CN116916927A

CN116916927A - Protocols for treating alopecia with deuterated JAK inhibitors

Info

Publication number: CN116916927A
Application number: CN202180087409.XA
Authority: CN
Inventors: J·V·卡塞拉
Original assignee: Sun Pharmaceutical Industries Ltd
Current assignee: Sun Pharmaceutical Industries Ltd
Priority date: 2020-10-28
Filing date: 2021-10-28
Publication date: 2023-10-20

Abstract

Disclosed is a method of treating alopecia in a subject, the alopecia being beneficially treated by administering JAK1 and/or JAK2 inhibitors. The method comprises administering to the subject an effective amount of compound (I) or a pharmaceutically acceptable salt thereof.

Description

Protocols for treating alopecia with deuterated JAK inhibitors

RELATED APPLICATIONS

The present application claims the benefit of U.S. provisional application No. 61/106,790 filed on 28 of 10 in 2020 and U.S. provisional application No. 63/155,637 filed on 02 of 3 of 2021. The entire teachings of the above application are incorporated herein by reference.

Background

Alopecia Areata (AA) is an autoimmune disease that causes partial or complete loss of hair from the scalp and body. The scalp is the most commonly affected area, but any hair-containing site may be affected alone or in combination with the scalp. In the united states, up to 650,000 patients are affected by Alopecia Areata (AA) at any given time, including men, women, and children. AA has profound effects on patients; AA is associated with serious psychological consequences (including anxiety and depression) and with other autoimmune conditions.

There is no known cure for AA. Improved treatment of AA and other alopecia is needed.

Disclosure of Invention

It has now been found that deuterated analogues of ruxolitinib (ruxolitinib) (comprising compound (I), also known as (R) -3- (4- (7H-pyrrolo [2, 3-d))]Pyrimidin-4-yl) -1H-pyrazol-1-yl) -3- (cyclopentyl-2, 3,4, 5-d ₈ ) Propionitrile, or D8-pontine or CTP-543) can be used to treat alopecia, including alopecia areata. Published PCT application WO17/192905 describes the use of CTP-543 for the treatment of alopecia areata. Compound (I) is represented by the following structural formula:

in certain embodiments, compound (I) is administered as a pharmaceutically acceptable salt, such as a phosphate salt. Compound (I) may be administered in a dose ranging from about 8mg to about 32mg per day (or based on the equivalent weight of salt, such as compound (I) phosphate), in a single daily dose or in divided doses (e.g., twice daily). Based on these findings, disclosed herein are novel therapies using compound (I) or a pharmaceutically acceptable salt thereof for treating alopecia in a mammalian subject.

In one aspect, the invention provides a method of treating alopecia in a human subject, the method comprising administering to the subject a compound represented by the structural formula:

or a pharmaceutically acceptable salt thereof, wherein each position specified as deuterium incorporates at least 95% deuterium;

Wherein (1) the compound or pharmaceutically acceptable salt thereof is administered in an amount ranging from about 8mg to about 32mg per day for a first period of 8-24 weeks followed by (2) the compound or pharmaceutically acceptable salt thereof is administered for a second period of at least 8 weeks, wherein the compound or pharmaceutically acceptable salt thereof is administered in an amount of 50 to 75% of the daily amount administered during the first period, such that the alopecia is treated.

In certain embodiments, the alopecia is alopecia areata.

In certain embodiments, the compound or pharmaceutically acceptable salt thereof is administered at about 12 mg/day, about 16 mg/day, about 24 mg/day, or about 32mg per day during the first period.

In certain embodiments, in the second period, the compound or pharmaceutically acceptable salt thereof is administered at about 6 mg/day, about 8 mg/day, about 12 mg/day, or about 16mg per day.

In certain embodiments, in the first period, the compound or pharmaceutically acceptable salt thereof is administered at about 24 mg/day, and in the second period, the compound or pharmaceutically acceptable salt thereof is administered at about 16 mg/day. In certain embodiments, the about 24 mg/day of the compound or salt is administered once a day and the about 16 mg/day of the compound or salt is administered once a day. In certain embodiments, the about 24 mg/day of the compound or salt is administered twice daily at about 12mg, and the about 16 mg/day of the compound or salt is administered twice daily at about 8 mg.

In certain embodiments, in the first period, the compound or pharmaceutically acceptable salt thereof is administered at about 16 mg/day, and in the second period, the compound or pharmaceutically acceptable salt thereof is administered at about 8 mg/day. In certain embodiments, the about 16 mg/day of the compound or salt is administered once a day and the about 8 mg/day of the compound or salt is administered once a day. In certain embodiments, the about 16 mg/day of the compound or salt is administered at about 8mg twice daily, and the about 8 mg/day of the compound or salt is administered at about 4mg twice daily.

In certain embodiments, the compound or a pharmaceutically acceptable salt thereof is administered orally.

In certain embodiments, the compound or pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical formulation, which is a tablet.

In certain embodiments, the compound or pharmaceutically acceptable salt thereof is administered once daily during the first period. In certain embodiments, the compound or pharmaceutically acceptable salt thereof is administered twice daily during the first period.

In certain embodiments, the compound or pharmaceutically acceptable salt thereof is administered once daily in the second period. In certain embodiments, the compound or pharmaceutically acceptable salt thereof is administered twice daily during the second period.

In certain embodiments, the first period of time is about 8-24 weeks. In certain embodiments, the first period of time is about 12 weeks. In certain embodiments, the first period of time is about 16 weeks. In certain embodiments, the first period of time is about 20 weeks. In certain embodiments, the first period of time is about 24 weeks. In certain embodiments, the second period of time is at least 12 weeks. In certain embodiments, the second period of time is at least 24 weeks.

In certain embodiments, the first period of time is about 8-12 weeks. In certain embodiments, the first period of time is about 8 weeks. In certain embodiments, the first period of time is about 12 weeks. In certain embodiments, the first period of time is at least 8 weeks.

In certain embodiments, in compound (I), at least 97% of deuterium is incorporated into each position specifically designated as deuterium.

Another aspect of the invention is a compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate salt) for use in the treatment of alopecia treatable by a compound that modulates the activity of Janus-related kinase 1 (JAK 1) and/or Janus-related kinase 2 (JAK 2). The compounds may be administered in the dosing regimen disclosed herein. In certain embodiments, the alopecia is alopecia areata.

Still another aspect of the invention is the use of compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate salt) for the manufacture of a medicament for the treatment of alopecia treatable by compounds that modulate the activity of Janus-related kinase 1 (JAK 1) and/or Janus-related kinase 2 (JAK 2). The compounds may be administered in the dosing regimen disclosed herein. In certain embodiments, the alopecia is alopecia areata.

Drawings

FIG. 1 shows the percentage of respondents at week 24 of the phase 2a trial (patients with a SALT score decrease of 50% or more from baseline), containing placebo, 4mg BID, 8mg BID and 12mg BID cohorts.

FIG. 2 shows the percentage of respondents (patients with a.gtoreq.50% decrease in SALT score from baseline) visited in phase 2a trial, including placebo, 4mg BID, 8mg BID and 12mg BID cohorts.

FIG. 3 shows the percentage of respondents (patients with a SALT score reduced by ≡75% from baseline) visited in phase 2a trial, including placebo, 4mg BID, 8mg BID and 12mg BID cohorts.

FIG. 4 shows the percentage of respondents (patients with a SALT score reduced by 90% or more from baseline) visited in phase 2a trial, including placebo, 4mg BID, 8mg BID and 12mg BID cohorts.

FIG. 5 shows patient SALT score improvement after 24 weeks of phase 2a trial, including placebo, 4mg BID, 8mg BID and 12mg BID cohorts.

FIG. 6 shows the relative change in SALT scores seen in phase 2a trial, including placebo, 4mg BID, 8mg BID and 12mg BID cohorts.

FIG. 7 shows the design of a study in which 8mg BID or 12mg BID of compound (I) (CTP-543) was administered during a first period followed by a lower dose of compound (I) or placebo during a second period.

FIG. 8 shows patient entry and placement of subjects in an Open Label Extension (OLE) study of compound (I) (CTP-543).

Detailed Description

Definition of the definition

The term "treating" means reducing, inhibiting, attenuating, reducing, arresting or stabilizing the development or progression of a disease (e.g., a disease or disorder described herein), reducing the severity of a disease, or ameliorating symptoms associated with a disease. For example, treatment of alopecia includes hair regrowth, preventing further alopecia, or reducing the rate of alopecia.

"alopecia" means any condition or disorder that causes one or more parts of the body to lose hair. Alopecia includes, but is not limited to, androgenetic alopecia, alopecia areata, telogen effluvium, alopecia areata, alopecia totalis, and alopecia universalis.

Efficacy of treatment for alopecia, such as alopecia areata, can be measured in a number of ways, some of which are known in the art. For example, a "hair loss severity tool," also known as SALT, is a validated evaluation scale developed by the national committee for the foundation of alopecia areata (National Alopecia Areata Foundation working committee) to evaluate the extent of hair loss. See, e.g., lsen EA, hordinky MK, price VH et al, alopecia areata study evaluation guide-Part II (Alopecia areata investigational assessment guidelines-Part II.) (journal of dermatology (J Am Acad Dermatol)) (2004:51:440-447), incorporated herein by reference. The SALT score of the patient was calculated by measuring the percentage of hair loss in each of the 4 regions of the scalp and summing to obtain a composite score. A decrease in SALT score reflects hair regrowth. For example, a SALT score of 100 for no hair on the scalp would be found, while a SALT score of 0 for complete hair regrowth would be found. In certain embodiments, a treatment method as described herein can provide at least a 10 point improvement in SALT score after treatment (e.g., from a SALT score of 100 before treatment to a SALT score of 90 after treatment). In further embodiments, a method of treatment as described herein can provide at least a 20 point, 30 point, 40 point, 50 point, 60 point, 70 point, 80 point, 90 point, or 100 point SALT score improvement. In certain embodiments, a method of treatment as described herein can provide at least a 20% improvement in a patient's SALT score relative to baseline, or at least a 30% improvement in a patient's SALT score relative to baseline, or at least a 40% improvement in a patient's SALT score relative to baseline, or at least a 50% improvement in a patient's SALT score relative to baseline, or at least a 60% improvement in a patient's SALT score relative to baseline, or at least a 70% improvement in a patient's SALT score relative to baseline, or at least a 75% improvement in a patient's SALT score relative to baseline, or at least a 80% improvement in a patient's SALT score relative to baseline, or at least a 90% improvement in a patient's SALT score relative to baseline after treatment.

As used herein, the term "subject" includes humans, as well as non-human mammals, such as cats, dogs, sheep, cattle, pigs, goats, non-human primates (including monkeys and apes), and the like.

As used herein, the term "about" means "about," i.e., within acceptable tolerances of the particular value determined by one of ordinary skill in the art. For example, "about" may mean a range of up to 10% higher or lower than a particular value, up to 5% higher or lower than a particular value, or up to 1% higher or lower than a particular value. In addition, when a particular value is the length of time in weeks, the term "about" may mean more or less than two weeks, more or less than one week.

It will be appreciated that, depending on the source of the chemical materials used in the synthesis, some variation in natural isotopic abundance will occur in the synthesized compounds. Thus, the preparation of ponatinib will inherently contain a small amount of deuterated isotopologues. In spite of this variation, the concentrations of naturally abundant stable hydrogen and carbon isotopes are small and insignificant compared to the extent of stable isotope substitution of the compounds of the present invention. See, e.g., wada, E et al, biochemical industries, inc. (Seikagaku), 1994,66:15; gannes, LZ et al, comparison biochemistry and physiology a: molecular and general physiology (Comp Biochem Physiol Mol Integr Physiol), 1998,119:725.

In the compound (I), any atom not specifically designated as a specific isotope means any stable isotope representing the atom. Unless otherwise indicated, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen in accordance with its natural abundance isotopic composition. However, in certain embodiments set forth herein, when a position is specifically designated as "H" or "hydrogen," the position has at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% hydrogen. In some embodiments, when a position is specifically designated as "H" or "hydrogen," the position incorporates less than or equal to 20% deuterium, less than or equal to 10% deuterium, less than or equal to 5% deuterium, less than or equal to 4% deuterium, less than or equal to 3% deuterium, less than or equal to 2% deuterium, or less than or equal to 1% deuterium. Further, unless otherwise specified, when a position is specifically designated as "D" or "deuterium," the position is understood to be deuterium having an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., incorporating at least 50.1% deuterium). The amount of deuterium incorporated at a given position can be measured by analytical methods known to those of ordinary skill in the art, for example by proton NMR.

As used herein, the term "isotopically enriched factor" means the ratio between the isotopic abundance and the natural abundance of a particular isotope.

In other embodiments, compound (I) has an isotopic enrichment factor of at least 3500 (incorporating 52.5% deuterium at each specified deuterium position), at least 4000 (incorporating 60% deuterium), at least 4500 (incorporating 67.5% deuterium), at least 5000 (75% deuterium), at least 5500 (incorporating 82.5% deuterium), at least 6000 (incorporating 90% deuterium), at least 6333.3 (incorporating 95% deuterium), at least 6466.7 (incorporating 97% deuterium), at least 6600 (incorporating 99% deuterium), or at least 6633.3 (incorporating 99.5% deuterium) for each specified deuterium position (or atom).

In some embodiments, in the compounds of the invention, each designated deuterium position (or atom) incorporates at least 52.5% deuterium. In some embodiments, in the compounds of the invention, at least 60% of deuterium is incorporated per designated deuterium position. In some embodiments, in the compounds of the invention, at least 67.5% deuterium is incorporated per designated deuterium position. In some embodiments, in the compounds of the invention, at least 75% of deuterium is incorporated into each designated deuterium position. In some embodiments, in the compounds of the invention, at least 80% of deuterium is incorporated into each designated deuterium position. In some embodiments, in the compounds of the invention, at least 85% of deuterium is incorporated per designated deuterium position. In some embodiments, in the compounds of the invention, at least 90% of deuterium is incorporated into each designated deuterium position. In some embodiments, in the compounds of the invention, at least 95% of deuterium is incorporated into each designated deuterium position. In some embodiments, in the compounds of the invention, at least 97% of deuterium is incorporated per designated deuterium position. In some embodiments, in the compounds of the invention, at least 98% of deuterium is incorporated per designated deuterium position. In some embodiments, in the compounds of the invention, at least 99% of deuterium is incorporated into each designated deuterium position. In some embodiments, in the compounds of the invention, at least 99.5% deuterium is incorporated per designated deuterium position.

The term "isotopologue" refers to a molecule in which the chemical structure differs from that shown for compound (I) only in its isotopic composition.

The term "compound" when referring to a compound of the present invention refers to a collection of molecules having the same chemical structure, except that there may be isotopic variations between the constituent atoms of the molecules. Thus, it will be apparent to those skilled in the art that although compound (I) is represented by a particular chemical structure having deuterium atoms at eight specified positions, compound (I) will contain molecules having deuterium at each of the eight specified positions, and may also contain isotopologues having hydrogen atoms at one or more of the specified deuterium positions in the structure. The relative amounts of such isotopologues in compound (I) will depend on a number of factors, including the isotopic purity of the deuterating reagent used to prepare the compound and the efficiency of incorporation of deuterium in the various synthetic steps used to prepare the compound. In certain embodiments, the relative amount of all such isotopologues will be less than 49.9% of the compound. In other embodiments, the relative amount of all such isotopologues will be less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1% or less than 0.5% of the compound.

The invention also provides salts of compound (I). Salts of the compounds of the invention are formed between the acidic groups and basic groups (e.g., amino functions) of the compounds or between the basic groups and acidic groups (e.g., carboxyl functions) of the compounds. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt, such as a phosphate salt.

As used herein, the term "pharmaceutically acceptable" refers to a composition that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and other mammals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. By "pharmaceutically acceptable salt" is meant any non-toxic salt capable of providing a compound of the invention directly or indirectly when administered to a recipient. A "pharmaceutically acceptable counterion" is an ionic portion of the salt that is non-toxic when released from the salt upon administration to a recipient.

Acids commonly used to form pharmaceutically acceptable salts include mineral acids such as hydrogen disulfide (hydrogen bisulfide), hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid; and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, benzenesulfonic acid (besilic acid), fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromobenzenesulfonic acid (para-bromophenylsulfonic acid), carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, as well as related inorganic and organic acids. Thus, such pharmaceutically acceptable salts include sulfate, pyrophosphate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate (decanoate), octanoate, acrylate, formate, isobutyrate, decanoate (caprate), heptanoate, propionate, oxalate, malonic acid, succinate, suberate, sebacate, fumarate, maleate, butane-1, 4-diacid, hexane-1, 6-diacid, benzoate, chlorobenzoate, benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β -hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and other salts. In one embodiment, the pharmaceutically acceptable acid addition salts include acid addition salts formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially with organic acids such as maleic acid.

As used herein, the term "stable compound" refers to a compound (e.g., a therapeutic product formulated to treat a disease or condition responsive to a therapeutic agent, an intermediate for producing a therapeutic compound, an isolatable or storable intermediate compound) having a period of time sufficient to allow for its manufacture and to maintain the integrity of the compound sufficient for the purposes detailed herein.

Both "D" and "D" refer to deuterium. "stereoisomers" refers to both enantiomers and diastereomers. "Tert" and "t-" each refer to three. "US" refers to the United states.

"substitution with deuterium" refers to replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.

It has now been found that the administration of compound (I) or an equivalent amount of a pharmaceutically acceptable salt thereof can cause hair growth after a first period of application. According to the invention, the amount of compound (I) or a salt thereof to be administered to a patient or subject may then be reduced (after the first administration period) within the second treatment period while maintaining and/or extending (increasing) the hair growth achieved during the first period. In general, the amount of compound (I) or SALT thereof administered during the second period is sufficient to maintain hair growth achieved during the first period (e.g., as measured by a hair loss severity tool (SALT) score), for example, about 50 to 75% of the daily amount administered during the first period (e.g., if 16 mg/day of compound (I) or SALT thereof is administered during the first period, 8 to 12 mg/day may be administered during the second period). In certain embodiments, the maintenance dose (the daily amount administered during the second period) is about 33.3% of the daily amount administered during the first period.

or a pharmaceutically acceptable salt thereof; wherein each position specifically designated as deuterium incorporates at least 90% deuterium; wherein (1) the compound or pharmaceutically acceptable salt thereof is administered for a first period of time, wherein the compound or pharmaceutically acceptable salt thereof is administered in an amount in the range of 8mg to 32mg per day, followed by (2) the compound or pharmaceutically acceptable salt thereof is administered for a second period of time, wherein the compound or pharmaceutically acceptable salt thereof is administered in an amount of 50 to 75% of the amount per day administered during the first period of time, such that the alopecia is treated. In certain embodiments, the first period of time is about 8-24 weeks, e.g., 8 weeks, 12 weeks, 16 weeks, 20 weeks, or 24 weeks. In certain embodiments, the second period of time is at least 8 weeks, e.g., 8 weeks, 12 weeks, 16 weeks, 20 weeks, or 24 weeks (or longer).

Or a pharmaceutically acceptable salt thereof; wherein each position specified as deuterium incorporates at least 95% deuterium;

wherein (1) the compound or pharmaceutically acceptable salt thereof is administered for a first period of time, wherein the compound or pharmaceutically acceptable salt thereof is administered in an amount in the range of 8mg to 32mg per day, followed by (2) the compound or pharmaceutically acceptable salt thereof is administered for a second period of time, wherein the compound or pharmaceutically acceptable salt thereof is administered in an amount of 50 to 75% of the amount per day administered during the first period of time, such that the alopecia is treated. In certain embodiments, the first period of time is about 8-24 weeks, e.g., 8 weeks, 12 weeks, 16 weeks, 20 weeks, or 24 weeks. In certain embodiments, the second period of time is at least 8 weeks, e.g., 8 weeks, 12 weeks, 16 weeks, 20 weeks, or 24 weeks (or longer).

In certain embodiments, alopecia is treated when the subject's SALT score changes by ≡50% from the subject's baseline SALT score before treatment at the end of the first period. In certain embodiments, alopecia is treated when the subject's SALT score is less than or equal to 20 at the end of the second period. In certain embodiments, alopecia is treated when the subject's SALT score varies by greater than or equal to 50% from the baseline SALT score of the subject prior to treatment at the end of the first period, and the subject's SALT score is less than or equal to 20 at the end of the second period.

In certain embodiments, the length of the first period is sufficient to achieve a SALT score of less than or equal to 50, less than or equal to 40, less than or equal to 30, less than or equal to 20, less than or equal to 15, less than or equal to 10, less than or equal to 5, less than or equal to 1, or zero at the end of the first period. In certain embodiments, the first period is long enough to achieve a SALT score of less than or equal to 20 at the end of the first period. In certain embodiments, the first period is long enough to achieve a SALT score of less than or equal to 15 at the end of the first period. In certain embodiments, the first period is long enough to achieve a SALT score of less than or equal to 10 at the end of the first period. In certain embodiments, the first period is long enough to achieve a SALT score of less than or equal to 5 at the end of the first period. In certain embodiments, the first period is long enough to achieve a SALT score of less than or equal to 1 at the end of the first period. In certain embodiments, the first period is long enough to achieve a SALT score of zero at the end of the first period.

In certain embodiments, the alopecia is alopecia areata.

In certain embodiments, the compound or pharmaceutically acceptable salt thereof is administered at about 8 mg/day, about 12 mg/day, about 16 mg/day, about 24 mg/day, or about 32mg per day for a first period of time.

In certain embodiments, the compound or pharmaceutically acceptable salt thereof is administered at about 6 mg/day, about 8 mg/day, about 12 mg/day, about 16 mg/day, about 18 mg/day, about 20 mg/day, or about 24mg per day during the second period. In certain embodiments, the maintenance dose (the daily amount administered during the second period) is about 33.3% of the daily amount administered during the first period. In certain embodiments, the maintenance dose is about 50% of the daily amount administered during the first period. In certain embodiments, the maintenance dose is about 66.7% of the daily amount administered during the first period. In certain embodiments, the maintenance dose is about 75% of the daily amount administered during the first period.

In certain embodiments, in the first period, the compound or pharmaceutically acceptable salt thereof is administered at about 24 mg/day, and in the second period, the compound or pharmaceutically acceptable salt thereof is administered at about 16 mg/day. In certain embodiments, about 24 mg/day is administered in a single dose (i.e., once a day), and about 16 mg/day is administered in a single dose (i.e., once a day). In certain embodiments, about 24 mg/day is administered as two doses of about 12mg each (i.e., about 12mg twice daily), and about 16 mg/day is administered as two doses of about 8mg each (i.e., about 8mg twice daily).

In certain embodiments, in the first period, the compound or pharmaceutically acceptable salt thereof is administered at about 16 mg/day, and in the second period, the compound or pharmaceutically acceptable salt thereof is administered at about 8 mg/day. In certain embodiments, about 16 mg/day is administered in a single dose (i.e., once a day), and about 8 mg/day is administered in a single dose (i.e., once a day). In certain embodiments, about 16 mg/day is administered as two doses of about 8mg each (i.e., about 8mg twice daily), and about 8 mg/day is administered as two doses of about 4mg each (i.e., about 4mg twice daily).

In certain embodiments, in the first period, the compound or pharmaceutically acceptable salt thereof is administered at about 24 mg/day, and in the second period, the compound or pharmaceutically acceptable salt thereof is administered at about 8 mg/day. In certain embodiments, about 24 mg/day is administered in a single dose (i.e., once a day), and about 8 mg/day is administered in a single dose (i.e., once a day). In certain embodiments, about 24 mg/day is administered as two doses of about 12mg each (i.e., about 12mg twice daily), and about 8 mg/day is administered as two doses of about 4mg each (i.e., about 4mg twice daily).

In certain embodiments, the compound or pharmaceutically acceptable salt thereof is administered once daily (QD) for a first period of time. In certain embodiments, the compound or pharmaceutically acceptable salt thereof is administered twice daily (BID) for a first period of time.

In certain embodiments, the compound or pharmaceutically acceptable salt thereof is administered once daily (QD) over a second period. In certain embodiments, the compound or pharmaceutically acceptable salt thereof is administered twice daily (BID) for a second period of time.

In certain embodiments, the first period of time is about 8-24 weeks. In certain embodiments, the first period of time is about 8 weeks. In certain embodiments, the first period of time is about 10 weeks. In certain embodiments, the first period of time is about 12 weeks. In certain embodiments, the first period of time is about 16 weeks. In certain embodiments, the first period of time is about 20 weeks. In certain embodiments, the first period of time is about 24 weeks.

In certain embodiments, the second period of time is at least 8 weeks. In certain embodiments, the second period of time is at least 12 weeks. In certain embodiments, the second period of time is at least 24 weeks.

In certain embodiments, the daily amount administered during the second period is about 50% of the daily amount administered during the first period. In certain embodiments, the daily amount administered during the second period is about 66.7% of the daily amount administered during the first period. In certain embodiments, the daily amount administered during the second period is about 75% of the daily amount administered during the first period.

It is to be understood that reference to a specified amount of compound (I) or a pharmaceutically acceptable salt thereof comprises both said amount of compound (I) as the free base, and an amount of a pharmaceutically acceptable salt of compound (I), such as a phosphate, as the free base equal to said amount of compound (I) (in moles), e.g. 10.5mg of compound (I) phosphate corresponds to 8mg of compound (I) free base.

In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate salt) administered in a method for treating alopecia (e.g., in a first period or a second period) is about 4 mg/day (e.g., 4 mg/day), about 8 mg/day (e.g., 8 mg/day), about 16 mg/day (e.g., 16 mg/day), about 24 mg/day (e.g., 24 mg/day), or about 32 mg/day (e.g., 32 mg/day).

In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate salt) administered in a method for treating alopecia (e.g., in a first period or a second period) is about 8 mg/day (e.g., 8 mg/day), about 16 mg/day (e.g., 16 mg/day), about 24 mg/day (e.g., 24 mg/day), or about 32 mg/day (e.g., 32 mg/day).

In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in a method for treating alopecia (e.g., in the first period or the second period) is about 8 mg/day (e.g., 8 mg/day), about 16 mg/day (e.g., 16 mg/day), about 24 mg/day (e.g., 24 mg/day), or about 32 mg/day (e.g., 32 mg/day). In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is about 8 mg/day (e.g., 8 mg/day), about 12 mg/day (e.g., 12 mg/day), about 16 mg/day (e.g., 16 mg/day), or about 24 mg/day (e.g., 24 mg/day).

In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in a method for treating alopecia (e.g., in the first period or the second period) is about 8 mg/day (e.g., 8 mg/day), about 16 mg/day (e.g., 16 mg/day), about 24 mg/day (e.g., 24 mg/day), or about 32 mg/day (e.g., 32 mg/day). In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is from about 16 mg/day to about 32 mg/day, e.g., about 16 mg/day (e.g., 16 mg/day), about 24 mg/day (e.g., 24 mg/day), or about 32 mg/day (e.g., 32 mg/day).

In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in a method for treating alopecia (e.g., in the first period or the second period) is 10.6 mg/day of compound (I) phosphate, e.g., once daily as a 10.6mg dose, or twice daily as a 5.3mg dose. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 21.1 mg/day of compound (I) phosphate, e.g., once daily at a dose of 21.1mg, or twice daily at a dose of 10.5 mg. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 31.6 mg/day of compound (I) phosphate, e.g., once daily at a 31.6mg dose, or twice daily at a 15.8mg dose. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 42.2 mg/day of compound (I) phosphate, e.g., once daily at a dose of 42.2mg, or twice daily at a dose of 21.1 mg.

In certain embodiments, the amount of compound (I), or a pharmaceutically acceptable salt thereof, administered in a method for treating alopecia (e.g., during a first period or a second period) is about 8mg (e.g., 8 mg) twice daily. In a specific embodiment, compound (I) is administered twice daily as about 10.5mg (e.g., 10.5 mg) of the phosphate salt of compound (I).

In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in a method for treating alopecia (e.g., during a first period or a second period) is about 8mg (e.g., 8 mg) once daily or twice daily in divided doses in a single dose. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in a method for treating alopecia (e.g., during a first period or a second period) is about 12mg (e.g., 12 mg) once daily or twice daily in divided doses in a single dose. In specific embodiments, compound (I) is administered once daily in a single dose, or twice daily in divided doses, at about 15.8mg (e.g., 15.8 mg) of the phosphate salt of compound (I). In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in a method for treating alopecia (e.g., during a first period or a second period) is about 16mg (e.g., 16 mg) once daily in a single dose or twice daily in divided doses. In specific embodiments, compound (I) is administered once daily in a single dose, or twice daily in divided doses, at about 21.1mg (e.g., 21.1 mg) of the phosphate salt of compound (I). In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in a method for treating alopecia (e.g., during a first period or a second period) is about 24mg (e.g., 24 mg) once daily or twice daily in divided doses in a single dose. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in a method for treating alopecia (e.g., during a first period of time) is about 32mg (e.g., 32 mg) once daily or twice daily in divided doses.

In certain embodiments, the alopecia is alopecia areata. In certain embodiments, the subject is a human. In one embodiment, the subject is a human aged 6 years or older. In certain embodiments, compound (I) or a pharmaceutically acceptable salt thereof (e.g., phosphate) is administered orally at any of the dosages described herein. In certain embodiments, compound (I) or a pharmaceutically acceptable salt thereof is administered orally in any dose described herein in the form of a pharmaceutical formulation, which is a tablet.

In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered during the second period is about 50% of the daily amount of the amount administered during the first period. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered during the second period is about 66.7% of the daily amount of the amount administered during the first period. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered during the second period is about 75% of the daily amount of the amount administered during the first period.

Exemplary amounts of compound (I) or a pharmaceutically acceptable salt thereof to be administered are shown in the following table:

First period of time	A second period of time
		8 mg/day	6 mg/day
8 mg/day	4 mg/day
		12 mg/day	8 mg/day
12 mg/day	6 mg/day
		16 mg/day	12 mg/day
16 mg/day	8 mg/day
		24 mg/day	16 mg/day
24 mg/day	18 mg/day
		24 mg/day	12 mg/day
32 mg/day	24 mg/day
		32 mg/day	16 mg/day

In another aspect, the invention provides a method of treating alopecia areata in a human subject in need thereof, the method comprising:

a) Administering to the human subject an initial dose of a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof,

wherein each position specified as deuterium incorporates at least 95% deuterium,

wherein the first period of time is of a length sufficient to effect a decrease in the SALT score of the patient, and

wherein the initial dose is about 8 to about 32mg per day, followed by;

b) Administering a maintenance dose of the compound or pharmaceutically acceptable SALT thereof to the human subject over a second period of time, wherein the maintenance dose is 50% to 75% of the initial dose, and wherein the maintenance dose is sufficient to maintain hair growth (e.g., a SALT score of less than or equal to 20).

In certain embodiments, the length of the first period is sufficient to achieve at least a 10% decrease in the SALT score of the patient relative to baseline (e.g., from a SALT score of 100 before treatment to a SALT score of 90 after treatment). In further embodiments, the first period of time is of a length sufficient to achieve at least a 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 75%, at least 80%, or at least 90% decrease in the SALT score of the patient relative to baseline. In certain embodiments, the length of the first period is sufficient to achieve at least a 50% decrease in the SALT score of the patient relative to baseline. In certain embodiments, the length of the first period is sufficient to achieve at least a 75% decrease in the SALT score of the patient relative to baseline. In certain embodiments, the length of the first period is sufficient to achieve at least a 90% decrease in the SALT score of the patient relative to baseline.

In certain embodiments, the maintenance dose is about 25% of the initial dose. In certain embodiments, the maintenance dose is about 33.3% of the initial dose. In certain embodiments, the maintenance dose is about 50% of the initial dose. In certain embodiments, the maintenance dose is about 66.7% of the initial dose. In certain embodiments, the maintenance dose is about 75% of the initial dose.

In certain embodiments, the maintenance dose administered during the second period is sufficient to achieve a SALT score of less than or equal to 50, less than or equal to 40, less than or equal to 30, less than or equal to 20, less than or equal to 15, less than or equal to 10, less than or equal to 5, less than or equal to 1, or zero at the end of the second period. In certain embodiments, the maintenance dose administered during the second period is sufficient to achieve a SALT score of less than or equal to 20 at the end of the second period. In certain embodiments, the maintenance dose administered during the second period is sufficient to achieve a SALT score of less than or equal to 15 at the end of the second period. In certain embodiments, the maintenance dose administered during the second period is sufficient to achieve a SALT score of less than or equal to 10 at the end of the second period. In certain embodiments, the maintenance dose administered during the second period is sufficient to achieve a SALT score of less than or equal to 5 at the end of the second period. In certain embodiments, the maintenance dose is sufficient to maintain the SALT score achieved in the first period (e.g., in certain embodiments, the maintenance dose administered during the second period is sufficient to achieve a <10 score or <5 score increase in the SALT score of the subject at the end of the second period relative to the SALT score of the subject at the end of the first period). In certain embodiments, the maintenance dose administered during the second period is sufficient to achieve a <30% increase in the SALT score of the subject at the end of the second period relative to the SALT score of the subject at the end of the first period. In certain embodiments, the maintenance dose administered during the second period is sufficient to achieve a <5 score increase in the subject's SALT score at the end of the second period and a <30% increase in the subject's SALT score relative to the subject's SALT score at the end of the first period. In certain embodiments, the maintenance dose is sufficient to achieve a <4 score increase, a <3 score increase, a <2 score increase, or a <1 score increase in the subject's SALT score at the end of the second period relative to the subject's SALT score at the end of the first period. In certain embodiments, the maintenance dose is sufficient to achieve a <20%, a <15%, a <10% or a <5% increase in the subject's SALT score at the end of the second period relative to the subject's SALT score at the end of the first period.

In another aspect, the invention provides a method of treating alopecia in a human subject, the method comprising administering to the subject a compound represented by the structural formula:

or a pharmaceutically acceptable salt thereof, wherein each position specified as deuterium incorporates at least 95% deuterium; wherein the compound or pharmaceutically acceptable salt thereof is administered first for an induction period to induce hair growth and then for a second period to further treat alopecia, wherein the induction period is at least 8 weeks and no more than 24 weeks, the amount of compound or pharmaceutically acceptable salt thereof administered during the induction period is in the range of 16mg per day and 32mg per day, and after the induction period the amount of compound or pharmaceutically acceptable salt thereof administered during the second period is reduced by 50 to 75% (e.g., 50, 66.7, or 75%).

In the above aspect:

in certain embodiments, the first period of time is 8 to 24 weeks in length. In certain embodiments, the first period of time is about 12 weeks. In certain embodiments, the first period of time is about 16 weeks. In certain embodiments, the first period of time is about 20 weeks. In certain embodiments, the first period of time is about 24 weeks.

In certain embodiments, the second period of time is at least 12 weeks in length. In certain embodiments, the second period of time is at least 24 weeks.

Exemplary dosages for the first and second periods are described above.

In certain embodiments, wherein the decrease in baseline SALT score of the patient during the first period is from about 10% to about 50%. In certain embodiments, the decrease in baseline SALT score is from about 20% to about 50%. In certain embodiments, the decrease in baseline SALT score for the patient during the first period is about 50%. In certain embodiments, the decrease in baseline SALT score is about 30% to about 50%. In certain embodiments, the decrease in baseline SALT score for the patient during the first period is at least 50%. In certain embodiments, the decrease in baseline SALT score is from about 50% to about 99%. In certain embodiments, the decrease in baseline SALT score is from about 50% to about 90%. In certain embodiments, the decrease in baseline SALT score is from about 50% to about 75%. In certain embodiments, the decrease in baseline SALT score is about 75% to about 90%.

In certain embodiments, in the first period, the compound or pharmaceutically acceptable salt thereof is administered at about 24 mg/day, and in the second period, the compound or pharmaceutically acceptable salt thereof is administered at about 16 mg/day. In certain embodiments, the about 24 mg/day is administered once daily and the about 16 mg/day is administered once daily. In certain embodiments, the about 24 mg/day is administered about 12mg twice daily (divided doses) and the about 16 mg/day is administered about 8mg twice daily (divided doses).

In certain embodiments, in the first period, the compound or pharmaceutically acceptable salt thereof is administered at about 16 mg/day, and in the second period, the compound or pharmaceutically acceptable salt thereof is administered at about 8 mg/day.

In certain embodiments, the compound or pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical formulation, which is a tablet. In certain embodiments, the compound or pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical formulation that is a capsule.

In certain embodiments, the compound or pharmaceutically acceptable salt thereof is administered once daily during the first period.

In certain embodiments, the compound or pharmaceutically acceptable salt thereof is administered twice daily during the first period.

In the methods of the invention, the first period and the second period may vary in length depending on factors such as the amount of hair growth induced in the first period (e.g., as determined by SALT scores measured before and after the first period) and the duration of treatment desired. The first period of time may be, for example, 8-24 weeks, such as 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 22 weeks, or 24 weeks. The second period of time may be, for example, 8 weeks, 16 weeks, 24 weeks, 52 weeks, 2 years, 5 years, 10 years, or 20 years.

In one embodiment, the first period of time is at least 24 weeks (e.g., 24 weeks) and the second period of time is at least 24 weeks (e.g., 24 weeks).

In another embodiment, the first period of time is at most 24 weeks, and the second period of time is at least 24 weeks (e.g., 24 weeks).

In another aspect, the invention provides a method for inducing hair growth in a subject. The method comprises administering to the mammalian subject an effective amount of compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt such as a phosphate salt), wherein each position specified as deuterium incorporates at least 95% of deuterium; or a pharmaceutically acceptable salt thereof; wherein (1) the compound or pharmaceutically acceptable salt thereof is administered in an amount ranging from about 8mg to about 32mg per day for a first period of 8-24 weeks followed by (2) the compound or pharmaceutically acceptable salt thereof is administered for a second period of at least 8 weeks, wherein the compound or pharmaceutically acceptable salt thereof is administered in an amount of 50 to 75% (e.g., 50%, 66.7%, 75%) per day of the amount administered during the first period, such that hair growth is induced in the subject.

In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in a method for inducing hair growth is about 4 mg/day (e.g., 4 mg/day), about 8 mg/day (e.g., 8 mg/day), about 16 mg/day (e.g., 16 mg/day), about 24 mg/day (e.g., 24 mg/day), about 32 mg/day (e.g., 32 mg/day), or about 48 mg/day (e.g., 48 mg/day).

In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in a method for inducing hair growth is about 16 mg/day (e.g., 16 mg/day), about 24 mg/day (e.g., 24 mg/day), or about 32 mg/day (e.g., 32 mg/day).

In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in a method for inducing hair growth is about 8 mg/day (e.g., 8 mg/day), about 16 mg/day (e.g., 16 mg/day), about 24 mg/day (e.g., 24 mg/day), or about 32 mg/day (e.g., 32 mg/day). In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in a method for inducing hair growth is about 8 mg/day (e.g., 8 mg/day), about 12 mg/day (e.g., 12 mg/day), about 16 mg/day (e.g., 16 mg/day), or about 24 mg/day (e.g., 24 mg/day).

In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in the method for inducing hair growth is 10.6 mg/day of compound (I) phosphate, e.g., once daily at a dose of 10.6mg or twice daily at a dose of 5.3 mg. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 21.1 mg/day of compound (I) phosphate, e.g., once daily at a dose of 21.1mg or twice daily at a dose of 10.5 mg. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 31.6 mg/day of compound (I) phosphate, e.g., once daily at a dose of 31.6mg or twice daily at a dose of 15.8 mg. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 42.2 mg/day of compound (I) phosphate, e.g., once daily at a dose of 42.2mg or twice daily at a dose of 21.1 mg.

In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in a method for inducing hair growth (e.g., during the second period of time) is about 4mg (e.g., 4 mg) twice daily. In a specific embodiment, compound (I) is administered twice daily as about 5.3mg (e.g., 5.3 mg) of the phosphate salt of compound (I).

In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in a method for inducing hair growth (e.g., during the first or second period of time) is about 8mg (e.g., 8 mg) twice daily. In a specific embodiment, compound (I) is administered twice daily as about 10.5mg (e.g., 10.5 mg) of the phosphate salt of compound (I).

In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in a method for inducing hair growth (e.g., during the first or second period of time) is about 12mg (e.g., 12 mg) twice daily. In a specific embodiment, compound (I) is administered twice daily as about 15.8mg (e.g., 15.8 mg) of the phosphate salt of compound (I).

In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof administered in a method for inducing hair growth (e.g., during a first period of time) is about 16mg (e.g., 16 mg) twice daily. In a specific embodiment, compound (I) is administered twice daily as about 21.1mg (e.g., 21.1 mg) of the phosphate salt of compound (I).

In certain embodiments, the subject suffers from alopecia; in further embodiments, the alopecia is alopecia areata. In certain embodiments, the subject is a human. In one embodiment, the subject is a human aged 6 years or older. Preferably, compound (I) or a pharmaceutically acceptable salt thereof (e.g. phosphate) is administered orally at any of the aforementioned doses. Preferably, compound (I) or a pharmaceutically acceptable salt thereof is administered orally in any of the aforementioned doses in the form of a pharmaceutical formulation, which is a tablet or capsule.

Alopecia includes, but is not limited to, androgenetic alopecia, alopecia areata, telogen effluvium, alopecia totalis, and alopecia universalis.

In particular embodiments of any of the methods described herein, the condition is alopecia areata in a subject in need thereof, such as a mammalian (e.g., human) patient. In certain embodiments, alopecia areata is moderate to severe alopecia areata (e.g., at least 30% of the scalp is alopecia, at least 40% of the scalp is alopecia, at least 50% of the scalp is alopecia, or at least 75% of the scalp is alopecia).

In one embodiment of any aspect, the compound is administered orally once per day. In other embodiments of any aspect, the compound is administered orally twice daily.

As will be appreciated by those of skill in the art, the effective dosage may also vary depending on the disease being treated, the severity of the disease, the route of administration, the sex, age and general health of the subject, excipient usage, the likelihood of co-usage with other therapeutic treatments (e.g., the use of other agents), and the discretion of the treating physician.

Administration of compound (I) or a pharmaceutically acceptable salt thereof (e.g., phosphate) may be continued for a period of time necessary to treat alopecia, for example, for one week, two weeks, one month, three months, four months, six months, one year, two years, five years, ten years or more.

In certain embodiments, the treatment lasts for a period of at least 8 weeks, or at least 12 weeks, or at least 16 weeks, or at least 20 weeks, or at least 24 weeks, or at least 28 weeks, or at least 32 weeks, or at least 36 weeks, or at least 40 weeks, or at least 44 weeks, or at least 48 weeks, or at least 52 weeks.

In certain embodiments, compound (I), or a pharmaceutically acceptable salt thereof, is administered in combination with an additional therapeutic agent. Preferably, the additional therapeutic agent is an agent useful for treating alopecia or autoimmune conditions, such as an inhibitor of JAK1, JAK2 or JAK3 and/or STAT 1. Such inhibitors include rucotinib, tofacitinib (tofacitinib), baratinib (baricitinib), agotinib (filgotinib), and the like. Other orally administered additional therapeutic agents include agents for treating alopecia areata, including, for example, oral corticosteroids.

For pharmaceutical compositions comprising additional therapeutic agents, an effective amount of the additional therapeutic agent is between about 20% and 100% of the dose typically used in monotherapy regimens using only the agent. Preferably, the effective amount is between about 70% and 100% of the normal monotherapy dose. The normal monotherapy doses of these additional therapeutic agents are well known in the art. See, e.g., wells et al, editors, handbook for drug treatment (Pharmacotherapy Handbook), 2 nd edition, aprton and Lange press (Lange, stamford, conn.) (2000); the PDR pharmacopoeia-2000 tala Kang Xiuzhen pharmacopoeia (PDR Pharmacopoeia, tarascon Pocket Pharmacopoeia 2000), the essence, talaskan publishing company (Tarascon Publishing, loma Linda, calif.) (2000) of Loma-reach, california; FDA approved tag information for rucotinib and tofacitinib; and clinical trial information of barytinib and regoratinib, each of which is incorporated herein by reference in its entirety.

Some of the additional therapeutic agents mentioned above may act synergistically with the compounds of the present invention. When this occurs, the effective dose of the additional therapeutic agent and/or compound (I) or a pharmaceutically acceptable salt thereof will be allowed to decrease relative to the dose required in monotherapy. This has the advantage of minimizing the toxic side effects of the additional therapeutic agent or compound (I) or a pharmaceutically acceptable salt thereof, synergistic improvements in efficacy, improved ease of administration or use and/or reduced overall cost of the compound formulation or formulation.

In another embodiment, any of the above methods of treatment comprise the further step of co-administering one or more additional therapeutic agents to a subject in need thereof. The selection of the additional therapeutic agent may be made by any additional therapeutic agent known to be useful in the treatment of alopecia, such as alopecia areata. The choice of additional therapeutic agents also depends on the particular disease or condition to be treated. Examples of additional therapeutic agents that may be used in the methods of the invention are the additional therapeutic agents listed above for use in a combination composition comprising compound (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent. Additional therapeutic agents include agents useful in the treatment of alopecia areata, including, for example, topical Mi Nuoxi molar (minoxidil), injected corticosteroids, and anthralin creams or ointments.

As used herein, the term "co-administration" means that the additional therapeutic agent may be administered with compound (I) or a pharmaceutically acceptable salt thereof, either as part of a single dosage form (e.g., a composition of the invention comprising a compound of the invention and a second therapeutic agent as described above), or as separate multiple dosage forms. Alternatively, the additional agent may be administered before, sequentially with, or after administration of compound (I) or a pharmaceutically acceptable salt thereof. The administration of a composition of the invention comprising compound (I) or a pharmaceutically acceptable salt thereof and an additional therapeutic agent to a subject does not preclude the separate administration of the same therapeutic agent, any other additional therapeutic agent or compound (I) or a pharmaceutically acceptable salt thereof to the subject at another time during the course of treatment.

Effective amounts of these additional therapeutic agents are well known to those skilled in the art and guidelines for administration are found in the patents and published patent applications cited herein, and in Wells et al, handbook of drug treatment, 2 nd edition, alston and Langerhans Press (2000) of Stnford, connecticut; the PDR pharmacopoeia-the TaLaplace Kanphoxypeganum (2000), the essence, taraschikun publication company of Loma-reach, california (Tarascon Publishing, loma Linda, calif.); as well as other medical text. However, it is well within the purview of the skilled artisan to determine the optimal effective amount range of the additional therapeutic agent.

In one embodiment of the invention, wherein an additional therapeutic agent is administered to the subject, the effective amount of compound (I) or a pharmaceutically acceptable salt thereof will be less than the effective amount wherein no additional therapeutic agent is administered. In another embodiment, the effective amount of the additional therapeutic agent will be less than the effective amount thereof in which compound (I) or a pharmaceutically acceptable salt thereof is not administered. In this way, the undesirable side effects associated with either agent at high doses can be minimized. Other potential advantages, including but not limited to improved dosing regimens and/or reduced drug costs, will be apparent to those skilled in the art.

In yet another aspect, the invention provides the use of compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate salt), alone or together with one or more of the additional therapeutic agents described above, in the manufacture of a medicament for use in treating or preventing a disease, disorder or symptom shown above in a subject, either as a single composition or as a separate dosage form. Another aspect of the invention is the use of compound (I) or a pharmaceutically acceptable salt thereof in a subject for the treatment or prophylaxis of a disease, disorder or condition described herein.

Another aspect of the invention is a pharmaceutical composition comprising compound (I) or an equivalent amount of a pharmaceutically acceptable salt thereof in the range of about 4mg to about 50mg (e.g., about 5mg, about 10mg, about 20mg, about 30mg, about 40mg, or about 50 mg), together with a pharmaceutically acceptable carrier or diluent. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is about 4mg, 8mg, 16mg, 24mg, 32mg, or 48mg. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 4mg, 8mg, 12mg, or 16mg. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 5.3mg of compound (I) phosphate. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 10.5 or 10.6mg of compound (I) phosphate. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 15.8mg of compound (I) phosphate. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 21.1mg of compound (I) phosphate. In certain embodiments, the pharmaceutical composition is a tablet or capsule.

Another aspect of the invention is a unit dosage form comprising compound (I) or an equivalent amount of a pharmaceutically acceptable salt thereof in a range of about 4mg to about 50mg (e.g., about 5mg, about 10mg, about 20mg, about 30mg, about 40mg, or about 50 mg), together with a pharmaceutically acceptable carrier or diluent. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is about 4mg, 8mg, 16mg, 24mg, 32mg, or 48mg. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 4mg, 8mg, 12mg, or 16mg. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 5.3mg of compound (I) phosphate. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 10.5 or 10.6mg of compound (I) phosphate. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 15.8mg of compound (I) phosphate. In certain embodiments, the amount of compound (I) or a pharmaceutically acceptable salt thereof is 21.1mg of compound (I) phosphate. In certain embodiments, the unit dosage form is a tablet or capsule.

In one embodiment, any atom not designated as deuterium is present in compound (I) or a pharmaceutically acceptable salt thereof in its natural isotopic abundance.

The synthesis of compound (I) or a pharmaceutically acceptable salt thereof (e.g., phosphate) can be readily achieved by the methods described in us patent No. 9,249,149, PCT patent publication WO2017/192905 or PCT patent publication WO2020/163653, the teachings of which are incorporated herein by reference as if set forth in their appropriate modifications. For example, U.S. patent No. 9,249,149 describes the use of D9-intermediate 15 to produce a D9-pontine product; intermediate A is used

Compound (I) is provided in the process described in us patent No. 9,249,149. In addition, intermediate B

Can be used in place of intermediate 14 of U.S. patent No. 9,249,149 to prepare compound (I); removal of the amino protecting group may be accomplished by alkaline cleavage (e.g., with sodium hydroxide). Phosphoric acid can be used to convert compound (I) (free base) to its phosphate. An additional method of preparing tricutinib (i.e., non-deuterated compound (I)) is disclosed in U.S. patent No. 9,000,161 and may be used to prepare compound (I) with a suitable deuterating reagent.

Such methods may be carried out using the corresponding deuterated and optionally other isotopic-containing reagents and/or intermediates to synthesize the compounds described herein, or to incorporate standard synthetic protocols known in the art for introducing isotopic atoms into chemical structures.

The present invention also provides a pharmaceutical composition comprising an effective amount of compound (I) or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate salt); and a pharmaceutically acceptable carrier. The carrier is "acceptable" in the sense of being compatible with the other ingredients of the formulation, and in the case of a pharmaceutically acceptable carrier, is used in a pharmaceutical in an amount that is not deleterious to the recipient thereof. In certain embodiments, the pharmaceutical composition is provided as a unit dosage form.

The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and 4 to 50mg of a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof (i.e., an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate salt). For example, the amount of compound (I) is 4mg, 8mg, 12mg, 16mg or 24mg.

Pharmaceutically acceptable carriers, adjuvants and vehicles that can be used in the pharmaceutical compositions of the invention include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g. human serum albumin), buffer substances (e.g. phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g. protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

The solubility and bioavailability of the compounds of the invention in pharmaceutical compositions can be enhanced, if desired, by methods well known in the art. One method comprises using a lipid excipient in the formulation. See "oral lipid-based formulations: enhancing the bioavailability of poorly water-Soluble Drugs (pharmaceutical Lipid-Based Formulations: enhancing the Bioavailability of Poorly Water-solution Drugs (Drugs and the Pharmaceutical Sciences))', david J.Hauss editors Infuman healthcare (Informa Healthcare), 2007; and "Lipid excipients have been used to modify the roles of Oral and parenteral drug delivery: basic principles and biological examples (Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: basic Principles and Biological Examples)", kishor M.Wasan editors Wiley-Interscience, 2006.

Another known method of improving bioavailability is the use of amorphous forms of the compounds of the invention, optionally with poloxamers (poloxamers), such as LUTROL ^TM And PLURONIC ^TM (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See U.S. patent 7,014,866; U.S. patent publications 20060094744 and 20060079502.

The pharmaceutical compositions of the present invention comprise pharmaceutical compositions suitable for oral administration. Other formulations may conveniently be presented in unit dosage form, e.g., tablets, extended release capsules, granules, and in liposomes, and may be prepared by any method well known in the pharmaceutical arts. See, for example, ramington: pharmaceutical science and practice (Remington: the Science and Practice of Pharmacy), lepidopter williams and Wilkins (Lippincott Williams & Wilkins, baltimore, MD) (20 th edition 2000).

Such preparation methods comprise the step of associating the molecule to be administered with the ingredient (e.g., a carrier constituting one or more accessory ingredients). In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.

In certain embodiments, the compounds are administered orally. Compositions of the invention suitable for oral administration may be presented in discrete units, such as capsules, sachets or tablets, each containing a predetermined amount of the active ingredient; powder or granules; a solution or suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packaging in liposome; or presented as a bolus, etc. Soft gelatin capsules may be used to contain such suspensions, which may advantageously increase the absorption of the compound. In particular embodiments, the compounds are administered orally as tablets. In another specific embodiment, the compound is administered orally in a capsule.

In the case of tablets for oral use, the usual carriers include lactose and corn starch. Typically, a lubricant such as magnesium stearate is also added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweeteners and/or flavoring and/or coloring agents may be added. In another embodiment, the composition is in the form of a tablet. In certain embodiments, exemplary formulations of tablets are disclosed in U.S. patent No. 8,754,224, the teachings of which are incorporated herein by reference.

In particular embodiments, the tablet formulation contains from about 4mg to about 50mg of compound (I) or an equivalent amount of a pharmaceutically acceptable salt thereof (e.g., phosphate salt), and the following inactive ingredients: colloidal silica, magnesium stearate, microcrystalline cellulose and povidone. Wet granulation followed by compression provides a tablet comprising compound (I) or a pharmaceutically acceptable salt thereof. For example, to prepare a 200mg tablet comprising an equivalent of 16mg of compound (I), 10.6wt% (based on total formulation weight) of compound (I) phosphate and 64.44wt%Avicel PH-101 microcrystalline cellulose were mixed in a higher shear granulator and 8.5% w/w aqueous Kollidon 30 (containing Kollidon 30, i.e. polyvinylpyrrolidone; 5 wt%) was added during mixing to form granules. The particles were tray dried in an oven at 60±10 ℃ and ground using a Quadro Comil U5 grinder. The particles remaining on the cis screen were passed through a #20 mesh screen using a stainless steel doctor blade. The resulting abrasive particles were mixed with Avicel PH-200 microcrystalline cellulose (18.5 wt%), aerosil 200 colloidal silicon dioxide (0.5 wt%) and hyquat magnesium stearate (1 wt%) in a Turbula mixer to form the final blend. The final blend was compressed into 200mg tablets using a Riva Piccola rotary press with a 0.451 "x 0.229" d modified capsule mold. Each tablet contains 21.1mg of compound (I) (corresponding to 16mg of compound (I) free base).

In a particular embodiment, the tablet contains about 10.5mg or about 10.6mg of the phosphate salt of compound (I) (corresponding to 8mg of compound (I) free base).

In a particular embodiment, the tablet comprises the following ingredients:

4mg tablet

* Equivalent to 4mg of the free base of Compound (I)

In another particular embodiment, the tablet comprises the following ingredients:

8mg tablet

* Equivalent to 8mg of the free base of Compound (I)

In an alternative specific embodiment, the tablet comprises the following ingredients:

8mg tablet

* Equivalent to 8mg of the free base of Compound (I)

In yet another particular embodiment, the tablet comprises the following ingredients:

16mg tablet

* Equivalent to 16mg of the free base of Compound (I)

In another embodiment, the composition of the invention further comprises an additional therapeutic agent. When administered with a compound having the same mechanism of action as that of pontine, the additional therapeutic agent may be selected from any compound or therapeutic agent known to have or exhibit beneficial properties.

Preferably, the additional therapeutic agent is an agent useful for treating alopecia or an autoimmune condition comprising an inhibitor of JAK1, JAK2 or JAK3 and/or STAT 1. Such inhibitors include rucotinib, tofacitinib, barytinib, agotinib, and other additional therapeutic agents including oral corticosteroids.

In another embodiment, the present invention provides a single dosage form of compound (I) or a pharmaceutically acceptable salt thereof, and one or more of any of the additional therapeutic agents described above, wherein compound (I) or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are associated with each other. As used herein, the term "associated with each other" means that the individual dosage forms are packaged together or otherwise attached to each other such that it is readily apparent that the individual dosage forms are intended to be sold and administered together (continuously or simultaneously within less than 24 hours of each other).

In the pharmaceutical composition of the present invention, the compound (I) or a pharmaceutically acceptable salt thereof is present in an effective amount. As used herein, the term "effective amount" refers to an amount sufficient to treat a targeted disorder when administered in an appropriate dosing regimen.

The interrelation of dosages for animals and humans (milligrams per square meter based on body surface) is described in Freireich et al, cancer chemoreport (Cancer chemother. Rep), 1966,50:219. The body surface area may be approximately determined based on the height and weight of the subject. See, e.g., scientific table (Scientific Tables), jia-base pharmaceutical company (Geigy Pharmaceuticals, ardsley, n.y.), 1970,537, of az, new york.

In one embodiment, an effective amount of compound (I) (as the free base, or as an equivalent amount of a pharmaceutically acceptable salt, such as a phosphate salt) may range from about 8mg to 32mg per day (e.g., 8mg to 32mg per day), such as about 10mg per day (e.g., 10mg per day), about 20mg per day (e.g., 20mg per day), or about 30mg per day (e.g., 30mg per day). In certain embodiments, the amount is about 8 mg/day (e.g., 8 mg/day), about 12 mg/day (e.g., 12 mg/day), about 16 mg/day (e.g., 16 mg/day), about 24 mg/day (e.g., 24 mg/day), or about 32 mg/day (e.g., 32 mg/day). In one embodiment, a dose of about 8 mg/day (e.g., 8 mg/day), about 16 mg/day (e.g., 16 mg/day), about 24 mg/day (e.g., 24 mg/day), or about 32 mg/day (e.g., 32 mg/day) is administered once daily. In a specific example, a dose of 16 mg/day is administered together (i.e., as a single dose) as two 8mg tablets of compound (I) (as the free base, or as an equivalent amount of a pharmaceutically acceptable salt, such as phosphate). In another embodiment, a dose of 16 mg/day is administered as a 16mg tablet of compound (I) (as the free base, or as an equivalent amount of a pharmaceutically acceptable salt, such as phosphate). In another embodiment, a dose of 8 mg/day, 16 mg/day, 24 mg/day, or 32 mg/day is administered twice daily in divided doses (e.g., a dose of 16 mg/day is administered twice daily at 8mg, or a dose of 24 mg/day is administered twice daily at 12 mg). In another embodiment, a dose of 8 mg/day, 16 mg/day, 24 mg/day, or 32 mg/day is administered twice daily (e.g., a dose of 32 mg/day is administered twice daily as the free base, or as an equivalent amount of a pharmaceutically acceptable salt, such as phosphate) compound (I) (i.e., as a separate dose), in a specific embodiment, a dose of 16 mg/day is administered twice daily as 8mg of compound (I) (as the free base, or as an equivalent amount of a pharmaceutically acceptable salt, such as phosphate), i.e., as a separate dose).

In certain embodiments, the effective amount of compound (I) or a pharmaceutically acceptable salt thereof is about 4mg (e.g., 4 mg) twice daily. In a specific embodiment, an effective amount of compound (I) is administered twice daily as about 5.3mg (e.g., 5.3 mg) of the phosphate salt of compound (I). In certain embodiments, the effective amount of compound (I) or a pharmaceutically acceptable salt thereof is about 8mg (e.g., 8 mg) twice daily. In a specific embodiment, compound (I) is administered twice daily as about 10.5mg (e.g., 10.5 mg) of the phosphate salt of compound (I).

In certain embodiments, the effective amount of compound (I) or a pharmaceutically acceptable salt thereof is about 12mg (e.g., 12 mg) twice daily. In a specific embodiment, the effective amount of compound (I) is about 15.8mg (e.g., 15.8 mg) of the phosphate salt of compound (I) twice daily. In certain embodiments, the effective amount of compound (I) or a pharmaceutically acceptable salt thereof is about 16mg (e.g., 16 mg) twice daily. In a specific embodiment, the effective amount of compound (I) is about 21.1mg (e.g., 21.1 mg) of the phosphate salt of compound (I) twice daily.

Examples

Example 1 human study phase-2 a

A phase 2a trial was performed to evaluate the safety and efficacy of compound (I) (CTP-543) in subjects with alopecia, with a preliminary efficacy analysis at week 24. The phase 2a trial was a double blind, randomized, placebo controlled trial to evaluate the safety and efficacy of compound (I) in adult patients suffering from moderate to severe alopecia areata. The patient is sequentially randomized to receive one of three doses of compound I in the form of phosphate (e.g., 10.5mg of compound (I) phosphate corresponds to 8mg of compound (I) free base). The doses of compound (I) were 4, 8 (i.e., about 10.5mg of compound (I) phosphate) and 12mg twice daily, and there were also patient groups receiving placebo. The primary outcome measure utilized the hair loss severity tool (SALT) 24 weeks after administration.

Mid-term top line analysis of the 4mg, 8mg and 12mg groups is discussed below. The primary endpoint of the study was a 50% relative decrease in SALT between week 24 and baseline.

Demographic data for subjects who entered the group trial and received 4, 8, or 12mg (twice daily) or placebo are shown in table 1 below:

TABLE 1

The baseline characteristics of the subjects are shown in table 2 below:

TABLE 2

Adverse events (. Gtoreq.10%) occurring in the most common treatments divided by patient are shown in Table 3 below:

TABLE 3 Table 3

No serious adverse events were reported. In the preliminary analysis of placebo, 4mg and 8mg groups, there were only 3 grade 3/4 hematological events equally distributed between placebo, 4mg and 8mg groups.

In summary, the primary efficacy endpoint of the study was achieved. 58% of patients treated with 12mg BID (twice daily) and 47% of patients treated with 8mg BID (twice daily) of CTP-543 achieved an overall SALT score decrease of > 50% compared to 8.6% placebo (p < 0.001). In addition, 42% of patients treated with 12mg BID (p < 0.001) and 29% of patients treated with 8mg BID (p < 0.05) achieved an overall SALT score decrease of > 75% compared to 7% placebo. In addition, 36% of patients treated with 12mg BID (p < 0.001) and 16% of patients treated with 8mg BID (p < 0.05) achieved an overall SALT score decrease of ≡90% compared to 2% placebo. 21% of patients treated with 4mg BID of CTP-543 achieved a reduction in their overall SALT score of > 50% (not significant) compared to 8.6% placebo. The 12mg BID and 8mg BID dose groups were significantly different from the 4mg BID dose group (p < 0.05). Compared to placebo (p < 0.05), the 12mg and 8mg groups began to observe a significant change in SALT score at week 12.

Treatment is generally well tolerated without serious adverse events. The 4mg BID dose was not separated from placebo on all measurements. At week 24, the end of the trial, the 8mg BID dose and the 12mg BID dose were significantly different from placebo on all SALT measurements. The 12mg BID dose is numerically better than the 8mg BID dose and generally produces a faster onset and greater effect.

EXAMPLE 2 open Label extension Studies

In the ongoing open label extension study, the subjects previously enrolled in the qualification clinical study (including the study described in example 1) and received a total daily dose of 16mg of compound (I) (CTP-543, phosphate), a total daily dose of 24mg of CTP-543, or placebo, and completed a 24 week treatment period were eligible to the group open label extension study (OLE) and continued treatment with CTP-543 phosphate. A total of 152 subjects were enrolled in group OLE. In OLE, subjects were treated daily with CTP-543 at either a dose of 8mg BID or 12mg BID (see figure 8). Dose adjustments are allowed to be made as appropriate by the investigator. One subject enrolled in OLE received a daily dose of 24mg QD of CTP-543 for approximately 9 months (i.e., 24 week study period and the first 3 months of OLE) with hair growth occurring at the dose (SALT score is zero, i.e., hair is fully regrown prior to reduction). Subsequently, the dose of the subject was reduced to a daily dose of 8mg BID of CTP-543 phosphate. After approximately 7 months in OLE receiving the lower daily dose of 8mg BID of CTP-543, the subject continued to substantially maintain hair regrowth with a SALT score of 7.92.

EXAMPLE 3-phase 2 persistence study

Phase 2 clinical trials were conducted as two-part, double blind, randomized, multicentric studies to evaluate regrowth of hair following treatment with compound (I) (CTP-543) and subsequent persistence of the regrowth following reduction or withdrawal in adult patients with moderate to severe alopecia areata. The patient is between 18 and 65 years of age and experiences an onset of alopecia associated with alopecia areata for at least 6 months and no more than 10 years. Patients who are not currently treated for alopecia areata or other treatments that may affect hair regrowth or immune response must have at least 50% alopecia, as measured by the alopecia severity tool (SALT) at screening and baseline. Up to about 75% of patients with complete or near complete (SALT 95) hair loss are recruited.

The study was divided into 2 parts:

part A: period 1 (treatment period) and period 2 (dose adjustment period)

Part B: period of retreatment

Part A: period 1

Part a, part 1, period 1 is a double blind treatment period in which about 200 or 300 patients are randomized to receive compound (I) (CTP-543) in the form of phosphate of one of the two doses (e.g., 10.5mg of compound (I) phosphate corresponds to 8mg of compound (I) free base) for 24 weeks. The dose is 8mg of compound (I) twice daily (BID) (i.e., about 10.5mg of compound (I) phosphate), or 12mg of compound (I) BID (i.e., about 15.8mg of compound (I) phosphate). Randomization is stratified by scalp hair loss, and is divided into one of two categories: 1) Partial scalp alopecia (SALT. Gtoreq.50 and < 95); 2) Complete or near complete scalp hair loss (SALT. Gtoreq.95). The patient took the first dose of study medication at the clinic on day 1 and was instructed to take the study medication approximately every 12 hours a day for the duration of period 1. Other baseline evaluations of part a, period 1, included overall impressions of disease severity by patients and clinicians (CGI-S and PGI-S), as well as patient reported satisfaction results (SPRO) and hair Quality (QPRO). Blood samples for pharmacokinetic evaluation were collected periodically. Photographs of the scalp were also taken to provide visual recordings at the time of SALT evaluation, and were made at additional selection visits throughout the study. When all patients completed week 24 of part a, period 1, a preliminary efficacy analysis was performed to determine responders for each dose group. In some embodiments, at the end of treatment (EOT) of part a, period 1, patients with a change in SALT score of <50% from baseline are defined as non-responders and have an opportunity to continue receiving treatment in an open label extension study, or can complete treatment at week 24 and return to post-treatment safety follow-up after 4 weeks.

In some embodiments, patients from each dose group that have a SALT score that varies by ≡50% from baseline at week 24 are defined as responders and enter part a, period 2.

In some embodiments, at the end of treatment (EOT) of part a, time period 1, treatment success (responders) is defined as patients with a SALT score of ∈20 at 24 weeks per dose group. These responders entered part a, period 2 of the study. Patients with SALT scores >20 were defined as non-responders and had the opportunity to continue to receive treatment in the open label extension study, or completed treatment at week 24 and returned after 4 weeks for post-treatment safety follow-up.

Part a, period 1 (treatment period) lasted 24 weeks. Treatment response assessment using SALT to determine efficacy occurs at weeks 4, 8, 12, 16, 20 and 24.

Part A: time period 2

In part a, part 2, period 2, patients were re-randomized to receive lower doses of compound (I) (4 mg BID for patients previously receiving 8mg BID, or 8mg BID for patients previously receiving 12mg BID) or placebo. Patients in part a, period 2, remain at the dose dispensed for up to 24 weeks, or until they meet regrowth maintenance Loss (LOM) criteria. The standard for LOM is a SALT score greater than 20. Any patient meeting LOM criteria at any evaluation time point during part a, period 2, entered part B of the study and returned to its original compound (I) treatment of part a, period 1 (8 mg BID or 12mg BID). Patients who did not meet LOM criteria at the end of 24 weeks (i.e., patients with SALT scores less than or equal to 20) had the opportunity to continue to receive treatment in the open label extension study at their original part a, part 1 dose, or could complete treatment at week 24 and return to post-treatment safety follow-up after 4 weeks. The study design is depicted in fig. 7.

Part a, period 2 (dose modification) lasts for up to 24 weeks or until the patient meets LOM criteria. Treatment responses using SALT to assess efficacy were conducted once a month until LOM criteria were met or 24 week period was completed.

Part B

Any patient meeting part a, part 2, of the LOM standard (SALT > 20) enters part B of the study and from part a, part 1, returns to its original 8mg BID or 12mg BID dose. In some embodiments, the patient remains at the prescribed dose for 24 weeks, regardless of whether they meet the criteria for regrowth recovery (ROR). In some embodiments, the patient holds his prescribed dose for 24 weeks or until he meets the criteria for regrowth recovery (ROR). In some embodiments, ROR is defined as the patient achieving a SALT score +.ltoreq.its original EOT SALT score at the end of part a, period 1. In some embodiments, ROR is defined as the patient achieving a SALT score of 20. In some embodiments, any patient meeting ROR criteria at any point in time of evaluation during part B exits the study and qualifies for a group open label extension study. Treatment responses using SALT to assess efficacy will be conducted once a month until the regrowth recovery (ROR) criteria are met or a 24 week period is completed. Patients that did not meet ROR criteria had the opportunity to continue to receive treatment in the open label extension study, or could complete treatment at week 24 and return after 4 weeks for post-treatment safety follow-up.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description and illustrative examples, utilize the compounds of the present invention and practice the claimed methods. It should be understood that the foregoing discussion and examples merely present a detailed description of certain preferred embodiments. It will be apparent to those skilled in the art that various modifications and equivalents can be made without departing from the spirit and scope of the invention.

Claims

1. A method of treating alopecia in a human subject, the method comprising administering to the subject a compound represented by the structural formula:

or a pharmaceutically acceptable salt thereof;

wherein each position specified as deuterium incorporates at least 95% deuterium;

2. The method of claim 1, wherein the alopecia is alopecia areata.

3. The method of any one of claims 1-2, wherein in the first period of time the compound or pharmaceutically acceptable salt thereof is administered at about 16 mg/day, about 24 mg/day, or about 32mg per day.

4. The method of any one of claims 1 to 3, wherein in the second period of time the compound or pharmaceutically acceptable salt thereof is administered at about 8 mg/day, about 12 mg/day, or about 16mg per day.

5. The method of any one of claims 1 to 4, wherein in the first period the compound or pharmaceutically acceptable salt thereof is administered at about 24 mg/day and in the second period the compound or pharmaceutically acceptable salt thereof is administered at about 16 mg/day.

6. The method of claim 5, wherein the about 24 mg/day of the compound or salt thereof is administered once daily and the about 16 mg/day is administered once daily.

7. The method of claim 5, wherein the about 24 mg/day of the compound or salt thereof is administered at about 12mg twice daily and the about 16 mg/day of the compound or salt thereof is administered at about 8mg twice daily.

8. The method of any one of claims 1 to 4, wherein in the first period the compound or pharmaceutically acceptable salt thereof is administered at about 16 mg/day and in the second period the compound or pharmaceutically acceptable salt thereof is administered at about 8 mg/day.

9. The method of any one of claims 1 to 8, wherein the compound or pharmaceutically acceptable salt thereof is administered orally.

10. The method of any one of claims 1 to 9, wherein the compound or pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical formulation, which is a tablet.

11. The method of any one of claims 1 to 6 or 8 to 10, wherein the compound or pharmaceutically acceptable salt thereof is administered once daily in the first period of time.

12. The method of any one of claims 1 to 5 or 7 to 10, wherein the compound or pharmaceutically acceptable salt thereof is administered twice daily in the first period of time.

13. The method of any one of claims 1 to 12, wherein the first period of time is about 8-12 weeks.

14. The method of any one of claims 1 to 12, wherein the first period of time is about 24 weeks.

15. The method of any one of claims 1 to 14, wherein the second period of time is at least 12 weeks.

16. The method of any one of claims 1 to 15, wherein the second period of time is at least 24 weeks.

17. The method of any one of claims 1 to 16, wherein in compound (I), each position specified as deuterium incorporates at least 97% of deuterium.

18. The method of any one of claims 1-17, wherein the subject experiences a decrease in SALT score of.

19. The method of any one of claims 1-18, wherein the subject's SALT score is less than or equal to 20 at the end of the second period.

20. The method of any one of claims 1-17, wherein the subject's SALT score is less than or equal to 20 at the end of the first period.