Methods, Dosage Regimen, and Compositions for Treating Hidradenitis - Patent application

Abstract

There are methods, dosing regimens, and compositions for treating hidradenitis suppurativa.

Description

[Technical field]

[0001] The present disclosure provides methods, dosing regimens, and compositions for treating hidradenitis suppurativa. [Background technology]

[0002] Protein kinases are a family of enzymes that catalyze the phosphorylation of specific residues in proteins, and are broadly classified into tyrosine kinases and serine / threonine kinases. Abnormal kinase activity resulting from mutation, overexpression, or inappropriate regulation, abnormal regulation or deregulation, as well as overproduction or underproduction of growth factors or cytokines, has been implicated in many diseases, including but not limited to cancer, cardiovascular disease, allergy, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative diseases, such as Alzheimer's disease. Abnormal kinase activity leads to various biological cellular responses related to cell proliferation, cell differentiation, cell function, survival, apoptosis, and cell mobility, which are involved in the above-mentioned related diseases.

[0003] Thus, protein kinases have emerged as an important class of enzymes as targets for therapeutic intervention. In particular, the JAK family of cellular protein tyrosine kinases (JAK1, JAK2, JAK3, and Tyk2) plays a central role in cytokine signaling (Kisseleva et al., Gene, 2002, 285, 1; Yamaoka et al. Genome Biology 2004, 5, 253). Upon binding to their receptors, cytokines activate JAKs and phosphorylate cytokine receptors, thereby generating docking sites for signaling molecules, particularly members of the signal transducer and activator of transcription (STAT) family that ultimately trigger gene expression. A number of cytokines are known to activate the JAK family. These cytokines include the interferon (IFN) family (IFN-α, IFN-β, IFN-ω, limitin, IFN-γ, IL-10, IL-19, IL-20, IL-22), gp130 family (IL-6, IL-11, OSM, LIF, CNTF, NNT-1 / BSF-3, G-CSF, CT-1, leptin, IL-12, IL-23), gamma C family (IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), IL-3 family (IL-3, IL-5, GM-CSF), single chain family (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF-1, HGF), and G protein-coupled receptors (AT1).

[0004] Hidradenitis suppurativa (HS) is a chronic, inflammatory, recurrent, debilitating skin disease that usually presents after puberty with deep, painful inflammatory lesions in areas of the body that contain apocrine glands. Zouboulis, C., et al., Dermatology, 231(2), pp.184-190 (2015). HS has a variable clinical course. Although other areas of the skin may also be affected, one of the main features of the disease is that it occurs in intertriginous areas. The most commonly affected areas are the groin, axilla, perineum, and perianal area, as well as the sub- and / or intermammary sulcus in women, buttocks, mons pubis, scalp, area behind the ears, and eyelids.

[0005] The prevalence of self-reported disease is about 1% in Western Europe. The average interval from onset of symptoms to diagnosis is 7.2 years. Women are affected 2-5 times more frequently than men, and the disease may be more common in blacks than in whites. Disease severity ranges from mild (focal disease) to severe (multiple areas of widely dispersed disease, including interconnected sinus tracts, and hypertrophic scars). Pain, drainage, and limited range of motion due to scarring may reduce quality of life. Jemec, GB, New Eng. J. Med., 366: 158-64 (2012); Kimball, A., et al., New Eng. J. Med., 375(5), pp.422-434 (2016).

[0006] Pain is a prominent feature of HS, which is reflected in the recently defined primary outcome to be evaluated in future clinical trials. Thorlacius, L., et al., Brit. J. Derm., 179(3), pp.642-650 (2018). The majority of patients rated their pain on a numerical rating scale-11 (NRS11) ranging from 4 / 10 to 10 / 10 and described it at various times as hot, burning, pressure-elastic, cutting, sharp, pinching, tearing, unpleasant, pressing, aching, throbbing, and aching. Currently, adalimumab is the only approved pharmacotherapy for moderate-to-severe HS. It is based on two similarly designed (PIONEER I, and PIONEER II) phase 3 multicenter trials of adalimumab for HS. Kimball, A., et al., New Eng. J. Med., 375(5), pp.422-434 (2016). A total of 307 patients were enrolled in PIONEER I and 326 in PIONEER II. Clinical response rates at week 12 [hidradenitis suppurativa clinical response (HiSCR): defined as at least a 50% reduction from baseline in abscess and inflammatory nodule counts, with no increase in abscess or draining fistula counts] were significantly higher in those given adalimumab once weekly than in those given placebo: 41.8% vs. 26.0% in PIONEER I (P=0.003) and 58.9% vs. 27.6% in PIONEER II (P<0.001). Patients who received adalimumab had significantly greater improvement in hierarchically ordered secondary outcomes (modified Sartorius score of lesions, pain, and disease severity) than the placebo group at week 12 only in PIONEER II. Kimball, A., et al., supra. The main difference between the study designs was that in PIONEER I, patients who received oral antibiotic preparations for HS were required to stop treatment for at least 28 days before baseline; in PIONEER II, patients continued treatment with antibiotics (tetracyclines) on a stable dose.

[0007] Thus, a significant number of patients with moderate to severe HS (about 40%) do not respond to treatment with adalimumab, and therefore there remains an unmet need for an effective, safe, and well-tolerated treatment in patients with moderate to severe HS. Disclosed herein is the discovery that compounds and analogs that inhibit certain kinases, such as JAK1 and Tyk2, are useful for treating HS. Accordingly, methods of reducing the severity of HS symptoms in a human subject are described herein. These methods can include administering to the subject a pharmaceutical composition comprising such a compound that is effective to reduce the number and / or size of inflammatory lesions (e.g., nodules, abscesses, or draining fistulas), prevent their progression, reduce the pain caused thereby, or delay the development of further lesions. Summary of the Invention

[0008] The present disclosure provides methods for treating hidradenitis suppurativa in a subject to achieve a reduction in flares and a high level of HiSCR response.

[0009] The methods include administering to a subject in need thereof certain compounds disclosed herein that inhibit JAK, e.g., JAK1 and Tyk2, at a particular dosage and / or in a particular manner or treatment regimen.

[0010] In some embodiments, the disclosure provides a method for treating hidradenitis suppurativa in a subject, the method comprising administering to a subject in need thereof [(1S)-2,2-difluorocyclo-propyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone, or a pharma- ceutically acceptable salt thereof, in a daily dose of about 50 mg to about 300 mg, preferably about 100 mg to about 240 mg, per day for a total daily period of about 16 weeks or more.

[0011] In a further aspect, the disclosure provides a method for treating hidradenitis suppurativa in a subject, the method comprising administering to a subject in need thereof [(1R)-2,2-difluorocyclo-propyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone at a dose of about 50 mg to about 300 mg per day, preferably about 100 mg to about 240 mg per day, for a total daily period of about 16 weeks or more.

[0012] Other embodiments of the present disclosure include a daily oral dosage regimen having the compound described above, or a pharma- ceutically acceptable salt thereof, in the disclosed daily amounts. Yet another embodiment is a composition having the compound described above, or a pharma- ceutically acceptable salt thereof, and one or more pharma- ceutically acceptable excipients.

[0013] The clinical benefit of the treatments of the present disclosure can be measured, for example, by the Hidradenitis Suppurativa Clinical Response Score (HiSCR).

[0014] In some embodiments, JAK inhibitors effectively improve HiSCR.

[0015] Also provided is the use of a JAK inhibitor in the manufacture of a medicament for use in a method of treating and preventing hidradenitis suppurativa in a subject as described herein. The present disclosure will be further understood from the following description, which is given by way of example only. Without the present disclosure being so limited, an understanding of various aspects of the present disclosure will be gained from the following discussion and examples.

[0016] As used herein, a "subject" refers to a mammal, a companion animal, or a livestock animal. Mammals include humans.

[0017] The term "companion animal" or "companion animals" refers to animals that are kept as pets or household animals. Examples of companion animals include dogs, cats, and rodents, including hamsters, guinea pigs, gerbils, rabbits, ferrets, and birds.

[0018] The term "livestock" refers to animals that are kept or raised in an agricultural environment to produce products, such as food or fiber, or for their operation. In some embodiments, livestock are suitable for food consumption by mammals, such as humans. Examples of livestock animals include cows, goats, horses, pigs, sheep, including lambs, and rabbits, as well as birds, such as chickens, ducks, and turkeys.

[0019] The term "treating" or "treatment" refers to the alleviation of symptoms associated with a disease, disorder, or condition, or the halting of further progression or worsening of those symptoms. Depending on the patient's disease and condition, the term "treatment" as used herein may include one or more of curative, palliative, and preventive treatment. Treatment may also include administering the pharmaceutical formulations of the present disclosure in combination with other therapeutic agents.

[0020] The term "therapeutically effective" refers to the ability of an agent to prevent or ameliorate the severity of a disorder while avoiding the adverse side effects typically associated with alternative therapeutic agents. The term "therapeutically effective" is understood to be equivalent to the term "effective for treating, preventing, or ameliorating," both of which are intended to optimize the amount of each agent used in a combination therapy that is expected to achieve the goal of improving the severity and incidence of a disease, or pain or other symptoms, and the frequency of occurrence of each agent's own treatment, while avoiding the adverse side effects typically associated with alternative therapeutic agents.

[0021] "Pharmaceutically acceptable" means suitable for use in a "subject."

[0022] Embodiments of the present disclosure are described herein with reference to the following figures. [Brief description of the drawings]

[0023] [Figure 1] 1 is a schematic diagram of the methods of the studies performed in Example 9. [Diagram 2] 1 is a plot showing the HiSCR response of Example 9 versus placebo. [Diagram 3] 1 is a forest plot of several clinical variables of Example 9 versus placebo. [Figure 4] 1 is a collection of bar graphs of HISCR response at 16 weeks by Hurley stage at baseline for Example 9 versus placebo. [Diagram 5] 1 is a Kaplan Meier plot of time to first flare (FAS) for Example 9. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] The present disclosure relates to a method for treating hidradenitis suppurativa in a subject, comprising administering to a subject in need thereof a compound that inhibits certain JAKs, such as JAK1 and Tyk2. The present disclosure further provides a pharmaceutical composition comprising such an inhibitor. Thus, the present disclosure provides a method for treating hidradenitis suppurativa in a subject with lesions associated with hidradenitis suppurativa, comprising administering to a subject in need thereof a compound of [(1S)-2,2-difluorocyclo-propyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone, or a pharma- ceutically acceptable salt thereof. The present disclosure further provides a method, wherein the salt is a p-toluenesulfonate salt.

[0025] The disclosure also provides the method, wherein the compound is [(1R)-2,2-difluorocyclo-propyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone, or a pharma- ceutically acceptable salt thereof.

[0026] The present disclosure also provides the above methods, wherein the subject's HiSCR is improved following administration of the compound.

[0027] The present disclosure also provides the method, wherein the median size of hidradenitis suppurativa lesions in the subject is reduced following administration of the pharmaceutical composition.

[0028] The disclosure also provides said methods, wherein pain in a subject associated with a hidradenitis suppurativa lesion in the subject is reduced following administration of the compound.

[0029] The disclosure also provides the methods, wherein the time to the subject to develop new hidradenitis suppurativa lesions following administration of the compound is increased.

[0030] The present disclosure also provides the methods, wherein the incidence of flare in a subject is reduced.

[0031] The disclosure further provides a pharmaceutical or veterinary composition comprising any of the compounds described above, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, for use in the treatment and prevention of hidradenitis suppurativa.

[0032] The disclosure also provides a method for treating hidradenitis suppurativa in a subject having lesions associated with hidradenitis suppurativa, comprising administering to a subject in need thereof a compound that inhibits JAK, including JAK1 and Tyk2, in an amount effective to treat the symptoms of hidradenitis suppurativa in the subject.

[0033] The disclosure also provides methods, wherein the effective amount is from about 0.01 to about 100 mg / kg body weight per day, or more preferably from about 0.1 to about 10.0 mg / kg, in a single dose or in divided doses administered two, three, or four times per day.

[0034] The present disclosure also provides a method for treating hidradenitis suppurativa in a subject having lesions associated with hidradenitis suppurativa, comprising administering to a subject in need thereof the compound [(1S)-2,2-difluorocyclo-propyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone, or a pharma- ceutically acceptable salt thereof, in an amount effective to treat the symptoms of hidradenitis suppurativa in the subject.

[0035] The disclosure also provides methods, wherein the effective amount is about 0.01 to about 100 mg / kg body weight / day, or more preferably about 0.1 to about 10.0 mg / kg, administered in a single dose or in divided doses administered two, three, or four times per day. The disclosure also provides methods, wherein the effective amount is about 45 mg administered QD.

[0036] The disclosure also provides a method, wherein the salt is a p-toluenesulfonate salt.

[0037] The disclosure also provides methods, wherein the effective amount is about 0.01 to about 100 mg / kg body weight / day, or more preferably about 0.1 to about 10.0 mg / kg, administered in a single dose or in divided doses administered two, three, or four times per day. The disclosure also provides methods, wherein the effective amount is about 400 mg administered QD.

[0038] In therapeutic use for treating disorders in mammals, the compounds of the present disclosure, or pharmaceutical compositions thereof, can be administered orally, parenterally, topically, rectally, transmucosally, or intestinally. Parenteral administration includes indirect injection to produce a systemic effect, or direct injection into the diseased area. Topical administration includes treatment of the skin, or organs easily accessible by topical application, such as the eye or ear. It also includes transdermal delivery to produce a systemic effect. Rectal administration includes the form of suppositories. The preferred routes of administration are oral, topical, and parenteral.

[0039] The pharmaceutical compositions of the present disclosure may be manufactured by methods well known in the art, such as by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, freeze-drying processes, or spray-drying.

[0040] The pharmaceutical composition used according to the present disclosure may be formulated in a conventional manner using one or more pharma- ceutically acceptable carriers, including excipients and auxiliaries that facilitate the processing of active compounds into pharma- ceutically usable preparations. The appropriate formulation depends on the route of administration selected. Pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art, and are therefore included in the present disclosure. Such excipients and carriers are described, for example, in Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991). The formulation of the present disclosure can be designed to be short-acting, immediate-release, long-acting, and sustained-release. Thus, pharmaceutical formulations can also be formulated for controlled release or sustained release.

[0041] Pharmaceutical compositions suitable for use in the present disclosure include compositions in which the active ingredient is contained in an amount sufficient to achieve its intended purpose, i.e., control or treatment of HS. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms / signs of disease or prolong the survival of the subject being treated.

[0042] The amount of active ingredient, which is the compound of the present disclosure, in the pharmaceutical composition and its unit dosage form may vary widely or be adjusted depending on the mode of administration, the potency of the particular compound, and the desired concentration. Generally, the amount of active ingredient ranges between 0.01% by weight and 99% by weight of the composition.

[0043] In general, the therapeutically effective dosage of the active ingredient is within the range of about 0.01 to about 100 mg / kg body weight / day, preferably about 0.1 to about 10 mg / kg body weight / day, more preferably about 0.3 to 3 mg / kg body weight / day, and even more preferably about 0.3 to 1.5 mg / kg body weight / day. It is understood that dosages may vary depending on the needs of each subject and the disorder or disease severity being treated.

[0044] The desired dose may be conveniently expressed as a single dose or as divided doses administered at appropriate intervals, for example, two, three, four or more sub-doses per day. The sub-dose itself may be further divided, for example, into a number of discrete loosely spaced administrations, such as multiple inhalations from an insufflator or a number of drops applied to the eye.

[0045] It is also understood that the initial dosage administered may be increased beyond the above upper limit in order to rapidly achieve the desired blood plasma concentration. On the other hand, the initial dosage may be less than the optimal value, and the daily dosage may be gradually increased in the course of treatment depending on the specific situation. If necessary, the daily dosage may also be divided into multiple doses for administration, for example, 2 to 4 times per day.

[0046] In a preferred embodiment, hidradenitis suppurativa lesions are treated by administering to a human subject, or patient, in need thereof, the compound [(1S)-2,2-difluorocyclo-propyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone (also called brepositinib, or PF-06700841), or a pharma- ceutically acceptable salt thereof. The compound is administered at a dose of about 50 mg to about 300 mg per day for a total daily period of about 16 weeks or more, preferably about 100 mg to about 240 mg per day for a total daily period of about 16 weeks or more. A particularly preferred dose is about 25 mg to about 100 mg, four times per day, for about 16 weeks or more. The most preferred dosage is about 45 mg, four times per day for about 16 weeks or more. The preferred dose is effective to enable a Hurley 2 subject or patient to achieve a HiSCR response of 50% or more within 16 weeks of initiation of treatment. The preferred dose is effective to enable a Hurley 3 subject or patient to achieve a HiSCR response of 30% or more within 16 weeks of initiation of treatment. The preferred dose is effective to enable a subject or patient to achieve a flare probability of 20% or less by 16 weeks after initiation of treatment. Oral administration is preferred.

[0047] Suitable agents for use in combination therapy with the compounds described herein, or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable solvate of said compounds or salts, particularly in the treatment of diseases, include 5-lipoxygenase-activating protein (FLAP) antagonists; leukotriene antagonists (LTRAs), such as antagonists of LTB4, LTC4, LTD4, LTE4, CysLT1, or CysLT2, such as montelukast, or zafirlukast; histamine receptor antagonists, such as histamine type 1 receptor antagonists, or histamine type 2 receptor antagonists. antidepressants, such as loratadine, fexofenadine, desloratadine, levocetirizine, methapyrilene, or cetirizine; α1-adrenergic receptor agonists, or α2-adrenergic receptor agonists, such as phenylephrine, methoxamine, oxymetazoline, or methylnorephrine; muscarinic M3 receptor antagonists, such as tiotropium, or ipratropium; dual muscarinic M3 receptor antagonists / β2 agonists; PDE inhibitors, such as PDE3 inhibitors, PDE4 inhibitors, or PDE5 inhibitors, e.g. for example theophylline, sildenafil, vardenafil, tadalafil, ibudilast, cilomilast, or roflumilast; sodium cromoglycate, or nedocromil sodium; cyclooxygenase (COX) inhibitors, for example nonselective inhibitors (for example aspirin, or ibuprofen), or selective inhibitors (for example celecoxib, or valdecoxib); glucocorticosteroids, for example fluticasone, mometasone, dexamethasone, prednisolone, budesonide, ciclesonide, or beclamethasone hasone); anti-inflammatory monoclonal antibodies, such as infliximab, adalimumab, tanezumab, ranibizumab, bevacizumab, or mepolizumab; beta2 agonists, such as salmeterol, albuterol, salbutamol, fenoterol, or formoterol, especially long-acting beta2 agonists; intigrin antagonists, such as natalizumab; adhesion molecule inhibitors, such as VLA-4 antagonists; kinin B1 or B2 receptor antagonists; immunosuppressants, such as inhibitors of the IgE pathway (e.g. omalizumab), or cyclosporine;Matrix metalloproteinase (MMP) inhibitors, such as inhibitors of MMP-9, or MMP-12; tachykinin NK1, NK2, or NK3 receptor antagonists; protease inhibitors, such as inhibitors of elastase, chymase, or cathepsin G; adenosine A; 2a Receptor agonist; adenosine A 2b receptor agonists; urokinase inhibitors; dopamine receptor agonists (e.g. ropinirole), in particular dopamine D2 receptor agonists (e.g. bromocriptine); modulators of the NFκB pathway, e.g. IKK inhibitors; further modulators of cytokine signaling pathways, e.g. inhibitors of syk kinase, p38 kinase, SPHK-1 kinase, Rho kinase, EGF-R, or MK-2; mucolytics, mucodynamics, or antitussives; antibiotics; antivirals; vaccines; chemokines; epithelial sodium channel (ENaC) blockers or epithelial sodium channel (ENaC) inhibitors; nucleotide receptor agonists, e.g. P2Y2 agonists; thromboxane inhibitors; niacin; 5-lipoxygenase (5-LO) inhibitors, e.g. zileuton; adhesion factors soluble human TNF receptors, such as etanercept; HDAC inhibitors; phosphoinositotide 3-kinase gamma (PI3Kγ) inhibitors; phosphoinositide 3-kinase delta (PI3Kδ) inhibitors; CXCR-1, or CXCR-2 receptor antagonists; IRAK-4 inhibitors; and TLR-4, or TLR-9 inhibitors, as well as pharmacologic and therapeutically acceptable salts of the specifically named compounds, and pharmacologic and therapeutically acceptable solvates of the specifically named compounds and salts.

[0048] Pharmaceutically acceptable excipients can include, but are not limited to, binders, lubricants, glidants, inert diluents, preservatives, disintegrants, and dispersing agents. Tablets and other solid dosage forms, such as, but not limited to, capsules, pills, powders, and granules, can include coatings, such as enteric coatings.

[0049] chemical synthesis The compounds of the present disclosure may be prepared by any method known in the art. In particular, the compounds of the present disclosure may be prepared by the procedures described in the prior art documents in which they are disclosed.

[0050] For those compounds that specifically inhibit Tyk2 and JAK1, including [(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]methanone, methods for preparing them are disclosed in U.S. Pat. No. 9,663,526, the contents of which are incorporated herein by reference in their entirety.

[0051] The contents of U.S. Provisional Application No. 62 / 899,133, filed September 11, 2019, referenced in International Publication No. 2021 / 048736, are incorporated herein by reference in their entirety. EXAMPLES

[0052] The following non-limiting examples are given solely to illustrate the present disclosure, those skilled in the art will recognize that there are numerous equivalents and variations that are not illustrated but which form a part of the present teachings.

[0053] [Example 1] Hidradenitis Suppurativa Clinical Response (HiSCR) The study provided data on the efficacy, safety, tolerability, and pharmacokinetics of therapeutic agents tested in the oral treatment of moderate-to-severe HS. The study had a maximum duration of approximately 26 weeks. It included a screening period of up to 6 weeks, a dosing period of 16 weeks, and a follow-up period of 4 weeks. The study enrolled approximately 192 participants in total (expected to yield approximately 156 completers). After the screening period, participants who met the eligibility criteria at the baseline visit were randomly assigned to receive one of six treatments. One oral dose level of each treatment, one of which was [(1S)-2,2-difluorocyclo-propyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone (45 mg QD), or a matching placebo in a 3:1 ratio was investigated. For analysis, placebo groups were combined to obtain a final treatment:placebo ratio of 1:1:1:1 for each treatment, and for the pooled placebo. Less than 30% of enrolled participants were inadequate anti-TNF responders. Participants were stratified according to whether they were inadequate anti-TNF responders.

[0054] Additionally, 20% or less of enrolled participants entered the study on a background of concomitant oral antibiotic therapy for the treatment of HS, and the dosing regimen (dose and frequency) had to have been stable for at least 8 weeks (56 days) prior to the baseline (Day 1) visit and remained stable throughout study participation. Antibiotics given on an "as needed" (PRN) basis were not considered stable dosing. Participants were stratified according to whether they were on a background of concomitant antibiotic therapy. The chronic toxicity package of each resource supported the planned study treatment period of 16 weeks. The primary endpoint used, abscess clinical response, was defined as: At least a 50% reduction in the combined abscess and inflammatory nodule (AN) counts versus baseline, no increase in abscess counts, and no increase in draining fistula counts.

[0055] [Example 2] Lesion counting The number of inflammatory and noninflammatory nodules, abscesses, draining and nondraining fistulas, and hypertrophic scars, as well as the body locations (right / left axilla, right / left submammary, intermammary, right / left buttock, right / left inguinal-femoral groove, perianal, perineum, other) were assessed according to field standards.

[0056] [Example 3] Abscess count The number of abscesses (fluctuating, with or without drainage, tender, or painful) in each of the above defined areas was counted.

[0057] [Example 4] Inflammatory nodule count The number of inflammatory nodules (tender, erythematous, suppurating granulomatous lesions) in each of the above defined areas was counted.

[0058] [Example 5] Fistula counting The number of fistulas (sinus tracts, connecting to the skin surface and draining purulent fluid) was counted in each of the above defined areas.

[0059] [Example 6] Hurley Diagnostics The Hurley diagnosis is defined as follows: Stage I: Single or multiple abscess formation without sinus tracts and cicatricial formation (scarring). Stage II: One or more widely dispersed recurrent abscesses with duct formation and scar formation (cicatrization). Stage III: Extensive or near-extensive involvement with numerous interconnecting ducts and abscesses throughout the area. Hurley diagnostics were performed according to art-specific criteria.

[0060] [Example 7] Modified Sartorius scale A modified Sartorius score was calculated by counting lesions in the following 12 anatomical regions: left axilla, right axilla, left submammary / inframammary area, right submammary / inframammary area, intermammary area, left buttock, right buttock, left inguinofemoral groove, right inguinofemoral groove, perianal area, perineal area, etc. For each anatomical region, a local Sartorius score was calculated as follows: Anatomical region involved: 3 points per area involved (i.e., any lesion in this anatomical region counts >0; otherwise, 0 point). Number of lesions (abscesses, nodules, fistulas, scars) and score: 2 points for each nodule (inflammatory and non-inflammatory), 4 points for each abscess, 4 points for each fistula (draining and non-draining), 1 point for each hypertrophic scar, and 1 point for each "other". The longest distance between the two relative areas (i.e., 0 if there is no active disease; 2 if the longest distance between the two relative areas or the size is less than 50 mm; 4 if the longest distance between the two relative areas or the size is 50 mm or more but less than 100 mm; 6 if the longest distance between the two relative areas or the size is 100 mm or more). Lesions clearly separated by normal skin in their respective areas: if all lesions are clearly separated by normal appearing skin, score 0; otherwise score 6. The total modified Sartorius score is the sum of all 12 regional scores.

[0061] [Example 8] Assessment of erythema The overall degree of erythema was assessed for each anatomical area affected by HS using a 4-point ordinal scale ranging from 0 (no redness), 1 (faint but discernible pink coloration), 2 (moderate red coloration), or 3 (very red or bright red coloration).

[0062] [Example 9 and Comparative Example 1] overview The above example was a Phase 2A, double-blind, parallel-group study evaluating the efficacy of PF-06700841, a dual inhibitor of human tyrosine kinase 2 (TYK2) and Janus kinase 1 (JAK1), compared to placebo in human patients with moderate-to-severe hidradenitis suppurativa (HS). PF-06700841 met the predefined primary efficacy criteria (multiplicity-adjusted p-value <0.1).

[0063] The studies performed on PF-06700841 constitute Example 9. PF-06700841 refers to brepocitinib, which is (1S)-2,2-difluorocyclo-propyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone.

[0064] The study carried out with a placebo constitutes Comparative Example 1.

[0065] The placebo-adjusted percentage of HiSCR rate (50% reduction from baseline in abscess and inflammatory nodule (AN) counts, no increase from baseline in abscess and draining fistula counts) at 16 weeks for PF-06700841 was 18.7 (p=0.0298). The PF-06700841 group (along with the placebo group) had a relatively high response rate among moderate HS participants (Hurley stage II at baseline) for the primary endpoint of HiSCR response rate at 16 weeks. A statistically significant reduction from placebo in the percentage of participants who experienced at least one flare (defined as at least a 25% increase in AN counts with at least an increase of 2 versus baseline) by week 16 was observed in the PF-06700841 (δ=-22.3 p=0.006) group. Pain is an important symptom in participants with HS. For the percentage of participants with a baseline score of 3 or more with an NRS30 response rate (≥30% reduction from baseline on the PGA-Cutaneous Pain Numerical Scale at worst and ≥1 unit reduction (NRS30)) at week 16, the difference for PF-06700841 versus placebo was 6.5 (p=0.265). Overall consistent and robust efficacy was observed across the primary and secondary endpoints for PF-06700841. PF-06700841 appeared generally safe and well tolerated. The majority of treatment-emergent adverse events (TEAEs) reported were mild and moderate. There were no deaths or cases of herpes zoster / herpes simplex in the study. Based on preliminary population PK analysis, the predicted dosing in HS appears to be achieved when compared to either the healthy population or other patient populations for the compound.

[0066] Test Design This was a randomized, double-blind, parallel-group, multicenter study that enrolled approximately 192 participants (approximately 156 completers) with moderate-to-severe HS. Participants were randomized to PF-06700841 (along with two other treatments studied simultaneously) and matching placebo in a 3:1 ratio. Each randomized participant progressed to a 16-week treatment period and a 4-week follow-up period. For analysis, placebo groups were combined to obtain a 1:1:1:1 ratio for each treatment and pooled placebo. As ≤30% of participants with an inadequate anti-TNF response were enrolled and ≤20% of participants were on background antibiotic therapy, a stratified randomization strategy was employed in the study. Efficacy data from all randomized participants through week 16 are within the scope of this report.

[0067] Primary objectives and primary endpoints The primary objective of this study was to evaluate the efficacy and safety of PF-06700841 versus placebo in participants with HS. The primary efficacy outcome measure was the percentage of participants with a HiSCR response (50% reduction from baseline in abscess and inflammatory nodule (AN) counts, no increase from baseline in abscess and draining fistula counts) at 16 weeks.

[0068] Secondary objectives and secondary endpoints Percentage of participants who experienced at least one flare event (defined as at least a 25% increase in AN counts after week 4 with an increase of at least 2 versus baseline) by week 16 Percentage of participants who achieved a total AN count of 0, 1, or 2 at 16 weeks Percentage of participants with a baseline NRS of 3 or greater who achieved a 30% or greater reduction from baseline and a 1-unit or greater reduction in the PGA-Cutaneous Pain Numerical Scale at worst at week 16 (NRS30) Percent change from baseline in International Hidradenitis Suppurativa Severity Scoring System (IHS4) at Week 16. The IHS4 score is a weighted scoring system calculated as 1x number of nodules + 2x number of abscesses + 4x number of draining tunnels (fistulas / sinuses). Mild HS is defined as an IHS4 of 11 points.

[0069] Primary and secondary efficacy analyses were performed using data from all participants, but treatment effects were also evaluated among participants with different disease severity based on baseline Hurley stage. The study population consisted of 67% stage II participants (recurrent abscesses, single or multiple, widely dispersed lesions, including duct formation and scarring) and 33% stage III participants (multiple interconnected ducts and abscesses over the entire area, with extensive or near-extensive involvement).

[0070] The safety and tolerability of PF-06700841 over time were assessed using the incidence of treatment-emergent adverse events (TEAEs) and the incidence of selected laboratory abnormalities including, but not limited to, vital signs, hemoglobin, neutrophils, platelets, lymphocytes, lipids, eGFR, liver function tests (LFTs), and CPK.

[0071] Analysis population and methods All participants with baseline who received at least one dose of randomized study drug are included in the Full Analysis Set (FAS), the population for efficacy analysis. The Safety Analysis Set (SAS) includes all participants who received at least one dose of study drug. After treating missing data as non-responders and adjusting for the stratification factor of prior anti-TNF failure status, the HiSCR response data at week 16 comparing active treatment and placebo groups were analyzed using the Cochran Mantel Hanzel (CMH) test with a minimal risk (MR) weighting strategy. Because there were very few participants with concomitant antibiotic status at baseline in some subgroups, this was not included as a stratification factor in the model. To address any multiplicity arising from the analysis of three different treatments within the same study, the Hochberg step-up procedure was employed to control the overall family-wise error rate to the 0.1 level. All continuous secondary endpoints were analyzed using ANCOVA models in which missing observations were imputed using multiple imputation (MI) methods.

[0072] Pharmacokinetics Blood was collected for PK samples pre-dose, at weeks 1, 2, 4, 6, 8, and 16, and at 0.5, 1, 2, and 4 hours post-dose at week 8. Population PK modeling was used to analyze the available data.

[0073] Participant population, baseline, and disease characteristics There were 359 participants screened (67% moderate, and 33% severe), with HS participants enrolled in the study at over 60 locations in three countries (USA, Canada, and Australia). Data from these moderate-to-severe participants were included in the efficacy analysis set (FAS) and safety analysis set (SAS). Patient demographics and baseline characteristics (Table 1) were similar and generally well balanced. Treated participants had a mean total AN count baseline score of 13 (SD=10.9). The majority of participants (77.8%) were female. The mean total AN count was 12 (SD=10.0) for PF-06700841. At baseline, there were participants with inadequate anti-TNF responses, and participants were on background concomitant oral antibiotic therapy. Treatment groups appeared to be comparable with respect to age, sex, total AN count, fistula count, IHS4 score, and pain score at baseline.

[0074] Figure 2 is a plot showing the HiSCR response of Example 9 versus placebo. The plot shows the estimate of the percentage of participants with HiSCR response over time, and the 90% confidence interval (CI) [placebo (red), PF-06700841 (yellow)]. The yellow plot shows the highest response at 16 weeks. The red plot shows the lowest response at 16 weeks.

[0075] Figure 3 is a forest plot of AN counts for Example 9 versus placebo. Forest plots of the estimates of the difference (90% CI) at 16 weeks for the percentage of participants who experienced at least one flare event, AN counts of 0, 1, or 2, NRS-30 (30% reduction in average weekly pain score, baseline score of at least 3), and percent change from baseline in IHS4 score at 16 weeks compared to placebo [PF-06700841 (yellow)].

[0076] Figure 4 is a collection of bar graphs of HISCR response at 16 weeks by baseline Hurley stage for Example 9 versus placebo. The percentage of participants who achieved a HiSCR response at 16 weeks by baseline Hurley stage (FAS, NRI) is shown.

[0077] Figure 5 is a Kaplan Meier plot comparing time to first flare (FAS) for placebo (red) and PF-06700841 (yellow). The plot for placebo shows the highest likelihood of flare at 16 weeks. The plot for PF-06700841 shows the lowest likelihood of flare at 16 weeks.

[0078] [Table 1]

[0079] Effectiveness PF-06700841 met the prespecified efficacy criteria for the primary endpoint. The stratified CMH test estimate of the difference from placebo in HiSCR response rate (90% CI) at 16 weeks was 18.7 [90% CI = (2.7, 34.6)]. Results of sensitivity analyses (unstratified analyses using the exact method of Chan and Zhang (1999)) were similar to the primary analysis.

[0080] [Table 2]

[0081] No statistical separation of HiSCR response rates from placebo was observed by week 12 for all three compounds (Figure 1). Participants with moderate disease severity at baseline (Hurley stage II) had higher response rates with all three active treatments, and placebo, compared with participants with severe HS (Hurley stage III at baseline). A numerically higher response rate in the primary endpoint at week 16 (HiSCR response rate = 59.4%) was observed among Hurley stage II participants compared with Hurley stage III participants with PF-06700841 treatment (40%) and the overall population (51.9%) (Figure 4).

[0082] Secondary endpoint results About PF-06700841 1. The percentage of participants who achieved at least one flare event by week 16, 2. The percentage of participants who achieved a total AN count of 0, 1, or 2 at 16 weeks, 3. The percentage of participants who achieved an NRS30 response, and 4. Percentage change from baseline in IHS4 at 16 weeks is shown in Figure 3. Flare events (defined as at least a 25% increase in AN counts after week 4 with an increase of at least 2 over baseline 25%) was a pre-specified secondary endpoint in the study, and a statistically significant reduction in flare event rate (at least one flare event by week 16) was observed with the PF-06700841 (δ=-22.3, p=0.006) treatment group. The treatment groups had a significant reduction in time to first flare as depicted in Figure 5. A Cox proportional model estimates the hazard ratio for time to first flare to be 0.4 for PF-06700841. A clinically meaningful reduction in AN counts was demonstrated by achieving an AN count of 0, 1, or 2 by the end of 16 weeks of treatment in this study. Compared with placebo (p=0.046), more participants in the PF-06700841 treatment group (15.6%) achieved a total AN count of 0, 1, or 2 at 16 weeks.

[0083] The Patient Global Assessment of Skin Pain Numerical Scale (NRS) was used to assess worst skin pain and average skin pain due to HS. Assessments were completed by participants in a daily diary before going to bed, with items answered based on a recall period of the past 24 hours. A significant amount (%) of data was missing for this endpoint. Missing data were imputed using the last observation carried forward (LOCF) method. No compound was distinguishable from placebo for skin pain NRS30 at 16 weeks (Figure 2). The difference in skin pain NRS30 from placebo at 16 weeks for PF-06700841 was 6.5 (p=0.265). Results for other patient-reported outcome endpoints, such as change from baseline in the Dermatology Life Quality Index (DLQI) over time and change from baseline in domains of the Short Form Health Survey version 2 Acute (SF36v2 Acute) over time, were consistent with other endpoints. The difference in percent change from baseline in IHS4 score at week 16 in the PF-06700841 treatment group compared with placebo was 14.6 (p=0.145).

[0084] It should be understood that the above description is merely illustrative of the present disclosure. Various alternatives and modifications can be devised by those skilled in the art without departing from the present disclosure. Accordingly, the present disclosure is intended to embrace all such alternatives, modifications, and variations that fall within the scope of the appended claims.

Claims

1. A pharmaceutical product for treating hidradenitis suppurativa in a human subject with lesions associated with hidradenitis suppurativa, comprising [(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazole-4-yl)amino]pyrimidine-4-yl}-3,8-diazabicyclo[3.2.1]octa-8-yl]methanone, or a pharmaceutically acceptable salt thereof, wherein the compound or a salt thereof is administered in a total dose of approximately 50 mg to approximately 300 mg per day.

2. A pharmaceutical product for treating hidradenitis suppurativa in a human subject with lesions associated with hidradenitis suppurativa, comprising [(1R)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazole-4-yl)amino]pyrimidine-4-yl}-3,8-diazabicyclo[3.2.1]octa-8-yl]methanone, or a pharmaceutically acceptable salt thereof, wherein the compound or a salt thereof is administered in a total dose of approximately 50 mg to approximately 300 mg per day.

3. The pharmaceutical product according to claim 1 or 2, wherein the salt is p-toluenesulfonate.

4. The pharmaceutical product according to claim 1 or 2, wherein the compound or a salt thereof is administered in a total dose of about 100 mg to about 240 mg over a period of one day.

5. The pharmaceutical product according to claim 1 or 2, wherein the compound or a salt thereof is administered four times a day in a dose of about 25 mg to about 100 mg.

6. The pharmaceutical product according to claim 1 or 2, wherein the compound or a salt thereof is administered four times a day in a dose of about 45 mg.

7. The pharmaceutical product according to claim 1 or 2, wherein the subject is a subject of Hurley 2, and the HiSCR response of 50% or more is achieved within 16 weeks of the start of administration.

8. The pharmaceutical product according to claim 1 or 2, wherein the subject is a subject of Hurley 3, and the HiSCR response of 30% or more is achieved within 16 weeks of the start of administration.

9. The pharmaceutical product according to claim 1 or 2, wherein the probability of flare in the subject is 20% or less up to 16 weeks after the start of administration.

10. The pharmaceutical agent according to claim 1 or 2 for reducing inflammatory nodules, abscesses, and drainage fistulas as measured by the HiSCR score of the subject.

11. The pharmaceutical agent according to claim 1 or 2 for reducing the median diameter of the suppurative hidradenitis lesion of the subject.

12. The pharmaceutical product according to claim 1 or 2 for reducing pain associated with suppurative hidradenitis lesions in the subject.

13. The pharmaceutical agent according to claim 1 or 2, for increasing the time of the subject to develop a new suppurative hidradenitis lesion.

14. The pharmaceutical product according to claim 1 or 2, wherein the administration is a single dose or two, three, or four doses per day.

15. A pharmaceutical composition for treating hidradenitis suppurativa in a subject with lesions associated with hidradenitis suppurativa, comprising approximately 50 mg to approximately 300 mg of [(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazole-4-yl)amino]pyrimidine-4-yl}-3,8-diazabicyclo[3.2.1]octa-8-yl]methanone or a pharmaceutically acceptable salt thereof, and comprising a pharmaceutically acceptable excipient.

16. A pharmaceutical composition for treating hidradenitis suppurativa in a subject with lesions associated with hidradenitis suppurativa, comprising approximately 50 mg to approximately 300 mg of [(1R)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazole-4-yl)amino]pyrimidine-4-yl}-3,8-diazabicyclo[3.2.1]octa-8-yl]methanone or a pharmaceutically acceptable salt thereof, and comprising a pharmaceutically acceptable excipient.

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