How to treat hidradenitis suppurativa

Abstract

The present disclosure relates to methods for treating hidradenitis suppurativa (HS) using the selective JAK1 inhibitor upadacitinib.

Description

[Technical Field]

[0001] The present disclosure relates to methods for treating hidradenitis suppurativa (HS) with upadacitinib, a selective JAK1 inhibitor. [Background technology]

[0002] Hidradenitis suppurativa (HS) is a debilitating skin disorder of apocrine glands (sweat glands found in specific areas of the body) and hair follicles, resulting in swollen, painful, chronically inflamed lesions or masses. HS is limited to areas of the body containing apocrine glands, such as the axilla, nipple areola, groin, perineum, perianal, and periumbilical regions. Immunological abnormalities of hair follicles are suspected to be involved in the pathogenesis of the disease. HS is a recurrent or chronic inflammatory condition that primarily affects young adults, with an average age of onset of 23 years. This poorly understood disease is thought to be underreported by affected individuals, but it is estimated to affect approximately 1% of the general population in Europe and the United States, with a 2-5 times higher prevalence in women than in men (Naldi, L., Epidemiology. In: Hidradenitis Suppurativa; eds. Jemec et al.; Heidelberg: Springer. 2006).

[0003] HS is characterized by recurrent inflammatory nodules, abscesses, and fistulas and occurs when apocrine gland outlets are unable to drain normally due to blockage by sweat or incomplete glandular development. The trapped secretions push sweat and bacteria into the surrounding tissue, leading to subcutaneous induration, inflammation, and infection. HS lesions (i.e., nodules, abscesses, and sinuses) can be painful and foul-smelling, accompanied by purulent discharge. These various signs and symptoms result in substantial disability and social stigma in patients, severely impacting their quality of life.

[0004] Current treatments for moderate to severe HS include short- or long-term oral or topical antibiotics, retinoids, intralesional steroids, oral steroids, immunosuppressants such as cyclosporine or methotrexate, radiation, laser therapy, and the tumor necrosis factor-α (TNF-α) antagonist adalimumab. However, adalimumab is the only approved treatment for HS, and other TNF antagonists, such as etanercept, have failed to show improvement in HS over a 24-week treatment period (Adams et al., Arch Dermatol. 146(5):501-504, 2010). Given the limited success of treatments for HS and the debilitating nature of the disease, there is an urgent need for effective treatments. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Naldi, L. Epidemiology. In: Hidradenitis Suppurativa; edited by Jemec et al.; Heidelberg: Springer. 2006. [Non-patent document 2] Adams et al., Arch Dermatol. 146(5):501-504, 2010 Summary of the Invention [Problem to be solved by the invention]

[0006] (Summary of the Invention) The present disclosure provides methods for treating hidradenitis suppurativa (HS) with upadacitinib, a selective JAK1 inhibitor. [Means for solving the problem]

[0007] In one aspect, a method is provided for treating a human patient with moderate to severe hidradenitis suppurativa (HS), comprising orally administering 30 mg of upadacitinib once daily to the patient.

[0008] In some embodiments, the patient is an adult.

[0009] In some embodiments, the methods involve orally administering upadacitinib to a patient daily for up to 12 weeks. In some embodiments, the methods involve orally administering upadacitinib to a patient daily for at least 12 weeks. In some embodiments, the methods involve orally administering upadacitinib to a patient daily for at least 16 weeks. In some embodiments, the methods involve orally administering upadacitinib to a patient daily for up to 16 weeks, up to 20 weeks, up to 24 weeks, up to 28 weeks, up to 36 weeks, up to 44 weeks, up to 52 weeks, up to 64 weeks, up to 76 weeks, up to 88 weeks, up to 100 weeks, or up to 104 weeks.

[0010] In some embodiments, the number of inflammatory lesions (AN counts) is reduced by at least 50% 12 weeks after the first daily administration compared to the AN counts before treatment began.

[0011] In some embodiments, a reduction in Pain Numerical Rating Scale 30 (PNRS30) is achieved 12 weeks after the first daily administration.

[0012] In some embodiments, a patient achieving a Hidradenitis Suppurativa Clinical Response 50 (HiSCR50) is achieved 12 weeks after the first daily dose.

[0013] In some embodiments, the patient has had an inadequate response to or is intolerant to oral antibiotics.

[0014] In some embodiments, the patient has had an inadequate response or intolerance to anti-TNF therapy.

[0015] In some embodiments, the patient has HS lesions in at least two different anatomical regions before treatment begins.

[0016] In some embodiments, the patient has a total AN count of 5 or greater before treatment begins.

[0017] In some embodiments, the patient has a draining fistula count of 20 or less before treatment begins.

[0018] In some embodiments, the patient experiences a reduction in flare-ups through week 12, where a flare-up is defined as an increase in AN counts of at least 25% and a minimum of 2 counts compared to baseline.

[0019] In some embodiments, patients achieve an improvement from baseline in Dermatological Life Quality Index (DLQI) 12 weeks after the first daily administration compared to patients not receiving the treatment.

[0020] In some embodiments, patients achieve an improvement from baseline in Hidradenitis Suppurativa Symptom Assessment (HSSA) at 12 weeks after the initial daily administration compared to patients not receiving the treatment compared to patients not receiving the treatment.

[0021] In some embodiments, the patient achieves an improvement from baseline in HS-associated swelling as assessed by the HSSA at 12 weeks after the initial daily administration compared to patients not receiving the treatment compared to patients not receiving the treatment.

[0022] In some embodiments, the patient achieves an improvement from baseline in HS-related odor as assessed by the HSSA at 12 weeks after the initial daily administration compared to patients not receiving the treatment.

[0023] In some embodiments, the patient achieves an improvement from baseline in HS-associated worst drainage as assessed by HSSA compared to patients not receiving the treatment at 12 weeks after the initial daily administration compared to patients not receiving the treatment.

[0024] In another aspect, a method is provided for treating a human patient with moderate to severe hidradenitis suppurativa (HS), wherein the patient has not responded to or is intolerant to anti-TNF therapy, comprising orally administering 30 mg of upadacitinib once daily to the patient.

[0025] In some embodiments, the patient is at least 12 years of age. In some embodiments, the patient is an adult.

[0026] In some embodiments, the methods comprise orally administering upadacitinib to the patient daily for at least 16 weeks.

[0027] In some embodiments, a Hidradenitis Suppurativa Clinical Response 50 (HiSCR50) is achieved at week 16. In some embodiments, a Hidradenitis Suppurativa Clinical Response 75 (HiSCR75) is achieved at week 16. In some embodiments, a Hidradenitis Suppurativa Clinical Response 90 (HiSCR90) is achieved at week 16.

[0028] In some embodiments, the number of inflammatory lesions (AN count) in the patient is reduced compared to the AN count before treatment began.

[0029] In some embodiments, the patient has a decreased draining fistula count compared to the draining fistula count before treatment began.

[0030] In some embodiments, a Numerical Rating Scale of 30 (NRS30) is achieved on the patient's global assessment of HS-related skin pain at week 2, where the patient had an NRS of ≥ 3 before treatment began.

[0031] In some embodiments, a reduction in the experience of a relapse is achieved compared to patients not receiving said treatment.

[0032] In some embodiments, patients achieve an improvement from baseline in Dermatological Life Quality Index (DLQI) 16 weeks after the first daily administration compared to patients not receiving the treatment.

[0033] In some embodiments, patients achieve an improvement from baseline in Hidradenitis Suppurativa Symptom Assessment (HSSA) 16 weeks after the first daily administration compared to patients not receiving the treatment.

[0034] In some embodiments, the patient achieves an improvement from baseline in International Hidradenitis Suppurativa Severity Scoring System score 16 weeks after the first daily administration, compared to a patient not receiving the treatment.

[0035] In some embodiments, the patient achieves an improvement from baseline in HS-related odor as assessed by the HSSA at 16 weeks after the initial daily administration compared to a patient not receiving the treatment.

[0036] In some embodiments, patients achieve an improvement from baseline in the Hidradenitis Suppurativa Impact Assessment (HSIA) 16 weeks after the first daily administration compared to patients not receiving the treatment.

[0037] In some embodiments, patients achieve a "much improved" or "very improved" Patient Global Impression of Change (PGIC-Total) score 16 weeks after the first daily dose.

[0038] In some embodiments, the patient achieves a ≧1 grade improvement in overall patient global impression of severity compared to baseline at 16 weeks after the first daily administration.

[0039] In some embodiments, the patient achieves an improvement from baseline in Euro-QoL 5 Item 5 Level Health Status (EQ-5D-5L) at 16 weeks after the first daily administration.

[0040] In some embodiments, the patient achieves an improvement from baseline in Work Productivity and Activity Impairment (WPAI) at 16 weeks after the first daily administration.

[0041] In some embodiments, the treatment reduces the incidence of disease progression over 16 weeks of treatment.

[0042] In some embodiments, the treatment reduces cumulative analgesic use for HS-associated skin pain compared to patients not receiving the treatment at one or more of 16 weeks, 28 weeks, 36 weeks, 52 weeks, and 104 weeks.

[0043] In some embodiments, the methods comprise administering an induction dose of 30 mg of upadacitinib orally once daily to a patient for 16 weeks, followed by a maintenance dose of 15 mg of upadacitinib orally once daily to the patient. [Brief explanation of the drawings]

[0044] [Figure 1] FIG. 1 is a schematic diagram of a clinical trial according to an embodiment of the present disclosure. [Figure 2] Graphical representation of response rate over time for the primary endpoint (HiSCR) in subjects treated with placebo and upadacitinib 30 mg QD. [Figure 3] FIG. 1 is a graphical representation of response rate over time for the secondary endpoint (NRS30 for pain) in subjects treated with placebo and upadacitinib 30 mg QD. [Figure 4] Graphical representation of response rate over time for the secondary endpoint (NRI-C) in subjects treated with placebo and upadacitinib 30 mg QD. [Figure 5A] Graphical representation of the proportion of patients achieving the primary endpoint (HiSCR) (NRI-C) at week 12. [Figure 5B] 1 is a graphical representation of the proportion of patients achieving the secondary endpoint (NRS30 for pain) (NRI-C) at 12 weeks. [Figure 6A] Graphical representation of the proportion of patients achieving the primary endpoint (HiSCR) through Week 40 based on non-responder imputation. [Figure 6B] Graphical representation of the proportion of patients achieving the primary endpoint (HiSCR) through Week 40, based on observed cases. [Figure 7A] Graphical representation of the proportion of patients achieving the primary endpoint (HiSCR) at week 12 by TNF-α inhibitor exposure status. [Figure 7B] Graphical representation of the proportion of patients achieving the primary endpoint (HiSCR) (NRI-C) at week 12 by Hurley stage classification. DETAILED DESCRIPTION OF THE INVENTION

[0045] This written description uses examples to disclose the invention and to enable one of ordinary skill in the art to practice the invention, including making and using any of the disclosed compositions and performing any of the disclosed methods or steps. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they contain elements that do not differ from the literal language of the claims or if they contain equivalent elements.

[0046] I. Definition The section headings used herein and throughout this disclosure are not intended to be limiting.

[0047] When numerical ranges are recited, each intervening number within the range is specifically contemplated with the same precision. For example, for a range of 6 to 9, the numbers 7 and 8 are specifically contemplated in addition to 6 and 9, and for a range of 6.0 to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are specifically contemplated. Similarly, all recited ratios include all subratios within the broader ratio range.

[0048] The singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0049] The term "about" generally refers to a range of numbers that one of ordinary skill in the art would consider equivalent to the recited value (i.e., having the same function or result). In many instances, the term "about" may include numbers that are rounded to the nearest significant figure.

[0050] Unless the context otherwise requires, the words "comprise," "comprises," and "comprising" are used with the understanding and express understanding that they are to be interpreted inclusively and not exclusively, and that applicant intends each of those words to be so interpreted in interpreting this patent, including the claims that follow.

[0051] "Pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the free base, as well as salts obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or organic acids such as sulfonic acids, carboxylic acids, organophosphoric acids, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, tartaric acids such as mono-malic acid, monooxalic acid, monotartaric acid (e.g., (+) or (-)-tartaric acid or mixtures thereof), amino acids (e.g., (+) or (-)-amino acids or mixtures thereof), etc. These salts can be prepared by methods known to those skilled in the art.

[0052] In some embodiments, moderate to severe HS is defined herein as a total AN count of ≧5, the presence of HS lesions in at least two different anatomical regions, and a draining fistula count of ≦20.

[0053] As used herein, the term "Hidradenitis Suppurativa Clinical Response 90" or "HiSCR90" is defined as at least a 90% reduction in total inflammatory lesion (abscess and nodule) count (AN count) compared to baseline, with no increase in abscess count and no increase in draining fistula count compared to baseline.

[0054] As used herein, the term "Hidradenitis Suppurativa Clinical Response 75" or "HiSCR75" is defined as at least a 75% reduction in total inflammatory lesion (abscess and nodule) count (AN count) compared to baseline, with no increase in abscess count and no increase in draining fistula count compared to baseline.

[0055] As used herein, the term "Hidradenitis Suppurativa Clinical Response 50" or "HiSCR50" is defined as at least a 50% reduction in total inflammatory lesion (abscess and nodule) count (AN count) compared to baseline, with no increase in abscess count and no increase in draining fistula count compared to baseline.

[0056] The "Numerical Rating Scale 30 (NRS30)" is a patient's global assessment of HS-related skin pain, defined as at least about a 30% reduction from baseline and at least a 1-unit reduction on the Numerical Rating Scale (NRS). The Numerical Rating Scale 30 is based on the worst skin pain (maximum pain of the day) over a 24-hour recall period. The NRS is a segmented numeric version of a visual analog scale in which the respondent selects the integer (0-10) that best reflects the respondent's pain intensity, with 10 being the maximum.

[0057] A subject "in need of treatment" includes a mammal, eg, a human already with hidradenitis suppurativa, including a subject in which the disease or disorder is to be prevented.

[0058] As used within the context of the present disclosure, the term "treatment" is intended to include preventative or suppressive measures for the treatment of hidradenitis suppurativa, as well as therapeutic treatment. For example, the term treatment may include administering upadacitinib before or after the onset of hidradenitis suppurativa, thereby preventing or eliminating symptoms of the disease or disorder. As another example, administration of upadacitinib after clinical signs of hidradenitis suppurativa to address the symptoms and / or complications and disorders associated with hidradenitis suppurativa constitutes "treatment" of the disease. Furthermore, administration of the agent after onset and after clinical symptoms and / or complications have arisen, which affects the clinical parameters of the disease or disorder and possibly the remission of the disease, constitutes "treatment" of hidradenitis suppurativa.

[0059] As used herein, the terms "subject" and "patient" are used interchangeably.

[0060] In one embodiment, a subject refers to an individual being therapeutically treated with upadacitinib.

[0061] II. JAK1 Inhibition Upadacitinib (ABT-494; 3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide; C17H19F3N6O) or a pharmaceutically acceptable salt or solid form thereof is an oral Janus kinase (JAK) inhibitor that exhibits unique selectivity for the JAK1 receptor. In particular, upadacitinib inhibits JAK1 with minimal inhibitory effect on JAK2 and JAK3, potentially minimizing some of the safety concerns reported with non-selective JAK inhibitors that are thought to be mediated by inhibition of the JAK2 and JAK3 signaling pathways.

[0062] Upadacitinib has the structure shown below:

[0063] [ka]

[0064] The active ingredient strengths of upadacitinib recited in this application are based on the mass of upadacitinib anhydrous free base contained in the active ingredient administered to a patient. For example, a dose of "upadacitinib 15 mg" or "UPA 15MG" refers to a 15 mg amount of neutral upadacitinib free base contained in the active ingredient, without any coformers (e.g., solvents or water molecules) of solvates or hydrates (including hemihydrates) that may also be contained in the active ingredient, or counteranions of pharmaceutically acceptable salts. Thus, for example, administering "upadacitinib 15 mg" would involve administering 15.4 mg of crystalline upadacitinib free base hemihydrate (containing ½ water coformer molecule per upadacitinib free base molecule), which would provide the patient with 15 mg of upadacitinib anhydrous free base.

[0065] The active ingredient strengths of upadacitinib recited in this application are based on the mass of upadacitinib anhydrous free base contained in the active ingredient administered to a patient. For example, a dose of "upadacitinib 30 mg" or "UPA 30 MG" refers to a 30 mg amount of neutral upadacitinib free base contained in the active ingredient, without any coformers (e.g., solvents or water molecules) of solvates or hydrates (including hemihydrates) that may also be contained in the active ingredient, or counteranions of pharmaceutically acceptable salts. Thus, for example, administering "upadacitinib 30 mg" would involve administering 30.7 mg of crystalline upadacitinib free base hemihydrate (containing ½ water coformer molecule per upadacitinib free base molecule), which would provide the patient with 30 mg of upadacitinib anhydrous free base.

[0066] The active ingredient strengths of upadacitinib recited in this application are based on the mass of upadacitinib anhydrous free base contained in the active ingredient administered to a patient. For example, a dose of "45 mg of upadacitinib" or "UPA 45 MG" refers to a 45 mg amount of neutral upadacitinib free base contained in the active ingredient, without any coformers (e.g., solvents or water molecules) of solvates or hydrates (including hemihydrates) that may also be contained in the active ingredient, or counteranions of pharmaceutically acceptable salts. Thus, for example, administering "45 mg of upadacitinib" would involve administering 46.1 mg of crystalline upadacitinib free base hemihydrate (containing ½ water coformer molecule per upadacitinib free base molecule), providing the patient with 45 mg of anhydrous free base upadacitinib.

[0067] Upadacitinib is approved under the trade name Rinvoq® for the treatment of patients with rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ankylosing spondylitis, and ulcerative colitis.

[0068] III. Treatment of Hidradenitis Suppurativa (HS) with Upadacitinib The present disclosure generally provides methods for treating a human patient with hidradenitis suppurativa (HS), comprising administering to the patient a selective JAK1 inhibitor, upadacitinib. The disclosed methods generally comprise orally administering upadacitinib to the patient. The upadacitinib is administered in a therapeutically effective amount. The disclosed methods generally comprise orally administering upadacitinib to the patient daily for a period of time.

[0069] Thus, in one aspect, there is provided a method for treating a human patient with moderate to severe hidradenitis suppurativa (HS), comprising orally administering 30 mg of upadacitinib once daily to the patient.

[0070] The patient may be of various ages. In some embodiments, the patient is an adult patient (e.g., at least 18 years old). In some embodiments, the patient is an adolescent patient (e.g., from about 12 to about 18 years old). In some embodiments, the patient is at least 12 years old.

[0071] The method includes orally administering upadacitinib to a patient daily for a period of time that may vary. In some embodiments, the period is at least 12 weeks. In some embodiments, the period is up to 12 weeks. In some embodiments, the period is at least 16 weeks, e.g., 16, 20, 24, 28, 36, 44, 52, 64, 76, 88, 100, or 104 weeks.

[0072] In some embodiments, the methods involve orally administering upadacitinib to a patient daily for up to 16 weeks. In some embodiments, the methods involve orally administering upadacitinib to a patient daily for up to 20 weeks. In some embodiments, the methods involve orally administering upadacitinib to a patient daily for up to 24 weeks. In some embodiments, the methods involve orally administering upadacitinib to a patient daily for up to 28 weeks. In some embodiments, the methods involve orally administering upadacitinib to a patient daily for up to 36 weeks. In some embodiments, the methods involve orally administering upadacitinib to a patient daily for up to 44 weeks. In some embodiments, the methods involve orally administering upadacitinib to a patient daily for up to 52 weeks. In some embodiments, the methods involve orally administering upadacitinib to a patient daily for up to 64 weeks. In some embodiments, the methods involve orally administering upadacitinib to a patient daily for up to 76 weeks. In some embodiments, the methods involve orally administering upadacitinib to a patient daily for up to 88 weeks. In some embodiments, the methods involve orally administering upadacitinib to a patient daily for up to 100 weeks. In some embodiments, the methods involve orally administering upadacitinib to a patient daily for up to 104 weeks.

[0073] In some embodiments, the methods comprise administering an induction dose of 30 mg of upadacitinib orally once daily to a patient for 16 weeks, followed by a maintenance dose of 15 mg of upadacitinib orally once daily to the patient.

[0074] In some embodiments, the patient has moderate HS. In some embodiments, the patient has severe HS. In some embodiments, the severity of HS before treatment is initiated is determined by the Hurley staging system. The Hurley staging system assigns subjects with HS to one of three different "stages" according to the level of disease. More specifically, Stage I refers to single or multiple abscess formation without fistulas and scarring; Stage II refers to widely separated lesions, accompanied by fistulas and scarring, and single or multiple recurrent abscess formation; and Stage III refers to diffuse or near-diffuse lesions or multiple interconnected fistulas and abscesses throughout the area. Hurley staging III is the most severe form and represents diffuse or near-diffuse lesions in the affected area. See, for example, (Poli et al., Clinical Presentation. In: Hidradenitis Suppurativa, Jemec et al., editors, Springer, New York, 2006, pp. 11-24, incorporated herein by reference).

[0075] In some embodiments, the patient has HS lesions in at least two different anatomical regions before treatment. In one embodiment, a subject with HS has HS lesions present in at least two different anatomical regions (e.g., left and right axillae; or left axilla and left inguinal-femoral fold), one of which is at least Hurley stage II. In another embodiment, a subject being treated has at least one lesion that is at least Hurley stage II. In some embodiments, before treatment begins, the patient has a total AN count of 5 or more. In some embodiments, before treatment begins, the patient has a draining fistula count of 20 or less.

[0076] In some embodiments, the patient has not responded to or is intolerant to anti-TNF therapy. In some embodiments, the patient has not responded to or is intolerant to oral antibiotics for the treatment of the patient's hidradenitis suppurativa. In one embodiment, such a patient has been diagnosed with moderate to severe hidradenitis suppurativa for at least one month, e.g., at least six months prior to baseline, and the HS involves at least two different anatomical regions (e.g., the left and right axillae; or the left axilla and left inguinal-femoral fold).

[0077] The methods disclosed herein generally provide an improvement in one or more aspects of HS based on the indicators used to evaluate the disease state. The effectiveness of treating HS with upadacitinib may be determined using evaluation criteria known in the art, including the evaluation criteria described herein. In some embodiments, after a period of treatment, the patient achieves a clinical response. As used herein, the term "clinical response" refers to an improvement in an indicator of the therapeutic effectiveness of upadacitinib, such as a specific HiSCR, or in the evaluation of one or more symptoms.

[0078] In some embodiments, patients achieve a Hidradenitis Suppurativa Clinical Response 50 (HiSCR50) at 12 weeks after the first daily administration. In some embodiments, a Hidradenitis Suppurativa Clinical Response 50 (HiSCR50) is achieved at week 16. In some embodiments, a Hidradenitis Suppurativa Clinical Response 75 (HiSCR75) is achieved at week 16. In some embodiments, a Hidradenitis Suppurativa Clinical Response 90 (HiSCR90) is achieved at week 16.

[0079] In some embodiments, a Numerical Rating Scale of 30 (NRS30) is achieved on the patient's global assessment of HS-related skin pain at week 2, where the patient had an NRS of ≥ 3 before treatment began.

[0080] In some embodiments, the number of inflammatory lesions (AN counts) in the patient is reduced compared to the AN counts before treatment began, hi some embodiments, the AN counts are reduced by at least 50% 12 weeks after the first daily administration compared to the AN counts before treatment began.

[0081] In some embodiments, the methods disclosed herein result in a reduction in experiencing a relapse compared to patients not receiving said treatment, where a relapse is defined as an increase in AN counts of at least 25% compared to baseline, with a minimum increase of 2.

[0082] In some embodiments, the methods disclosed herein result in a reduction in the incidence of HS progression, where HS progression is defined as at least one of the following: enlargement of the lesion in any anatomical area, spreading of scars, and progression of the Hurley staging system.

[0083] In some embodiments, patients achieve an improvement from baseline in Dermatological Life Quality Index (DLQI) 12 weeks after the first daily administration compared to patients not receiving the treatment. In some embodiments, patients achieve an improvement from baseline in DLQI 16 weeks after the first daily administration compared to patients not receiving the treatment. The DLQI consists of 10 questions regarding the patient's perception of the impact of their skin condition on different aspects of their health-related quality of life over the past week.

[0084] In some embodiments, patients achieve an improvement from baseline in Hidradenitis Suppurativa Symptom Assessment (HSSA) at 12 weeks after the first daily administration compared to patients not receiving the treatment. In some embodiments, patients achieve an improvement from baseline in HSSA at 16 weeks after the first daily administration compared to patients not receiving the treatment. The HSSA is a patient-reported outcome (PRO) questionnaire developed to assess the signs, symptoms, and effects of HS in treatment efficacy studies.

[0085] In some embodiments, patients achieve an improvement from baseline in HS-related swelling as assessed by HSSA at 12 weeks after the first daily administration compared to patients not receiving the treatment, compared to patients not receiving the treatment. In some embodiments, patients achieve an improvement from baseline in HS-related odor as assessed by HSSA at 12 weeks after the first daily administration compared to patients not receiving the treatment, compared to patients not receiving the treatment.

[0086] In some embodiments, the patient achieves an improvement from baseline in HS-associated worst drainage as assessed by HSSA compared to patients not receiving the treatment at 12 weeks after the initial daily administration compared to patients not receiving the treatment.

[0087] In some embodiments, the patient has a decreased draining fistula count compared to the draining fistula count before treatment began.

[0088] In some embodiments, the patient achieves an improvement from baseline in International Hidradenitis Suppurativa Severity Scoring System score 16 weeks after the first daily administration, compared to a patient not receiving the treatment.

[0089] In some embodiments, the patient achieves an improvement from baseline in HS-related odor as assessed by the HSSA at 16 weeks after the initial daily administration compared to a patient not receiving the treatment.

[0090] In some embodiments, patients achieve an improvement from baseline in the Hidradenitis Suppurativa Impact Assessment (HSIA) 16 weeks after the first daily administration compared to patients not receiving the treatment.

[0091] In some embodiments, patients achieve a "much improved" or "very improved" Patient Global Impression of Change (PGIC-Total) score 16 weeks after the first daily dose.

[0092] In some embodiments, the patient achieves a ≧1 grade improvement in overall patient global impression of severity compared to baseline at 16 weeks after the first daily administration.

[0093] In some embodiments, the patient achieves an improvement from baseline in Euro-QoL 5 Item 5 Level Health Status (EQ-5D-5L) at 16 weeks after the first daily administration.

[0094] In some embodiments, the patient achieves an improvement from baseline in Work Productivity and Activity Impairment (WPAI) at 16 weeks after the first daily administration.

[0095] In some embodiments, the treatment reduces the incidence of disease progression over 16 weeks of treatment.

[0096] In some embodiments, the treatment reduces cumulative analgesic use for HS-associated skin pain compared to patients not receiving the treatment at one or more of 16 weeks, 28 weeks, 36 weeks, 52 weeks, and 104 weeks.

[0097] IV. Pharmaceutical Compositions and Routes of Administration Upadacitinib may be administered to a human patient, either by itself or as a pharmaceutical composition mixed with biologically suitable carriers or excipients, in doses to treat or ameliorate the diseases or conditions described herein. Mixtures of these compounds may also be administered to a patient, either as a simple mixture or as a suitably formulated pharmaceutical composition.

[0098] The pharmaceutical compositions of the present disclosure may be manufactured in a manner that is itself known, for example, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing procedures.

[0099] Thus, pharmaceutical compositions for use in accordance with the present disclosure may be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and auxiliaries that facilitate processing of the active compound into a pharmaceutically usable preparation. The appropriate formulation will vary depending on the selected route of administration. [Example]

[0100] Examples 1 and 2 demonstrate that the JAK1 inhibitor upadacitinib is effective and safe in treating hidradenitis suppurativa (HS) in human patients, particularly those with moderate to severe chronic HS.

[0101] Example 1: Safety and efficacy of upadacitinib in subjects with moderate to severe chronic hidradenitis suppurativa (HS) This was a Phase II, multicenter, randomized, double-blind, parallel-group, placebo-controlled study to evaluate the efficacy and safety of upadacitinib in adult human subjects with moderate to severe chronic hidradenitis suppurativa (HS). Figure 1 shows the study design.

[0102] Study design The study duration was 57 weeks, including an approximately 35-day screening period, followed by a 48-week double-blind treatment period and a 30-day follow-up visit after the last dose of study drug. Subjects were randomized 2:1 to one of two groups: Upadacitinib 30 mg once daily (QD) (N=40): Upadacitinib 30 mg administered orally daily from the baseline visit through Period 1 and Period 2. Placebo (N=20): Upadacitinib placebo from the baseline visit through the week 12 visit (period 1). At week 12, subjects were switched to blinded upadacitinib 15 mg QD throughout period 2.

[0103] Objectives and efficacy evaluation items The primary objective of this study was to evaluate the efficacy and safety of upadacitinib 30 mg QD in adult subjects with moderate to severe HS. The primary efficacy objective was based on achievement of HiSCR after 12 weeks of treatment.

[0104] Primary endpoint The primary endpoint was Hidradenitis Suppurativa Clinical Response (HiSCR) at Week 12, where HiSCR was defined as at least a 50% reduction in the combined abscess and inflammatory nodule (AN) counts compared to baseline, with no increase in abscess counts and no increase in draining fistula counts.

[0105] Secondary endpoints Secondary endpoints were Numerical Rating Scale for Pain (NRS30) at Week 12: achievement of at least about a 30% reduction from baseline and at least a 1-unit reduction in NRS30 on the Patient Global Assessment of Cutaneous Pain (PGA Cutaneous Pain) at Week 12 among subjects with a baseline NRS of ≥ 3.

[0106] Additional evaluation items The following additional efficacy endpoints were assessed: 1. Experienced a relapse, defined as at least a 25% increase in AN counts, with a minimum increase of 2 counts compared to baseline 2. Change from baseline in the Dermatological Life Quality Index (DLQI) 3. Change from baseline in Hidradenitis Suppurativa Symptom Assessment (HSSA) 4. Change from baseline in HS-related swelling assessed according to the HSSA 5. Change from baseline in HS-related odor as assessed by the HSSA 6. Change from baseline in HS-related worst drainage as assessed by HSSA

[0107] For the primary and secondary endpoints, upadacitinib versus placebo was compared using three different analysis strategies, as summarized in Table 1 below.

[0108] [Table 1]

[0109] Additional endpoints included comparisons of upadacitinib versus placebo reference values ​​from previous studies and upadacitinib versus placebo controls in the study.

[0110] Main methods for handling missing data For categorical variables, the primary method for handling missing data was non-response imputation (NRI) incorporating multiple imputation (MI). For continuous variables, missing data were handled by a mixed-effects model for repeated measures (MMRM). Missing data for long-term efficacy in Period 2 were handled based on observed cases (OC).

[0111] Study population and number of subjects enrolled A total of 68 subjects were randomized (21 to PBO and 47 to UPA 30 mg). A total of 60 subjects (88.2%) completed study drug in Period 1 (Table 2). Demographic and baseline characteristics were generally balanced between treatment groups (Table 3). The subject breakdown in the ongoing Period 2 is shown in Table 4.

[0112] [Table 2]

[0113] [Table 3]

[0114] [Table 4]

[0115] Effectiveness Primary and secondary endpoints The study met its primary endpoint and demonstrated superiority of UPA 30 mg versus placebo in previous studies (one-sided p-value = 0.018). Results from the primary and secondary endpoints are summarized in Table 5. Results from selected additional endpoints are presented in Table 6.

[0116] HiSCR (NRI-C) at 12 weeks: Treatment with UPA 30 mg demonstrated a statistically significantly higher percentage of subjects achieving a HiSCR response at week 12 (38.3%) compared with the placebo rate of 25% in previous studies. A combined placebo sensitivity analysis of upadacitinib vs. placebo subjects in the study showed similar results in favor of UPA 30 mg (38.3% vs. 29.2% placebo, one-sided p=0.142). A sensitivity analysis of only upadacitinib vs. placebo subjects in the study showed similar results in favor of UPA 30 mg (38.3% vs. 23.8% placebo, one-sided p=0.087).

[0117] [Table 5]

[0118] [Table 6]

[0119] Efficacy over time The response rates and 95% confidence intervals (CIs) for HiSCR using NRI-C and pain NRS30 at each visit in Period 1 for the following three groups are shown in Figures 2 and 3: UPA 30 mg; synthetic placebo with combined placebo subjects; and placebo subjects only. In particular, Figure 2 shows the response rates and 95% CIs for HiSCR by visit in Period 1 (NRI-C), and Figure 3 shows the response rates and 95% CIs for pain NRS30 by visit in Period 1. The response rates and 95% CIs for HiSCR based on OC at each visit up to the cutoff date for UPA 30 mg and placebo in Period 1, followed by UPA 15 mg in Period 2 up to the cutoff date, are shown in Figure 4. Table 7 summarizes HiSCR at Week 12 overall and by stratification.

[0120] [Table 7]

[0121] safety Treatment-emergent adverse events (TEAEs), adverse events of interest (AESIs), and potentially clinically important (PCI) laboratory changes were monitored during Period 1. The most frequently reported TEAEs (≥5%) included headache, dizziness, and urinary tract infection in the UPA 30 mg QD group and myalgia, cellulitis, and dermatitis in the placebo group.

[0122] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the scope of the following claims. The contents of all references, patents and published patent applications cited throughout this application are hereby incorporated by reference.

[0123] Example 2: Safety and Efficacy of Upadacitinib in Subjects with Moderate to Severe Chronic Hidradenitis Suppurativa (HS) - Post-hoc Analysis Post-hoc efficacy assessments through Week 40 were conducted in the study of Example 1. This analysis included the proportion of patients achieving a ≥ 75% and ≥ 90% reduction from baseline in AN counts, with no increase in abscess counts or draining fistula counts (HiSCR75 and HiSCR90, respectively), and the proportion of patients achieving a ≥ 55% reduction in the International HS Severity Scoring System endpoint (IHS4-55), which dynamically assesses inflammatory nodules, abscesses, and draining tracts.

[0124] As described above, this phase 2 study met its primary endpoint, with the primary analysis demonstrating that a statistically significantly higher proportion of patients with moderate to severe HS treated with upadacitinib 30 mg achieved HiSCR at week 12 compared with the prespecified placebo rate in a single prior study in adults. Specifically, a statistically significantly higher proportion of patients receiving upadacitinib 30 mg achieved HiSCR at week 12 (primary endpoint) compared with the prespecified single prior study placebo rate (upadacitinib 30 mg, 38.3%; prior study placebo, 25.0%; difference = 13.3% [95% CI, -0.6 to 27.2]; one-sided P = 0.018) (Figure 5A). Relative to placebo, a higher proportion of patients on UPA 30 mg achieved HiSCR75 (21.3%, nominal P<0.001) and HiSCR90 (8.5%, nominal P=0.015) at week 12, and no patients in the placebo group achieved HiSCR75 or HiSCR90.

[0125] A similar trend was seen when the effect of upadacitinib was compared with that of investigational placebo on HiSCR, with a numerically greater proportion of patients taking upadacitinib 30 mg achieving HiSCR (adjusted difference = 14.7%; nominal P = 0.087). Similar results were seen in supplemental analyses when the effect of upadacitinib was compared with that of synthetic and investigational placebo combined (Table 8).

[0126] A higher proportion of patients taking upadacitinib 30 mg achieved NRS30 compared with the pre-specified rate for placebo in a previous study. Specifically, a numerically greater proportion of patients taking upadacitinib 30 mg with a baseline NRS ≥ 3 achieved NRS30 at Week 12 compared with the pre-specified rate for placebo in a single previous study (secondary endpoint; upadacitinib 30 mg, 36.4% vs. previous study placebo, 22.5%; difference = 13.9%; nominal P = 0.028) (Figure 5B). A numerically greater proportion of patients taking upadacitinib 30 mg achieved NRS30 at Week 12 compared with patients taking investigational placebo (upadacitinib 30 mg, 36.4% vs. investigational placebo, 33.3%; adjusted difference = 2.2%, nominal P = 0.421) or compared with synthetic and investigational placebo combined (Table 8).

[0127] [Table 8]

[0128] Achievement of HiSCR with upadacitinib 30 mg at Week 12 continued to improve or persist through Week 40 (Figures 6A and 6B and Table 9). Nineteen of 21 patients (90.5%) randomized to placebo switched to upadacitinib 15 mg, and the proportion of these patients achieving HiSCR increased within the first 4 weeks of the blinded extension period, and this proportion of patients persisted through Week 40, demonstrating a trend toward improvement from baseline similar to that observed in patients receiving upadacitinib 30 mg. Achievement of HiSCR with upadacitinib 30 mg through Week 12 persisted through Week 40, regardless of baseline Hurley staging or prior TNF-α inhibitor exposure. At Week 40 (OC), HiSCR, HiSCR75, and HiSCR90 were achieved by 75.9% and 31.0%, respectively, of patients taking UPA 30 mg (n=29), and by 71.4%, 50.0%, and 28.6%, respectively, of patients switched to UPA 15 mg (n=14) (Table 9). Given that none were achieved by placebo-treated patients, these higher HiSCR efficacy levels may more clearly distinguish responders. Responses to upadacitinib were durable, and the proportion of patients achieving HiSCR75 and HiSCR90 increased throughout Week 40.

[0129] The analysis using IHS4-55 was consistent with that reported for HiSCR. Specifically, IHS4-55, which emphasizes drainage, was achieved by 72.4% of patients taking UPA 30 mg and 85.7% of patients switched to UPA 15 mg at week 40 (Table 9). Of patients in the UPA 30 mg group, 40.4% achieved IHS4-55 at week 12 compared with 19.0% of patients in the placebo group (nominal P = .020 vs. placebo). The proportion of patients taking UPA 30 mg who achieved these criteria at week 12 was slightly higher in the OC analysis (Table 9).

[0130] [Table 9]

[0131] Subgroup analysis In subgroup analyses, a higher proportion of patients receiving upadacitinib 30 mg achieved HiSCR compared with patients receiving study placebo, both in patients with a prior inadequate response to TNF-α inhibitor therapy (upadacitinib, 41.7%; placebo, 16.7%; nominal P = 0.115) and in patients naive to TNF-α inhibitor therapy (upadacitinib, 37.1%; placebo, 26.7%; nominal P = 0.228) (Figure 7A). HiSCR response rates with upadacitinib 30 mg were similar across all Hurley staging subgroups and were comparable to those observed in the overall population (Figure 7B).

[0132] conclusion Overall, the study met its primary endpoint, and the primary analysis demonstrated that a statistically significantly higher proportion of patients with moderate to severe HS treated with upadacitinib 30 mg achieved HiSCR at Week 12 compared with placebo rates in previous pre-specified studies in adults. The proportion of patients treated with upadacitinib 30 mg achieving HiSCR further improved and continued through Week 40, demonstrating the durability of the response to upadacitinib. Among patients who switched from placebo to upadacitinib 15 mg at Week 12, a similar proportion of patients in the upadacitinib 15 mg group achieved HiSCR at Week 40 compared with patients who had been taking upadacitinib 30 mg from baseline; however, the study was not designed to compare the efficacy of upadacitinib 15 mg versus upadacitinib 30 mg. Findings from this Phase 2 study demonstrate that treatment with upadacitinib improved persistent lesion and pain control in adults with moderate to severe HS. In summary, upadacitinib may provide higher levels of clinical efficacy across all HS lesion types, including drainage tract, to address unmet needs in patients with moderate to severe HS.

Claims

1. A method for treating a human patient with moderate to severe hidradenitis suppurativa (HS), comprising orally administering 30 mg of upadacitinib to the patient once daily.

2. 10. The method of claim 1, wherein the patient is an adult.

3. 3. The method of claim 1 or 2, wherein upadacitinib is administered to the patient for at least 12 weeks.

4. 4. The method of any one of claims 1 to 3, wherein the number of inflammatory lesions (AN count) is reduced by at least 50% 12 weeks after the first daily administration compared to the AN count before treatment began.

5. 5. The method of any one of claims 1 to 4, wherein a reduction in pain numeric rating scale 30 (PNRS30) is achieved 12 weeks after the initial daily administration.

6. 6. The method of any one of claims 1 to 5, wherein the patient achieves a Hidradenitis Suppurativa Clinical Response 50 (HiSCR50) 12 weeks after the first daily administration.

7. The method of any one of claims 1 to 6, wherein the patient has HS lesions in at least two different anatomical regions before treatment begins.

8. The method of any one of claims 1 to 7, wherein the patient has had an inadequate response to or is intolerant to oral antibiotics.

9. The method of any one of claims 1 to 8, wherein the patient has failed to respond to or is intolerant to anti-TNF therapy.

10. 10. The method of any one of claims 1 to 9, wherein the patient has a total AN count of 5 or more before treatment begins.

11. 11. The method of any one of claims 1 to 10, wherein the patient has a draining fistula count of 20 or less before treatment begins.

12. 12. The method of any one of claims 1-11, wherein the patient experiences a reduction in flare-ups through week 12, where a flare-up is defined as an increase in AN counts of at least 25% and a minimum of 2 counts compared to baseline.

13. below: Improvement from baseline in the Dermatological Quality of Life Index (DLQI), improvement from baseline in Hidradenitis Suppurativa Symptom Assessment (HSSA); Improvement from baseline in HS-related swelling as assessed by HSSA; Improvement from baseline in HS-related odor as assessed by the HSSA; Improvement from baseline in HS-associated worst drainage as assessed by HSSA 13. The method of any one of claims 1 to 12, wherein one or more of the following is achieved 12 weeks after the initial daily administration compared to patients not receiving treatment.

14. A method for treating a human patient with moderate to severe hidradenitis suppurativa (HS), wherein the patient has not responded to or is intolerant to anti-TNF therapy, comprising orally administering 30 mg of upadacitinib to the patient once daily.

15. 15. The method of claim 14, wherein the patient is at least 12 years old.

16. 15. The method of claim 14, wherein the patient is an adult.

17. 17. The method of any one of claims 1-2 or 14-16, wherein the method comprises administering upadacitinib orally to the patient daily for at least 16 weeks.

18. 18. The method of any one of claims 1-2 or 14-17, wherein a Hidradenitis Suppurativa Clinical Response 50 (HiSCR50) is achieved at 16 weeks.

19. 19. The method of any one of claims 1-2 or 14-18, wherein a Hidradenitis Suppurativa Clinical Response 75 (HiSCR75) is achieved at 16 weeks.

20. 20. The method of any one of claims 1-2 or 14-19, wherein a Hidradenitis Suppurativa Clinical Response 90 (HiSCR90) is achieved at 16 weeks.

21. 21. The method of any one of claims 1-2 or 14-20, wherein the number of inflammatory lesions (AN count) in the patient is reduced compared to the AN count before treatment began.

22. 22. The method of any one of claims 1-2 or 14-21, wherein the draining fistula count in the patient is reduced compared to the draining fistula count before treatment began.

23. 23. The method of any one of claims 1-2 or 14-22, wherein a Numeric Rating Scale of 30 (NRS30) is achieved in the patient's global assessment of HS-related skin pain at week 2, wherein the patient had an NRS > 3 before initiating treatment.

24. 24. The method of any one of claims 1-2 or 14-23, wherein a reduction in relapse experience is achieved compared to patients not receiving treatment.

25. below: Improvement from baseline in the Dermatological Quality of Life Index (DLQI), improvement from baseline in Hidradenitis Suppurativa Symptom Assessment (HSSA); improvement from baseline in the International Hidradenitis Suppurativa Severity Scoring System score; Improvement from baseline in HS-related odor as assessed by the HSSA; Improvement from baseline in Hidradenitis Suppurativa Impact Assessment (HSIA) 25. The method of any one of claims 1-2 or 14-24, wherein one or more of the following are achieved at week 16 compared to patients not receiving treatment.

26. 26. The method of any one of claims 1-2 or 14-25, wherein the patient achieves a "much improved" or "very improved" Patient Global Impression of Change (PGIC-Total).

27. 27. The method of any one of claims 1-2 or 14-26, wherein the patient achieves an improvement of ≧1 grade in overall patient global impression of severity compared to baseline.

28. 28. The method of any one of claims 1-2 or 14-27, wherein the patient achieves an improvement from baseline in Euro-QoL 5 item 5 health status (EQ-5D-5L).

29. 29. The method of any one of claims 1-2 or 14-28, wherein the patient achieves an improvement from baseline in Work Productivity and Activity Impairment (WPAI).

30. 30. The method of any one of claims 1-2 or 14-29, wherein the treatment reduces the incidence of disease progression.

31. 31. The method of any one of claims 1-2 or 14-30, wherein the treatment reduces cumulative analgesic use for HS-related cutaneous pain compared to patients not receiving the treatment at one or more of 16 weeks, 28 weeks, 36 weeks, 52 weeks, and 104 weeks.

32. 32. The method of any one of claims 1-2 or 14-31, comprising administering to the patient an induction dose of 30 mg upadacitinib orally once daily for 16 weeks, followed by a maintenance dose of 15 mg upadacitinib orally once daily.

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