WO2022174269A1 - Irak4 degraders and uses thereof - Google Patents
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- WO2022174269A1 WO2022174269A1 PCT/US2022/070664 US2022070664W WO2022174269A1 WO 2022174269 A1 WO2022174269 A1 WO 2022174269A1 US 2022070664 W US2022070664 W US 2022070664W WO 2022174269 A1 WO2022174269 A1 WO 2022174269A1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
Definitions
- the present invention relates to methods of administering IRAK4 degrader 5-((lR,4R)- 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-l-((lr,4R)-4-((4-((3-(l-(2,6- dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)prop-2-yn-l- yl)oxy)piperidin- 1 -yl)methyl)cyclohexyl)- lH-pyrazol-4-yl)pyrazolo[ 1 ,5 -a]pyrimidine-3 - carboxamide (Compound A), and uses thereof for treating autoinflammatory/autoimmune diseases and hematological malignancies.
- Compound A Compound A
- Ubiquitin-Proteasome Pathway is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPP is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.
- UPP plays a key role in the degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen presentation.
- Interleukin- 1 receptor-associated kinase-4 (IRAK4) is a key component of the myddosome, a multiprotein complex involved in innate immunity that mediates signaling through toll-like receptors (TLRs) and interleukin (IL)-l receptors (Patra and Choi, Molecule 2016, 21(11): 1529).
- TLRs toll-like receptors
- IL interleukin-l receptors
- IRAK4 The function of IRAK4 is dependent both on its kinase activity and on its scaffolding properties, which is required for the assembly of the myddosome complex following TLR or IL-IR engagement and myeloid differentiation factor 88 (MyD88) activation (De Nardo et ah, J. Bio. Chem. 2018, 293(39): 15195; Cushing et ah, J. Bio. Chem. 2014, 289(15): 10865).
- MyD88 myeloid differentiation factor 88 activation
- the no observed adverse effect level (NOAEL) in dogs is 60 mg/kg/day, which corresponded to average, sex-combined, maximum observed concentration (Cmax) in plasma and area under the concentration-time curve (AUCo-24) values of 561 ng/mL and 11,700 ng*hr/mL, respectively for Compound A; 288 ng/mL and 6090 ng*hr/mL, respectively, for Compound B; and 265 ng/mL and 5620 ng*hr/mL, respectively, for Compound C on Day 42 of the dosing phase.
- NOAEL no observed adverse effect level
- a method of treating an autoimmune/autoinflammatory disease and/or a hematological malignancy comprising administering to a patient in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof, wherein a Cmax of Compound A in plasma is up to about 561 ng/mL.
- a method of treating an autoimmune/autoinflammatory disease and/or a hematological malignancy comprising administering to a patient in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof, wherein a C max of Compound B in plasma is up to about 288 ng/mL.
- a method of treating an autoimmune/autoinflammatory disease and/or a hematological malignancy comprising administering to a patient in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof, wherein a C max of Compound C in plasma is up to about 265 ng/mL.
- a method of treating an autoimmune/autoinflammatory disease and/or a hematological malignancy comprising administering to a patient in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof, wherein an AUCo-24 of Compound A in plasma is up to about 11700 ng*hr/mL.
- a method of treating an autoimmune/autoinflammatory disease and/or a hematological malignancy comprising administering to a patient in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof, wherein an AUCo-24 of Compound B in plasma is up to about 6090 ng*hr/mL.
- a method of treating an autoimmune/autoinflammatory disease and/or a hematological malignancy comprising administering to a patient in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof, wherein an AUCo-24 of Compound C in plasma is up to about 5620 ng*hr/mL.
- Compound A is administered at a dose of about 10 mg/kg to about 200 mg/kg, for example, Compound A is administered at a dose selected from about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, and about 90 mg/kg.
- the T max of Compound A is achieved in about 4 hrs to about 12 hrs, for example, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hrs.
- the autoimmune/autoinflammatory disease is selected from a cutaneous, rheumatic, and gastrointestinal autoimmune/autoinflammatory disease.
- the autoimmune/autoinflammatory disease is a cutaneous autoimmune/autoinflammatory disease selected from atopic dermatitis (AD) and hidradenitis suppurativa (HS).
- Compound A is a potent, highly selective, orally administered heterobifunctional small molecule therapeutic targeting IRAK4 and the E3 ligase CRBN to mediate the selective degradation of IRAK4 via the ubiquitin-proteasome system.
- Compound A is composed of a CRBN-targeting ligand and an IRAK4-targeting ligand joined by a chemical linker.
- Compound A forms a ternary complex through non-covalent binding to both CRBN and IRAK4, bringing the E3 ligase (CRBN) in close proximity to IRAK4, that now serves as its neosubstrate. This proximity leads to IRAK4 ubiquitination and proteosomal degradation and eventual release of Compound A, which is then free to mediate additional rounds of ternary complex formation and IRAK4 degradation.
- cytokine release assays confirmed Compound A’s ability to inhibit TLR agonist (lipopoly saccharide and R848) and IL-1 b-induced proinflammatory cytokine production (including IL-6, TNF-a, granulocyte-macrophage colony-stimulating factor, and IL-8) in PBMCs with IC50 values also in the low nM range.
- TLR agonist lipopoly saccharide and R848
- IL-1 b-induced proinflammatory cytokine production including IL-6, TNF-a, granulocyte-macrophage colony-stimulating factor, and IL-8
- MS mass spectrometry
- PK pharmacokinetics
- PD pharmacodynamics
- the present disclosure provides a method of treating an autoimmune/autoinflammatory disease and/or a hematological malignancy, comprising administering to a patient in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof, wherein a C max of Compound A in plasma is up to about 561 ng/mL.
- the present disclosure provides a method of treating an autoimmune/autoinflammatory disease and/or a hematological malignancy, comprising administering to a patient in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof, wherein an AUCo-24 of Compound A in plasma is up to about 11700 ng*hr/mL.
- an autoimmune/autoinflammatory disease is selected from atopic dermatitis (AD) and hidradenitis suppurativa (HS).
- Compound A refers to IRAK4 degrader 5-((lR,4R)-2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-l-((lr,4R)-4-((4-((3-(l-(2,6-dioxopiperidin- 3-yl)-3-methyl-2-oxo-2,3-dihydro-lH-benzo[d]imidazol-4-yl)prop-2-yn-l-yl)oxy)piperidin-l- yl)methyl)cyclohexyl)-lH-pyrazol-4-yl)pyrazolo[l,5-a]pyrimidine-3-carboxamide, of formula: “Compound B” refers to IRAK4 degrader 5-((lR,4R)-2-oxa-5-azabicyclo[2.2.
- Compound A contains three chiral centers, including two fixed/ stable centers around the morphine ring ( R,R ) and one epimerizable chiral center (R S) resulting in the two diastereomers, (S,R,R)- Compound A and (R,R,R)- Compound A, which are designated as Compound B and Compound C, respectively.
- Compound A is Compound B.
- Compound A is Compound C.
- Compound A is a mixture of Compound B and Compound C.
- Compound A is an approximately 1:1 mixture of Compound B and Compound C. Both diastereomers interconvert rapidly in vitro and in vivo.
- Compound A, or a pharmaceutically acceptable salt thereof is amorphous. In some embodiments, Compound A, or a pharmaceutically acceptable salt thereof, is in crystal form. In some embodiments, Compound A is the hydrochloride (HC1) salt. In some embodiments, Compound A HC1 salt is amorphous. In some embodiments, Compound A HC1 salt is in crystal form.
- the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
- Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al ., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference.
- Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases.
- Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
- inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
- organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
- salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
- Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (Ci ⁇ alkyl)4 salts.
- Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
- the terms “about” or “approximately” have the meaning of within 20% of a given value or range. In some embodiments, the term “about” refers to within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.
- the present disclosure provides a method of treating an autoimmune/autoinflammatory disease and/or a hematological malignancy, comprising administering to a patient in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof, wherein C max of Compound A in plasma is up to about 561 ng/mL.
- the present disclosure provides a method of treating an autoimmune/autoinflammatory disease and/or a hematological malignancy, comprising administering to a patient in need thereof a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof, wherein an AUCo-24 of Compound A in plasma is up to about 11700 ng*hr/mL.
- an autoimmune/autoinflammatory disease is selected from atopic dermatitis (AD) and hidradenitis suppurativa (HS).
- treatment refers to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein.
- treatment may be administered after one or more symptoms have developed.
- treatment may be administered in the absence of symptoms.
- treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g. , in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.
- a patient or subject "in need of prevention,” “in need of treatment,” or “in need thereof,” refers to one, who by the judgment of an appropriate medical practitioner (e.g, a doctor, a nurse, or a nurse practitioner in the case of humans; a veterinarian in the case of non human mammals), would reasonably benefit from a given treatment or therapy.
- an appropriate medical practitioner e.g, a doctor, a nurse, or a nurse practitioner in the case of humans; a veterinarian in the case of non human mammals
- a “therapeutically effective amount” or “therapeutically effective dosage” of a drug or therapeutic agent, such as Compound A, is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a patient or subject against the onset of a disease, such as AD, or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
- the ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.
- a therapeutically effective amount of the drug promotes regression to the point of eliminating the disease.
- the terms "effective” and “effectiveness” with regard to a treatment includes both pharmacological effectiveness and physiological safety.
- Pharmacological effectiveness refers to the ability of the Compound A to treat the disease in the patient.
- Physiological safety refers to the level of toxicity, or other adverse physiological effects at the cellular, organ and/or organism level (adverse effects) resulting from administration of the drug.
- therapeutic benefit refers to an improvement in one or more of overall survival, progression-free survival, partial response, complete response, and overall response rate and can also include a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction.
- patient means an animal, preferably a mammal, and most preferably a human.
- the present disclosure provides a method of administering Compound A to a patient in need thereof, comprising administering to said patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof, wherein a Cmax of up to about 561 ng/mL of Compound A in plasma is achieved.
- a Cmax of Compound A in plasma is up to about 550 ng/mL. In some embodiments, a Cmax of Compound A in plasma is up to about 500 ng/mL. In some embodiments, a Cmax of Compound A in plasma is up to about 450 ng/mL. In some embodiments, a Cmax of Compound A in plasma is up to about 400 ng/mL. In some embodiments, a Cmax of Compound A in plasma is up to about 350 ng/mL. In some embodiments, a Cmax of Compound A in plasma is up to about 300 ng/mL. In some embodiments, a Cmax of Compound A in plasma is up to about 250 ng/mL.
- a Cmax of Compound A in plasma is up to about 200 ng/mL. In some embodiments, a Cmax of Compound A in plasma is up to about 150 ng/mL. In some embodiments, a Cmax of Compound A in plasma is up to about 100 ng/mL. [0046] In some embodiments, a Cmax of Compound A in plasma is about 100 ng/mL. In some embodiments, a Cmax of Compound A in plasma is about 150 ng/mL. In some embodiments, a Cmax of Compound A in plasma is about 200 ng/mL. In some embodiments, a Cmax of Compound A in plasma is about 250 ng/mL.
- a Cmax of Compound A in plasma is about 300 ng/mL. In some embodiments, a Cmax of Compound A in plasma is about 350 ng/mL. In some embodiments, a Cmax of Compound A in plasma is about 400 ng/mL. In some embodiments, a Cmax of Compound A in plasma is about 450 ng/mL. In some embodiments, a Cmax of Compound A in plasma is about 500 ng/mL. In some embodiments, a Cmax of Compound A in plasma is about 550 ng/mL. In some embodiments, a Cmax of Compound A in plasma is about 561 ng/mL.
- a Cmax of Compound A in plasma is about 500 ng/mL to about 561 ng/mL, about 450 ng/mL to about 550 ng/mL, about 400 ng/mL to about 500 ng/mL, about 350 ng/mL to about 450 ng/mL, about 300 ng/mL to about 400 ng/mL, about 250 ng/mL to about 350 ng/mL, about 200 ng/mL to about 300 ng/mL, about 150 ng/mL to about 250 ng/mL, about 100 ng/mL to about 200 ng/mL, or about 50 ng/mL to about 150 ng/mL.
- the present disclosure provides a method of administering Compound A to a patient in need thereof, comprising administering to said patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof, wherein a Cmax of up to about 288 ng/mL of Compound B in plasma is achieved.
- a Cmax of Compound B in plasma is up to about 280 ng/mL, up to about 260 ng/mL, up to about 250 ng/mL, up to about 240 ng/mL, up to about 220 ng/mL, up to about 200 ng/mL, up to about 180 ng/mL, up to about 160 ng/mL, up to about 150 ng/mL, up to about 140 ng/mL, up to about 120 ng/mL, or up to about 100 ng/mL.
- a Cmax of Compound B in plasma is about 280 ng/mL, about 260 ng/mL, about 250 ng/mL, about 240 ng/mL, about 220 ng/mL, about 200 ng/mL, about 180 ng/mL, about 160 ng/mL, about 150 ng/mL, about 140 ng/mL, about 120 ng/mL, or about 100 ng/mL.
- a Cmax of Compound B in plasma is about 260 ng/mL to about 288 ng/mL, about 240 ng/mL to about 260 ng/mL, about 220 ng/mL to about 240 ng/mL, about 200 ng/mL to about 220 ng/mL, about 180 ng/mL to about 200 ng/mL, about 160 ng/mL to about 180 ng/mL, about 140 ng/mL to about 160 ng/mL, about 120 ng/mL to about 140 ng/mL, about 100 ng/mL to about 120 ng/mL, or about 80 ng/mL to about 100 ng/mL.
- the present disclosure provides a method of administering Compound A to a patient in need thereof, comprising administering to said patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof, wherein a Cmax of up to about 265 ng/mL of Compound C in plasma is achieved.
- a Cmax of Compound C in plasma is up to about 260 ng/mL, up to about 250 ng/mL, up to about 240 ng/mL, up to about 220 ng/mL, up to about 200 ng/mL, up to about 180 ng/mL, up to about 160 ng/mL, up to about 150 ng/mL, up to about 140 ng/mL, up to about 120 ng/mL, up to about 100 ng/mL, or up to about 80 ng/mL.
- a Cmax of Compound C in plasma is about 260 ng/mL, about 250 ng/mL, about 240 ng/mL, about 220 ng/mL, about 200 ng/mL, about 180 ng/mL, about 160 ng/mL, about 150 ng/mL, about 140 ng/mL, about 120 ng/mL, about 100 ng/mL, or about 80 ng/mL.
- a Cmax of Compound C in plasma is about 240 ng/mL to about 265 ng/mL, about 220 ng/mL to about 240 ng/mL, about 200 ng/mL to about 220 ng/mL, about 180 ng/mL to about 200 ng/mL, about 160 ng/mL to about 180 ng/mL, about 140 ng/mL to about 160 ng/mL, about 120 ng/mL to about 140 ng/mL, about 100 ng/mL to about 120 ng/mL, about 80 ng/mL to about 100 ng/mL, or about 60 ng/mL to about 80 ng/mL.
- the present disclosure provides a method of administering Compound A to a patient in need thereof, comprising administering to said patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof, wherein an AUCo- 24 of up to about 11700 ng*hr/mL of Compound A in plasma is achieved.
- an AUCo-24 of Compound A in plasma is up to about 11500 ng*h/mL, up to about 11000 ng*h/mL, up to about 10500 ng*h/mL, up to about 10000 ng*h/mL, up to about 9500 ng*h/mL, up to about 9000 ng*h/mL, up to about 8500 ng*h/mL, up to about 8000 ng*h/mL, up to about 7500 ng*h/mL, up to about 7000 ng*h/mL, up to about 6500 ng*h/mL, up to about 6000 ng*h/mL, up to about 5500 ng*h/mL, up to about 5000 ng*h/mL, up to about 4500 ng*h/mL, up to about 4000 ng*h/mL, up to about 3500 ng*h/mL, or up to about 3000 ng*h/mL
- an AUCo-24 of Compound A in plasma is about 3,000 ng*h/mL, about 3,500 ng*h/mL, or about 4,000 ng*h/mL. In some embodiments, an AUCo-24 of Compound A in plasma is about 5,000 ng*h/mL. In some embodiments, an AUCo-24 of Compound A in plasma is about 5,500 ng*h/mL. In some embodiments, an AUCo-24 of Compound A in plasma is about 6,000 ng*h/mL. In some embodiments, an AUCo-24 of Compound A in plasma is about 6,500 ng*h/mL.
- an AUCo-24 of Compound A in plasma is about 7,000 ng*h/mL. In some embodiments, an AUCo-24 of Compound A in plasma is about 7,500 ng*h/mL. In some embodiments, an AUCo-24 of Compound A in plasma is about 8,000 ng*h/mL. In some embodiments, an AUCo-24 of Compound A in plasma is about 8,500 ng*h/mL. In some embodiments, an AUCo-24 of Compound A in plasma is about 9,000 ng*h/mL. In some embodiments, an AUCo-24 of Compound A in plasma is about 9,500 ng*h/mL.
- an AUCo-24 of Compound A in plasma is about 10,000 ng*h/mL. In some embodiments, an AUCo-24 of Compound A in plasma is about 10,500 ng*h/mL. In some embodiments, an AUCo-24 of Compound A in plasma is about 11,000 ng*h/mL. In some embodiments, an AUCo-24 of Compound A in plasma is about 11,500 ng*h/mL. In some embodiments, an AUCo-24 of Compound A in plasma is about 11,700 ng*h/mL.
- an AUCo-24 of Compound A in plasma is about 11,000 ng*h/mL to about 11,700 ng*h/mL, about 10,000 ng*h/mL to about 11,000 ng*h/mL, about 9,000 ng*h/mL to about 10,000 ng*h/mL, about 8,000 ng*h/mL to about 9,000 ng*h/mL, about 7,000 ng*h/mL to about 8,000 ng*h/mL, about 6,000 ng*h/mL to about 7,000 ng*h/mL, about 5,000 ng*h/mL to about 6,000 ng*h/mL, or about 4,000 ng*h/mL to about 5,000 ng*h/mL.
- the present disclosure provides a method of administering Compound A to a patient in need thereof, comprising administering to said patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof, wherein an AUCo-24 of up to about 6090 ng*h/mL of Compound B in plasma is achieved.
- an AUCo-24 of Compound B in plasma is up to about 6000 ng*h/mL, up to about 5500 ng*h/mL, up to about 5000 ng*h/mL, up to about 4500 ng*h/mL, up to about 4000 ng*h/mL, up to about 3500 ng*h/mL, up to about 3000 ng*h/mL, up to about 2500 ng*h/mL, up to about 2000 ng*h/mL, or up to about 1500 ng*h/mL.
- an AUCo-24 of Compound B in plasma is about 6000 ng*h/mL, about 5500 ng*h/mL, about 5000 ng*h/mL, about 4500 ng*h/mL, about 4000 ng*h/mL, about 3500 ng*h/mL, about 3000 ng*h/mL, about 2500 ng*h/mL, about 2000 ng*h/mL, or about 1500 ng*h/mL.
- an AUCo-24 of Compound B in plasma is about 5500 ng*h/mL to about 6090 ng*h/mL, about 5000 ng*h/mL to about 5500 ng*h/mL, about 4500 ng*h/mL to about 5000 ng*h/mL, about 4000 ng*h/mL to about 4500 ng*h/mL, about 3500 ng*h/mL to about 4000 ng*h/mL, about 3000 ng*h/mL to about 3500 ng*h/mL, about 2500 ng*h/mL to about 3000 ng*h/mL, about 2000 ng*h/mL to about 2500 ng*h/mL, or about 1500 ng*h/mL to about 2000 ng*h/mL.
- the present disclosure provides a method of administering Compound A to a patient in need thereof, comprising administering to said patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof, wherein an AUCo-24 of up to about 5620 ng*h/mL of Compound C in plasma is achieved.
- an AUCo-24 of Compound C in plasma is up to about 5500 ng*h/mL, up to about 5000 ng*h/mL, up to about 4500 ng*h/mL, up to about 4000 ng*h/mL, up to about 3500 ng*h/mL, up to about 3000 ng*h/mL, up to about 2500 ng*h/mL, up to about 2000 ng*h/mL, or up to about 1500 ng*h/mL.
- an AUCo-24 of Compound C in plasma is about 5620 ng*h/mL, about 5500 ng*h/mL, about 5000 ng*h/mL, about 4500 ng*h/mL, about 4000 ng*h/mL, about 3500 ng*h/mL, about 3000 ng*h/mL, about 2500 ng*h/mL, about 2000 ng*h/mL, or about 1500 ng*h/mL.
- an AUCo-24 of Compound C in plasma is about 5000 ng*h/mL to about 5620 ng*h/mL, about 4500 ng*h/mL to about 5000 ng*h/mL, about 4000 ng*h/mL to about 4500 ng*h/mL, about 3500 ng*h/mL to about 4000 ng*h/mL, about 3000 ng*h/mL to about 3500 ng*h/mL, about 2500 ng*h/mL to about 3000 ng*h/mL, about 2000 ng*h/mL to about 2500 ng*h/mL, or about 1500 ng*h/mL to about 2000 ng*h/mL.
- the present methods and uses achieve two, three, four, five, or six of the following PK parameters:
- Compound A is administered to a patient in thereof at a dose to achieve a C max of Compound A or a therapeutically effective AUCo-24 of Compound A.
- Compound A is administered at a dose of about 10 mg/kg to about 200 mg/kg, for example, Compound A is administered at a dose selected from about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, and about 90 mg/kg.
- Compound A is administered at a dose of about 20 mg/kg to about 60 mg/kg. In such embodiments, Compound A is administered at a dose of about 25 mg/kg to about 65 mg/kg. In some embodiments, Compound A is administered at a dose of about 30 mg/kg to about 70 mg/kg. In some embodiments, Compound A is administered at a dose of about 35 mg/kg to about 75 mg/kg. In such embodiments, Compound A is administered at a dose of about 40 mg/kg to about 80 mg/kg. In some embodiments, Compound A is administered at a dose of about 45 mg/kg to about 85 mg/kg.
- Compound A is administered at a dose of about 50 mg/kg to about 90 mg/kg. In some embodiments, Compound A is administered at a dose of about 55 mg/kg to about 95 mg/kg. In such embodiments, Compound A is administered at a dose of about 60 mg/kg to about 100 mg/kg.
- Compound A is administered at a dose of about 30 mg/kg. In some embodiments, Compound A is administered at a dose of about 35 mg/kg. In some embodiments, Compound A is administered at a dose of about 40 mg/kg. In some embodiments, Compound A is administered at a dose of about 45 mg/kg. In some embodiments, Compound A is administered at a dose of about 50 mg/kg. In some embodiments, Compound A is administered at a dose of about 55 mg/kg. In some embodiments, Compound A is administered at a dose of about 60 mg/kg. In some embodiments, Compound A is administered at a dose of about 65 mg/kg.
- Compound A is administered at a dose of about 70 mg/kg. In some embodiments, Compound A is administered at a dose of about 75 mg/kg. In some embodiments, Compound A is administered at a dose of about 80 mg/kg. In some embodiments, Compound A is administered at a dose of about 85 mg/kg. In some embodiments, Compound A is administered at a dose of about 90 mg/kg. In some embodiments, Compound A is administered at a dose of about 95 mg/kg. In some embodiments, Compound A is administered at a dose of about 100 mg/kg. In certain embodiments, Compound A is administered at a dose of about 60 mg/kg per dose.
- the T max of Compound A is achieved in about 4 hrs to about 12 hrs, for example, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, or about 12 hrs. In some embodiments, the T max of Compound A is achieved in about 4 hrs. In some embodiments, the T max of Compound A is achieved in about 5 hrs. In some embodiments, the T max of Compound A is achieved in about 6 hrs. In some embodiments, the T max of Compound A is achieved in about 74 hrs. In some embodiments, the T PMC of Compound A is achieved in about 8 hrs. In some embodiments, the T max of Compound A is achieved in about 9 hrs. In some embodiments, the T max of Compound A is achieved in about 10 hrs. In some embodiments, the T max of Compound A is achieved in about 11 hrs. In some embodiments, the T max of Compound A is achieved in about 12 hrs.
- the t1 ⁇ 2 of Compound A is about 5 hrs to 10 hrs. In some embodiments, t1 ⁇ 2 is about 5 hrs. In some embodiments, t1 ⁇ 2 is about 6 hrs. In some embodiments, t1 ⁇ 2 is about 7 hrs. In some embodiments, t1 ⁇ 2 is about 8 hrs. In some embodiments, t1 ⁇ 2 is about 9 hrs In some embodiments, t1 ⁇ 2 is about 10 hrs.
- Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof is administered (e.g., orally) to the patient in need thereof.
- a method of the present disclosure comprises orally administering to a patient up to about 10,000 mg of Compound A, or a pharmaceutically acceptable salt thereof, for example up to about 500 mg, up to about 1,000 mg, up to about 1,500 mg, up to about 2,000 mg, up to about 2,500 mg, up to about 3,000 mg, up to about 3,500 mg, up to about 4,000 mg, up to about 4,500 mg, up to about 5,000 mg, up to about 5,500 mg, up to about 6,000 mg, up to about 6,500 mg, up to about 7,000 mg, up to about 7,500 mg, up to about 8,000 mg, up to about 8,500 mg, up to about 9,000 mg, up to about 9,500 mg, or up to about 10,000 mg of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof.
- a method of the present disclosure comprises administering to a patient about 500- 5,000 mg (for example, about 1,000 to about 4,000 mg, about 1,000 to about 4,000 mg, about 1,000 to about 4,000 mg, about 1,000 to about 4,000 mg, about 1,000 to about 4,000 mg, about 1,000 to about 4,000 mg, about 1,000 to about 4,000 mg, or about 1,000 to about 4,000 mg) of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof.
- a method of the present disclosure comprises administering to a patient about 3,000 mg of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof, for example in a single 3,000 mg dose.
- a method of the present disclosure comprises administering daily to a patient about 3,000 mg of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof, for example as two 1,500 mg doses. In some embodiments, a method of the present disclosure comprises administering daily to a patient about 3,000 mg of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof, for example as three 1,000 mg doses. In some embodiments, a method of the present disclosure comprises administering Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof as described herein once daily. In some embodiments, a method of the present disclosure comprises administering a Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof as described herein twice daily.
- a method of the present disclosure comprises administering a Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof as described herein three times daily. In some embodiments, a method of the present disclosure comprises administering a Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof as described herein four to fourteen times daily. [0076] In some embodiments, where the patient is administered daily about 600 mg of Compound A, or a pharmaceutically acceptable salt thereof, the dosing is twice daily or BID, /. e. , two separate about 300 mg doses.
- the dosing is thrice daily or TID, i.e ., three separate about 200 mg doses. In some embodiments, where the patient is administered daily about 600 mg of Compound A, or a pharmaceutically acceptable salt thereof, the dosing is four-times daily or QID, i.e ., four separate about 150 mg doses.
- the dosing is twice daily or BID, i.e ., two separate about 400 mg doses. In some embodiments, where the patient is administered daily about 800 mg of Compound A, or a pharmaceutically acceptable salt thereof, the dosing is thrice daily or TID, i.e ., three separate about 267 mg doses. In some embodiments, where the patient is administered daily about 800 mg of Compound A, or a pharmaceutically acceptable salt thereof, the dosing is four-times daily or QID, i.e ., four separate about 200 mg doses.
- the dosing is twice daily or BID, i.e ., two separate about 500 mg doses. In some embodiments, where the patient is administered daily about 1000 mg of Compound A, or a pharmaceutically acceptable salt thereof, the dosing is thrice daily or TID, i.e ., three separate about 333 mg doses. In some embodiments, where the patient is administered daily about 1000 mg of Compound A, or a pharmaceutically acceptable salt thereof, the dosing is four-times daily or QID, i.e ., four separate about 250 mg doses.
- the dosing is twice daily or BID, i.e ., two separate about 600 mg doses. In some embodiments, where the patient is administered daily about 1200 mg of Compound A, or a pharmaceutically acceptable salt thereof, the dosing is thrice daily or TID, i.e ., three separate about 400 mg doses. In some embodiments, where the patient is administered daily about 1200 mg of Compound A, or a pharmaceutically acceptable salt thereof, the dosing is four-times daily or QID, i.e ., four separate about 300 mg doses.
- the dosing is twice daily or BID, i.e ., two separate about 700 mg doses. In some embodiments, where the patient is administered daily about 1400 mg of Compound A, or a pharmaceutically acceptable salt thereof, the dosing is thrice daily or TID, i.e ., three separate about 467 mg doses. In some embodiments, where the patient is administered daily about 1400 mg of Compound A, or a pharmaceutically acceptable salt thereof, the dosing is four-times daily or QID, i.e ., four separate about 350 mg doses.
- the dosing is twice daily or BID, /. e. , two separate about 800 mg doses. In some embodiments, where the patient is administered daily about 1600 mg of Compound A, or a pharmaceutically acceptable salt thereof, the dosing is thrice daily or TID, i.e ., three separate about 533 mg doses. In some embodiments, where the patient is administered daily about 1600 mg of Compound A, or a pharmaceutically acceptable salt thereof, the dosing is four-times daily or QID, i.e., four separate about 400 mg doses.
- a method of the present disclosure comprises orally administering about 100 mg, about 150 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 800 mg, about 1000 mg, about 1200 mg, or about 1400 of Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof, once a day in a single dose.
- a method of the present disclosure comprises administering a Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof as described herein, wherein there is about 4-24 hours between two consecutive administrations. In some embodiments, there is about 4 hrs, about 6 hrs, about 8 hrs, about 12 hrs, about 18 hrs, or about 24 hrs between two consecutive administrations.
- a method of the present disclosure comprises administering a Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof as described herein, wherein there are about 1-7 days between two consecutive administrations. In some embodiments, there are about 1, about 2, about 3, about 4, about 5, about 6, or about 7 days between two consecutive administrations.
- a method of the present disclosure comprises administering a Compound A, or a pharmaceutically acceptable salt thereof, and/or composition thereof as described herein, wherein there is about 1-4 weeks between two consecutive administrations. In some embodiments, there is about 1, about 2, about 3, or about 4 weeks between two consecutive administrations.
- a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
- the methods of the present disclosure are practiced by administering a composition comprising Compound A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
- compositions of this disclosure refers to a non toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
- Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene
- compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
- parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
- the compositions are administered orally, intraperitoneally or intravenously.
- Sterile injectable forms of the compositions of this disclosure may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
- a non-toxic parenterally acceptable diluent or solvent for example as a solution in 1,3-butanediol.
- acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or di-glycerides.
- Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
- These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
- Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
- compositions of this disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
- carriers commonly used include lactose and com starch.
- Lubricating agents such as magnesium stearate, are also typically added.
- useful diluents include lactose and dried cornstarch.
- aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
- compositions of this disclosure may be administered in the form of suppositories for rectal administration.
- suppositories for rectal administration.
- suppositories can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug.
- suitable non-irritating excipient include cocoa butter, beeswax and polyethylene glycols.
- compositions of this disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
- Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
- provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
- Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
- compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
- suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
- compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride.
- the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.
- compositions of this disclosure may also be administered by nasal aerosol or inhalation.
- Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
- compositions of this disclosure are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this disclosure are administered without food. In other embodiments, pharmaceutically acceptable compositions of this disclosure are administered with food.
- compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.
- Compound A may be administered orally at a dose of about 10 mg/kg to about 200 mg/kg, particularly at a dose of selected from about 30 mg/kg, about 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 55 mg/kg, about 60 mg/kg, about 65 mg/kg, about 70 mg/kg, about 75 mg/kg, about 80 mg/kg, about 85 mg/kg, and about 90 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
- Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- the oral compositions can also include adj
- Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
- the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil can be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid are used in the preparation of injectables.
- Injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
- delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle.
- injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
- compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol
- Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- Compound A can also be in micro- encapsulated form with one or more excipients as noted above.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
- the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
- Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
- additional substances other than inert diluents e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
- the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
- Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
- the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
- Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this disclosure.
- the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
- Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
- Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
- the present disclosure provides a method of administering Compound A to a patient in need thereof, wherein the patient suffers from an autoimmune/autoinflammatory disease or a hematological malignancy.
- the autoimmune/autoinflammatory disease is a cutaneous autoimmune/autoinflammatory disease.
- the autoimmune/autoinflammatory disease includes inflammatory or allergic conditions of the skin, for example psoriasis, generalized pustular psoriasis (GPP), psoriasis vulgaris, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, hidradenitis suppurativa, Sweet Syndrome, pyoderma gangrenosum, and other inflammatory or allergic conditions of the skin.
- GPP generalized pustular psorias
- the inflammatory disease of the skin is selected from contact dermatitits, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, or hidradenitis suppurativa.
- the Compound A may also be used for the treatment of other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g.
- hemolytic anemia aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia
- systemic lupus erythematosus rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g.
- ulcerative colitis and Crohn's disease irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren’s syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g.
- idiopathic nephrotic syndrome or minal change nephropathy including idiopathic nephrotic syndrome or minal change nephropathy), chronic granulomatous disease, endometriosis, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, musclewasting, catabolic disorders, obesity, fetal growth retardation, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet’s disease, incontinentia pigmenti, Paget’s disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases
- the inflammatory disease which can be treated according to the methods of this disclosure is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin associated periodic syndrome (CAPS), adult onset Still’s disease, macrophage activation syndrome (MAS), primary and secondary hemophagocytic lymphohistiocytosis (HLH), familial Mediterranean fever, NLRP12 autoinflammatory syndrome, and osteoarthritis.
- SJIA systemic juvenile idiopathic arthritis
- CAS cryopyrin associated periodic syndrome
- MAS macrophage activation syndrome
- HH primary and secondary hemophagocytic lymphohistiocytosis
- familial Mediterranean fever familial Mediterranean fever
- NLRP12 autoinflammatory syndrome and osteoarthritis.
- the inflammatory disease which can be treated is a TH17 mediated disease.
- the TH17 mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, psoriasis vulgaris, hidradenitis suppurativa, and inflammatory bowel disease (including Crohn’s disease or ulcerative colitis).
- the inflammatory disease which can be treated according to the methods of this disclosure is selected from Sjogren’s syndrome, allergic disorders, osteoarthritis, conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis or chronic rhinosinusitis with nasal polyps (CRSwNP).
- the present disclosure provides a method for treating a cutaneous autoimmune/autoinflammatory disease in a patient, such as atopic dermatitis (AD) and hidradenitis suppurativa (HS), comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
- a cutaneous autoimmune/autoinflammatory disease such as atopic dermatitis (AD) and hidradenitis suppurativa (HS)
- AD atopic dermatitis
- HS hidradenitis suppurativa
- the present disclosure provides a method for treating AD in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
- the present disclosure provides a method for treating HS in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
- the present disclosure provides a method for treating rheumatoid arthritis (RA) in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
- RA rheumatoid arthritis
- the present disclosure provides a method for treating hematological malignancy in a patient, comprising administering to the patient a therapeutically effective amount of Compound A, or a pharmaceutically acceptable salt thereof.
- the hematological malignancy is leukemia, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom’s macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, AML, orMDS.
- WM macroglobulinemia
- splenic marginal zone lymphoma multiple myeloma
- plasmacytoma intravascular large B-cell
- Compound A can be prepared by methods known to one of ordinary skill in the art, for example, as described in WO 2019/133531 and WO 2020/010227, the contents of which are incorporated herein by reference in their entireties.
- AR Accumulation ratio calculated as (Day 8, 28, or 42 Cmax or AUCo-24) / (Day 1 or 15 Cmax or AUCo-24)
- I:P Isomer to Parent ratio calculated as (Isomer C max or AUCo- 24 ) / (Parent Cmax or AUCo-24)
- Example 1 4-Week Oral Gavage Toxicity and Toxicokinetic Study with Compound A in Dogs with a 2-Week Recovery
- TK Toxicokinetics
- the control article was 25% (w/w) Hydroxypropyl-P-cyclodextrin (HPBCD; Kleptose Oral Grade HPB) prepared in reverse osmosis water; pH 3.5 ⁇ 0.1.
- HPBCD Hydroxypropyl-P-cyclodextrin
- doses were administered to all animals in Groups 1, 2, and 3 at a volume of 2.5 mL/kg.
- doses were administered to all animals in Group 4 at a volume of 2.5 mL/kg.
- doses continued to be administered to animals in Group 5 at a volume of 5 mL/kg.
- Compound A mean Cmax and AUCo-24 values were generally higher on Days 8 and 28 when compared to Day 1 at the 30 and 100 mg/kg/dose levels, as applicable, indicating potential accumulation of Compound A after multiple doses in dogs.
- mean accumulation ratio values ranged from 1.16 to 1.86 for Cmax and from 1.12 to 2.14 for AUCo-24.
- mean accumulation ratio values were 1.38 and 1.28 for C max and AUCo-24, respectively, for Group 2 and 1.96 and 2.12 for Cmax and AUCo-24, respectively, for Group 3.
- Compound B appeared in plasma, with median T max values ranging from 6.00 to 9.00 hours on Day 1, and 4.00 hours on Days 8, 15 (Group 4 only), 28 (Groups 2 and 3 only), and 42 (Group 4 only). After reaching Cmax, Compound B concentrations declined, with mean ti/2 values of 7.60, 8.18, and 8.19 hours on Days 1, 8, and 28, respectively, for Group 2. Due to the lack of a distinct elimination phase, estimation of elimination phase tm was not attempted for most profiles. Mean concentration values for Compound B were measurable through 24 hours postdose on all collection intervals.
- Mean concentrations of Compound B generally increased with the increase in Compound A dose level from 5 to 100 mg/kg/dose on Days 1 and 8, and from 5 to 30 mg/kg/dose on Day 28. No increase in exposure was observed with a further increase in dose level from 100 to 200 mg/kg/dose on Days 1 and 8. Mean concentrations of Compound B were generally similar after multiple doses of Compound A when compared to a single dose.
- Exposure, as assessed by Compound B mean C max and AUCo-24 values, increased with the increase in Compound A dose level from 5 to 100 mg/kg/dose on Days 1 and 8, and from 5 to 30 mg/kg/dose on Day 28. No increase in exposure was observed with a further increase in dose level from 100 to 200 mg/kg/dose on Days 1 and 8.
- the increases in Compound B mean Cmax and AUCo-24 values were less than dose proportional.
- Compound B mean C max and AUCo-24 values were generally were generally higher on Days 8 and 28 when compared to Day 1 at the 30 and 100 mg/kg/dose levels, as applicable, indicating potential accumulation of Compound B after multiple doses in dogs.
- mean accumulation ratio values were 1.10 to 1.07 for C max and AUCo-24, respectively, for Group 2 and 1.70 and 1.93 for Cmax and AUCo-24, respectively for Group 3.
- mean accumulation ratio values were 1.40 and 1.32 for C max and AUCo-24 for Groups 2 and 3, respectively, and 1.81 and 1.98 for Cmax and AUCo-24, respectively, for Group 3.
- the mean Compound B isomer to parent ratios ranged from 0.621 to 0.677 for Cmax and from 0.605 to 0.712 for AUCo-24.
- the mean isomer to parent ratios ranged from 0.584 to 0.613 for Cmax and from 0.571 to 0.595 for AUCo-24.
- the mean isomer to parent ratios were 0.551 for Cmax and 0.542 for AUCo-24 for Group 4.
- the mean isomer to parent ratios were 0.630 and 0.623 for Cmax and AUCo-24, respectively, for Group 2 and 0.578 and 0.629 for Cmax and AUCo-24, respectively, Group 3.
- the mean isomer to parent ratios were 0.509 for Cmax and 0.513 for AUCo-24 for Group 4.
- Compound C appeared in plasma, with a median T max value of 6.00 hours on Day 1 and 4.00 hours on Days 8, 15 (Group 4 only),
- Mean concentrations of Compound C generally increased with the increase in Compound A dose level from 5 to 100 mg/kg/dose on Days 1 and 8, and from 5 to 30 mg/kg/dose on Day 28. No increase in exposure was observed with a further increase in dose level from 100 to 200 mg/kg/dose on Days 1 and 8. Mean concentrations of Compound C were generally similar after multiple doses of Compound A when compared to a single dose.
- Compound C mean C max and AUCo-24 values were generally were generally higher on Days 8 and 28 when compared to Day 1 at the 30 and 100 mg/kg/dose levels, as applicable, indicating potential accumulation of Compound C after multiple doses in dogs.
- mean accumulation ratio values ranged from 1.11 to 1.63 for Cmax and from 1.11 to 1.79 for AUCo-24.
- mean accumulation ratio values were 1.45 and 1.36 for Cmax and AUCo-24, respectively for Group 2 and 1.73 and 1.86 for Cmax and AUCo-24, respectively, for Group 3.
- the mean Compound C isomer to parent ratios ranged from 0.584 to 0.635 for Cmax and from 0.597 to 0.655 for AUCo-24.
- the mean isomer to parent ratios ranged from 0.508 to 0.584 for Cmax and from 0.504 to 0.574 for AUCo-24.
- the mean isomer to parent ratios were 0.521 for Cmax and 0.509 for AUCo-24 for Group 4.
- the mean isomer to parent ratios were 0.651 and 0.636 for Cmax and AUCo-24, respectively, for Group 2 and 0.527 and 0.571 for Cmax and AUCo-24, respectively, for Group 3.
- the mean isomer to parent ratios were 0.476 for Cmax and 0.481 for AUCo-24 for Group 4.
- Sex differences in Compound A, Compound B, and Compound C mean C max and AUCo-24 values were less than 2-fold. Exposure, as assessed by Compound A, Compound B, and Compound C mean C max and AUCo-24 values, increased with the increase in Compound A dose level from 5 to 100 mg/kg/dose on Days 1 and 8, and from 5 to 30 mg/kg/dose on Day 28. No increase in exposure was observed with a further increase in dose level from 100 to 200 mg/kg/dose on Days 1 and 8. The increases in Compound A, Compound B, and Compound C mean C max and AUCo-24 were less than dose proportional. Potential accumulation of Compound A, Compound B, and Compound C, up to 2.14-, 1.98-, and 1.86-fold, respectively, was observed after multiple doses in dogs.
- Compound A-related microscopic findings included minimal or slight infiltrates of vacuolated macrophages in the lamina intestinal of the jejunum and ileum of animals administered >30 mg/kg/dose and in the duodenum of animals administered 200/60 mg/kg/dose and in one female administered 100 mg/kg/dose.
- Minimally or slightly increased infiltrates of vacuolated macrophages in the gut- associated lymphoid tissues (GALT)/Peyer’s patches of animals administered >5 mg/kg/dose and in the mesenteric and mandibular lymph nodes and spleen of animals administered >30 mg/kg/dose were also considered Compound A related.
- Compound A-related minimal increases of vacuolated alveolar macrophages were observed in animals administered >30 mg/kg/dose.
- the Compound A-related increases of vacuolated macrophages in the small intestine, lymphoid tissues, and lung were considered nonadverse due to the low severity and lack of associated degenerative or inflammatory changes.
- cytoplasmic vacuolation was consistent with phospholipidosis as demonstrated by the ultrastructural (transmission electron microscopy) finding of whorled lamellar bodies (interpreted as myelin figures) within secondary lysosomes in the lung, mesenteric lymph node, and ileum of dogs administered 100 mg/kg/dose Compound A in a prior 2-week oral toxicity and toxicokinetics study (Charles River 20.345; Charles River Laboratories, Inc., 2020).
- vacuolated macrophages in the small intestine (jejunum and/or ileum), GALT/Peyer’s patches, and mandibular lymph nodes of animals administered 30 or 200/60 mg/kg/dose and minimally increased vacuolated macrophages in the lung of one male administered 200/60 mg/kg/dose indicating partial reversal.
- No increases of vacuolated macrophages were noted in the spleen at either dose level, indicating complete reversal.
- male and female beagles were administered control article or Compound A via oral gavage at 100 mg/kg/dose for 10 days, 5 and 30 mg/kg/dose Compound A for 4 weeks, and 200 mg/kg/dose for one week followed by one week dose suspension and then resuming dosing at 60 mg/kg/dose for 4 weeks.
- the dose level of 60 mg/kg/day was determined to be the no observed adverse effect level (NOAEL) based on no clear or adverse test article- related findings in animals that had been previously dosed for 10 days at 200 mg/kg/dose.
- NOAEL no observed adverse effect level
- the dose levels of 100 and 200 mg/kg/dose were considered adverse due to the mortality at 100 mg/kg/dose, while the 200 mg/kg/dose formulation was not tolerated and necessitated a dose suspension and dose reduction.
- the dose level of 60 mg/kg/dose corresponded to average, sex- combined, maximum observed concentration (Cmax) and area under the concentration-time curve (AUCo- 24 ) values of 561 ng/mL and 11,700 ng*hr/mL, respectively for Compound A; 288 ng/mL and 6090 ng*hr/mL, respectively, for Compound B; and 265 ng/mL and 5620 ng*hr/mL, respectively, for Compound C on Day 42 of the dosing phase.
Abstract
Description
Claims
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- 2022-02-15 KR KR1020237031404A patent/KR20230145446A/en unknown
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- 2022-02-15 CA CA3207380A patent/CA3207380A1/en active Pending
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CA3207380A1 (en) | 2022-08-18 |
CN116867494A (en) | 2023-10-10 |
KR20230145446A (en) | 2023-10-17 |
US20230405012A1 (en) | 2023-12-21 |
AU2022220869A1 (en) | 2023-08-24 |
IL304905A (en) | 2023-10-01 |
EP4291197A1 (en) | 2023-12-20 |
TW202245789A (en) | 2022-12-01 |
US20220274993A1 (en) | 2022-09-01 |
JP2024506657A (en) | 2024-02-14 |
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