 5 to 10 days, the second dose level is administered to the subject over a period of from about 2 weeks to about 1, 2 or 3 months, 9 months or more, and an optional third dose level is administered to the subject at for about 5-10 days, and an optional fourth dose level is administered to the subject over a period of from about 2 weeks to about 1, 2 or 3 months or more. It may be preferable that the first and second doses can be repeated.

In some embodiments of the methods described in this invention, antitumor

- 127 046076 left activity is assessed by an endpoint selected from the group consisting of objective response rate, disease control rate (eg, at 12 weeks), time to best response, progression-free survival, duration of response, and both objective response rate , and the frequency of disease control (for example, over periods of 6 months and 1 year). In some embodiments, DTGCT is not assessed for disease control rate.

In some embodiments of the methods described in this invention, tumor response in DTGCT and solid tumors is assessed using RECIST, version 1.1.

Combination therapy.

Compound 1 or a pharmaceutically acceptable salt thereof can be administered in combination with one or more additional therapeutic agents to treat a disorder described herein, such as cancer. For example, the present invention provides a pharmaceutical composition comprising Compound 1 or a pharmaceutically acceptable salt thereof, one or more additional therapeutic agents and a pharmaceutically acceptable excipient. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof and one additional therapeutic agent are administered. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof and two additional therapeutic agents are administered. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each formulated and administered separately. For example, compound 1 or a pharmaceutically acceptable salt thereof and the additional therapeutic agent can be formulated and administered separately. The implementation of combination therapy can be achieved by administering two or more therapeutic agents in a single formulation, for example a pharmaceutical composition containing compound 1 as one therapeutic agent and one or more additional therapeutic agents. For example, Compound 1 or a pharmaceutically acceptable salt thereof and the additional therapeutic agent can be administered as a single formulation. Other combinations are also covered by combination therapy. Although two or more agents in combination therapy can be administered simultaneously, this is not required. For example, administration of the first agent (or combination of agents) may precede administration of the second agent (or combination of agents) by minutes, hours, days or weeks. Thus, two or more agents can be administered with an interval of several minutes between administrations, or with an interval of 1, 2, 3, 6, 9, 12, 15, 18 or 24 hours between administrations, or with an interval of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days between injections, or with an interval of 2, 3, 4, 5, 6, 7, 8, 9 weeks between injections. In some cases, even longer intervals are possible. Although many cases require that two or more agents used in combination therapy be present in the patient's body at the same time, this is not mandatory.

Combination therapy (or cotherapy) involves administering a CSF1R inhibitor described herein and at least a second agent, such as an anti-PD1 antibody therapy, such as an anti-PD1 antibody, or a chemotherapeutic agent, as part of a specific treatment regimen designed to ensuring a beneficial effect from the combined action of such therapeutic agents. The beneficial effect of the combination includes, without limitation, the joint pharmacokinetic or pharmacodynamic effect provided by the combination of therapeutic agents. Administration of such therapeutic agents in combination can be carried out over a period of time (usually minutes, hours, days or weeks depending on the combination chosen) or until the disease progresses. Combination therapy is intended to involve administering multiple therapeutic agents sequentially, that is, in a manner where each therapeutic agent is administered at different times, as well as administering such therapeutic agents or at least two therapeutic agents substantially simultaneously. As such, simultaneous administration can be accomplished, for example, by administering to a subject a single tablet or capsule containing a fixed ratio of each therapeutic agent, or multiple separate single doses for each therapeutic agent. Sequential or substantially simultaneous administration of each therapeutic agent can be accomplished through any suitable route, including, without limitation, oral routes, intravenous routes, intramuscular routes, subcutaneous, intratumoral injection, and direct absorption through mucosal tissue. Therapeutics can be administered through the same route or through different routes. For example, the first therapeutic agent of a selected combination may be administered by intravenous injection, while other therapeutic agents of the combination may be administered orally. Alternatively, for example, all therapeutic agents may be administered orally, or all therapeutic agents may be administered by intravenous injection. The sequence in which therapeutic agents are administered is not critical.

Combination therapy may also involve the administration of therapeutic agents, opiates

- 128 046076 above, additionally in combination with other biologically active ingredients and types of non-drug therapy. If the combination therapy additionally includes a non-drug treatment, the non-drug treatment may be administered at any appropriate time, provided that it achieves a beneficial effect from the combined action of the combination of therapeutic agents and the non-drug treatment. For example, in appropriate cases, a beneficial effect is still achieved when the administration of therapeutic agents is temporarily relieved of non-drug treatment, perhaps for days or even weeks.

The components of the combination can be administered to the patient simultaneously, sequentially, or in combination. It is preferred that when using a composition or method, the components can be present in the same pharmaceutically acceptable carrier and therefore can be administered simultaneously. They may be in separate pharmaceutical carriers, such as traditional oral dosage forms that are administered concomitantly. The term combination further refers to the case where the compounds are provided in separate dosage forms and are administered sequentially.

While not limited by theory, it is believed that administration of CSF1R inhibitors according to the methods described herein in combination with one or more anti-PD1 antibody therapies may provide additive effects of significant degree of inhibition of primary tumor growth and modulation of the immune system towards an anti-tumor status, which may be beneficial for the treatment of disorders associated with proliferation, survival or biological action of macrophages, including TGCT treatment. Examples of anti-PD1 antibody therapies that can be administered in combination with the CSF1R inhibitors described herein include, but are not limited to, nivolumab, pidilizumab, cemiplimab, tislelizumab, AMP-224, AMP-514, and pembrolizumab.

The CSF1R inhibitors described herein, such as Compound 1, may be used in combination with other immunomodulatory agents, including but not limited to anti-PD-L1 antibody therapies, including atezolizumab, durvalumab, BMS-936559, and avelumab, antibody therapies anti-TIM3, including TSR-022 and MBG453, anti-LAG3 antibody therapies, including relatlimab, LAG525 and TSR-033, anti-CD40 agonist therapies, including SGN-40, CP-870,893 and RO7009789, anti-TIM3 anti-TIM3 therapeutics, including SGN-40, CP-870,893 and RO7009789, anti-TIM3 anti-CD47, including Hu5F9-G4, anti-CD20, anti-CD38, or other immunomodulatory therapies including thalidomide, lenalidomide, pomalidomide, prednisone, and dexamethasone.

Types of sarcoma include a heterogeneous group of malignant tumors, including more than fifty subtypes with origin in bone and soft tissue. In some embodiments, a method of treating cancer includes administering to a patient with locally advanced and metastatic high-grade sarcoma Compound 1 in combination with avelumab. In some embodiments, a method of treating cancer includes administering to a patient with locally advanced sarcoma Compound 1 in combination with avelumab. In some embodiments, a method of treating cancer includes administering Compound 1 in combination with avelumab to a patient with locally advanced high-grade sarcoma. In some embodiments, a method of treating cancer includes administering to a patient with advanced metastatic sarcoma Compound 1 in combination with avelumab. In some embodiments, a method of treating cancer includes administering to a patient with undifferentiated pleomorphic sarcoma (UPS) Compound 1 in combination with avelumab. In some embodiments, a method of treating cancer includes administering Compound 1 in combination with avelumab to a patient with myxofibrosarcoma (MFS). In some embodiments, a method of treating cancer includes administering Compound 1 in combination with avelumab to a patient with leiomyosarcoma (LMS). In some embodiments, a method of treating cancer includes administering to a patient with dedifferentiated liposarcoma (DDLPS) Compound 1 in combination with avelumab.

The CSF1R inhibitors described herein, such as Compound 1, may also be used in combination with one or more chemotherapeutic agents, including, but not limited to, agents that target tubulin (e.g., paclitaxel, paclitaxel protein-bound injectable suspension particles, eribulin, abraxane, docetaxel, ixabepilone, taxiterem, vincristine or vinorelbine), LHRH antagonists, including without limitation leuprolide, goserelin, triptorelin or histrelin, antiandrogens, including without limitation abiraterone, flutamide, bicalutamide, nilutamide, cyproterone acetate, enzalutamide and apalutamide, antiestrogens including, without limitation, tamoxifen, fulvestrant, anastrozole, letrozole and exemestane, DNA alkylating agents (including cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide and temozolomide), DNA intercalating agents (including doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin and epirubicin), 5-fluorouracil, capecitabine, cytarabine, decitabine, 5azacytadine, gemcitabine methotrexate, bortezomib and carfilzomib.

CSF1R inhibitors described in this invention, for example compound 1, can also be

- 129 046076 change in combination with a targeted therapy agent including kinase inhibitors - erlotinib, gefitinib, lapatanib, everolimus, temsirolimus, abemaciclib, LEE011, palbociclib, crizotinib, cabozantinib, sunitinib, pazopanib, sorafenib, regorafenib, axi tinib, dasatinib, imatinib, nilotinib, vemurafenib, dabrafenib, trametinib, cobimetinib, binimetinib, idelalisib, quizartinib, avapritinib, BLU-667, BLU-263, Loxo 292, larotrectinib and quizartinib, antiestrogens, including but not limited to tamoxifen, fulvestrant, anastrozole, letrozole and exemestane, anti androgenic agents including, without limitation, abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, cyproterone acetate, steroid agents, including without limitation prednisone and dexamethasone, PARP inhibitors, including without limitation neraparib, olaparib and rucaparib, topoisomerase I inhibitors, including without limitation irinotecan, camptothecin and topotecan, topoisomerase II inhibitors including, without limitation, etoposide, etoposide phosphate, and mitoxantrone, histone deacetylase (HDAC) inhibitors, including without limitation, vorinostat, romidepsin, panobinostat, valproic acid, and belinostat, DNA methylation inhibitors, including without limitation, DZNep and 5- aza-2'-deoxycytidine, proteasome inhibitors, including without limitation bortezomib and carfilzomib, thalidomide, lenalidomide, pomalidomide, biological agents, including without limitation trastuzumab, ado-trastuzumab, pertuzumab, cetuximab, panitumumab, ipilimumab, tremelimumab, vaccines, including without limitation sipuleucel-T, and radiation therapy.

In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof may be used in combination with a TIE2 immunokinase inhibitor including rebastinib or ARRY-614. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof may be used in combination with an anti-PD1 antibody therapy. In some embodiments, Compound 1 or a pharmaceutically acceptable salt thereof may be used in combination with a TIE2 immunokinase inhibitor including rebastinib or ARRY-614 and an anti-PD1 antibody therapy. In some embodiments, a method of treating cancer, such as cancers selected from the group consisting of solid tumors, acute myeloid leukemia, myelodysplastic syndrome, acute lymphocytic leukemia, and chronic lymphocytic leukemia, in a patient in need thereof (e.g., a human patient suffering from cancer) involves administering to a patient in need thereof a therapeutically effective amount of a compound that is 2-(isopropylamino)-3-methyl-5-(6-methyl-5-((2-(1-methyl-1H- pyrazol-4-yl)pyridin-4yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof, and a TIE2 immunokinase inhibitor. In some embodiments, a method of treating cancer, such as cancers selected from the group consisting of melanoma, solid tumors, acute myeloid leukemia, myelodysplastic syndrome, acute lymphocytic leukemia, and chronic lymphocytic leukemia, in a patient in need thereof (e.g., a patient- person suffering from cancer) involves administering to a patient in need thereof a therapeutically effective amount of a compound that is 2-(isopropylamino)-3-methyl-5-(6-methyl-5-((2-(1-methyl- 1H-pyrazol-4-yl)pyridin-4yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof, a TIE2 immunokinase inhibitor and anti-PD1 antibody therapy. In some embodiments, a method of treating cancer, such as cancers selected from the group consisting of melanoma, solid tumors, acute myeloid leukemia, myelodysplastic syndrome, acute lymphocytic leukemia, and chronic lymphocytic leukemia, in a patient in need thereof (e.g., a patient- person suffering from cancer) involves administering to a patient in need thereof a therapeutically effective amount of a compound that is 2-(isopropylamino)-3-methyl-5-(6methyl-5-((2-(1-methyl-1H- pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one or a pharmaceutically acceptable salt thereof, and anti-PD1 antibody therapies. In some embodiments, the cancer is breast, cervical, pancreatic, bladder, prostate, gastric, ovarian, melanoma, glioma, glioblastoma multiforme, osteosarcoma, osteolytic cancers, chondrosarcoma, histiocytosis, or lung cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the breast cancer is ductal carcinoma in situ (DCIS). In some embodiments, the breast cancer is an invasive (or infiltrating) breast cancer (ILC or IDC). In some embodiments, the breast cancer is invasive ductal carcinoma. In some embodiments, the breast cancer is invasive lobular carcinoma. In some embodiments, the pancreatic cancer is exocrine pancreatic cancer. In some embodiments, the exocrine pancreatic cancer is a pancreatic adenocarcinoma. In some embodiments, the exocrine pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the pancreatic cancer is pancreatic adenocarcinoma. In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC). In some embodiments it will be carried out

- 130 046076 pancreatic cancer is a PanNET.

The CSF1R inhibitors described herein, such as Compound 1, may also be used in combination with antiangiogenic agents including AMG386, bevacizumab and aflibercept, and antibody-drug conjugates (ADCs) including brentuximab vedotin, trastuzumab emtansine, payload-containing ADCs , such as a camptothecin derivative, pyrrolobenzodiazepine dimer (PBD), indolinobenzodiazepine dimer (IGN), DM1, DM4, MMAE or MMAF.

In some embodiments, the additional therapeutic agent is selected from a luteinizing hormone release hormone (LHRH) analogue including goserelin and leuprolide.

In some embodiments, the additional therapeutic agent is selected from the group consisting of, selected from the group consisting of everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA739358, R-763, AT-9263, pemetrexed, erlotinib, dazatani bah, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, azd2171, batabulin, atumtunab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifen, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131 -I-TM-601 , ALT-110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR, KRX-0402, lucanton, LY 317615, neuradiab, witespan, Rta 744, Sdx 102, talampanel, atrasentan, Xr 311 , romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N[4-[2-(2-amino-4,7-dihydro-4-oxo-III-pyrrolo[2,3^]pyrimidin-5-yl) ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES (diethylstilbestol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258 ); 3-[5-(methylsulfonylpiperadinemethyl)indolyl]-quinolone, vatalanib, AG-013736, AVE-0005, acetate salt [D-Ser(But) 6, Azgly 10] (pyro-GluHis-Trp-Ser-Tyr-D- Ser(But)-Leu-Arg-Pro-Azgly-NH2 acetate [C ₅ 9H ₈₄ Ni8Oi ₄ -(C ₂ H ₄ O ₂ )x, where x is from 1 to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutanide, nilutamide, megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibodies, Erbitux, EKB- 569, PKI-166, GW-572016, lonafarnib, BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacry on, anagrelide, L -asparaginase, bacillus Calmette-Guerin vaccine (BCG), bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone acetate, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone , flutamide, gemcitabine, glivac, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplate ina, pamidronate, pentostatin, plicamycin , porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cisretinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deoxyuridine , cytosine arabinoside, 6-mercaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862 , angiostatin, Vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimetidine, trastuzumab, denileukin diftitox, gefitinib, bortesimibe, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody) and erbitux, paclitaxel, without general Cremophor, Epitilon B, BMS- 247550, BMS-310705, droloxifene, 4-hydroxytamoxifene, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR3339, ZK186619, PTK787/ZK 222584, VX-74 5, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, P EG-filgrastim, darbepoetin , erythropoietin, granulocyte colony-stimulating factor, zoledronate, prednisone, cetuximab, granulocyte-macrophage colony-stimulating factor, histrelin, pegylated interferon alpha^, interferon alpha^, pegylated interferon alpha-2K interferon alpha2b, azacitidine, PEG-L-asparaginase, lenalidomide, heme tuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-trans retinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, mustard nitrogen, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cor tizone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Erwinia asparaginase, strontium 89, caso

- 131 046076 pitant, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron , dolasetron, tropisetron, pegfilgrastim, erythropoietin , epoetin alfa and darbepoetin alfa, ipilimumab, vemurafenib and mixtures thereof.

In some embodiments, a CSF1R inhibitor described herein, such as Compound 1, can be used in combination with both a chemotherapeutic agent and an immunomodulatory therapy, eg, a chemotherapeutic agent and an anti-PD1 antibody therapy described herein.

Examples

The compounds described in this invention can be prepared in a variety of ways based on the concepts contained in this invention and synthesis procedures known in the prior art. With respect to the description of the synthetic methods described below, it should be understood that for all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration and work-up procedures, conditions may be selected that are standard for the given reaction unless otherwise indicated. One skilled in the art of organic synthesis will appreciate that the functional groups present on different parts of the molecule must be compatible with the proposed reagents and reactions. Which substituents are incompatible with the reaction conditions will be apparent to one skilled in the art, and alternative methods are therefore indicated. The starting materials for these examples are either commercially available or readily prepared by standard methods from known materials.

In the present invention, the following abbreviations are used and have the following definitions.

DCM is dichloromethane;

DMA is N.N-dimethylacetamide;

DMF is N,N-dimethylformamide;

dppf is 1,1'-bis(diphenylphosphino)ferrocene;

DMSO is dimethyl sulfoxide;

ESI is electrospray ionization;

EtOAc is ethyl acetate;

h represents the hour or hours;

Hex represents hexane;

LiHMDS is lithium bis(trimethylsilyl)amide;

MeOH represents methanol;

Me ₄ tBuXPhos is di-tert-butyl(2',4',6'-triisopropyl-3,4,5,6-tetramethyl-[1,1'biphenyl]-2-yl)phosphine;

MHz represents megahertz;

MS stands for mass spectrometry;

NMR stands for nuclear magnetic resonance;

Pd(PPh ₃ ) ₄ is tetrakis(triphenylphosphine)palladium(0);

temperature is room temperature, which is also known as ambient temperature, which should be understood to include the range of normal temperatures in the laboratory, which range from 15 to 25°C; and sat. represents saturated.

Example 1. Synthesis route for compound 1.

Compound A: 3-((2-chloropyridin-4-yl)oxy)-6-iodo-2-methylpyridine.

Compound A

A solution of 3-hydroxy-2-methylpyridine (20.0 g, 183 mmol) and Na ₂ CO ₃ (38.8 g, 367 mmol) in H ₂ O (320 ml) and MeOH (200 ml) was treated with I2 ( 46.5 g, 183 mmol) and stirred at RT for 1 hour. The mixture was acidified with HCl (2 M), extracted with EtOAc (2x) and the combined organics were washed with brine, dried over Na ₂ SO ₄ and concentrated to dryness. The material was suspended in EtOAc/Hex 1:1, sonicated and the solid was collected by filtration and dried. The filtrate was concentrated to dryness, treated with DCM, the solid was collected by filtration and combined with the first solid to give 6-iodo-2-methylpyridin-3-ol (20.5 g, 48%).

MS (ESI) mass/charge: 236.0 (M+H+).

A mixture of 6-iodo-2-methylpyridin-3-ol (6.8 g, 28.9 mmol), 2,4-dichloropyridine (8.56 g, 57.9 mmol) and K ₂ CO ₃ (4.00 g , 28.9 mmol) in DMA (50 ml) was heated at 110°C for 16 h under argon. Mixture

- 132 046076 cooled to rt, treated with H2O, extracted with EtOAc (2x) and the combined organics washed with H2O, then the brine was dried over Na ₂ SO ₄ , concentrated to dryness and purified by chromatography on silica gel (EtOAc/Hex) to give 3-((2-chloropyridin-4-yl)oxy)-6-iodo-2-methylpyridine (7.35 g, 73%) as a white solid.

MS (ESI) mass/charge: 346.9 (M+H+).

Compound B: 3-methyl-2-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin4(3H)-one.

Connection B

A suspension of 2-(methylthio)pyrimidin-4(3H)-one (2.0 g, 14.1 mmol) in DMF (40 ml) at 0°C was treated using LiHMDS as a solid (3.06 g, 18 .3 mmol), and then methyl iodide (1.14 ml, 18.3 mmol), heated to room temperature and stirred overnight. The mixture was quenched with water, extracted with EtOAc (3x) and the combined organics were dried over Na ₂ SO ₄ , concentrated to dryness and purified by silica gel chromatography (EtOAc/Hex) to give 3-methyl-2-(methylthio)pyrimidine- 4(3H)-one (1.37 g, 62%).

^1H NMR (400 MHz, DMSO-de) δ 7.83 (d, J=6.5 Hz, 1H), 6.17 (d, J=6.5 Hz, 1H), 3.39 (s, 3H), 2.54 (s, 3H);

MS (ESI) mass/charge: 157.1 (M+H+).

A solution of 3-methyl-2-(methylthio)pyrimidin-4(3H)-one (1.37 g, 8.77 mmol) in CHCl ₃ (15 ml) at 0°C was treated with bromine (0.54 ml, 10. 5 mmol), stirred at 0°C for 1 hour, quenched with sat. NaHCO ₃ (15 ml), warmed slowly to room temperature and stirred overnight. The mixture was extracted with DCM (3x) and the combined organics were dried over Na2SO4 and concentrated to dryness to give 5-bromo-3-methyl-2-(methylthio)pyrimidin-4(3H)-one (2.0 g, yield 97%).

^1H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H), 3.45 (s, 3H), 2.55 (s, 3H);

MS (ESI) mass/charge: 235.0 (M+H+).

Mixture of 5-bromo-3-methyl-2-(methylthio)pyrimidin-4(3H)-one (1.0 g, 4.25 mmol), bis(pinacolato)diborane (1.30 g, 5.10 mmol) and KOAc (1.25 g, 12.7 mmol) in dioxane (10 ml) bubbled with Ar, treated with PdCl ₂ (dppf)-DCM adduct (0.17 g, 0.21 mmol), bubbled again with Ar and heated at 85°C overnight. The mixture was cooled to room temperature, quenched using sat. NaHCO3, extracted with EtOAc (3x) and the combined organics dried over _Na2SO4 and concentrated to dryness to give 3-methyl-2-(methylthio)-5- ₍ 4,4,5,5-tetramethyl-1 ,3,2dioxaborolan-2-yl)pyrimidin-4(3H)-one (calculated yield 100%).

MS (ESI) mass/charge: 202.1 (boronic acid mass+H+).

Compound C: 3-methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)-oxy)pyridin-2yl)-2-( methylthio)pyrimidin-4(3H)-one.

Connection C

A mixture of compound B (0.35 g, 1.73 mmol), compound A (0.50 g, 1.44 mmol) and K ₂ CO ₃ (0.60 g, 4.33 mmol) in dioxane/water in 5:1 ratio (12 ml) was bubbled with Ar, treated with Pd(PPh ₃ ) ₄ (0.17 g, 0.14 mmol), bubbled again with Ar and heated at 90°C overnight. The mixture was quenched using sat. NaHCO3, extracted with EtOAc (3x) and the combined organics dried over _Na2SO4 , concentrated to dryness and purified by silica gel chromatography (EtOAc/Hex) to give 5- ₍ 5-((2-chloropyridin-4yl) oxy)-6-methylpyridin-2-yl)-3-methyl-2-(methyl-thio)pyrimidin-4(3H)-one (0.52 g, 67%).

MS (ESI) mass/charge: 375.1 (M+H+).

Mixture of 5-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-methyl-2-(methyl-thio)pyrimidin4(3H)-one (0.52 g , 0.97 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.22 g, 1.07 mmol ) and K2CO3 (0.40 g, 2.9 mmol) in a 5:1 dioxane/water mixture (6 ml) was bubbled with Ar, treated with Pd(PPh ₃ ) ₄ (0.12 g, 0. 10 mmol), bubbled again with

- 133 046076 using Ar and heated at 90°C overnight. Solids were removed by filtration and the filtrate was treated with sat. NaHCO3, extracted with EtOAc (3x) and the combined organics dried over _Na2SO4 , concentrated to dryness and purified by silica gel chromatography (MeOH/ _DCM ) to give 3-methyl-5-(6-methyl-5- ((2-(1methyl-1H-pyrazol-4-yl)pyridin-4-yl)-oxy)pyridin-2-yl)-2-(methylthio)pyrimidin-4(3H)-one (140 mg, 34% ).

MS (ESI) mass/charge: 421.1 (M+H+).

Compound 1: 2-(isopropylamino)-3-methyl-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4yl)oxy)pyridin-2-yl )pyrimidin-4(3N)-one.

Connection 1

A mixture of compound C (0.14 g, 0.33 mmol) and isopropylamine (3 ml, 35.0 mmol) was heated at 100°C for 2 days in a sealed tube. The mixture was cooled to rt, the solid was removed by filtration and the filtrate was concentrated to dryness and purified by silica gel chromatography to give 2-(isopropylamino)-3-methyl-5-(6-methyl-5-((2- (1-methyl-1H-pyrazol-4yl)pyridin-4-yl)oxy)pyridin-2-yl)pyrimidin-4(3H)-one (88 mg, 59%).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.68 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.28 (d, J=8.7 Hz , 1H), 8.25 (s, 1H), 7.96 (d, J=0.7 Hz, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.23 (d , J=2.4 Hz, 1H), 7.05 (d, J=7.6 Hz, 1H), 6.60 (dd, J=5.7, 2.4 Hz, 1H), 4.33 (m, 1H), 3.85 (s, 3H), 3.37 (s, 3H), 2.35 (s, 3H), 1.23 (d, J=6.6 Hz, 6H);

MS (ESI) mass/charge: 432.2 (M+H+).

Example 2: Depletion of Tumor Associated Macrophages in a Syngeneic Mouse Model of Colorectal Cancer.

Prior to implementation, the following protocol and procedures regarding animal care and use for the MC38 syngeneic mouse xenograft models were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of CrownBio (Taicang, Jiangsu Province, China). During the study, animals were kept and used in accordance with the requirements of the International Association for the Assessment and Accreditation of Laboratory Animal Research (AAALAC). All mice had free access to food and water. All mice were examined for clinical signs at least once daily. In the first experiment, six- to eight-week-old female C57BL/6 mice were inoculated subcutaneously in the lower right flank using one million MC38 tumor cells in phosphate-buffered saline. When tumor load values reached 102 mm ³ on average by day 12, mice were randomly divided into groups. Groups of mice (n=10) were gavaged on days 12-18 as follows: vehicle control (0.4% hydroxypropyl methylcellulose in water) QD; compound 1.5 mg/kg QD; compound 1, 10 mg/kg QD; or compound 1, 15 mg/kg QD. Tumor volume and body weight were measured three times a week. Tumor load (mg) was estimated from measurements with calipers using the formula tumor load (mg= ^mm3 )=( ^{lengthxwidth2} )/2

Tumor samples were collected 2 hours after the 7th dose on day 18 and processed fresh to assess infiltrating tumor-associated macrophages by flow cytometry using antibodies to CD11b+, F4/80, and CD45+. First, tumor samples were washed in phosphate-buffered saline and treated with collagenase and DNase. After treatment, cells were repeatedly passed through a 70-μm cell sieve. The cells were washed further, resuspended in red blood cell lysis buffer, and then washed again. The cell concentration was adjusted to 1x10 ⁷ cells/ml and incubated with antibodies conjugated to a fluorescent tag (CD45-FITC, CD11b-PE and F4/80-APC; BioLegend). Stained cells were washed several times before flow cytometry analysis.

In a second experiment using a syngeneic MC38 xenograft, seven to nine week old female C57BL/6 mice were inoculated with MC38 tumor cells as described above. When tumor load values reached 104 mm ³ on average by day 12, mice were randomly divided into groups. Groups of mice (n=5) were gavaged on days 12-32 as follows: vehicle control (0.4% hydroxypropyl methylcellulose in water) QD; isotype control group (no oral treatments); compound 1.5 mg/kg QD; or compound 1, 10 mg/kg QD. Vehicle-treated mice were also treated intraperitoneally twice weekly with phosphate-buffered saline, and all other mice were also treated intraperitoneally twice weekly with rat IgG2a isotype control antibody, which served as a control for treatment with the vehicle combination.

- 134 046076 munotherapy in other cohorts not described in this invention. Tumor samples were collected at day 32 and processed for flow cytometry as described above, except that cells were incubated with fluorescently labeled antibodies (CD45-FITC, CD11b-PE-Cy7, F4/80-APC, and CD335PE; BioLegend).

Fig. 1 and 2 are graphical representations demonstrating depletion of tumor associated macrophages compared to vehicle control. In fig. 1 demonstrates that after seven days of treatment with Compound 1, there is a dose-dependent reduction in the number of CD11b+/F4/80+ macrophages within the tumor (as a percentage of CD45+ cells in the tumor). At high dose, intratumoral macrophage numbers were reduced by ~67% (as a percentage of CD45+ cells in the tumor). In fig. 2 demonstrates that after 21 days of treatment with Compound 1 there is a >80% reduction in the number of intratumor macrophages compared to vehicle or isotype control (as a percentage of total cells in the tumor). Such data demonstrate that treatment of mice with compound 1 for seven days or 21 days results in depletion of macrophages within the tumor.

Example 3: Pharmacokinetic (PK) properties and depletion of circulating monocytes expressing CSF1R in treated patients.

Doses of Compound 1 were administered orally and evaluated in seven dose-based cohorts of 40 patients with solid tumor malignancies and advanced TGCT. The cohorts included one dose-based cohort that received 10 mg QD, five dose-based cohorts that received a once-weekly or twice-weekly maintenance regimen followed by a loading regimen. doses for five days at doses no more than 40 mg per dose, and one cohort received a loading dose of 50 mg QD for 5 days followed by 20 mg QD. These five cohorts were as follows: 1-10 mg QD cohort (n=7); Cohort 2 - loading dose of 10 mg QD for 5 days, followed by a maintenance dose of 10 mg twice weekly (twice weekly or BIW) (5x QD/BIW; n=3); Cohort 3 - loading dose of 20 mg QD for 5 days, followed by a maintenance dose of 20 mg once a week (5x QD/Q1W; n=4); Cohort 4 - loading dose of 20 mg QD for 5 days, followed by a maintenance dose of 20 mg twice weekly (5x QD/BIW; n=4); Cohort 5 - loading dose of 30 mg QD for 5 days, followed by a maintenance dose of 30 mg twice weekly (5x QD/BIW; n=6); Cohort 6 - loading dose of 40 mg QD for 5 days, followed by a maintenance dose of 40 mg twice weekly (5x QD/BIW; n=5); Cohort 7 - loading dose of 50 mg QD for 3 days, followed by a maintenance dose of 20 mg (3x QD/QD; n=8).

PK analysis was performed on all 38 patients. For PK, serial blood samples were collected and collection was performed according to any of the following: on day -7, day 1 of cycle 1 (C1D1) and C2D1 pre-dose, time points 0.5, 1, 2, 4, 6, 8, 10-12 and 24 hours, or day -7, C1D1, C1D8 and C2D1 pre-dose, time points 1, 2, 4, 6 and 8 hours, or C1D1, C1D8 and C2D1 pre-dose, time points 1, 2 , 4, 6 and 8 hours. On day -7, a high-fat meal was provided before dosing with Compound 1. PD effects were measured by two techniques: 1) measuring depletion of CSF1R-expressing monocytes in peripheral blood samples (cohorts 1-7) obtained in C1D1, C1D15 and C2D1; and 2) measuring increases in plasma levels of CSF1 and IL-34, CSF1R ligands (cohorts 1–7) in C1D1, C1D15, and C2D1. To perform the CD16+ monocyte assay, whole blood collected in an EDTA vacuum container was aliquoted into tubes and incubated with fluorescently labeled antibodies (CD14-Alexa488 (BD Pharmingen), CD16-PE-Cy7 (BD Pharmingen) and TIE2APC (R&D Systems)). After incubation, red blood cells were lysed and the remaining cells were washed several times before being analyzed on a flow cytometer. To perform analysis of CSF1 or IL-34 in plasma, whole blood collected in a vacuum container with EDTA was centrifuged and the plasma was collected and frozen. Plasma levels of CSF1 or IL-34 were measured using a commercial ELISA kit (R&D Systems).

The average values of pharmacokinetic parameters for each cohort of patients are shown in table. 1. AUC values _{0-8 h} (area under the curve of plasma concentration versus time over the time period 0-8 h) in C2D1; C _max (maximum concentration in blood plasma); and C _residual (residual plasma concentration) are shown for all cohorts. In cohort 1, doses were administered every day. In cohorts from Cohort 2 onwards, a loading dose was administered for 5 days followed by a maintenance dose once or twice a week. Cohort 7 received a loading dose for 3 days followed by a maintenance dose once daily. In C2D1, AUC _{0-8 h} , C _max and C _residual values showed approximately dose-dependent increases in cohorts 1-7.

Fig. 3 is a graphical representation demonstrating the depletion of CSF1R-expressing monocytes in peripheral blood obtained from patients treated with Compound 1. The number of CSF1R-expressing monocytes was reduced in cohorts 2-5, with the most pronounced reduction occurring in cohorts with highest dosage of compound 1.

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Cohort 2 (n=2) had ~48% reduction in the levels of CSF1R-expressing monocytes in C2D1 compared with the levels of CSF1R-expressing monocytes in C1D1. Cohort 3 (n=1) had ~54% reduction in CSF1R-expressing monocyte levels in C2D1 compared to CSF1R-expressing monocyte levels in C1D1. Cohort 4 (n=2) had a ~79% reduction in the levels of CSF1R-expressing monocytes in C2D1 compared with the levels of CSF1R-expressing monocytes in C1D1. Cohort 5 (n=2) had ~98% reduction in the levels of CSF1R-expressing monocytes in C2D1 compared with the levels of CSF1R-expressing monocytes in C1D1.

Fig. 15 is a graphical representation demonstrating the depletion of CD16+ monocytes in peripheral blood obtained from patients treated with Compound 1. The CD16+ monocyte subset is known to be sensitive to treatment with CSF-1 and thus serves as a pharmacodynamic marker of CSF-1 inhibition. 1R. PD data obtained from patients treated with Compound 1 showed that CD16+ monocyte levels decreased with increasing dose and concentration of Compound 1, indicating a blockade of CSF1R-mediated signaling. In the lower dose cohorts (cohorts 1-4), the percentage of CD16+ monocytes from total blood monocytes at baseline decreased by between 18 and 9% after 2 weeks of treatment with Compound 1. In the higher dose cohorts (cohorts 5-7) the percentage of CD16+ monocytes from total blood monocytes at baseline decreased by a value ranging from 68 to 94% after 2 weeks of treatment with compound 1.

Fig. 4 is a graphical representation demonstrating increased plasma CSF1 levels obtained from patients treated with Compound 1. Patients from all five cohorts had increased plasma CSF1 levels in C1D15 and C2D1 compared to C1D1. On average in C2D1, cohort 1 had a 6-fold increase in plasma CSF1 levels, cohort 2 had a 1.5-fold increase, cohort 3 had a 2.9-fold increase, cohort 4 had a 3.2-fold increase, and cohort 5 characterized by a 43-fold increase.

Fig. 16 is a graphical representation demonstrating the increase in CSF1 and IL34 levels in plasma obtained from patients treated with Compound 1. In C1D1, all patients had detectable levels of CSF1, with the average across all cohorts being 520.7 pg/ml. Serum CSF1 concentrations increased with increasing dose and concentration of compound 1. CSF1 levels in the lower dose cohorts (cohorts 1–4) increased approximately 3–5-fold in C2D1 compared with baseline. In higher dose cohorts (cohorts 5-7), patients experienced 22- to 36-fold increases in CSF1 levels in C2D1. Doses in cohorts 6 and 7 had similar effects on serum CSF1 levels. Compound 1 showed a dose-dependent effect on circulating CSF1 concentrations. A similar trend was observed for IL-34 levels. In C1D1, all patients had detectable levels of IL-34, with a mean across all cohorts of 9.3 pg/mL. In patients enrolled in the lower dose cohorts (cohorts 1–4), IL-34 levels increased 2–5-fold over baseline by C2D1. In higher dose cohorts (cohorts 5-7) to C2D1, patients experienced 26- to 100-fold increases in IL-34 levels. Doses in cohorts 6 and 7 had similar effects on serum IL-34 levels.

Table 1

Parameters for day -7, day 1 of cycle 1, day 8 of cycle 1 and day 1 of cycle 2

Cohort Visit N Spach (ng/ml) AUCo-8 4. (h*ng/ml) Sostatol (ng/ml) Cohort 1 10 mg QD -7 Average, geom. 7 75.9 429 - CV% 36.1 44.3 - C1D1 Average, geom. 7 155 770 - CV% 36 44.3 -

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C1D8 Average, geom. 6 - - 331 CV% - - 23.9 C2D1 Average, geom. 3 767 4470 447 ^e CV% 12.3 17.4 65.2 Cohort 2 10 mg QD x 5 days Maintenance dose BIW -7 Average, geom. 1 119 781 - CV% - - - C1D1 Average, geom. 2 168 1080 - CV% 20.8 24.3 - C1D8 Average, geom. 3 248 1730 184 CV% 89.9 89.5 76.5 C2D1 Average, geom. 3 149 1030 122 CV% 68.7 63.0 63.3 Cohort 3 20 mg QD x 5 days Maintenance dose QW -7 Average, geom. 4 242 1320 - CV% 31.2 24.9 - C1D1 Average, geom. 3 466 2510 - CV% 36.7 24.2 - C1D8 Average, geom. 3 1160 7410 ^b 850 CV% 6.2 15.3 14.2 C2D1 Average, geom. 2 530 3380 205 CV% 27.9 20 10.0 Cohort 4 20 mg QD x 5 days Maintenance dose BIW -7 Average, geom. 4 183 1090 - CV% 32.7 29.7 - C1D1 Average, geom. 4 268 1610 - CV% 29.9 40.7 - C1D8 Average, geom. 4 685 4660 483 CV% 35.3 44.3 55.9 C2D1 Average, geom. 3 642 4300 441 CV% 8.21 2.82 19.9 Cohort 5 30 mg QD x 5 days Maintenance dose BIW -7 Average, geom. 6 278 1390 - CV% 42.1 49.8 - C1D1 Average, geom. 6 600 3390 ^e - CV% 52.9 37.9 - C1D8 Average, geom. 3 1400 8800 1020 CV% 17.9 32.4 33.6 C2D1 Average, geom. 3 953 5420 574 CV% 85.5 65.8 61.6 Cohort 6 30 mg QD x 5 days Maintenance dose BIW C2D1 Average, geom. 3 1150 7290 570 Cohort 7 50 mg QD x 3 days Maintenance dose QD C2D1 Average, geom. 3 1250 7980 1040

AUC0-8 h=area under the plasma concentration-time curve for the time period 0-8 hours;

^^maximum concentration in blood plasma;

_Costatic = residual concentration in blood plasma;

CV% = coefficient of variability in percent;

avg. geom.=geometric mean;

N= ⁱ iucjo patients under observation;

PK=pharmacokinetics;

- 137 046076

T _max = time until maximum concentration is reached.

a N=6, ^b N=2, ^c N=5.

table 2

Parameters for day -7, day 1 of cycle 1, day 8 of cycle 1 and day 1 of cycle 2

Cohort Visit N Tmax (h.) Stakh (ng/ml) AUCo-8 (p.* ng/ml) Cohort 1 10 mg QD ^b Day -7 7 6 (2, 24) 75.9 (36.1) 425 (44) C1D1 7 1 (0.5, 24) 155(36) 770 (44.3) C1D8 6 N.A. N.A. N.A. C2D1 5 0.5 (0.5, 1/ 767 (12.3) ^s 4510(15.9/ Cohort 2 10 mg twice weekly ¹¹ Day -7 2 6 (4, 8) 80.2 353 C1D1 3 2(1.8) 94(134) 467 (275) C1D8 3 1(1.8) 248 (89.9) 1730 (89.5) C2D1 3 1 (0.5, 4) 149 (68.7) 1030 (63) Cohort 3 Day -7 4 4(1.4) 242 (31.2) 1320 (24.9) 20 mg once a ^week C1D1 3 1(1, 1) 466 (36.7) 2510 (24.2) C1D8 3 1 (0.5, 1) 1160 (6.2) 7290(11.1) C2D1 2 1(1, 1) 530 3380 Cohort 4 20 mg twice a week ^b Day -7 4 4 (2, 4) 183 (32.7) 1090 (29.7) C1D1 4 0.75 (0.5, 8) 268 (29.9) 1610 (40.7) C1D8 4 2.25 (0.5, 4) 685 (35.3) 4660 (44.3) C2D1 3 0.5 (0.5, 2) 642 (8.21) 4300 (2.82) Cohort 5 30 mg twice weekly ¹¹ Day -7 6 6 (4, 8) 278 (42.1) 1390 (49.8) C1D1 9 1 (0.5, 6) 422 (79.3) 2250 (77.3) C1D8 7 1 (1.2/ 1160 (29/ 7160 (33.9/ C2D1 6 1.5 (0.5, 2) 822(58) 4750 (53.2) Cohort 6 40 mg twice weekly ¹ ' Day -7 5 4 (4, 8) 454 (28.3) 2250 (28.9) C1D1 5 2 (0.5, 6) 830 (36.9) 4790 (28.7) C1D8 4 1 (0.5, 6) 1860 (25.9) 12000 (26.1) C2D1 3 1 (0, 2) 1150 (29.8) 7290 (28.1) Cohort 7 20 mg QD ^e Day -7 2 5 (2, 8) 272 800 C1D1 7 2 (0.5, 8) 440 (84.1) 2310(77.4) C1D8 7 2(1.4) 1010 (42) 6740 (33.3) C2D1 4 2 (0.5, 6) 840 (99.8) 5580 (86.8)

AUC _{0-8 h} = area under the plasma concentration versus time curve for the time period 0-8 h;

C _max = maximum concentration in blood plasma;

C _residual = residual concentration in blood plasma;

C^% coefficient of variability as a percentage;

GM=geometric mean;

max=maximum value;

pcs=minimum value;

N is the number of patients under observation;

NA not applicable;

PK=pharmacokinetics;

QD=every day;

T _max = time until maximum concentration is reached.

a Median (Min, Max) of the T _max value.

^b After administration of a loading dose of QD for 5 days.

^c N=3.

^d N=6.

^e Following a loading dose of 50 mg QD for 3 days.

When increasing doses, a 3+3 pharmacologically controlled study design is used, in which Compound 1 is administered orally in repeating 28-day cycles. Pharmaco-based

- 138 046076 kinetic data obtained from patients in cohorts 1-7 allocated based on dose magnitude, accurate half-life estimates are not available due to the relatively short sampling time for PK. Data available to date suggest that compound 1 has a long half-life, with QD dosing patterns near steady-state levels near C2D1. Simulations based on nonparametric alignment analysis show that steady state can be reached more quickly when a loading dose is applied. For example, administration of loading doses of 30 mg QD for 3 days followed by a maintenance dose of 10 mg QD could achieve and maintain steady-state concentrations for approximately one week (Figure 17). Also, modeling suggests that administration of a loading dose of 30 mg QD for 5 days followed by a dose of 30 mg twice weekly (i.e., twice weekly) can achieve steady-state concentrations within approximately one week, although the ratio ranges Peak and trough plasma concentrations will be wider compared to the maintenance regimen with 10 mg QD due to the _lower C ts at steady state (Fig. 17).

The plasma concentration of Compound 1 as a function of time for subjects in each cohort assessed in C2D1 is shown in Table. 1, shown in FIG. 5. In these subjects, treatment with Compound 1 caused increases in plasma CSF1 and IL-34 that were drug concentration dependent and a rapid and sustained decrease in CD16+ monocytes that were dose dependent (FIG. 6).

Changes in CD163+ macrophage populations were assessed in paired tumor biopsies collected at screening and on day 15 of cycle 2 (C2D15) (Fig. 7). Samples were processed for IHC analysis for CD163 (10D6). Whole tissue imaging was analyzed using Flagship's cTA platform for CD163 quantitation.

Example 4: Study involving patients with advanced tumors.

The antitumor activity and doses of Compound 1 in patients with advanced tumors were evaluated in a clinical trial in human patients.

The study included patients with solid tumors or cancer manifestations in which the involvement of macrophages or phagocytes was established, i.e. tumors known to express the colony stimulating factor 1 receptor (CSF1R) or its ligands, colony stimulating factor 1 (CSF1) or interleukin (IL) 34, as confirmed by literature or previous testing. An illustrative example of such diseases is diffuse-type tenosynovial giant cell tumor (DTGCT), where aberrant overproduction of CSF1 triggers macrophage recruitment, leading to local joint damage. Anti-CSF1R antibody-based therapy has demonstrated clinical efficacy in DTGCT. Patients with an advanced type of carcinoma, which is characterized by a high proportion of tumor-infiltrating macrophages, will be eligible for inclusion in the study. In addition, inclusion is considered in the presence of tumor-associated manifestations characterized by macrophage- or osteoclast-mediated pathophysiology, including bone metastases and ascites or effusions, which typically contain high levels of macrophages. Finally, since macrophages have been shown to be involved in the development of drug resistance or adaptive response to approved therapies, Compound 1 will also be studied in this paradigm.

The study consists of a screening period that occurs within 28 days prior to the first dose of study drug, a treatment period consisting of 28-day cycles, a treatment completion visit, and follow-up visits to assess safety on both days 30 and 75 ( ±5 days) after the last dose of the study drug. Patients will be eligible to receive the investigational drug for a maximum of 2 years until the tumor begins to progress, until toxicity develops to an unacceptable degree, or until informed consent is withdrawn, or until a commercial supply of the drug is available. This period may be extended for patients who demonstrate signs of improvement in clinical performance and tolerability of the drug and who comply with study procedures. Patients can continue receiving treatment after the tumor begins to progress.

Any of the following types of advanced solid tumors that have progressed after treatment with all available therapies known to provide clinical improvement, or for which conventional therapy is not considered effective in the opinion of one skilled in the art. Any of the following types of advanced solid tumors that have progressed after treatment with all available therapies known to provide clinical benefit, or for which conventional therapy is not considered effective, may include solid tumors, including but not limited to metastatic cancer breast or prostate cancer with bone disease; solid tumors including, without limitation, gastric, ovarian or non-small cell lung cancer, which are often characterized by the presence of malignant associated ascites or effusion(s); tumors for which

- 139 046076 where the participation of macrophages or phagocytes has been established, such as without limitation tumors with a high content of macrophages infiltrating the tumor; tumor types with high levels of tumor expression of the CSF1R receptor or its ligands, CSF1 or IL-34, in a prior trial; and prostate or breast cancer with disease affecting only the bones. (Therapies for osteoporosis or control of bone metastases with bisphosphonates or nuclear factor kappa B ligand receptor activity inhibitors are required to be stable for at least 2 months before starting treatment with Compound 1). Patients with NSCLC may also be included if they have the following: histologically or cytologically confirmed metastatic or unresectable locally advanced, recurrent NSCLC with known EGFR mutation(s); documented disease progression while receiving prior treatment with an EGFR tyrosine kinase inhibitor (TKI); the presence of tumors, including but not limited to metastatic breast cancer or prostate cancer with bone disease; solid tumors including, without limitation, gastric, ovarian or non-small cell lung cancer, which are often characterized by the presence of malignant associated ascites or effusion(s); tumors that have been shown to involve macrophages or phagocytes, such as, but not limited to, tumors with a high content of tumor-infiltrating macrophages; tumor types with high levels of tumor expression of the CSF1R receptor or its ligands, CSF1 or IL-34, in a prior trial; or prostate or breast cancer with disease affecting only the bones.

Patients with solid tumors received study drug orally at a starting dose of 10 mg QD based on preclinical toxicology and PK studies (cohort 1). Following the results for Cohort 1, Cohort 2 moved to loading doses followed by maintenance doses in a dose escalation schedule.

Dose escalation of the study drug is based on data obtained from a 3+3 pharmacologically controlled study design in patients with solid tumors (Table 3). Each dose-based cohort included a minimum of 3 patients. If a patient experienced a DLT in cycle 1, then the cohort was expanded to 6 patients. If >2 patients out of 3 to 6 patients experienced one or more dose-limiting toxicities (DLTs) during cycle 1, dose escalation was stopped and the lower dose cohort was expanded to determine the maximum tolerated dose (MTD). If there were no more patients experiencing DLT in the expansion cohort, the dose level was increased. Decisions were made regarding dose escalation and dose level for the next cohort. In the dose escalation phase, a patient is assessed if the patient either experienced a DLT during Cycle 1 or received >80% of the planned study drug dose in Cycle 1. Following dose escalation in Cohort 6, subsequent dose escalation cohorts will be determined based on safety analysis , PK and PD data. The total dose provided in the first cycle will be allowed to increase by no more than 50% of the dose of the previous cohort.

The MTD will be defined as the highest dose level at which DLT will occur in no more than 1 in 6 patients assessed for DLT in cycle 1 during dose escalation. An additional, lower, intermediate dose level may be considered to determine the recommended phase 2 dose (RP2D). RP2D will be the MTD or the biologically active dose or the maximum possible dose below the MTD. For patients with solid tumors and DTGCT, different RP2Ds may be defined. If no patients at the dose level considered experienced DLT during cycle 1, then the cohort could be expanded to 6 patients to investigate PK or evidence of sustained PD or antitumor activity. Determination of MTD or RP2D would require treating at least 6 patients at the same dose level.

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Table 3

Scheme for increasing loading and maintenance doses

Cohort Loading dose QD Maintenance dose (mg) Administration of loading doses in cycle 1 Total dose in cycle 1 (mg) Dose escalation (%) to cohort 2 Dose intensity (%) 10 mg QD in cycle 1 2 ^d 10 (50) ^a 10 ^b C1D8, 12, 15, 19, 22, 26 BY N.A. 39 ^3d 20 (100) ^{a 20th} C1D8, 15, 22 160 45 57 4 ^d 20 (100) ^a 20 ^b C1D8, 12, 15, 19, 22, 26 220 38 79 5 ^d 30 (150) ^a 30 ^b C1D8, 12, 15, 19, 22, 26 330 50 118 6 ^d 40 (200) ^a 40 ^b C1D8, 12, 15, 19, 22, 26 440 33 157 ^7th 50 (150) ^a 20 ^f C1D4-D28 650 48 232 7 and above The dose/schedule is determined based on new data obtained TBD

C=cycle;

D=day;

NA not applicable;

QD=once daily;

TBD=to be determined.

Note: Dosing in cohorts 2-5 has been completed.

^a Total loading dose shown in parentheses ^b Dose administered twice weekly.

^c Dose once weekly.

d The loading dose period occurred on cycle 1, days 1, 2, 3, 4 and 5.

^e The loading dose period occurred on cycle 1, days 1, 2, and 3. ^f Once-daily dosing.

Each dose-based cohort included a minimum of 3 patients, including a loading dose cohort followed by a maintenance dose. Dose increases in loading and maintenance dose regimens will be carried out as follows.

Cohort 2: Compound 1 was administered orally for 5 consecutive days in the first week of cycle 1 (C1D1-5, loading dose period) followed by twice weekly dosing (BID) (C1D8, 12, 15, 19, 22 and 26) in subsequent weeks of cycle 1 onwards (D1, 5, 8, 12, 15, 19, 22 and 26 of each cycle; maintenance dose period). The initial dose was 10 mg per day for a loading dose for 5 days and 10 mg twice a week for a maintenance dose. The level of exposure to Compound 1 in Cohort 2 resulted in a steady state AUC _0-8 in C2D1 of 1030 ng-hr/mL (Tables 1 and 2).

Cohort 3: Compound 1 was administered orally for 5 consecutive days in the first week of cycle 1 (C1D1-5, loading dose period) followed by once weekly dosing (C1D8, 15, 22) in subsequent weeks of cycle 1 onwards ( D1, 8, 15 and 22 of each cycle; maintenance dose period). The initial dose was 20 mg per day for a loading dose for 5 days and 20 mg once a week for a maintenance dose. The level of exposure to compound 1 in cohort 3 resulted in a steady-state AUC0-8 value in C2D1 of 3380 ng-h/mL (Tables 1 and 2).

Cohort 4: Compound 1 was administered orally for 5 consecutive days in the first week of cycle 1 (C1D1-5, loading dose period) followed by twice weekly dosing

- 141 046076 (twice a week) (C1D8, 12, 15, 19, 22 and 26) in the subsequent weeks of cycle 1 onwards (D1, 5, 8, 12, 15, 19, 22 and 26 of each cycle; maintenance period dose). The initial dose was 20 mg per day for a loading dose for 5 days and 20 mg twice a week for a maintenance dose. The level of exposure to compound 1 in cohort 4 resulted in a steady state AUC _0-8 in C2D1 of 4300 ng-h. /ml (Tables 1 and 2).

Cohort 5: Compound 1 was administered orally for 5 consecutive days in the first week of cycle 1 (C1D1-5, loading dose period) followed by twice weekly dosing (BID) (C1D8, 12, 15, 19, 22 and 26) in subsequent weeks of cycle 1 onwards (D1, 5, 8, 12, 15, 19, 22 and 26 of each cycle; maintenance dose period). The initial dose was 30 mg per day for a loading dose for 5 days and 30 mg twice a week for a maintenance dose. The level of exposure to compound 1 in cohort 5 resulted in an AUC0-8 value at steady state in C2D1. amounting to 5420 ng-h/ml (Tables 1 and 2).

Cohort 6: Compound 1 was administered orally for 5 consecutive days in the first week of cycle 1 (C1D1-5, loading dose period) followed by twice weekly dosing (BID) (C1D8, 12, 15, 19, 22 and 26) in subsequent weeks of cycle 1 onwards (D1, 5, 8, 12, 15, 19, 22 and 26 of each cycle; maintenance dose period). The initial dose was 40 mg per day with a loading dose for 5 days and 40 mg twice a week with a maintenance dose. The level of exposure to compound 1 in cohort 5 resulted in a steady-state AUC0-8 value in C2D1 of 7290 ng-h/mL (Tables 1 and 2).

Cohort 7: Compound 1 was administered orally for 3 consecutive days on the first three days of cycle 1 (C1D1-3, loading dose period) followed by dosing every day during cycle 1 onwards (D1-28 of each cycle; maintenance dose period ). The initial dose was 50 mg per day for a loading dose for 3 days and 20 mg once daily for a maintenance dose. The level of exposure to compound 1 in cohort 7 resulted in a steady-state AUC0-8 value in C2D1 of 7980 ng-h/mL (Tables 1 and 2).

Cohorts Above Cohort 7: If studies in Cohort 7 are successful, doses and schedules for the next and subsequent dose escalation cohorts (above Cohort 7) will be determined based on analysis of PK, PD and safety data obtained for previous cohorts. Dose escalation will be continued by increasing the total dose provided in the first cycle to no more than 50% of that in the previous cohort. It is possible to conduct a study of two cohorts simultaneously if the dose escalation values for both cohorts do not exceed the dose escalation step threshold (no more than 50%) when compared with the previous cohort that was tested and found to be safe. Additional dosing schedules (eg, loading dose periods of 3 to 7 days or modifications to maintenance dosing schedules) may be considered based on PK, PD, and safety data.

The patient may begin receiving Compound 1 at a higher dose level after completing Cycle 2. An increase of one dose level is allowed at a time. The dose level after escalation should not exceed the RP2D or MTD and should be considered safe and tolerable as the dose is escalated. Initiation of dose increases in the same patient should occur at the visit on Day 1 of the next treatment cycle.

Patients will be dosed at the RP2D level in Cohort A. This Cohort A can include up to 12 patients with solid tumors with high levels of CSF1, IL-34, or CSF1R expression in the tumor, high levels of tumor macrophage infiltration, bone metastases, ascites /effusions or drug-resistant tumors where macrophages are involved as a mechanism of resistance, including without limitation patients with non-small cell lung cancer (NSCLC) who have progressed on treatment with epidermal growth factor receptor (EGFR) kinase inhibitor(s) , patients with prostate or breast cancer with bone metastases and patients with pancreatic cancer. Patients in this cohort will be treated with RP2D or MTD compound 1.

Samples for pharmacokinetic (PK) analysis will be collected throughout the study and PK analysis will be performed. In addition to assessing safety and potential antitumor activity, the PD effects of Compound 1 will also be assessed. Pharmacodynamic (PD) biomarkers from plasma and whole blood samples will be assessed throughout the study. Tumors will be studied for pharmacodynamic (PD) parameters as evidence of response to treatment, with paired biopsies obtained at screening and after exposure to the study drug. One blood sample will be obtained to study pharmacogenomic markers regarding the pharmacology of Compound 1 or its target CSF1R-mediated signal transduction pathway. Because mucin accumulation in the skin is suspected to be responsible for the occurrence of facial and peripheral edema during treatment with anti-CSF1R antibody therapies, Cohort A will undergo pre- and post-dose skin biopsies. Without limitation, the following PK endpoints will be evaluated as for

- 142 046076 of the active compound 1, and for its metabolite if it is detected: time until the maximum observed concentration is reached ( _Tmax ); maximum observed concentration ( _Cmax ); residual observed concentration ( _Cmin ); area under the concentration-time curve (AUC); and half-life (t _1/2 ).

Exploratory endpoints include pharmacodynamics (PD) such as blood levels of specific monocyte populations (such as CD16+ or CSF1R+ monocytes; see, e.g., FIG. 6) by flow cytometry, plasma CSF1 levels, marker levels bone remodeling (including collagen fragments, - C-terminal fragment of collagen in blood serum and N-terminal fragment of collagen in urine), content and/or polarization of macrophages in the tumor or fluids associated with tumor ascites/effusion before and after treatment, effects of compound 1 in relation to the immunoregulatory milieu, including the number, location, activation status (including interferon gamma signature) of immune cell populations in tumor biopsies across cohorts, and the prevalence and localization of tumor associated macrophages (TAMs) in tumor biopsies before treatment compared with those after treatment.

Preliminary evidence of antitumor activity. For Compound 1, the following endpoints providing preliminary evidence will be assessed: objective response rate (ORR=confirmed complete response [CR]+partial response [PR]), disease control rate (DCR=CR+PR+stable disease [SD]) through 12 weeks excluding DTGCT, time to best response (defined as time from day 1 of cycle 1 to PR or CR), time to progression-free survival (PFS; defined as time from day 1 of cycle 1 to disease progression or death), duration of response (DOR; time from PR or CR to disease progression or death) and objective response rate (ORR) and DCR at 6 months and 1 year.

Tumor response will be assessed based on tumor type using the following criteria: for solid tumors and DTGCT: RECIST version 1.1; and disease affecting only the bones: new lesion(s) identified on a bone scan will be considered disease progression.

In the study, the median total treatment duration was 60.6 days. There were 5 patients with best response, representing stable disease (2 with colorectal cancer and 1 each with prostate cancer, thymoma and uveal melanoma). The patient with thymoma had stable disease for 6 months.

Additional case study descriptions of patients with DTGCT treated in this study are provided below.

Patient 1: A 24-year-old female patient who was diagnosed with diffuse-type TGCT in the posterior region of the right knee in June 2016. Previous surgical procedures included synovectomies/tumor removal in June 2016, July 2016, and December 2017. The patient was observed to have recurrence/progression on MRI by December 2018. The patient was subsequently enrolled in Cohort 5 in February 2019.

During the study, there was a reduction in tumor size of 48, 61, 75, and 84% from baseline in C3D1, C5D1, C7D1, and C10D1, respectively, as determined by RECIST version 1.1 (Figure 8A). MRI scans of the patient taken at specific time points during the study are shown in FIG. 9. The patient was taking Mobic and Percocet every day at baseline. From day 1 of cycle 10, the patient took Percocet only as needed approximately once per week. In the first cycle there was an improvement in pain and swelling and effusion were almost completely eliminated.

Patient 2: A 57-year-old female patient who was diagnosed with a diffuse type TGCT in the right hip in 2014. Previous surgical procedures included excision (May 2014), synovectomy (August 2015 and August 2016), total replacement hip (August 2016), hip inspection and removal (August 2018) and cryoablation (May 2019). Recurrence was observed on MRI in February 2019. The patient was included in July 2019 in Cohort 5.

During the study, there was a 25% reduction in tumor size from baseline in C3D1 as determined by RECIST version 1.1 (Figure 8B). MRI scans of the patient taken at specific time points during the study are shown in FIG. 10. The patient demonstrated improvement in pain, increased range of motion, and less stiffness.

Patient 3: A 28-year-old male patient who was diagnosed with diffuse-type TGCT in his left knee in January 2016 after several years of pain. Previous surgery included excision and subsequent synovectomy in January 2016. Shortly after surgery, pain, swelling, and stiffness reappeared due to disease progression. The patient was included in March 2019 in cohort 5.

During the study, there was a 24% reduction in tumor size from baseline in C3D1 as determined by RECIST version 1.1 (Figure 8C). The patient demonstrated rapid improvement in symptoms, including less pain and swelling and improvement in range of motion after the first cycle. The patient was also able to play basketball without feeling pain.

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In fig. 11 additionally shows the results of measurements in the cohorts presented in FIG. 6, together with the corresponding measurement results obtained for Patient 1, Patient 2 and Patient 3 described above. In particular, the corresponding results of measuring the concentration of CSF1 in blood plasma are shown in FIG. 11A, the corresponding results of measuring the concentration of IL-34 in blood plasma are shown in FIG. 11B, and the corresponding results of measuring the % change in the number of CD16+ monocytes are shown in FIG. 11C.

Example 5: Patient Study of Tenosynovial Giant Cell Tumors.

Evaluation of Compound 1 in patients with diffuse type tenosynovial giant cell tumor (DTGCT) (formerly known as pigmented villonodular synovitis or tendon sheath giant cell tumor) will be conducted in Cohort B, allocated on a dosage basis, as described below. The effects of Compound 1 on range of motion and/or symptomatic relief were assessed using patient-reported symptom intensity or treatment outcome (PRO) data, as well as the effects of Compound 1 on the level of macrophage infiltration in the injured joint and the level of circulating chemokines/cytokines associated with inflammation.

The study will consist of a screening period that will occur within 28 days prior to the first dose of study drug, a treatment period consisting of 28-day cycles, a treatment completion visit, and follow-up visits to assess safety at both 30 and 75 days. days (±5 days) after the last dose of study drug. Patients will be eligible to receive the investigational drug for a maximum of 2 years until the tumor begins to progress, until toxicity develops to an unacceptable degree, or until informed consent is withdrawn, or until a commercial supply of the drug is available. This period may be extended for patients who demonstrate signs of improvement in clinical performance and tolerability of the drug and who comply with study procedures. Patients can continue receiving treatment after the tumor begins to progress.

To evaluate the safety, PK, PD, and preliminary efficacy of Compound 1 in the patient population, Cohort B could be established based on dosage and include a maximum of 40 DTGCT patients. Patients in Cohort B were treated with Compound 1 at a dose level at or below the RP2D or MTD determined according to the protocol in Example 4. The objectives of the study were to evaluate the safety and preliminary efficacy of Compound 1. In Cohort B, to evaluate range of motion and PRO scores. carried out as additional assessments of safety and effectiveness. Functional assessment of Cohort B includes assessment of range of motion of the injured joint(s) and scores obtained.

Only in the case of Cohort B, patients may have a histologically confirmed diagnosis of DTGCT (formerly known as pigmented villonodular synovitis or giant cell tumor of the tendon sheath), a disease in which surgical removal potentially causes worsening functional limitation or severe complications, symptomatic disease with at least moderate pain or stiffness (score of 4 or more, with 10 being the worst) within 1 month of the first dose, and previous treatment with an anti-CSF1R antibody therapy is allowed. Additionally, patients with DTGCT are included in the dose escalation study if the criteria for inclusion in Cohort B are met.

Patient-reported outcome (PRO) may be based on analysis based on the following questionnaires: SF-36, Brief Pain Inventory (BPI), GP5 question side effect burden from FACT-G, and symptom questions regarding stiffness , joint swelling and laxity, plotted against change from baseline and the proportion of patients who reported improvement from baseline.

Patients with TGCT or DTGCT who were treated with the FDA-approved CSF1R inhibitor pexidartinib at a dose of 10 mg once daily achieved an overall response rate (ORR) of 52% in a phase 2 clinical trial (New England Journal of Medicine, 2015, 373:428). Shifts to higher dose regimens to potentially achieve a higher ORR were limited by establishing a maximum tolerated dose (the highest dose associated with an acceptable side effect profile) and a dose of 1000 mg per day was selected for phase 2. In the ENLIVEN randomized phase 3 trial, pexidartinib demonstrated an ORR of 39% at a maintenance dose of 400 mg twice daily (The Lancet, 2019, 394:478). Pexidartinib has been reported to cause liver injury, including mixed or cholestatic hepatotoxicity (The Lancet, 2019, 394:478). Pexidartinib also inhibits off-target kinases other than CSF1R, including FLT-3, KIT, PDGFRA, and PDGFRB.

Compound 1 of the present invention is effective in patients with TGCT or DTGCT at significantly lower doses compared to those of the FDA-approved CSF1R inhibitor pexidartinib. Improvement in clinical scores was realized with a maintenance dose of 30 mg twice weekly: Patient 1, Cohort 5, with tumor size reductions of 48, 61, 75, and 84%

- 144 046076 from the baseline in C3D1, C5D1, C7D1 and C10D1. Surprisingly, this response exceeds the overall response rate of 39% observed in clinical settings with pexidartinib administered at a dose of 400 mg twice daily (800 mg/day).

Clinical use of FDA-approved pexidartinib in patients with TGCT is limited to a dose of 400 mg twice daily, i.e. maximum tolerated dose. In addition, the specific caution for hepatotoxicity in the FDA-approved labeling of pexidartinib suggests that hepatotoxicity may be a limitation in patient treatment.

In clinical studies available to date, the MTD for Compound 1 was not reached until Cohort 7, in which exposure provided the full benefit of pharmacodynamic CSF1R kinase inhibition, as shown in FIG. 6, and an ORR of up to 84% was achieved in the DGCT patient. These unexpected findings regarding Compound 1 compared to pexidartinib allow Compound 1 to be dosed to patients with TGCT or DTGCT until maximum efficacy is achieved, rather than being limited by an upper dose limit due to treatment-emergent toxicities.

Example 6 Compound 1 surprisingly exhibits higher selectivity for CSF1R inhibition compared to pexidartinib.

The following assays demonstrate that Compound 1 surprisingly exhibits greater selectivity for CSF1R inhibition compared to pexidartinib. The ability of Compound 1 or pexidartinib to inhibit the kinase activity of CSF1R kinase, c-KIT kinase, PDGFRa kinase or FLT3 kinase was tested in enzymatic assays.

CSF1R kinase assay (SEQ ID NO: 1).

CSF1R kinase activity (CSF1R, SEQ ID NO: 1) was determined spectroscopically using a combination pyruvate kinase/lactate dehydrogenase assay that continuously monitors ATP hydrolysis-dependent NADH oxidation (e.g., Schindler et al., Science (2000), 289: 1938-1942). Assays were performed in 384-well plates (100 μl final volume) using 10 nM CSF1R (Eurofins), 1.5 units pyruvate kinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenolpyruvate, 0.28 mM NADH, 0.7 mg/mL PolyEY and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl ₂ , 0.5 mM DTT, 0.1% octyl glucoside, 0.002% (wt/vol) BSA and 0.002% Triton X100). CSF1R inhibition was measured by adding serial dilutions of the test compound (final concentration in the assay 1% DMSO). Absorbance decline at 340 nm was monitored continuously for 4 h at 30°C on a multi-mode microplate reader (BioTek). The reaction rate was calculated using a time span of 2-3 hours. The reaction rate at each compound concentration was converted to percentage inhibition using controls (i.e. reaction without test compound and reaction with known inhibitor) and IC ₅₀ values were calculated by fitting a four-parameter sigmoidal curve to data using Prism (GraphPad software).

CSF1R kinase sequence ^538-end) with N-terminal His tag (SEQ ID NO: 1).

MHHHHHHEFYKYKQKPKYQVRWKIIESYEGNSYTFIDPTQLPYNEKWEFPRNNL QFGKTLGAGAFGKVVEATAFGLGKEDAVLKVAVKMLKSTAHADEKEALMSELKIMSH LGQHENIVNLLGACTHGGPVLVITEYCCYGDLLNFLRRKAEAMLGPSLSPGQDPEGGVD YKNIHLEKKYVRRD SGFSSQGVDTYVEMRPVSTSSNDSFSEQDLDKEDGRPLELRDLLH F S SQ VAQGMAKO LB ANCIHRD VAARNVLLTNGHVAKIGDFGLARDIMND SN ΥΙΥΚΓΝΑ RLPVKWMAPESIFDCVYTVQSDVWSYGILLWEIFSLGLNPYPGILVNSKFYKLVKDGYQ MAQPAFAPKNIYSIM QACWALEPTHRPTFQQICSFLQEQAQEDRRERDYTNLPSSSRSGG SGSSSSELEEESSSEHLTCCEQGDIAQPLLQPNNYQFC

c-Kit kinase assay (SEQ ID NO: 2).

Non-phosphorylated c-KIT kinase (c-KIT, SEQ ID NO: 2) activity was determined spectroscopically using a combination pyruvate kinase/lactate dehydrogenase assay that continuously monitors ATP hydrolysis-dependent NADH oxidation (eg, Schindler et al., Science ( 2000), 289:1938-1942). Assays were performed in 384-well plates (100 μl final volume) using 16 nM c-KIT (DeCode Biostructures), 1.5 units pyruvate kinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenolpyruvate, 0.28 mM NADH, 0.7 mg/ml PolyEY and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl ₂ , 0.5 mM DTT, 0.1% octyl glucoside, 0.002% (w/v) BSA and 0.002% Triton X-100). c-KIT inhibition was measured by adding serial dilutions of the test compound (final concentration in the assay 1% DMSO). Absorbance decline at 340 nm was monitored continuously for 6 h at 30°C on a multi-mode microplate reader (BioTek). The reaction rate was calculated using a time span of 2-3 hours. The reaction rate at each compound concentration was converted to percentage inhibition using controls (i.e. reaction without test compound and reaction with known inhibitor) and IC ₅₀ values were calculated by fitting a four-parameter sigmoidal curve to data using Prism (software

- 145 046076

GraphPad), part of GraphPad's Prism software package.

Sequence of c-KIT kinase (T544-V976) with N-terminal His-GST tag (SEQ ID NO: 2).

MEHHHHHHHHEYMPMEMAPILGYWKIKrLVQPTRLLLEYLEEKYEEHLYERDE GDKWRNKKFELGLEFPNLPYYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLE GAVDIRYGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFML YDALDVVLYMDPMCLDAFPK LVCFKKRIEAIPQIDKYLKSSKYIWPLQGWQATFGGGD HPPKSDLVPRHNQTSLYKKAGSAAAVLEENLYFQGTYKYLQKPMYEVQWKVVEEING NNYVYIDPTQLPYDHKWEFPRNRLSFGKTLGAGAFGKVVEATAYGLIKSDAAMTVAVK MLKPSAHLTEREALMSELKVLSYLGNHMNIVN LLGACTIGGPTLVITEYCCYGDLLNFL RRKRDSFICSKQEDHAEAALYKNLLHSKESSCSDSTNEYMDMKPGVSYVVPTKADKRR SVRIGSYZERDVTPAIMEDDELALDLEDLLSFSYQVAKFMAKOJIBANCIHRDLAARNILL THGRITKICDFGLARDIKNDSNYVVKrNARLPVKWMAPESIFNCVYTFESDVWSYGIFL WELF SLGSSPYPGMPVDSKFYKMIKEGFRMLSPEHAPAEMYDIMKTCWDADPLKRPTF KQIVQLIEKQISESTNHIYSNLANCSPNRQKPVVDHSVRINSVGSTASSSQPLLVHDDV

PDGFRa kinase assay (SEQ ID NO: 3).

Nonphosphorylated PDGFRa kinase activity was determined spectroscopically using a combination pyruvate kinase/lactate dehydrogenase assay that continuously monitors ATP hydrolysis-dependent NADH oxidation (eg, Schindler et al., Science (2000), 289:1938-1942). Assays were performed in 384-well plates (100 μl final volume) using 11.7 nM PDGFRa (DeCode Biostructures), 1.5 units pyruvate kinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenolpyruvate, 0.28 mM NADH, 0.7 mg/ml PolyEY and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl ₂ , 0.5 mM DTT, 0.1% octyl glucoside, 0.002% (w/v) BSA and 0.002% Triton X-100). PDGFRa inhibition was measured by adding serial dilutions of the test compound (final concentration in the assay 1% DMSO). Absorbance decline at 340 nm was monitored continuously for 6 h at 30°C on a multi-mode microplate reader (BioTek). The reaction rate was calculated using a time period of 2-3 hours. The reaction rate at each compound concentration was converted to percentage inhibition using controls (i.e. reaction without test compound and reaction with a known inhibitor) and IC5o values were calculated by fitting a four-parameter sigmoidal curve to data using Prism (GraphPad software).

PDGFRa protein sequence (residues 550-1089) with N-terminal GST tag (SEQ ID NO: 3).

MEHHHHHHHHMAPILGYWKIKrLVQPTRLLLEYLEEKYEEHLYERDEGDKWRN KKFELGLEFPNLPYIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIR YGVSRIAYSKDFETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDV VLYMDPMCLDAFPKLVCFK KRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKSD LVPRHNQTSLYKKAGFEGDRTMKQKPRYEIRWRVIESISPDGHEYIYVDPMQLPYDSRW EFPRDGLVLGRVLGSGAFGKVVEGTAYGLSRSQPVMKVAVKMLKPTARSSEKQALMS ELKIMTHLGPHLNIVNLLGACTKSGPIYI ITEYCFYGDLVNYLHKNRDSFLSHHPEKPKKE LDIFGLNPADESTRSYVILSFENNGDYMDMKQADTTQYVPMLERKEVSKYSDIQRSLYD RPASYKKKSMLDSEVKNLLSDDNSEGLTLLLLLSFTYQVARGMEKOJIEANCVHRDLAA RNVLLAQGKIVKICDFGLARDIMHDSNYVSKrSTFLPVKWMAPESIFDNLY TTLSDVWS YGILLWEIFSLGGTPYPGMMVDSTFYNKIKSGYRMAKPDHATSEVYEIMVKCWNSEPE KRPSFYHLSEIVENLPGQYKKSYEKIHLDFLKSDHPAVARMRVDSDNAYIGVTYKNEE DKLKDWEGGLDEQRLSADSGYIIPLPDIDPVPEEEDLGKRNRHSSQTCM.SAIETGSSSST FIKREDETIED IDMMDDIGIDSSDLVEDSFL

FLT3 kinase assay (SEQ ID NO: 4).

FLT3 kinase activity was determined spectroscopically using a combination pyruvate kinase/lactate dehydrogenase assay that continuously monitors ATP hydrolysis-dependent NADH oxidation (eg, Schindler et al., Science (2000), 289:1938-1942). Assays were performed in 384-well plates (100 μl final volume) using 1.6 nM FLT3 (Invitrogen), 1.5 units pyruvate kinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenolpyruvate, 0.28 mM NADH, 0.7 mg /ml PolyEY and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl ₂ , 0.5 mM DTT, 0.1% octyl glucoside, 0.002% (w/v) BSA and 0.002% Triton X-100). FLT3 inhibition was measured by adding serial dilutions of the test compound (final concentration in the assay 1% DMSO). Absorbance decline at 340 nm was monitored continuously for 6 h at 30°C on a multi-mode microplate reader (BioTek). The reaction rate was calculated using a time period of 3-4 hours. The reaction rate at each compound concentration was converted to percent inhibition using controls

- 146 046076 (ie reaction without test compound and reaction with known inhibitor) and IC50 values were calculated by fitting a four-parameter sigmoidal curve to the data using Prism (GraphPad software).

FLT3 kinase sequence (564-958) with C-terminal His tag (SEQ ID NO: 4).

MHKYKKQFRYESQLQMVQVTGSSDNEYFYVDFREYEYDLKWEFPRENLEFGKV LGSGAFGKVMNATAYGISKTGVSIQVAVKMLKEKADSSEREALMSEKMMTQLGSHENI VNLLGACTLSGPIYLIFEYCCYGDLLNYLRSKREKFHRTWTEIFKEHNFSFYPTFQSHPNS SMPGSREVQIHPD SDQISGLHGNSFHSEDEIEYENQKRLEEEEDLNVLTFEDLLCFAYQV AKFMEFLEFK SC VHRDLAARNVLVTHGKVVKICDF GLARE)IMSDSNYVVRGNARLPVK WMAPESLFEGIYTIKSDVWSYGILLWEIFSLGVNPYPGIPVDANFYKLIQNGFKMDQPFY ATEEIYUMQSCWAFDSRKRPSFPNLTSFLGCQLA DAEEAMYQNVKFVEACQLGTDDYD IPTTHHHHHH

Using the enzymatic assay protocols described above, Compound 1 was unexpectedly shown to be selective for CSF1R kinase inhibition over pexidartinib in assays that measure the kinase activity of CSF1R kinase, c-KIT kinase, PDGFRa kinase, or FLT3 kinase , as indicated in the table below. 4.

Table 4

Activity of Compound 1 and Pexidartinib in CSF1R Kinase, c-KIT Kinase, PDGFRa Kinase, or FLT3 Kinase Enzymatic Assays

Example CSF1R c-KIT PDGFRa FLT3 1C ₅₀ (nM) 1C ₅₀ (nM) 1C ₅₀ (nM) 1C ₅₀ (nM) Connection 1 2.2 864 2500 2700 Pexidartinib 2.2 6.9 9.6 7.1

Example 7 Compound 1 surprisingly retains the ability to inhibit cellular CSF1R compared to pexidartinib when administered with increasing concentrations of the CSF1R ligand CSF1.

The ability of Compound 1 or pexidartinib to inhibit the proliferation of M-NFS-60 cells in the presence of different concentrations of the CSF1R ligand, CSF1, was tested in a cell assay. This is relevant to the treatment of TGCT and DTGCT due to genomic changes. caused by increased levels of expression of translocated CSF1, which triggers the process of tumor formation.

M-NFS-60 cell culture.

M-NFS-60 cells (catalog no. CRL-1838) were obtained from the American Type Culture Collection (ATCC, Manassas, VA). Briefly, cells were grown as a suspension in RPMI 1640 medium supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 0.05 mM 2-mercaptoethanol, and 20 ng/ml recombinant mouse macrophage colony-stimulating factor (CSF1) at 37°C. C, 5% CO ₂ and 95% humidity. Cells were allowed to grow until saturation point was reached, at which point they were subcultured or harvested for use in the assay.

M-NFS-60 cell proliferation assay.

Serial dilutions of the test compound were dispensed into a 96-well, black-walled, clear-bottom plate (Corning, Corning, NY). Ten thousand cells were added per well to 200 μl of complete growth medium containing different concentrations of CSF1. The plates were incubated for 67 h at 37 °C, 5% CO ₂ and 95% humidity. At the end of the incubation period, 40 μl of a 440 μΜ solution of resazurin (Sigma, St. Louis, MO) in PBS was added to each well and incubated for an additional 5 h at 37°C, 5% CO ₂ and 95% humidity. The plates were read on a plate reader using an excitation wavelength of 540 nM and an emission wavelength of 600 nM. IC ₅₀ values were calculated from a series of percent inhibition values determined over a range of inhibitor concentrations using software procedures used in GraphPad's Prism software package.

Compound 1 inhibited the proliferation of M-NFS-60 cells, a CSF1R-dependent murine myelogenous leukemia cell line, with an average IC ₅₀ value of 10.5 nM at 10 ng/ml CSF1. High concentrations of growth factor ligands for receptor tyrosine kinases may provide decreased activity of kinase inhibitors due to increased ligand-induced dimerization and kinase activation. Surprisingly, high levels of the CSF1R ligand CSF1 had only minor effects on the inhibition (<1.6-fold) of M-NFS-60 cell proliferation by Compound 1 (FIG. 12), with an average _IC50 of 15. 2 nM at 1000 ng/ml CSF1. Pexidartinib had lower activity at high CSF1 levels, with a mean _IC50 of 15.7 nM at 10 ng/mL CSF1 and a mean _IC50 of 59.6 nM at 1000 ng/mL CSF1, corresponding to an increased IC50 value. 3.8 times.

- 147 046076

Example 8 Surprisingly, Compound 1 was shown to exhibit no liver toxicity in toxicology studies compared to pexidartinib.

It has previously been reported that CSF1R-mediated inhibition of macrophage function promotes increased levels of AST, ALT, and GLDH without liver injury (Radi et al., 2011; and Wang et al., 2011). It is possible that the increases in AST, ALT, and GLDH levels in this study are, at least in part, a mechanistic consequence of CSF1R inhibition.

Compound 1 was evaluated for systemic toxicity in toxicity studies in rats and dogs. In a 4-week GLP-compliant pivotal study in Sprague-Dawley rats, Compound 1 was administered at doses of 5, 15 and 30 mg/kg/day. Minimal to moderate increases in aspartate transaminase (AST), alanine transaminase (ALT), glutamate dehydrogenase (GLDH), and alkaline phosphatase (ALP) were noted, but no microscopic changes were observed in the liver. The NOAEL (no adverse event level) for this study was 5 mg/kg/day with a safety margin of approximately 4.7x the clinical dose exposure for a loading dose of 30 mg QD for 5 days followed by 30 mg twice weekly in patients with TGCT, and a dose of 15 mg/kg/day as a toxic dose of concern in 10% of the cohort animals (STD ₁₀ ) with a safety margin of approximately 25x the exposure (AUC) at a clinical dose involving a 30 mg loading dose QD for 5 days followed by 30 mg twice weekly in TGCT patients as shown in FIG. 13). Similarly, in a 13-week GLP-compliant toxicity study with a 4-week recovery phase in SpragueDawley rats, Compound 1 was administered at doses of 1.876, 3.75 and 7.5 mg/kg/day. Clinical pathological effects were generally minimal to moderate in magnitude and included increased liver enzymes and indices of inflammation. Elevations in aspartate transaminase (AST), alanine transaminase (ALT), glutamate dehydrogenase (GLDH), and alkaline phosphatase (ALP) were minimal to moderate, and there were no corresponding microscopic changes in the liver. Most of the clinical observations disappeared during the recovery phase. The NOAEL for this 13-week study corresponded to a dose of 1.875 mg/kg/day, with a safety margin of approximately 2.3 x the clinical dose exposure (AUC) for a loading dose of 30 mg QD for 5 days followed by 30 mg twice. per week in TGCT patients (Fig. 13). The STD10 for the 13-week study corresponded to a dose of 7.5 mg/kg/day, with a safety margin of approximately 6.3x clinical dose exposure (AUC) for a loading dose of 30 mg QD for 5 days followed by 30 mg twice. per week in TGCT patients.

In a pivotal 4-week GLP study in Beagle dogs, Compound 1 was administered at doses of 2.5, 7.5, 15 and 25 mg/kg/day. Clinical observations associated with Compound 1 included minimal to moderate increases in AST activity in animals administered >2.5 mg/kg/day. Additional endpoints included minimal increases in ALT and GLDH activity in animals administered >7.5 mg/kg/day. Hepatocellular damage was not evident on microscopic histological examination. The NOAEL and HNSTD (highest dose without serious toxicity) for the 4-week canine study corresponded to a dose of 7.5 mg/kg/day, with a safety margin of approximately 2.1x clinical dose exposure (AUC) at a loading dose of 30 mg QD for 5 days followed by 30 mg twice weekly in patients with TGCT.

In a 13-week GLP-compliant toxicity study with a 4-week recovery period in Beagle dogs, Compound 1 was administered at 2.0, 4.0 or 8.0 mg/kg/day. Compound 1-associated clinical pathological effects were limited to animals administered 8 mg/kg/day and showed evidence of reversibility. Clinical pathological effects were generally minimal to moderate in magnitude and included increased liver enzymes and indices of inflammation. Elevations in aspartate transaminase (AST), glutamate dehydrogenase (GLDH), and creatine kinase were minimal to moderate, and no microscopic changes were noted in the liver. Most of the clinical observations disappeared during the recovery phase. Increased aspartate aminotransferase and creatine kinase activity may result from inhibition of macrophage CSF1R. Such clinical pathological changes did not correlate with any microscopic findings and had no effect on the general health of the animal. Thus, the NOAEL for Compound 1 corresponded to a dose of 8 mg/kg/day, with a safety margin of approximately 1.6x the clinical dose exposure (AUC) for a loading dose of 30 mg QD for 5 days followed by 30 mg b.i.d. week in patients with TGCT. In contrast, in a pivotal 4-week, two-week recovery period, GLP-compliant toxicity study, TURALIO™ (pexidartinib) was administered to Sprague-Dawley rats at doses of 20, 60, or 200 mg/kg/day using

- 148 046076 by using a gastric tube. Clinical observations for all dose-based groups showed increased liver enzyme levels and the presence of dose-dependent liver cell hypertrophy in the central part of the lobules, which correlated with corresponding higher liver enzyme levels and higher liver weights, and a higher incidence of and/ or severity of chronic progressive nephropathy in the 200 mg/kg/day groups. Establishment of NOAEL in rats treated with pexidartinib was not possible at any of the doses studied.

In a six-month GLP-compliant toxicity study with 16 weeks of recovery in rats, treatment with pexidartinib at a dose of 60 mg/kg once daily (approximately 1.6 times the clinical dose exposure of 154,930 ng-h/mL [value] AUC _0-24 calculated from the label value of 77465 AUC _M2 ] at the recommended human dose of 800 mg once daily) resulted in the death of 3 animals in the main study due to treatment-related immune deficiency. In the liver, hemosiderin deposition and necrotizing inflammation with elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels occurred at doses >20 mg/kg (approximately 0.6 times the clinical effect at 800 mg) (Fig. 14). Additionally, the occurrence of biliary cysts and increased gamma-glutamyl transferase (GGT) levels occurred in female rats at 60 mg/kg. The liver is a major target organ from a clinical point of view, as it frequently experiences elevated transaminase levels, including severe liver damage.

Compound 1 and pexidartinib were compared with respect to clinical dose/exposure levels and prevalence of liver enzyme and bilirubin elevations and liver-related AEs. Compound 1, which was administered at a dose of 10-40 mg QD or twice weekly (AUC _0-24 approximately 13500-31952 ng-h/ml), showed the lowest clinical dose/effect ratio with a smaller increase in liver enzyme levels. Compound 1 did not demonstrate any clinical evidence of liver toxicity at any of these dose levels. Pexidartinib, which was administered at a dose of 800 mg per day (AUC _0-24 exposure levels of 154,930 ng-h/mL), showed exposure levels that were almost an order of magnitude greater than those of Compound 1. Overall severity of all AEs (cases of increased AST/ Grade 3/4 ALT, elevated bilirubin, and serious liver-related AEs) is consistent with a pattern of increasing severity of liver toxicity associated with higher exposure levels. In comparison, Compound 1 showed a greater prevalence of grade 1/2 AST/ALT elevation events in the absence of liver toxicity as determined in the Sprague Dawley rat and Beagle dog toxicity study, suggesting that the increase AST/ALT levels in the absence of hepatotoxicity refers to the class of effects provided by a CSF1R inhibitor due to a decrease in the level of AST/ALT clearance from the circulatory system. Compound 1 was not shown to have grade 3/4 AST/ALT elevation events or liver-related bilirubin or AE elevation events at clinically relevant and effective doses. The lack of demonstrated hepatotoxicity observed in Compound 1 in preclinical toxicology studies, coupled with the lack of observed hepatotoxicity in clinical trials, provides an unexpected advantage over pexidartinib, which exhibits hepatotoxicity in preclinical toxicology studies as well as hepatotoxicity in clinical trials. Thus, Compound 1 provides an unexpected profile compared to pexidartinib, allowing dosing of DTGCT patients to provide higher levels of efficacy without associated liver toxicity. This favorable efficacy/adverse event profile of Compound 1 is beneficial for the treatment of patients with DTGCT, since such patients are expected to be treated with a CSF1R inhibitor for extended periods of time throughout their lives.

Fig. 15 is a graphical representation demonstrating the depletion of CD16+ monocytes in peripheral blood obtained from patients treated with Compound 1. A subpopulation of CD16+ monocytes is known to be sensitive to treatment with CSF1 and thus serves as a pharmacodynamic marker of CSF1R inhibition. PD data obtained from patients treated with Compound 1 showed that CD16+ monocyte levels decreased with increasing dose and concentration of Compound 1, indicating a blockade of CSF1R-mediated signaling. In the lower dose cohorts (cohorts 1-4), the percentage of CD16+ monocytes from total blood monocytes at baseline decreased by between 18 and 9% after 2 weeks of treatment with Compound 1. In the higher dose cohorts (cohorts 5-7) the percentage of CD16+ monocytes from total blood monocytes at baseline decreased by a value ranging from 68 to 94% after 2 weeks of treatment with compound 1.

Elevated circulating levels of the CSF1R ligands CSF1 and IL-34 are a pharmacodynamic marker of CSF1R inhibition in vivo. Fig. 16 is graphy

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Claims (34)

clinical presentation demonstrating increased levels of CSF1 and IL-34 in plasma obtained from patients treated with Compound 1. In C1D1, all patients had detectable levels of CSF1, with a mean across all cohorts of 520.7 pg/mL. Serum CSF1 concentrations increased with increasing dose and concentration of compound 1. CSF1 levels in the lower dose cohorts (cohorts 1–4) increased approximately 3–5-fold in C2D1 compared with baseline. In higher dose cohorts (cohorts 5-7), patients experienced 22- to 36-fold increases in CSF1 levels in C2D1. Doses in cohorts 6 and 7 had similar effects on serum CSF1 levels. Compound 1 showed a dose-dependent effect on circulating CSF1 concentrations. A similar trend was observed for IL-34 levels. In C1D1, all patients had detectable levels of IL-34, with a mean across all cohorts of 9.3 pg/mL. In patients enrolled in the lower dose cohorts (cohorts 1–4), IL-34 levels increased 2–5-fold over baseline by C2D1. In higher dose cohorts (cohorts 5-7) to C2D1, patients experienced 26- to 100-fold increases in IL-34 levels. Doses in cohorts 6 and 7 had similar effects on serum IL-34 levels. CLAIM 1. A method of treating tenosynovial giant cell tumor in a patient in need thereof, comprising orally administering to the patient a therapeutically effective amount of a compound comprising or a pharmaceutically acceptable salt thereof. 2. The method according to claim 1, wherein the tenosynovial giant cell tumor is a diffuse type tenosynovial giant cell tumor. 3. The method according to claim 1, where the tumor is benign. 4. The method of any one of claims 1 to 3, wherein administration comprises administering from about 2 mg to about 60 mg of the compound every day, once a week, twice a week or three times a week. 5. The method according to any one of claims 1 to 3, wherein administration comprises administering from about 10 mg to about 90 mg of the compound every day, once a week, twice a week or three times a week. 6. The method according to any one of claims 1 to 3, wherein the administration involves administering a loading dose of the compound daily for a first period of time; and administering a maintenance dose of the compound every day, twice a week, or three times a week for a second period of time. 7. The method of claim 6, wherein the loading dose is from about 10 mg/day to about 80 mg/day. 8. The method of claim 6 or 7, wherein the loading dose is from about 20 mg/day to about 60 mg/day. 9. The method according to any one of claims 6 to 8, wherein the loading dose is about 20 mg, about 30 mg/day, about 40 mg/day, about 50 mg/day, or about 60 mg/day. 10. The method according to any one of claims 6 to 9, wherein the maintenance dose is from about 2 mg to about 60 mg. 11. The method according to any one of claims 6 to 10, where the maintenance dose is approximately 2 mg, approximately 10 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 40 mg or approximately 50 mg, each of which is administered twice times or three times a week. 12. The method according to any one of claims 6 to 11, wherein the duration of the first period of time is approximately one or two weeks. 13. The method according to any one of claims 6 to 12, wherein the duration of the first period of time is about 4 days, about 5 days, about 6 days or about 10 days. 14. The method according to any one of claims 6 to 13, wherein the duration of the second period of time is from one month to about two months, three months or more. 15. The method according to any one of claims 6 to 14, wherein the duration of the second period of time is from about one month to about nine months or more. - 150 046076 16. The method according to any one of claims 6 to 14, further comprising administering an additional loading dose for a third period of time. 17. The method of claim 16, further comprising administering an additional maintenance dose for a fourth period of time. 18. The method according to claim 15 or 16, where the third and/or fourth time periods follow the first and second time periods. 19. The method according to any one of claims 1 to 17, where after 1 month or more of administration, the patient has an improved tumor response as measured by CT, MRI and/or RECIST. 20. The method according to any one of claims 1 to 18, where after 1 month or more of administration, the patient has an improvement in range of motion. 21. The method according to any one of claims 1 to 19, where after 1 month or more of administration, the patient has a decrease in the level of macrophage infiltration in the injured joint and/or the number of circulating chemokines/cytokines associated with inflammation, compared with these values before administration. 22. The method according to any one of claims 6 to 21, wherein the size of the tenosynovial giant cell tumor is reduced to a value that is 90-10% of its size before administration. 23. A method of treating tenosynovial giant cell tumor in a patient in need thereof, comprising orally administering to the patient from about 2 mg to about 50 mg of a compound represented by the formula or a pharmaceutically acceptable salt thereof twice a week. 24. The method of claim 23, comprising orally administering to the patient about 5 mg to about 30 mg of the compound twice a week. 25. The method of claim 23, comprising orally administering to the patient approximately 20 mg of the compound twice a week. 26. The method of claim 23, comprising orally administering to the patient approximately 14 mg of the compound twice a week. 27. The method of claim 23, comprising orally administering to the patient approximately 10 mg of the compound twice a week. 28. The method according to any one of claims 23 to 27, wherein the tenosynovial giant cell tumor is a diffuse type tenosynovial giant cell tumor. 29. The method according to any one of claims 23-28, where the tumor is benign. 30. A method of treating tenosynovial giant cell tumor in a patient in need thereof, comprising orally administering to the patient approximately 30 mg of a compound represented by the formula twice a week. 31. The method of claim 30, wherein the tenosynovial giant cell tumor is a diffuse type tenosynovial giant cell tumor. 32. The method according to claim 30 or 31, where the tumor is benign. 33. The method according to any one of claims 30-32, comprising administering the compound to the patient twice a week for approximately six months. 34. The method according to any one of claims 30-33, comprising administering the compound to the patient twice a week for approximately one year. - 151 -