Methods of treating dermatomyositis using bbepotinib

Abstract

The present disclosure provides methods associated with treating chronic immune-mediated skin and muscle diseases. The present disclosure provides, inter alia, methods of treating dermatomyositis by oral administration of a JAK inhibitor or a pharmaceutically acceptable salt thereof.

Description

[0001] This application claims priority to U.S. Provisional Application No. 63 / 574,382, filed April 4, 2024, U.S. Provisional Application No. 63 / 603,280, filed November 28, 2023, and U.S. Provisional Application No. 63 / 506,265, filed June 5, 2023, the contents of which are incorporated herein by reference. TECHNICAL FIELD

[0002] The present disclosure provides methods related to the treatment of chronic immune-mediated skin and muscle diseases. The present disclosure provides, inter alia, methods of treating dermatomyositis with oral administration of a JAK inhibitor or a pharmaceutically acceptable salt thereof. BACKGROUND Dermatomyositis (DM) is a rare, debilitating, multisystem idiopathic inflammatory myopathy characterized by skin rash, perifascicular atrophy, and consequent muscle weakness. In the United States, approximately 1 to 10 per million people are affected by DM, regardless of race and ethnicity. The pathogenesis of DM is associated with dysregulation of the type I interferon (IFN-1) pathway. In addition, key cytokines such as IFN-γ, interleukin (IL)-12, and IL-23 are also implicated in the pathogenesis of DM, which significantly contribute to the manifestation of multiple organ systems including the skin and muscle. Many treatment approaches for DM involve immunosuppressive drugs, which can help control symptoms but do not directly address the underlying disease pathology, presenting certain challenges. These challenges include, but are not limited to, increased risk of infection due to a weakened immune system, and relapse, which can lead to dependence on the use of corticosteroids. Likewise, these drugs can cause various side effects and long-term issues, especially at high doses or with long-term use. To improve the treatment of DM, it is critical to seek future treatment regimens that are more effective, less dependent, require smaller doses, and are compatible with concurrent therapies, thereby reducing the need for corticosteroid use. SUMMARY Embodiments of the present disclosure include a method comprising administering to a subject in need thereof an effective amount of [(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octan-8-yl]methanone (brepocitinib), or a pharmaceutically acceptable salt thereof ; wherein the compound or salt thereof is administered at a dose of about 10 mg to about 60 mg. In some embodiments, the pharmaceutically acceptable salt is a p-toluenesulfonate salt.

[0005] Embodiments of the present disclosure also include administering to the subject an effective amount of brexpipatmib having one or more effects selected from the group consisting of reducing or inhibiting IFN-I activity in the subject; reducing or inhibiting dysregulation of cytokine signaling associated with DM; preventing or reducing damage to human muscle cells and microvasculature; and interfering with the life cycle of DM. In some embodiments, the compound is administered orally.

[0006] In some embodiments, the compound is administered at a dose of about 30 mg. In some embodiments, the compound is administered at a dose of less than about 30 mg. In some embodiments, the compound is administered at a dose of about 15 mg.

[0007] In some embodiments, the administered compound is taken daily. In some embodiments, the administered compound is administered twice, three times, or four times daily in divided doses.

[0008] In some embodiments, the compound is administered for less than or about 104 weeks. In some embodiments, the compound is administered for more than or about 4 weeks.

[0009] In some embodiments, the subject is a mammal.

[0010] In some embodiments, the mammal is a human.

[0011] In some embodiments, the mammal is a canine. BRIEF DESCRIPTION OF DRAWINGS The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0013] The subject matter of the present disclosure has been summarized above, and further described in detail below, with reference made to the drawings, which are not necessarily drawn to scale, and in which: Figure 1 : Schematic of an assay method for prevention of IFN-1 induced damage to cultured muscle cells and endothelial cells using brexpipatmib.

[0014] Figure 2: Shows different JAK pairing combinations used by various cytokine receptors. Upon binding of a cytokine to its receptor, the associated JAKs are activated and phosphorylate each other and the receptor at specific tyrosine sites. The phosphorylated receptor serves as docking sites for the STAT family of transcription factors (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6). STATs are subsequently phosphorylated by the co-localized JAKs, stabilizing homo- or hetero-dimeric complexes that translocate to the nucleus, where they bind to specific binding sites and modulate the transcription of a range of target genes.

[0015] Figure 3 : Demonstrates the efficacy of brepocitin against overlapping pathogenic cytokine profiles in various study populations.

[0016] Figure 4 : Brepocitin inhibits cytokine signaling pathways associated with DM that involve TYK2 and / or JAK1, including IFNα, IFNγ, IL-12, and IL-23. Projected inhibition of these cytokine signaling pathways at the average concentration (CAVG) of brepocitin 30 mg once daily.

[0017] Figure 5 : Demonstrates the dose-dependent efficacy of brepocitin.

[0018] Figure 6 : Shows the rapid dissolution capability of brepocitin from immediate release (IR) tablets (>85% within 30 minutes) using USP Apparatus II at 75 rpm in pH 6.8 phosphate buffer in the case of 30 mg tablets.

[0019] Figure 7 : Shows representative images of human skeletal muscle myoblast (HSMM) immunofluorescence staining, which were differentiated into myotubes in culture and treated with DMSO (vehicle control) or IFN-I (recombinant human IFN-alpha A and human IFN-alpha D) to induce cell damage (left panel), and a bar graph indicating the effect of brepocitin on IFN-I-induced myotube damage (right panel).

[0020] Figure 8 : Shows representative images of human dermal microvascular endothelial cells (HMEC-1) that were cultured and treated to show blood vessel network formation (left panel), and a bar graph indicating the effect of brepocitin on IFN-I-induced endothelial cell damage (right panel).

[0021] Figure 9: A bar chart showing the percentage inhibition of various DM-related cytokines by brepositinib 30 mg once daily, brepositinib 15 mg once daily, and tofacitinib 5 mg twice daily, based on cross-trial comparisons.

[0022] Figure 10 : A bar chart showing the efficacy of brepositinib 30 mg and tofacitinib 5 or 10 mg twice daily in patients with psoriatic arthritis, plaque psoriasis or ulcerative colitis based on cross-trial comparisons. Invention Details This disclosure provides methods related to the treatment of skin diseases. In particular, this disclosure provides a method for treating dermatomyositis by taking an oral JAK inhibitor or a pharmaceutically acceptable salt thereof.

[0024] Dermatomyositis (DM) is an idiopathic inflammatory myopathy, a chronic, often debilitating condition characterized by a signature skin rash (e.g., Gottron's sign, Gottron's papules, and sunspots) and perifascicular atrophy and associated muscle weakness. Muscle weakness and pain are the most common causes of onset, even affecting basic daily activities such as dressing, bathing, and climbing stairs. Notably, skin diseases like DM also contribute significantly to morbidity and have been shown to significantly impact patients' quality of life, sometimes even more so than other severe skin conditions. In addition to skin and muscle issues, other systemic manifestations include interstitial lung disease (ILD), arthralgia or arthritis, dysphagia, cardiovascular disease (myocarditis, heart failure, arrhythmias, etc.), and an increased risk of malignancies, all of which further contribute to disease-related morbidity and mortality. Furthermore, some DM patients may become disabled due to irreversible muscle damage and / or disfigured due to skin manifestations.

[0025] The pathogenesis of diabetes mellitus (DM) involves abnormal regulation of type I interferon (IFN-1) signaling and a variety of other cytokines, including but not limited to IL-12, IL-23, IL-6, IL-4, IL-22, IFN-γ, IL-15, and IL-21. Kinases TYK2 and JAK1 are important signaling pathways for these cytokines. Myositis-specific and myositis-associated antibodies have also been characterized in DM patients, including anti-TIF-1 antibodies, which are the most common antibodies in DM patients. Notably, these antibodies are often associated with specific phenotypes, allowing clinicians to better predict and manage DM patients. For example, some DM patients have high levels of expression of anti-melanoma differentiation-associated gene 5 (MDA5) autoantibodies and are particularly prone to rapidly progressive interstitial lung disease (RP-ILD). Cutaneous calcification, often associated with the presence of anti-NXP2 antibodies, is another severe manifestation of DM, occurring in up to 20% of adult DM patients.

[0026] Breparinib is an orally administered small-molecule inhibitor of TYK2 and JAK1, being developed for the treatment of diabetes mellitus (DM). The drug is expected to reduce signaling of multiple pro-inflammatory cytokines, including type I and II interferons, IL-6, and IL-12 / IL-23, and alleviate disease symptoms. The formulation is suitable for once-daily dosing. The JAK family comprises four structurally and functionally similar non-receptor tyrosine kinases: JAK1, JAK2, JAK3, and TYK2. Each member of the janus kinase (JAK) family is characteristically associated with an intracellular domain of one of nearly 40 cytokine receptor monomers. Cytokine signaling is mediated through this JAK-cytokine receptor complex, making it mechanistically feasible to inhibit multiple cytokines using a single molecule (i.e., a JAK inhibitor).

[0027] These findings regarding brepositinib are crucial because previous research has shown that one of the most debilitating aspects of dermatomyositis-related diabetes mellitus (DM) is muscle weakness, caused by perifascial atrophy, which severely impacts patients' quality of life. The data indicate that, at clinically relevant concentrations, brepositinib can prevent IFN-I-induced damage in cultured muscle cells and microvessels. This supports the pharmacological principles that suggest brepositinib as a potential treatment for DM.

[0028] As further disclosed herein, various embodiments of this disclosure include a method for treating DM, the method comprising administering to a subject requiring treatment an effective amount of brepositinib or a pharmaceutically acceptable salt thereof, wherein the compound or a salt thereof is administered at a dose of about 10 mg to about 60 mg in a manner significantly more effective than currently available oral administration treatments for DM.

[0029] 1. Definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, this document (including the definitions) shall prevail. Preferred methods and materials are described below, but similar or equivalent methods and materials may be used in practice or testing of this disclosure. The phrase "in some embodiments" as used herein does not necessarily refer to the same embodiment, although it may refer to the same embodiment. Therefore, various embodiments of the invention can be readily combined without departing from the scope or spirit of the invention, as described below. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and are not intended to be limiting.

[0030] The terms “comprising,” “including,” “having,” “having,” “may,” “containing,” and variations thereof, as used herein, are intended as open-ended transitional phrases, terms, or words that do not exclude the possibility of additional actions or structures. Unless the context explicitly specifies otherwise, the singular forms “a,” “and,” and “the” include the plural objects. Whether explicitly listed or not, this disclosure also contemplates other embodiments that “comprising (the embodiments or elements shown herein),” “consisting of (the embodiments or elements shown herein),” and “consisting substantially of (the embodiments or elements shown herein).”

[0031] For the numerical ranges described in this article, each intermediate value with the same precision is explicitly considered. For example, for the range of 6–9, the values ​​7 and 8 are considered in addition to 6 and 9; for the range of 6.0–7.0, the values ​​6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly considered.

[0032] Unless otherwise defined herein, scientific and technical terms used in connection with this disclosure shall have the meanings commonly understood by one of ordinary skill in the art. The meanings and scopes of these terms shall be clear; however, in the event of any potential ambiguity, the definitions provided herein shall prevail over any dictionary or external definition. Furthermore, unless the context otherwise requires, singular terms shall include plural forms, and plural terms shall include singular forms.

[0033] As used herein, the term "approximately" means approximately, roughly, roughly, or about. When the term "approximately" is used in conjunction with a numerical range, it modifies the range by extending the upper and lower boundaries of the listed numerical values. Typically, the term "approximately" is used herein to modify numerical values ​​to a range that varies by 10% above or below the stated value.

[0034] As used in this article, "dermatomyositis" refers to a rare autoimmune inflammatory disease characterized by a rash, perifascicular atrophy, and consequent muscle weakness. Muscle weakness typically affects proximal muscles close to the trunk, such as those in the hip, thigh, shoulder, upper arm, and neck. This weakness is usually symmetrical, meaning it affects both sides of the body. The rash can present as a sunspot rash, a purple or dark red rash that appears on the upper eyelids, sometimes accompanied by swelling. Gotelon papules are red or purple scaly bumps commonly found on the knuckles, elbows, knees, and other joints. The rash can also appear on the upper chest and back (V-sign) or shoulders and upper arms (shawl sign). Systemic symptoms of dermatomyositis include fatigue, joint pain and swelling, difficulty swallowing, and lung problems.

[0035] Diagnosis of dermatomyositis includes blood tests to detect elevated levels of muscle enzymes (e.g., creatine kinase) and autoantibodies; electromyography (EMG) to measure the electrical activity of the muscles; muscle biopsy to examine for signs of inflammation and damage in the tissue; and imaging studies, such as MRI, to detect muscle inflammation. Embodiments of this disclosure include a method of administering brepository to treat dermatomyositis.

[0036] As used herein, the terms “provide,” “administer,” and “introduce” are used interchangeably and refer to the placement of a protein or system of this disclosure into a subject by means of a method or route that causes at least partial localization to the intended site. Administration may be performed using any appropriate route that results in delivery to the intended location within the subject.

[0037] As used in this article, the term "life cycle" refers to the stages and progression of a particular disease from its initial introduction or onset to its development, spread, impact on the host or population, and, in some cases, its regression. The disease life cycle encompasses the complete process of a disease, including its origin, spread, impact, and potential outcomes. The stages of the disease life cycle include: disease onset, disease spread, incubation period, symptomatic period, recovery or chronic period, disease spread or outbreak, disease immunity or resistance period, disease regression and elimination, and potential recurrence.

[0038] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a substance that is compatible with the receiving subject (e.g., mammals, and more particularly humans) and suitable for delivering the active agent to the target site without terminating the activity of the agent. Carrier-related toxicities or adverse reactions, if any, are preferably proportionate to a reasonable risk / benefit ratio for the intended use of the active agent.

[0039] The terms “carrier,” “additive,” or “medium” are used interchangeably herein and include any and all solvents, diluents and other liquid media, dispersants or suspending agents, surfactants, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants, etc., as long as they are suitable for the specific dosage form required. Remington: The Science and Practice of Pharmacy. 20th Ed., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000 discloses various carriers for formulating pharmaceutically acceptable compositions and known techniques for the preparation of such compositions. Unless any conventional carrier medium is incompatible with the compounds of this disclosure, for example, producing any adverse biological effects or otherwise interacting harmfully with any other component of the pharmaceutically acceptable composition, its use should be within the scope of this disclosure. Examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffering substances (e.g., disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium hydroxide, and aluminum hydroxide), glycine, sorbic acid or potassium sorbate, mixtures of metaglycerides of saturated vegetable fatty acids, water, pyrogen-free water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, etc. Waxes, polyethylene-polyoxypropylene block polymers, lanolin, sugars (e.g., lactose, glucose, sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (e.g., sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate), tragacanth powder, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository waxes), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g., propylene glycol and polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, alginic acid, isotonic saline, Ringer's solution, alcohols (e.g., ethanol, isopropanol, cetyl alcohol, and glycerol), cyclodextrins, lubricants (e.g., sodium dodecyl sulfate and magnesium stearate), and petroleum hydrocarbons (e.g., mineral oil and petrolatum). According to the formulator's judgment, the composition may also contain colorants, releasing agents, coating agents, sweeteners, flavorings and aromas, preservatives and antioxidants.

[0040] As used herein, the phrase "pharmaceutically acceptable salt" refers to salts that, within reasonable medical judgment, are suitable for contact with the tissues of subjects (e.g., humans and other mammals) without causing excessive toxicity, irritation, allergic reactions, etc., and that are proportionate to a reasonable benefit / risk ratio. In some embodiments, pharmaceutically acceptable salts of brepositinib are derived from inorganic or organic acids or bases. For a review of suitable salts, see, for example, Berge et al. J. Pharm. Sci. 66:1-19 (1977) and Remington: The Science and Practice of Pharmacy. 20th Ed., ed. A. Gennaro, Lippincott Williams & Wilkins, 2000. Examples of suitable acid addition salts include the following: acetates, adipates, alginates, aspartates, benzoates, benzenesulfonates, hydrogen sulfates, butates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, disaccharides, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptates, glycerophosphates, hemisulfates, heptanates, hexanoates, hydrochlorides, hydrobromide, hydroiodates, 2-hydroxyethanesulfonate, lactates, maleates, methanesulfonate, mesylate, 2-naphthalenesulfonate, nicotinate, oxalate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, picrates, neopentanoate, propionate, succinates, tartrates, thiocyanates, toluenesulfonates, and undecanoates.

[0041] Suitable base addition salts include, but are not limited to, ammonium salts, alkali metal salts (e.g., sodium and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), salts with organic bases (e.g., dicyclohexylamine, N-methyl-D-glucosamine, tert-butylamine, ethylenediamine, ethanolamine, and choline), and salts with amino acids (e.g., arginine, lysine, etc.).

[0042] Furthermore, basic nitrogen-containing groups can be quaternized using reagents such as lower alkyl halides (e.g., chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl halides), dialkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate), long-chain halides (e.g., chlorides, bromides, and iodides of decyl, lauryl, myristyl, and stearyl halides), and aralkyl halides (e.g., benzyl bromide and phenethyl bromide). This yields water-soluble, oil-soluble, or dispersible products.

[0043] The terms “subject” and “patient” as used herein are used interchangeably, regardless of whether the subject has received or is receiving any form of treatment. The term “subject” as used herein can refer to any vertebrate, including but not limited to mammals (e.g., cattle, pigs, camels, alpacas, horses, goats, rabbits, sheep, hamsters, guinea pigs, cats, dogs, rats and mice, non-human primates (e.g., monkeys, such as macaques or rhesus monkeys, chimpanzees, etc.) and humans). In some embodiments, the subject may be human or non-human.

[0044] The phrases “therapeuticly effective” and “effective dose” refer to benefits, including but not limited to, the treatment or relief of the symptoms of dermatomyositis described herein. It should be understood that the therapeutically effective dose, or the amount of one or more agents required to provide a therapeutic effect, will vary depending on the intended use (in vitro or in vivo) or the subject being treated and the disease condition (e.g., the severity of the condition to be treated, the specific inhibitor, the route of administration, and the individual subject's age, weight, general health condition, and response), which can be readily determined by those skilled in the art. For example, if the amount of brepositinib is sufficient to achieve the treatment or relief of the symptoms of dermatomyositis described herein, then it is therapeutically effective.

[0045] Whether used alone or in combination with one or more other terms, the term "treatment" as used herein refers to and includes uses and outcomes of improvement, relief, and / or cure, or any combination thereof. In other embodiments, the methods described herein may be used preventively, i.e., preventively. It should be understood that "prevention" or preventive use or outcome does not mean, nor requires, absolute or complete prevention (i.e., 100% preventive or protective use or outcome). As used herein, preventive or preventive (preventive) use or outcome means that the application of a compound, therapeutic agent, or composition reduces or diminishes the severity of the specific condition, symptom, disorder, or disease described herein; reduces or diminishes the likelihood of the occurrence of the specific condition, symptom, disorder, or disease described herein; or delays the onset or recurrence (recurrence) of the specific condition, symptom, disorder, or disease described herein; or any combination thereof.

[0046] Preferred methods and materials are described below, but similar or equivalent methods and materials may also be used in the practice or testing of this disclosure. The entire contents of all publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference. The materials, methods, and examples disclosed herein are illustrative only and are not intended to be limiting.

[0047] Oral administration of brepotinib Embodiments of this disclosure include a method comprising administering to a subject requiring treatment (e.g., a subject with dermatomyositis) an effective amount of [(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methyl ketone (brepositinib) Brepository or its pharmaceutically acceptable salts. Brepository (which may be interchangeably referred to herein as "the compound") or its pharmaceutically acceptable salts may be administered to a subject in doses of about 10 mg to about 60 mg. For example, the compound or its pharmaceutically acceptable salts may be administered in doses of about 10 mg to about 50 mg. In some embodiments, the compound or its pharmaceutically acceptable salts may be administered in doses of about 10 mg to about 40 mg. In some embodiments, the compound or its pharmaceutically acceptable salts may be administered in doses of about 10 mg to about 30 mg. In some embodiments, the compound or its pharmaceutically acceptable salts may be administered in doses of about 10 mg to about 20 mg. In some embodiments, the compound or its pharmaceutically acceptable salts may be administered in doses of about 15 mg to about 60 mg. In some embodiments, the compound or its pharmaceutically acceptable salts may be administered in doses of about 15 mg to about 50 mg. In some embodiments, the compound or its pharmaceutically acceptable salts may be administered in doses of about 15 mg to about 40 mg. In some embodiments, the compound or its pharmaceutically acceptable salts may be administered in doses of about 15 mg to about 30 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 15 mg to about 20 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 20 mg to about 60 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 30 mg to about 60 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 40 mg to about 60 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg to about 60 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 20 mg to about 50 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 30 mg to about 40 mg. In some embodiments, the pharmaceutically acceptable salt is a pharmaceutically acceptable p-toluenesulfonate. In some embodiments, pharmaceutically acceptable p-toluenesulfonate is (1S)-2,2-difluorocyclopropyl][3-[2-[(1-methyl-1H-pyrazol-4-yl)amino]-4-pyrimidinyl]-3,8-diazabicyclo[3.2.1]oct-8-yl]-methyl ketone,4-methylbenzenesulfonate (1:1): .

[0048] The preparation method of brepositinib is described at least in WO 2016 / 027195 and U.S. Patent No. 9,663,526, the contents of which are incorporated herein by reference.

[0049] The embodiments disclosed herein also include administering an effective amount of brepositinib to a subject, which has one or more of the following effects: reducing or inhibiting IFN-I activity in the subject; reducing or inhibiting cytokine signaling regulation abnormalities associated with dermatomyositis (DM); preventing or reducing damage to human muscle cells and microvessels; and interfering with the life cycle of DM. In some embodiments, the compound is administered orally.

[0050] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 60 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 50 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 40 mg. In other embodiments, the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 30 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 25 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 20 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 15 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 5 mg.

[0051] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered in a dose of less than about 60 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered in a dose of less than about 50 mg. In one embodiment, the compound or a pharmaceutically acceptable salt thereof is administered in a dose of less than about 40 mg. In other embodiments, the compound or a pharmaceutically acceptable salt thereof is administered in a dose of less than about 30 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered in a dose of less than about 25 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered in a dose of less than about 20 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered in a dose of less than about 15 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered in a dose of less than about 10 mg. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered in a dose of less than about 5 mg.

[0052] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is taken daily. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is taken once daily at the dose described above. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered in divided doses two, three, or four times daily, as described above.

[0053] In some embodiments, the compound or its pharmaceutically acceptable salt is administered for less than or about 104 weeks. For example, the compound or its pharmaceutically acceptable salt is administered for less than or about 100 weeks. In some embodiments, the compound or its pharmaceutically acceptable salt is administered for less than or about 90 weeks. In some embodiments, the compound or its pharmaceutically acceptable salt is administered for less than or about 80 weeks. In some embodiments, the compound or its pharmaceutically acceptable salt is administered for less than or about 70 weeks. In some embodiments, the compound or its pharmaceutically acceptable salt is administered for less than or about 60 weeks. In some embodiments, the compound or its pharmaceutically acceptable salt is administered for less than or about 50 weeks. In some embodiments, the compound or its pharmaceutically acceptable salt is administered for less than or about 40 weeks. In some embodiments, the compound or its pharmaceutically acceptable salt is administered for less than or about 30 weeks. In some embodiments, the compound or its pharmaceutically acceptable salt is administered for less than or about 20 weeks. In some embodiments, the compound or its pharmaceutically acceptable salt is administered for less than or about 10 weeks. In some embodiments, the compound or its pharmaceutically acceptable salt is administered for less than or about 5 weeks. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered for less than or about 4 weeks. In some embodiments, the compound is administered for less than or about 3 weeks. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered for less than or about 2 weeks. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered for less than or about 1 week.

[0054] In some embodiments, the compound or its pharmaceutically acceptable salt is administered for more than or about 4 weeks. For example, the compound or its pharmaceutically acceptable salt is administered for more than or about 5 weeks. In some embodiments, the compound or its pharmaceutically acceptable salt is administered for more than or about 6 weeks. In some embodiments, the compound or its pharmaceutically acceptable salt is administered for more than or about 7 weeks. In some embodiments, the compound or its pharmaceutically acceptable salt is administered for more than or about 8 weeks. In some embodiments, the compound or its pharmaceutically acceptable salt is administered for more than or about 9 weeks. In some embodiments, the compound or its pharmaceutically acceptable salt is administered for more than or about 10 weeks. In some embodiments, the compound or its pharmaceutically acceptable salt is administered for more than or about 20 weeks. In some embodiments, the compound or its pharmaceutically acceptable salt is administered for more than or about 30 weeks. In some embodiments, the compound or its pharmaceutically acceptable salt is administered for more than or about 40 weeks. In some embodiments, the compound or its pharmaceutically acceptable salt is administered for more than or about 50 weeks. In some embodiments, the compound or its pharmaceutically acceptable salt is administered for more than or about 60 weeks. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered for more than or about 70 weeks. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered for more than or about 80 weeks. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered for more than or about 90 weeks. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered for more than or about 100 weeks. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered for more than or about 101 weeks. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered for more than or about 102 weeks. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered for more than or about 103 weeks. In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered for more than or about 104 weeks.

[0055] In some embodiments, the compound or a pharmaceutically acceptable salt thereof is administered for about 50 weeks, about 51 weeks, about 52 weeks, about 53 weeks, about 54 weeks, about 55 weeks, about 56 weeks, about 57 weeks, about 58 weeks, about 59 weeks, or about 60 weeks.

[0056] Brebotinib or a pharmaceutically acceptable salt thereof may be administered by any method known to those skilled in the art. For example, brebotinib or a pharmaceutically acceptable salt thereof may be administered in the form of a composition, such as a pharmaceutical composition of brebotinib or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier, such as those described herein. In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the pharmaceutical composition is an oral tablet, such as an enteric-coated tablet. In some other embodiments, the pharmaceutical composition is an oral liquid dosage form. In some embodiments, these compositions optionally also contain one or more additional therapeutic agents.

[0057] The pharmaceutical compositions described herein can be prepared by methods well known in the art, such as conventional granulation, mixing, dissolving, encapsulation, lyophilization, or emulsification processes. The compositions can be produced in various forms, including granules, precipitates or microparticles, powders (including lyophilized, rotary-dried, or spray-dried powders), amorphous powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions, or solutions. Formulations may optionally contain solvents, diluents and other liquid media, dispersing or suspending agents, surfactants, pH adjusters, isotonic agents, thickeners or emulsifiers, stabilizers and preservatives, solid binders, lubricants, etc., as long as they are suitable for the desired specific dosage form.

[0058] In some embodiments, the pharmaceutical composition is formulated for administration to mammals such as humans or dogs. Such pharmaceutical compositions can be administered orally, parenterally, via inhalation spray, topically, rectally, nasally, orally, vaginally, or through an implantable reservoir. The term "parenterectomy" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the composition is administered orally, intravenously, or subcutaneously. The formulations disclosed herein can be designed to be short-acting, immediate-release, or long-acting. Furthermore, the compounds can be administered locally rather than systemically, such as at the tumor site (e.g., by injection).

[0059] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may also contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, cyclodextrin, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

[0060] Injectable formulations can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques, such as sterile injectable aqueous or oily suspensions. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable media and solvents that can be used include water, Ringer's solution (USP), and isotonic sodium chloride solution. Furthermore, sterile fixative oils are commonly used as solvents or suspension media. For this purpose, any mild fixative oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids (e.g., oleic acid) are also used in the preparation of injectable formulations. Injectable formulations can be sterilized, for example, by filtration via a bacterial trap filter, or by adding a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use. Compositions formulated for parenteral administration can be injected by bolus or timed push, or administered by continuous infusion.

[0061] To prolong the action of a compound or therapeutic agent (e.g., brepositinib or its pharmaceutically acceptable salts), it is often necessary to slow the absorption of the compound after subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a poorly water-soluble crystalline or amorphous substance. In this case, the absorption rate of the compound depends on its dissolution rate, which in turn may depend on the crystal size and crystal form. Alternatively, delayed absorption of parenterally administered forms of compounds can be achieved by dissolving or suspending the compound in an oily medium. Injectable reservoir formulations are made by forming a microcapsule matrix of the compound in a biodegradable polymer, such as poly(lactide-polyglycolic acid). The release rate of the compound can be controlled depending on the ratio of the compound to the polymer and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Reservoir injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsions that are compatible with human tissues.

[0062] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing osimertinib and / or alicate with a suitable non-irritating excipient or carrier (e.g., cocoa butter, polyethylene glycol, or suppository wax) that is solid at room temperature but liquid at body temperature, thus melting and releasing the active ingredient within the rectal or vaginal cavity.

[0063] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the therapeutic agent is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or expanders, such as starch, lactose, sucrose, glucose, mannitol, and silica; b) binders, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; c) humectants, such as glycerin; d) disintegrants, such as agar, calcium carbonate, potato starch or cassava starch, alginate, certain silicates, and sodium carbonate; e) solution retarding agents, such as paraffin; f) absorption enhancers, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, and mixtures thereof. For capsules, tablets, and pills, dosage forms may also include buffers, such as phosphates or carbonates.

[0064] Similar solid compositions can also be used as fillers for soft and hard filled gelatin capsules, which use excipients such as lactose or milk candy and high molecular weight polyethylene glycol, etc. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells such as enteric coatings and other coatings known in the field of pharmaceutical formulations. They may optionally contain light-blocking agents and may also be compositions that optionally release the active ingredient in a delayed manner only or preferentially at a site in the intestine. Examples of encapsulation compositions that can be used include polymeric substances and waxes. Similar solid compositions can also be used as fillers for soft and hard filled gelatin capsules, which use excipients such as lactose or milk candy and high molecular weight polyethylene glycol, etc.

[0065] Brebotinib or pharmaceutically acceptable salts may also be microencapsulated forms containing one or more of the excipients described above. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings known in the pharmaceutical formulation field. In these solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Typically, these dosage forms may also include substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. For capsules, tablets, and pellets, the dosage forms may also include buffers. They may optionally contain light-blocking agents and may be compositions that optionally release the active ingredient in a delayed manner only or preferentially at a site in the intestine. Examples of encapsulation compositions that can be used include polymers and waxes.

[0066] The dosage forms of the therapeutic agents described herein for topical or transdermal application include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. Where necessary, the active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives or buffers. Ophthalmic preparations, ear drops, and eye drops are also considered within the scope of this disclosure. Furthermore, this disclosure contemplates the use of transdermal patches, which offer the additional advantage of providing controlled delivery of the compound into the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0067] For ease of administration and dosage uniformity, the compositions used in this disclosure can be formulated into unit dosage forms. As used herein, "unit dosage form" refers to a physically discrete unit of pharmaceutical preparation suitable for a subject to be treated. However, it should be understood that the total daily dosage of the compounds and pharmaceutical compositions described herein will be determined by the attending physician within reasonable medical judgment. Unit dosage forms for parenteral administration may be in ampoules or multi-dose containers.

[0068] Example 1 Timeline of in vitro efficacy assessment of brepositinib against IFN-I-induced characteristic pathological changes in diabetes mellitus. Figure 1 As illustrated in the diagram, human skeletal muscle myoblasts (HSMMs) were cultured and differentiated into myotubes, then treated with either a mediator control or IFN-I (recombinant human IFN-α A and human IFN-α D) to induce cell damage. Prior to IFN-I treatment, the myotubes were pre-incubated for 1 hour with brepositinib (1 µM or 130 nM, the latter equivalent to the mean free plasma concentration after a once-daily administration of 30 mg). 48 hours after IFN-I treatment, immunofluorescence staining was performed, followed by image analysis to determine the surface area of ​​myosin 4. Human dermal microvascular endothelial cells (HMEC-1) were cultured and treated with either IFN-I or a mediator control once the vascular network had formed. Cells were also pre-incubated with brepositinib for 1 hour. Nine hours after treatment, the number of nodes, principal segment length, and total network area were analyzed under a light microscope.

[0069] Main pharmacodynamics. The JAK family, including JAK1, JAK2, JAK3, and JYK2, is a group of cytoplasmic tyrosine kinases that mediate signal transduction of cytokine receptors. Figure 2This section demonstrates the different JAK pairing combinations used by various cytokine receptors. Upon binding of a cytokine to its receptor, the associated JAK is activated and phosphorylates each other, as well as the receptor at specific tyrosine residues. Phosphorylated receptors act as docking sites for the transcription factor STAT family (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6). STATs are subsequently phosphorylated by co-localized JAKs, thereby stabilizing homodimeric or heterodimeric complexes that translocate to the nucleus, where they bind to specific binding sites and regulate the transcription of a range of target genes.

[0070] The primary efficacy endpoint of brepositinib. Figure 3 As shown, brepositinib has been investigated in five completed phase 2 placebo-controlled studies in psoriatic arthritis, plaque psoriasis, ulcerative colitis, alopecia areata, and hidradenitis suppurativa. In each study, clinically significant and statistically significant results were obtained in multiple organ systems (e.g., skin, joints, gastrointestinal tract). These clinical data, along with overlapping pathogenic cytokine profiles, provide a basis for evaluating brepositinib in diabetes mellitus (DM).

[0071] Pharmacological and clinical evidence for brepositinib. In vitro, brepositinib potently and selectively inhibits TYK2 and JAK1, with an IC50 concentration of [missing information]. 50 The values ​​(23 and 17 nM respectively) are the IC values ​​for JAK2 and JAK3. 50 At most 1 / 3 of the value. In human whole blood, brepositinib inhibits DM-associated cytokine signaling pathways involving TYK2 and / or JAK1, including IFNα, IFNg, IL-12, and IL-23. Figure 4 The study showed predicted inhibition of these cytokine signaling pathways at a dose of 30 mg once daily (QD). In the phase 2 study, brepositinib demonstrated dose-dependent efficacy. Figure 5 This study demonstrates the relationship between standardized response rate and the average daily dose of brepositinib. The dose required to achieve a 50% maximum response was determined to be 15 mg once daily, and minimal improvement in efficacy was typically observed at doses greater than 30 mg once daily.

[0072] Brepportinib prevents IFN-1 damage in cultured cells. For example... Figure 7As shown, the surface area of ​​myosin in myotubes exposed to IFN-1 was reduced by ~40% compared to the mediator-treated control group (p<0.0001). Pre-incubation with brepositinib (130 nM and 1 μM) almost completely prevented this cytokine-induced damage, with the mean surface area of ​​myosin being 94.1% and 100% of that in the mediator-treated control group, respectively. The differences between IFN-I treatment alone and brepositinib were significant (p<0.0001 [1 µM] and p<0.001 [130 nM]).

[0073] Similarly, such as Figure 8 As shown, compared to the vector control group, HMEC-1 exposure to IFN-I significantly reduced the mean number of nodes, mean main segment length, and mean total network area by 47% to 50% (nodes and segments p < 0.0001, network area p < 0.001). This damage was prevented by pre-incubation with brepository, with mean number of nodes, main segment length, and total network area ranging from 89% to 111% of those in the vector control group. These differences were statistically significant with respect to both brepository concentrations and all endpoints compared to IFN-I treatment.

[0074] Example 2 A phase 3, randomized, double-blind, placebo-controlled study investigating the efficacy and safety of oral brepository in adult patients with dermatomyositis. Overall Design. This is a prospective, parallel-group, randomized, double-blind, placebo-controlled, international, multicenter phase 3 study, comprising a 52-week double-blind treatment period (blinded treatment period) followed by a 52-week open-label treatment period (OLE period). The study population includes individuals diagnosed with or highly probable idiopathic inflammatory myopathy (IIM) meeting the typical subclassification criteria for dermatomyositis. All participants can continue to receive approved standard-of-care medications for dermatomyositis. Study details include: • The study lasted up to 116 weeks and consisted of the following phases: a screening period of up to 8 weeks (screening period), followed by a double-blind treatment period of 52 weeks with placebo or active investigational drug (blinded treatment period), followed by a 52-week active investigational drug (OLE period), and then a 4-week safety follow-up (discontinuation follow-up period). • For participants using corticosteroids at baseline, all participants, except those receiving rescue therapy, were required to gradually taper their corticosteroids (between weeks 12 and 36) to a dose of ≤ 5 mg / day of oral prednisone (or an equivalent dose). The tapering to below 5 mg / day of prednisone (or an equivalent dose) was at the investigator's discretion. • The follow-up period after drug withdrawal will be conducted immediately after the blinded treatment period (if the participant does not continue into the OLE period) or immediately after the OLE period. • The treatment duration for investigational drugs is up to 104 weeks (the initial 52 weeks for double-blind investigational drugs [active drug or placebo] plus an additional 52 weeks for open-label investigational drugs [active drug]). • During blinded treatment, video visits are conducted every 4–6 weeks; during OLE, video visits are conducted every 4–12 weeks.

[0075] Number of participants. Approximately 225 participants will be randomly assigned (recruited) from about 110 research centers worldwide.

[0076] Randomization of the study treatment. Participants identified as eligible for the study during the screening period will be randomly assigned at baseline (Day 1 / Visit 2) in a 1:1:1 ratio to one of the following intervention groups (for the study drug administered during the double-blind treatment period): • Group 1: Oral brepository 30 mg once daily for 52 weeks (n = 75). • Group 2: Oral brepository 15 mg once daily for 52 weeks (n = 75); • Group 3: Oral placebo once daily for 52 weeks (n = 75).

[0077] During the OLE period, all participants (regardless of initial treatment allocation) will receive oral brepositinib 30 mg once daily for up to 52 weeks.

[0078] Throughout the study, all treatment groups were able to receive ongoing standard oral background therapy for dermatomyositis.

[0079] Random grouping will be stratified based on the following baseline factors: • PhGA-VAS baseline values ​​(0 to 4.9 cm, 5 to 10 cm).

[0080] Investigational drug and concomitant treatment. For the purposes of this protocol, “investigational drug” (IMP) is defined as brepotinib. “Investigational drug” is defined as either IMP (brepotinib) or placebo to be administered to subjects according to the investigation protocol.

[0081] Study drug administration. Participants should take the study drug orally once daily. For participants who have difficulty swallowing the study drug tablets, refer to the Pharmacy Manual for guidance.

[0082] Participants are encouraged to take the study drug in the morning after breakfast whenever possible; however, the study drug may be taken with or without food.

[0083] At baseline (Day 1 / Visit 2), participants will receive their first dose of the double-blind study drug at the research center and one dose of study drug to take home. At Week 4 / Visit 3 and Week 24 / Visit 7, participants should be informed not to take the medication at home on the day of their visits and to take the study drug at the research center during their visits. At Week 52 / Visit 12, participants should be informed not to take the medication at home on the day of their visit; participants who do not continue into the OLE period will take their last dose of the study drug the day before Week 52 / Visit 12, while participants who continue into the OLE period will receive their first dose of the open-label study drug at the research center.

[0084] If a dose is missed and the interval between doses is less than 8 hours, the missed dose should not be administered and should be recorded as a missed dose.

[0085] Breparinib and matched placebo are provided in tablet form for oral administration. The investigational drug is packaged to appropriately maintain blinding and labeled as required by regional regulatory requirements. During the blinded treatment period, participants will receive a dose of 15 mg breparinib, 30 mg breparinib, or placebo. During the OLE period, all participants will receive 30 mg breparinib.

[0086] As the study progresses, other brepository formulations or packaging configurations may be introduced to improve participant convenience or simplify administration of the investigational drug.

[0087] The allocation of investigational drugs. Interactive response technology (IRT) is used to centrally assign all participants to randomized, blinded investigational drug groups. Login information and instructions for the IRT will be provided to each research center prior to participant recruitment. Research center personnel (study coordinators or designated personnel) will need to enter or select information, including but not limited to user identification (ID) and password, protocol number, and participant number (subject ID). Research center personnel will then receive treatment allocation and randomization number.

[0088] Randomization will be stratified based on the following factors: • PhGA-VAS baseline values ​​(0 to 4.9 cm, 5 to 10 cm).

[0089] All distributed investigational drugs will be documented, including investigational drugs distributed to participants and any unused investigational drugs returned by participants.

[0090] If a participant is unable to travel to the research center and needs to return the study drug (e.g., the participant withdraws their consent to participate in the study), the study drug can be returned to the research center by mail or courier service.

[0091] Blinding and Unblinding. During blinded treatment, participants, research center staff, investigators, and sponsors are unaware of the investigational drug. Investigators and participants remain blinded to the investigational drug received during blinded treatment until the study is completed. After all participants have completed week 52 / visit 12 and undergone retesting (if necessary), and after all procedures related to data cleaning, data medicine review, final participant disposition agreements, and review of all protocol deviations and analyst agreements have been completed, the database will be temporarily locked. The sponsor / designated personnel will then be granted access to the unblinded database to analyze the data from the blinded treatment period. The 52-week double-blind treatment period data will be summarized in the Clinical Research Report (CSR).

[0092] As an independent party, the PK testing provider will be granted access to randomization codes for analysis during the trial. These codes will be securely archived in a manner that ensures proper blinding throughout the blinded treatment period. PK analysis results will not be shared until the database is locked at week 52.

[0093] The IRT will use unblinding instructions in its programming. Unblinding should only be performed in exceptional circumstances, when it is absolutely necessary to understand the actual treatment code for the participant's further management. In emergency situations, the investigator has full authority to determine whether unblinding of a participant's investigational drug allocation is necessary. The participant's safety must always be the primary consideration when making such decisions. If urgent unblinding of a participant's treatment allocation is required for the participant's safety, every effort should be made to contact the medical monitor and / or sponsor immediately (and prior to unblinding), unless this would delay the participant's urgent treatment. If a participant's investigational drug allocation is unblinded, the sponsor must be notified within 24 hours of the unblinding. The date and reason for unblinding must be recorded in the original documentation and the eCRF.

[0094] Screening period. Depending on when potential participants develop dermatomyositis symptoms, the screening period may last from 4 to 8 weeks. • Potential participants whose dermatomyositis symptoms have been present for <3 years prior to screening or whose symptom onset time is unknown: For these participants, their screening study visit can be conducted up to 8 weeks prior to baseline (Day 1 / Visit 2). The primary objective of Visit 1a is to identify individuals at elevated risk of malignancy or rapidly progressive ILD, and assessments during screening will include CT (or PET-CT) scans (if necessary) to help investigate this potential risk. • Potential participants with dermatomyositis symptoms for ≥ 3 years prior to screening: For such participants, their screening study visit will be Visit 1b, which can be conducted up to 4 weeks prior to baseline (Day 1 / Visit 2).

[0095] Criteria for temporarily delaying recruitment / randomization. An extension of the screening period may be approved after consultation between the researcher and the sponsor. Reasons for extending the screening period include, but are not limited to, the following: • The results of laboratory tests or other assessments required to determine eligibility are pending (e.g., if a CT [or PET-CT] scan is required and has been performed, but the results have not yet been reported within the specified screening period). • The results of the eligibility committee's review are pending (e.g., if the results have been submitted, but the committee has not yet reviewed them and made recommendations within the designated screening period). • Due to the global crisis or other unforeseen reasons, clinic visit arrangements or the delivery of supplies (e.g., research drugs or laboratory test kits) to research centers may be delayed.

[0096] Blinding during treatment. The blinding during treatment began at baseline (Day 1 / Visit 2) and ended at Week 52 / Visit 12, which was the primary analysis time point. After final confirmation of study eligibility, participants were randomized to their study intervention group on Day 1. Once randomized, participants began taking their double-blind study medication once daily for 52 weeks, starting on Day 1 (the last dose was the day before the visit at Week 52 / Visit 12).

[0097] During the blinded treatment period, in addition to the study drug, participants may receive salvage therapy with oral steroids.

[0098] Inclusion criteria. Only individuals who meet all of the following inclusion criteria are eligible to participate in this study: Age and gender.

[0099] 1. Male or female, and participants must be ≥ 18 and ≤ 75 years old when signing the informed consent form (ICF).

[0100] Participant type and disease characteristics.

[0101] 2. Participants diagnosed with dermatomyositis according to the 2017 EULAR / ACR classification of idiopathic inflammatory myopathy.

[0102] Note: Participants who may have IIM are ineligible. For patients who are highly likely to have IIM, diagnostic confirmation by an independent eligibility committee is required prior to randomization (Day 1 / Visit 2).

[0103] Note: Previous signs, symptoms, and diagnostic results (e.g., muscle biopsy results can come from previous surgeries) are sufficient to meet the classification criteria.

[0104] 3. Participants who meet two of the following disease severity criteria (at screening and randomization [Day 1 / Visit 2]): • MMT-8 score ≥ 80 and ≤ 142 (out of 150) and • Active skin manifestations of dermatomyositis are recorded as a CDASI activity score ≥ 6.

[0105] Note: For MMT-8, if there are muscles that cannot be assessed, the score in the electronic case report form [eCRF] will be automatically adjusted and a total score of 150 will be provided.

[0106] 4. For participants who developed symptoms of dermatomyositis within 3 years prior to screening, documented contrast computed tomography (CT) (or positron emission tomography-computed tomography [PET-CT]) scans of the chest, abdomen, and pelvis performed after the onset of symptoms and within 1 year prior to screening were provided, with no indication of malignancy.

[0107] Note: For participants who do not have available CT (or PET-CT) scan results, a CT (or PET-CT) scan can be performed during the screening period.

[0108] 5. Current treatment regimens include prednisone at ≤ 20 mg / day (including 0 mg dose [i.e., no corticosteroids]) or screening. The total duration of prescribed corticosteroid treatment should be at least 12 weeks prior to randomization (day 1 / visit 2), during which the dose must be stable for at least 4 weeks prior to randomization.

[0109] 6. At most one systemic nonsteroidal immunomodulatory / immunosuppressive therapy, with the dose stabilized for at least 12 weeks prior to randomization (day 1 / visit 2).

[0110] Note: In addition to nonsteroidal immunomodulatory / immunosuppressive therapy, antimalarial drugs may be added, and the dosage of antimalarial drugs must be stable for at least 12 weeks before randomization (day 1 / visit 2).

[0111] Note: Participants who have not received corticosteroids or nonsteroidal immunomodulatory / immunosuppressive therapy for dermatomyositis need to have documented response failure (which may include participant-reported medical history) or intolerance to at least one prior dermatomyositis-related corticosteroid and / or nonsteroidal immunomodulatory / immunosuppressive therapy (antimalarial drugs alone are not sufficient to meet this criterion), and must discontinue these therapies before randomization (day 1 / visit 2).

[0112] 7. Disease activity includes participants with abnormalities in at least two of the following five International Myositis Assessment and Clinical Study Group (IMACS) Disease Activity CSM (at least two must be present at both screening and randomization (day 1 / visit 2), but the two CSMs at these two time points do not need to be the same): i. PhGA-VAS ≥ 2 cm, ii. PtGA-VAS ≥ 2 cm, iii. HAQ (Disability Index) ≥ 0.25 iv. At screening, at least one muscle enzyme (creatine kinase [CK], aldolase, alanine aminotransferase [ALT], aspartate aminotransferase [AST], and lactate dehydrogenase [LDH]) is greater than 1.5 times the upper limit of normal (ULN). v. Extramuscular global assessment - VAS ≥ 2 cm.

[0113] weight.

[0114] 8. Weight > 40 kg and < 130 kg, and Body Mass Index (BMI) < 40 kg / m² 2 The participants.

[0115] Open-label extension period. Participants who complete the blinded treatment period and meet the eligibility requirements can enter the OLE period and receive open-label brepository 30 mg once daily. The OLE period begins immediately after assessment at week 52 / visit 12 and ends at week 104 / visit 17. During the OLE period, participants may receive rescue therapy in addition to permitted concomitant dermatomyositis medications.

[0116] Discontinuation follow-up period. To assess the safety of the 4-week discontinuation follow-up period, participants will return to the clinic for follow-up visits (at week 56 for participants who completed the blinded treatment period but did not enter the OLE period; at week 108 for participants who completed the OLE period; or 28 days after the last dose of study drug for participants who withdrew from the study during the blinded treatment period or early in the OLE period).

[0117] Treatment duration. The maximum total treatment duration is 104 weeks (52 weeks of investigational drug [active drug or placebo] during blinded treatment, and 52 weeks of active investigational drug during OLE).

[0118] Data Monitoring / Other Committees. This study will include the following external independent committees: an independent eligibility review committee to provide eligibility verification for disease diagnoses (for potential participants who are highly likely to have idiopathic inflammatory myopathy); an independent data monitoring committee to monitor participant safety; and a clinical event classification committee to adjudicate cardiovascular, thromboembolic, and malignant events.

[0119] Example 3 Solubility: Brepatinib is a highly soluble molecule within the physiological pH range and is completely soluble in 250 mL of medium within this pH range.

[0120] Permeability: Brebotinib is also a highly permeable compound, as demonstrated in a human mass balance study following a single oral administration of 60 mg (300 nCi) C-brebotinib, in which the total recovery of the orally administered radioactive dose was 96.7% ± 6.3% within 192 hours after administration, of which 88.0% ± 8.0% was in urine and 8.7% ± 2.1% was in feces.

[0121] Dissolution: Brepportinib showed rapid dissolution from immediate-release (IR) tablets (>85% within 30 minutes). Figure 6 This image shows an exemplary dissolution profile of a 30 mg prototype tablet in pH 6.8 phosphate buffer at 75 rpm using USP Apparatus II. Since brepository has similar solubility across the physiological pH range, rapid dissolution is expected at pH 1.0 and pH 4.5 as well. The final marketable product will be tested in all three pH media to confirm rapid dissolution. The marketable product will be manufactured at a commercial manufacturing facility, which is yet to be determined and is different from the facility used to manufacture the current clinical trial material.

[0122] Pharmacology. Breparinib inhibits various TYK2 and JAK1-dependent functions in different cell types, such as cytokine-induced phosphorylation of activating transcriptional proteins (STATs) in human peripheral blood mononuclear cells (PBMCs) and whole blood; differentiation of helper T cells (Th)1, Th17, and B cells; interleukin (IL)-12-induced IFNγ production in human PBMCs; and immune complex-induced IFN-1 gene signature in human PBMCs. The anti-inflammatory effect of breparinib has also been demonstrated in vivo using an adjuvant-induced rat model of arthritis.

[0123] Absorption, distribution, metabolism, and excretion. The ADME characteristics of brepositinib and its major circulating metabolite M1 have been investigated in multiple in vitro and in vivo studies. Based on exposure in toxicity studies, the pharmacologically inactive M1 is not specific to humans and is fully represented in rat plasma. The clearance pathway of brepositinib in humans mainly involves cytochrome P450 (CYP) metabolism, primarily via CYP3A4, and to a lesser extent via CYP1A2. M1 is primarily eliminated via urinary excretion.

[0124] Breparinib has a relatively low volume of distribution (60 L in adult study participants) and is a substrate of P-glycoprotein (P-gp; multidrug resistance protein 1 [MDR1] or adenosine triphosphate (ATP) binding box subfamily B member 1 [ABCB1]), therefore its likelihood of crossing the blood-brain barrier is expected to be low. Following oral administration of breparinib to humans, >95% of the dose was recovered within 8 days, indicating a low probability of long-term retention of drug-related substances. Breparinib has a low binding rate to plasma proteins (unbound fraction in humans was 0.609).

[0125] Based on in vitro analysis, brepositinib is unlikely to induce drug-drug interactions through direct inhibition and induction mechanisms. In vitro inhibitory effects were also observed on drug transporters P-gp, breast cancer resistance protein (BCRP), multidrug and toxin efflux protein (MATE) 1, organic cation transporter (OCT) 1, and OCT2. The M1 metabolite is also an inhibitor of MATE2K.

[0126] Toxicology. In vitro properties of brepositinib in various receptors, kinases, enzymes, ion channels, transport proteins, and phosphodiesterase subtypes, as well as in ligand binding or enzyme activity, suggest a low likelihood of off-target pharmacological effects.

[0127] Non-clinical toxicity studies conducted to support the clinical use of brepositinib via oral administration include Good Laboratory Practice (GLP) single-dose and repeated-dose oral systemic toxicity studies lasting up to 6 months in rats and up to 9 months in cynomolgus monkeys; in vitro and in vivo genotoxicity studies; carcinogenicity studies lasting 2 years in rats and 6 months in transgenic (Tg) mice; reproductive and developmental toxicity studies (fertility and embryonic development) in rats and rabbits; juvenile toxicity studies in rats; and phototoxicity studies in stained rats. Chronic oral toxicology studies in rats and monkeys showed exposure margins of 54-fold and 7.8-fold, respectively, from the end of study exposure at the no-observed-adverse-effect level (NOAEL) to clinical exposure to 30 mg brepositinib once daily. Toxicological results were consistent with the mechanism of action, showing changes in the immune and hematopoietic lymphoid systems, as well as target tissues including the thymus, spleen, lymph nodes, and bone marrow. In cardiovascular safety pharmacology studies following oral administration, effects of brepositinib on blood pressure, heart rate, and corrected QT interval (QTc) were observed.

[0128] Immunotoxicity and phototoxicity studies have also been conducted. Carcinogenicity studies in Tg mice (6 months) and rats (2 years) have been completed. In the 6-month mouse study, no neoplastic findings associated with brepositinib were observed. Brepositivity-related findings were also observed consistent with the mechanism of action (reduction in thymus weight and cellular structure, infection) or unrelated to humans (exacerbation of chronic progressive kidney disease in the kidneys). Rat fertility studies have been completed. At the highest tested dose (55 mg / kg / day, >50-fold margin of clinical exposure), no adverse reactions related to fertility in male rats were observed.

[0129] Absorption. The area under the concentration-time curve (AUC(0-∞)) and Cmax of brepositinib, extrapolated from time 0 to infinity, increase approximately proportionally to the dose in the range of 1 to 100 mg. Brepositinib is rapidly absorbed after oral administration, with the median time to reach maximum concentration (Tmax) typically less than 1.5 hours after single and multiple doses. The absolute bioavailability of brepositinib solution is approximately 75%, compared to approximately 96% for tablet administration. Furthermore, the fractional absorption of brepositinib after administration as a solution is approximately 100%. These results indicate that brepositinib is well absorbed after oral administration and is a highly permeable compound according to BCS criteria. Concomitant administration of brepositinib with food (high-fat meal) delays oral absorption, but this has no clinically relevant effect on the extent of absorption compared to administration on an empty stomach. Therefore, brepositinib can be administered without regard to meals.

[0130] Distribution. Breparinib has low binding affinity to plasma proteins. In human plasma, the unbound drug fraction of breparinib at 2 μM is 0.609. Following a single intravenous dose, the steady-state volume of distribution (Vss) of breparinib is 60.0 L, indicating distribution outside the plasma.

[0131] Metabolism. Breparinib is extensively metabolized following oral administration. The in vitro metabolic fractions were 0.77 (CYP3A4 / 5) and 0.14 (CYP1A2). Approximately 80% of the orally administered radiolabeled dose was recovered in the urine as breparinib metabolites. Within 12 hours following administration, inactive M1 metabolites were the major metabolites observed in plasma (37.1% of breparinib-related substances) and urine (58.4% of breparinib-related substances). Following a single 30 mg dose of breparinib, the mean (% coefficient of variation [CV]) ratio of M1 to breparinib for AUC (0–∞) and Cmax were 1.65 (126) and 0.849 (109), respectively. The inhibition of brepositinib metabolism by itraconazole (a potent CYP3A and P-gp inhibitor) reduced the mean (%CV) metabolite to parent ratio for AUC (0-∞) and Cmax to 1.22 (115) and 0.604 (101), respectively.

[0132] Elimination. The elimination half-life (t1 / 2) of brepositinib is typically 4 to 8 hours after a single dose. Steady state is reached on day 8 of once-daily administration, and after repeating a maximum of 100 mg of a single daily dose, plasma accumulation is <50%. Renal excretion is a secondary route of elimination for brepositinib. After a single 60 mg dose, approximately 8% of the radiolabeled dose is recovered in the urine as unchanged brepositinib, and after repeating daily doses of 10 to 175 mg, ≤16% of the dose is recovered in the urine. Less than 10% of the radiolabeled brepositib dose is recovered in the feces. The M1 metabolite is the major excretory metabolite, accounting for 52.1% of the total excretion in urine and feces.

[0133] Example 3 Breparinib prevents type I interferon-induced damage to cultured myocytes and endothelial cells. Human skeletal muscle myoblasts (Lonza, CC-2580) were cultured in SkGM™-2 medium (Lonza, CC-3245) and passaged using ReagentPack™ passager (Lonza, CC-5034). They were then differentiated into myotubes by culturing in differentiation medium [DMEM / F12 + 2% horse serum (Thermofisher, 16050122)] for 3–5 days until most myoblasts differentiated into multinucleated myotubes. The myotubes were then pre-incubated with a medium or brepository before exposure to different concentrations of type I interferon (R&D, 11200-2). Figure 7After 48 hours of treatment, cells were fixed and stained with myosin 4 monoclonal antibody (MF20; Thermofisher, 14-6503-82) and Hoechst staining for visualization of the cell nuclei. The effect on total surface area of ​​myotubes was assessed by fluorescence image analysis. Similarly, human dermal microvascular endothelial cells (HMEC-1; ATCC, CRL-3243) were cultured in complete medium [MCDB-131 (Thermofisher, 10372019) + 10% FBS (ATCC, 30-2020) + 10 ng / mL EGF (Thermofisher, PHG0314) + 1 μg / mL hydrocortisone (StemCell, 74142) + 2 mM L-glutamine (Thermofisher, 25030081)] and passaged using trypsin + 0.25% EDTA. HMECs were then cultured on Matrigel low-growth factor basement membrane matrix-coated culture plates (250 μL / well, 24-well plate; Corning, 356231) to allow for vascular network formation. Subsequently, HMECs were pretreated with brepositinib prior to exposure to the same concentration of type I interferon as for myotubes. The effects of type I interferon exposure ± brepositinib treatment on node number, master segment length, and total network area were assessed by acquiring bright-field images every 16 hours.

[0134] In myotubes and endothelial cells, at clinically relevant concentrations comparable to the mean unbound plasma concentrations following once-daily 30 mg, type I IFN-induced damage was almost completely prevented by pre-incubation with brepositinib. Figure 7 These biological studies support the potential of TYK2 / JAK1 inhibitors to treat skin and muscle inflammation in DM.

[0135] Example 4 Clinical development history of brepositinib As part of the clinical development program for oral brepositinib, several Phase 1 and Phase 2 studies have been completed or are in the process of being reported. Phase 2 studies evaluated the safety, tolerability, and efficacy of brepositinib across a wide dose range for plaque psoriasis, psoriatic arthritis, alopecia areata, Crohn's disease, ulcerative colitis, hidradenitis suppurativa, systemic lupus erythematosus (SLE), and non-segmental vitiligo, demonstrating statistically significant and / or clinically relevant efficacy. Clinical efficacy data for brepositinib have been observed in various autoimmune diseases with mechanistic pathways similar to those in diabetic diabetics. For example, psoriasis is driven by IL-17, which is downstream of IL-12 and IL-23 via TYK2 and / or JAK1 signaling; alopecia areata is characterized by hyperactivity of IFN-γ, a type II interferon that is also signaled via JAK1. Notably, in clinical studies of brepositinib, a dose-dependent decrease in the IFN-γ-induced gene IP-10 (CXCL10) was observed, distinct from the placebo group at doses ≥ 10 mg once daily. Importantly, in these phase 2 studies, the clinical response to brepositinib treatment rapidly differentiated from the placebo group. For example, in a phase 2 study evaluating the efficacy of brepositinib in psoriatic arthritis, after 4 weeks, 30 mg brepositinib achieved a 52% ACR20 response rate compared to a 19% response rate in the placebo group. This indicates that brepositinib has a rapid onset of action and can quickly begin to relieve patient symptoms.

[0136] To date, brepositinib has been generally well-tolerated in studies. It is currently being evaluated in a double-blind, randomized, placebo-controlled phase 3 study for diabetes mellitus (NCT0543726; the VALOR study). The VALOR study plans to enroll 225 participants, making it the largest and best-controlled trial in the field of diabetes mellitus to date. Adult patients with a confirmed diagnosis or high probability of having idiopathic inflammatory myopathy (IIM) who meet the subclassification criteria for diabetes mellitus, involve muscle and skin disease (typical DM), and are currently receiving corticosteroids and / or immunomodulatory / immunosuppressive therapy (or are unresponsive or intolerant to them) are eligible for enrollment. The primary endpoint is the total improvement score (TIS) at week 52. TIS is a composite endpoint based on the following six CSM scores: physician overall disease activity, patient overall disease activity, health assessment questionnaire, MMT-8, extramuscular disease activity, and muscle enzymes. To assess the steroid-sparing effect of brepositinib, participants using glucocorticoids at baseline must gradually reduce their oral prednisone dose to ≤ 5 mg / day (or equivalent) by week 36. In summary, clinical and molecular data support the use of the oral TYK2 / JAK1 inhibitor brepositinib as a rational and targeted approach for the treatment of diabetes mellitus (DM), and a double-blind, randomized, placebo-controlled phase 3 trial is currently underway to confirm this hypothesis.

[0137] It should be understood that the above detailed description and the appended embodiments are merely illustrative examples and should not be regarded as limiting the scope of this disclosure, which is defined only by the appended claims and their equivalents.

[0138] Various changes and modifications to the disclosed embodiments will be obvious to those skilled in the art and can be made without departing from their spirit and scope.

Claims

1. A method for treating dermatomyositis (DM), the method comprising administering to a subject requiring treatment an effective amount of [(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methyl ketone (brepositinib) Or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 mg to about 60 mg.

2. The method of claim 1, wherein administering an effective amount of brepositinib to the subject has one or more effects selected from the following: a. Reduce or inhibit IFN-I activity in the subject; b. Reduce or inhibit abnormal regulation of cytokine signaling associated with DM; c. To prevent or reduce damage to human muscle cells and microvessels; and d. Interference with the lifecycle of DM.

3. The method according to claims 1-2, wherein the pharmaceutically acceptable salt is p-toluenesulfonate.

4. The method according to any one of claims 1-3, wherein the compound is administered orally.

5. The method according to claims 1-4, wherein the compound is administered at a dose of about 30 mg.

6. The method according to claims 1-4, wherein the compound is administered at a dose of about 15 mg.

7. The method according to any one of claims 1-6, wherein the compound is taken daily.

8. The method according to any one of claims 1-6, wherein the compound is administered in divided doses twice, three or four times daily.

9. The method according to any one of claims 1-8, wherein the compound is administered for less than or about 104 weeks.

10. The method according to any one of claims 1-8, wherein the compound is applied for more than or about 4 weeks.

11. The method according to any one of claims 1-10, wherein the subject is a mammal.

12. The method of claim 11, wherein the mammal is a human.

13. The method of claim 11, wherein the mammal is a canine.

14. Use of brepositinib, which involves gradually tapering a steroid according to any one of claims 1-10, in the preparation of a medicament for the treatment of dermatomyositis in a subject in need.

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