Methods of treating hidradenitis suppurativa

Abstract

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

Description

Technical Field

[0001] The present disclosure relates to a method for treating hidradenitis suppurativa (HS) with the selective JAK1 inhibitor upadacitinib. Background Art

[0002] Hidradenitis suppurativa (HS) is a debilitating skin condition of the apocrine glands (sweat glands found on certain parts of the body) and hair follicles, in which there are swelling, pain, and chronic inflammatory lesions or nodules. HS is limited to body areas containing apocrine glands, such as the axillae, the areolae of the nipples, the groin, the perineum, the perianal area, and the periumbilical area. It is hypothesized that immunological abnormalities of the hair follicles play a role in the etiology of the disease. HS is a recurrent or chronic inflammatory condition that particularly affects young people, with an average age of onset of 23 years. This poorly understood disease is thought to be underreported by those who have it, but it is estimated to affect approximately 1% of the general population in the West, and the disease often affects women two to five times more frequently than men (Naldi, L. Epidemiology. In: Hidradenitis Suppurativa; edited by Jemec et al.; Heidelberg: Springer. 2006).

[0003] HS is characterized by recurrent inflammatory nodules, abscesses, and fistulas, and occurs when the apocrine gland outlets are blocked by sweat or are unable to drain properly due to incomplete gland development. The secretions trapped in the glands force sweat and bacteria into the surrounding tissues, causing subcutaneous induration, inflammation, and infection. HS lesions (i.e., nodules, abscesses, and sinuses) are painful and may be malodorous, with pus discharge. This series of signs and symptoms causes severe discomfort and social stigma in patients and has a profound impact on quality of life.

[0004] Current therapies for moderate to severe HS include short-term or long-term oral or topical administration of 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 HS treatment, and other TNF antagonists such as etanercept have failed to show HS improvement during a 24-week treatment period (Adams et al., Arch Dermatol. 146(5):501-504, 2010). Given the limited success of treating HS and the debilitating nature of the disease, there is an urgent need for an effective treatment method. Summary of the Invention

[0005] The present disclosure provides a method for treating hidradenitis suppurativa (HS) with the selective JAK1 inhibitor upadacitinib.

[0006] In one aspect, a method for treating human patients suffering from moderate to severe hidradenitis suppurativa (HS) is provided, the method comprising orally administering 30 mg of upadacitinib to the patient once daily.

[0007] In some embodiments, the patient is an adult.

[0008] In some embodiments, the method comprises orally administering upadacitinib to the patient daily for up to 12 weeks. In some embodiments, the method comprises orally administering upadacitinib to the patient daily for at least 12 weeks. In some embodiments, the method comprises orally administering upadacitinib to the patient daily for at least 16 weeks. In some embodiments, the method comprises orally administering upadacitinib to the patient once 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.

[0009] In some embodiments, relative to the number of inflammatory lesions (AN count) before starting treatment, at 12 weeks after the first daily administration, the AN count is reduced by at least 50%.

[0010] In some embodiments, a reduction in the pain numerical rating scale 30 (PNRS30) is achieved at 12 weeks after the first daily administration.

[0011] In some embodiments, the patient achieves a hidradenitis suppurativa clinical response 50 (HiSCR50) at 12 weeks after the first daily administration.

[0012] In some embodiments, the patient has an inadequate response or intolerance to oral antibiotics.

[0013] In some embodiments, the patient has an inadequate response or intolerance to anti-TNF therapy.

[0014] In some embodiments, the patient has HS lesions in at least two different anatomical regions before starting treatment.

[0015] In some embodiments, the patient has a total AN count equal to or greater than 5 before starting treatment.

[0016] In some embodiments, the patient has a draining fistula count less than or equal to 20 before starting treatment.

[0017] In some embodiments, the patient experiences a reduction in erythema within 12 weeks, defined as an increase in the AN count of at least 25% relative to baseline, with a minimum increase of 2%.

[0018] In some embodiments, 12 weeks after the first daily administration, the patient achieved an improvement in the Dermatology Life Quality Index (DLQI) relative to the untreated patient compared to baseline.

[0019] In some embodiments, 12 weeks after the first daily administration, the patient achieved an improvement in the Hidradenitis Suppurativa Symptom Assessment (HSSA) relative to the untreated patient compared to baseline.

[0020] In some embodiments, 12 weeks after the first daily administration, the patient achieved an improvement in HS-related swelling based on HSSA assessment relative to the untreated patient compared to baseline.

[0021] In some embodiments, 12 weeks after the first daily administration, the patient achieved an improvement in HS-related odor based on HSSA assessment relative to the untreated patient compared to baseline.

[0022] In some embodiments, 12 weeks after the first daily administration, the patient achieved an improvement in the worst drainage related to HS based on HSSA assessment relative to the untreated patient compared to baseline.

[0023] In another aspect, a method for treating a human patient suffering from moderate to severe hidradenitis suppurativa (HS) is provided, wherein the patient is non-responsive or intolerant to anti-TNF therapy, the method comprising orally administering 30 mg of upadacitinib to the patient once daily.

[0024] In some embodiments, the patient is at least 12 years old. In some embodiments, the patient is an adult.

[0025] In some embodiments, the method comprises orally administering upadacitinib to the patient daily for at least 16 weeks.

[0026] In some embodiments, Hidradenitis Suppurativa Clinical Response 50 (HiSCR 50) is achieved at week 16. In some embodiments, Hidradenitis Suppurativa Clinical Response 75 (HiSCR 75) is achieved at week 16. In some embodiments, Hidradenitis Suppurativa Clinical Response 90 (HiSCR 90) is achieved at week 16.

[0027] In some embodiments, the number of inflammatory lesions (AN count) in the patient is reduced relative to the AN count before starting treatment.

[0028] In some embodiments, the count of draining fistulas in the patient is reduced relative to the count of draining fistulas before starting treatment.

[0029] In some embodiments, at week 2, a numeric rating scale 30 (NRS30) is achieved in the overall HS-related skin pain assessment of the patient, and wherein prior to initiation of treatment, the patient has an NRS of ≥3.

[0030] In some embodiments, a reduction in the experience of erythema is achieved relative to patients not receiving treatment.

[0031] In some embodiments, at 16 weeks after the first daily administration, the patient has achieved improvement relative to patients not receiving treatment and the Dermatology Life Quality Index (DLQI) has improved relative to baseline.

[0032] In some embodiments, at 16 weeks after the first daily administration, the patient has achieved improvement relative to patients not receiving treatment and the Hidradenitis Suppurativa Symptom Assessment (HSSA) has improved relative to baseline.

[0033] In some embodiments, at 16 weeks after the first daily administration, the patient has achieved improvement relative to patients not receiving treatment and the International Hidradenitis Suppurativa Severity Scoring System score has improved relative to baseline.

[0034] In some embodiments, at 16 weeks after the first daily administration, the patient has achieved improvement relative to patients not receiving treatment and the HS-related odor based on HSSA assessment has improved relative to baseline.

[0035] In some embodiments, at 16 weeks after the first daily administration, the patient has achieved improvement relative to patients not receiving treatment and the Hidradenitis Suppurativa Impact Assessment (HSIA) has improved relative to baseline.

[0036] In some embodiments, at 16 weeks after the first daily administration, the patient has achieved "much improved" or "very much improved" on the Overall Patient Global Change Impression (Overall PGIC).

[0037] In some embodiments, at 16 weeks after the first daily administration, the patient has achieved an improvement of ≥1 grade in the Overall Patient Global Severity Impression relative to baseline.

[0038] In some embodiments, at 16 weeks after the first daily administration, the patient has achieved improvement in the Euro-QoL 5-dimension 5-level health state (EQ-5D-5L) relative to baseline.

[0039] In some embodiments, at 16 weeks after the first daily administration, the patient has achieved improvement in Work Productivity and Activity Impairment (WPAI) relative to baseline.

[0040] In some embodiments, during a 16-week treatment period, the treatment provides a reduction in the incidence of disease progression.

[0041] In some embodiments, the treatment provides a reduction in cumulative analgesic use for HS-related skin pain relative to patients who are untreated at one or more of 16 weeks, 28 weeks, 36 weeks, 52 weeks, and 104 weeks.

[0042] Thus, in some embodiments, the method comprises orally administering to a patient an induction dose of 30 mg of upadacitinib once daily for 16 weeks, followed by orally administering to the patient a maintenance dose of 15 mg of upadacitinib once daily. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 is a schematic diagram of a clinical study according to an embodiment of the present disclosure.

[0044] Figure 2 is a graphical description of the response rate over time for subjects treated with placebo and 30 mg of upadacitinib QD relative to the primary endpoint (HiSCR).

[0045] Figure 3 is a graphical description of the response rate over time for subjects treated with placebo and 30 mg of upadacitinib QD relative to the secondary endpoint (Pain NRS30).

[0046] Figure 4 is a graphical description of the response rate over time for subjects treated with placebo and 30 mg of upadacitinib QD relative to the secondary endpoint (NRI-C).

[0047] Figure 5A is a graphical description of the proportion of patients (HiSCR) who achieved the primary endpoint (NRI-C) at week 12.

[0048] Figure 5B is a graphical description of the proportion of patients (Pain NRS30) who achieved the secondary endpoint (NRI-C) at week 12.

[0049] Figure 6A is a graphical description of the proportion of patients (HiSCR) who achieved the primary endpoint based on non-responder imputation up to week 40.

[0050] Figure 6B is a graphical description of the proportion of patients (HiSCR) who achieved the primary endpoint based on observed cases up to week 40.

[0051] Figure 7A is a graphical description of the proportion of patients (HiSCR) who achieved the primary endpoint at week 12 by TNF-α inhibitor exposure status.

[0052] Figure 7B It is a graphical description of the proportion of patients (HiSCR) who reached the primary endpoint (NRI-C) at week 12 through the Herley phase. Detailed implementation mode

[0053] This written description uses examples to disclose the present invention and also enables any person skilled in the art to practice the present invention, including preparing and using any of the disclosed compositions and performing any of the disclosed methods or processes. The scope of the patent right of the present invention is defined by the claims and may include other examples that can be conceived by a person skilled in the art. If such other examples have elements that are not different from the literal language of the claims or if such other examples contain equivalent elements, then such other examples are intended to be within the scope of the claims.

[0054] I. Definitions

[0055] The section headings used in this section and throughout the disclosure are not intended to be restrictive.

[0056] In the case of setting forth a numerical range, it is clearly contemplated that each intermediate number within the range has the same precision. For example, for the range from 6 to 9, the numbers 7 and 8 other than 6 and 9 are contemplated, and for the range from 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 clearly contemplated. In the same manner, all the set forth ratios also include all sub-ratios that fall within a broader ratio.

[0057] Unless the context clearly indicates otherwise, the singular forms "a", "an", and "the" include plural referents.

[0058] The term "about" generally refers to a numerical range that a person skilled in the art would consider equivalent to the set forth value (i.e., having the same function or result). In many cases, the term "about" may include numbers that are rounded to the nearest significant digit.

[0059] Unless the context requires otherwise, the term "comprising" is used on the following basis: it is clearly understood that the term will be interpreted as being inclusive rather than exclusive, and the applicant intends that the term be so interpreted when interpreting this patent (including the claims below).

[0060] "Pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the free base and are 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 acid, carboxylic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, salicylic acid, lactic acid, malic acid, oxalic acid, tartaric acids such as L-tartaric acid (e.g., (+)-tartaric acid or (-)-tartaric acid or mixtures thereof), amino acids (e.g., (+)-amino acids or (-)-amino acids or mixtures thereof), etc. These salts can be prepared by methods known to those skilled in the art.

[0061] In some embodiments, moderate to severe HS is defined herein as a total AN count ≥5, the presence of HS lesions in at least 2 different anatomical regions, and a draining fistula count ≤20.

[0062] As used herein, the term "hidradenitis suppurativa clinical response 90" or "HiSCR 90" is defined as at least a 90% reduction in the total count of inflammatory lesions (abscesses and nodules) (AN count) relative to baseline, where the abscess count does not increase relative to baseline and the draining fistula count does not increase relative to baseline.

[0063] As used herein, the term "hidradenitis suppurativa clinical response 75" or "HiSCR 75" is defined as at least a 75% reduction in the total count of inflammatory lesions (abscesses and nodules) (AN count) relative to baseline, where the abscess count does not increase relative to baseline and the draining fistula count does not increase relative to baseline.

[0064] As used herein, the term "hidradenitis suppurativa clinical response 50" or "HiSCR 50" is defined as at least a 50% reduction in the total count of inflammatory lesions (abscesses and nodules) (AN count) relative to baseline, where the abscess count does not increase relative to baseline and the draining fistula count does not increase relative to baseline.

[0065] The term "numeric rating scale 30 (NRS30)" is defined as at least an approximately 30% reduction and at least a 1-unit reduction in the numeric rating scale (NRS) relative to baseline in the patient's overall HS-related skin pain assessment. The pain assessment scale 30 is based on the worst skin pain (maximum daily pain) within a 24-hour recall period. The NRS is a categorical numeric form of the visual analog scale, where the responder selects an integer (0-10) that best reflects his / her pain level, with 10 being the highest.

[0066] "In need of treatment" includes mammals, such as humans, that already have hidradenitis suppurativa, including mammals to be prophylactically treated for a disease or disorder.

[0067] As used within the context of the present disclosure, the term "treatment" is intended to include therapeutic treatment as well as prophylactic or inhibitory measures for the treatment of hidradenitis suppurativa. For example, the term treatment may include administering upadacitinib before or after the onset of hidradenitis suppurativa, thereby preventing or eliminating the signs and symptoms of the disease or disorder. As another example, after the clinical manifestation of hidradenitis suppurativa, administering upadacitinib to counteract the symptoms and / or complications and conditions associated with hidradenitis suppurativa constitutes "treatment" of the disease. In addition, administering the agent after onset and after clinical symptoms and / or complications have developed (where the administration affects the clinical parameters of the disease or disorder and may improve the disease) constitutes "treatment" of hidradenitis suppurativa.

[0068] As used herein, the terms "subject" and "patient" are used interchangeably. In one embodiment, a subject refers to an individual who can be therapeutically treated with upadacitinib.

[0069] II. JAK1 Inhibition

[0070] 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. Specifically, upadacitinib inhibits JAK1 with minimal inhibition of JAK2 and JAK3, which may potentially minimize some of the reported safety concerns associated with non-selective JAK inhibition, which are thought to be mediated through the inhibition of the JAK2 and JAK3 signaling pathways. Upadacitinib has the structure shown below:

[0071]

[0072] The dose strength of upadacitinib described in this application is based on the weight of anhydrous free base upadacitinib present in the active ingredient delivered to the patient. For example, "15 mg upadacitinib" or "UPA 15 MG" refers to 15 mg of neutral upadacitinib free base present in the active ingredient, excluding any co-formations of solvates or hydrates (including hemihydrates) or counter anions of pharmaceutically acceptable salts (e.g., solvent or water molecules) that may also be present in the active ingredient. Thus, for example, the administration of "15 mg upadacitinib" includes the administration of 15.4 mg of crystalline upadacitinib free base hemihydrate (each upadacitinib free base molecule contains 1 / 2 water co-formation molecule), delivering 15 mg of anhydrous free base upadacitinib to the patient.

[0073] The dose intensity of upadacitinib as described in this application is based on the weight of anhydrous free base upadacitinib present in the active ingredient delivered to the patient. For example, "30 mg upadacitinib" or "UPA 30 MG" refers to 30 mg of neutral upadacitinib free base present in the active ingredient, excluding any co-formations of solvates or hydrates (including hemihydrates) or counter anions of pharmaceutically acceptable salts (e.g., solvent or water molecules) that may also be present in the active ingredient. Thus, for example, the administration of "30 mg upadacitinib" includes the administration of 30.7 mg of crystalline upadacitinib free base hemihydrate (each upadacitinib free base molecule contains 1 / 2 water co-formation molecule), delivering 30 mg of anhydrous free base upadacitinib to the patient.

[0074] The dose intensity of upadacitinib as described in this application is based on the weight of anhydrous free base upadacitinib present in the active ingredient delivered to the patient. For example, "45 mg upadacitinib" or "UPA 45 MG" refers to 45 mg of neutral upadacitinib free base present in the active ingredient, excluding any co-formations of solvates or hydrates (including hemihydrates) or counter anions of pharmaceutically acceptable salts (e.g., solvent or water molecules) that may also be present in the active ingredient. Thus, for example, the administration of "45 mg upadacitinib" includes the administration of 46.1 mg of crystalline upadacitinib free base hemihydrate (each upadacitinib free base molecule contains 1 / 2 water co-formation molecule), delivering 45 mg of anhydrous free base upadacitinib to the patient.

[0075] Upadacitinib is marketed under the trade name and is approved for the treatment of patients suffering from rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, ankylosing spondylitis, and ulcerative colitis.

[0076] III. Treatment of Hidradenitis Suppurativa (HS) with Upadacitinib

[0077] The present disclosure generally provides methods for treating human patients having hidradenitis suppurativa (HS), the methods comprising administering to the patient the selective JAK1 inhibitor upadacitinib. The disclosed methods generally comprise orally administering upadacitinib to the patient. 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.

[0078] Thus, in one aspect, there is provided a method for treating a human patient having moderate to severe hidradenitis suppurativa (HS), the method comprising orally administering 30 mg of upadacitinib to the patient once daily.

[0079] The age of the patient can vary. 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 years old to about 18 years old). In some embodiments, the patient is at least 12 years old.

[0080] The method includes orally administering upadacitinib to a patient daily for a period of time. The period of time can vary. In some embodiments, the period of time is at least 12 weeks. In some embodiments, the period of time is up to 12 weeks. In some embodiments, the period of time is at least 16 weeks, such as 16 weeks, 20 weeks, 24 weeks, 28 weeks, 36 weeks, 44 weeks, 52 weeks, 64 weeks, 76 weeks, 88 weeks, 100 weeks, or 104 weeks.

[0081] In some embodiments, the method includes orally administering upadacitinib to a patient daily for up to 16 weeks. In some embodiments, the method includes orally administering upadacitinib to a patient daily for up to 20 weeks. In some embodiments, the method includes orally administering upadacitinib to a patient daily for up to 24 weeks. In some embodiments, the method includes orally administering upadacitinib to a patient daily for up to 28 weeks. In some embodiments, the method includes orally administering upadacitinib to a patient daily for up to 36 weeks. In some embodiments, the method includes orally administering upadacitinib to a patient daily for up to 44 weeks. In some embodiments, the method includes orally administering upadacitinib to a patient daily for up to 52 weeks. In some embodiments, the method includes orally administering upadacitinib to a patient daily for up to 64 weeks. In some embodiments, the method includes orally administering upadacitinib to a patient daily for up to 76 weeks. In some embodiments, the method includes orally administering upadacitinib to a patient daily for up to 88 weeks. In some embodiments, the method includes orally administering upadacitinib to a patient daily for up to 100 weeks. In some embodiments, the method includes orally administering upadacitinib to a patient daily for up to 104 weeks.

[0082] Thus, in some embodiments, the method includes orally administering a 30 mg induction dose of upadacitinib to a patient once daily for 16 weeks, followed by orally administering a 15 mg maintenance dose of upadacitinib to the patient once daily.

[0083] In some embodiments, the patient has moderate HS. In some embodiments, the patient has severe HS. In some embodiments, the severity of HS before starting treatment is determined according to the Hurley staging system. Hurley staging is based on assigning one of three different "stages" to a subject with HS according to the degree of the condition of the subject with HS. More specifically, stage I refers to the formation of single or multiple abscesses without sinus tract and scar formation; stage II refers to recurrent abscesses with sinus tract formation and scar formation, and single or multiple distant lesions; and stage III, which refers to diffuse or near-diffuse involvement, or multiple interconnected sinus tracts and abscesses across the entire area. Hurley stage III is the most severe form, reflecting diffuse or near-diffuse involvement of the affected area. See, e.g., (Poli et al., Clinical Presentation. In: Hidradenitis Suppurativa; Jemec et al., editors, Springer, New York, 2006, pp 11-24, which is incorporated herein by reference).

[0084] 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 axilla and right axilla; or left axilla and left inguinal femoral crease), where one anatomical region is at least Hurley stage II. In another embodiment, the subject being treated has at least one lesion that is at least Hurley stage II. In some embodiments, the patient has a total AN count equal to or greater than 5 before starting treatment. In some embodiments, the patient has a draining fistula count less than or equal to 20 before starting treatment.

[0085] In some embodiments, the patient is non-responsive or intolerant to anti-TNF therapy. In some embodiments, the patient is non-responsive or intolerant to oral antibiotics used to treat their hidradenitis suppurativa. In one embodiment, such a patient has been diagnosed with moderate to severe hidradenitis suppurativa for at least 1 month (such as at least 6 months) before baseline, and the HS involves at least two different anatomical regions (e.g., left axilla and right axilla; or left axilla and left inguinal femoral crease).

[0086] Based on an index for measuring the disease state, the methods disclosed herein generally provide improvement in one or more aspects of HS. The therapeutic efficacy of upadacitinib in treating HS can be determined using measures known in the art, including those 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 indicator of the therapeutic effectiveness of upadacitinib (such as a specific HiSCR) or an improvement in one or more symptom assessments.

[0087] In some embodiments, the patient achieves Hidradenitis Suppurativa Clinical Response 50 (HiSCR50) 12 weeks after the first daily administration. In some embodiments, Hidradenitis Suppurativa Clinical Response 50 (HiSCR50) is achieved at week 16. In some embodiments, Hidradenitis Suppurativa Clinical Response 75 (HiSCR75) is achieved at week 16. In some embodiments, Hidradenitis Suppurativa Clinical Response 90 (HiSCR90) is achieved at week 16.

[0088] In some embodiments, at week 2, a Numerical Rating Scale 30 (NRS30) is achieved in the patient's overall HS-related skin pain assessment, where the patient had an NRS of ≥3 before starting treatment.

[0089] In some embodiments, the number of inflammatory lesions (AN count) in the patient is reduced relative to the AN count before starting treatment. In some embodiments, the AN count is reduced by at least 50% 12 weeks after the first daily administration relative to the AN count before starting treatment.

[0090] In some embodiments, the methods disclosed herein result in a reduction in erythema relative to untreated patients, where erythema is defined as an increase in the AN count of at least 25% relative to baseline, with a minimum increase of 2%.

[0091] 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: spread of lesions in any anatomical area, spread of scars, and progression of Hurley stage.

[0092] In some embodiments, 12 weeks after the first daily administration, the patient achieves an improvement in the Dermatology Life Quality Index (DLQI) relative to untreated patients compared to baseline. In some embodiments, 16 weeks after the first daily administration, the patient achieves an improvement compared to baseline, with the DLQI improving relative to baseline. The DLQI consists of 10 questions that address the patient's perception of the impact of skin disease on different aspects of their health-related quality of life in the past week.

[0093] In some embodiments, at 12 weeks after the first daily administration, the patient achieved an improvement in Hidradenitis Suppurativa Symptom Assessment (HSSA) relative to baseline compared to untreated patients. In some embodiments, at 16 weeks after the first daily administration, the patient achieved an improvement relative to baseline compared to untreated patients, with the HSSA improving relative to baseline. The HSSA is a Patient Reported Outcome (PRO) questionnaire developed to measure the signs, symptoms, and impact of HS in treatment efficacy studies.

[0094] In some embodiments, at 12 weeks after the first daily administration, the patient achieved an improvement in HS-related swelling based on HSSA assessment relative to baseline compared to untreated patients. In some embodiments, at 12 weeks after the first daily administration, the patient achieved an improvement in HS-related odor based on HSSA assessment relative to baseline compared to untreated patients.

[0095] In some embodiments, at 12 weeks after the first daily administration, the patient achieved an improvement in the worst drainage related to HS based on HSSA assessment relative to baseline compared to untreated patients.

[0096] In some embodiments, the count of drainage fistulas in the patient decreased relative to the count of drainage fistulas before the start of treatment.

[0097] In some embodiments, at 16 weeks after the first daily administration, the patient achieved an improvement relative to baseline compared to untreated patients, with the International Hidradenitis Suppurativa Severity Scoring System score improving relative to baseline.

[0098] In some embodiments, at 16 weeks after the first daily administration, the patient achieved an improvement relative to baseline compared to untreated patients, with the HS-related odor based on HSSA assessment improving relative to baseline.

[0099] In some embodiments, at 16 weeks after the first daily administration, the patient achieved an improvement relative to baseline compared to untreated patients, with the Hidradenitis Suppurativa Impact Assessment (HSIA) improving relative to baseline.

[0100] In some embodiments, at 16 weeks after the first daily administration, the patient achieved "much improved" or "very much improved" on the Overall Patient Global Impression of Change (Overall PGIC).

[0101] In some embodiments, at 16 weeks after the first daily administration, the patient achieved an improvement of ≥1 grade in the Overall Patient Global Severity Impression relative to baseline.

[0102] In some embodiments, 16 weeks after the first daily administration, patients achieved an improvement in the Euro-QoL 5-Dimension 5-Level health status (EQ-5D-5L) compared to baseline.

[0103] In some embodiments, 16 weeks after the first daily administration, patients achieved an improvement in work productivity and impairment (WPAI) compared to baseline.

[0104] In some embodiments, during a 16-week treatment period, the treatment provided a reduction in the incidence of disease progression.

[0105] In some embodiments, the treatment provided a reduction in cumulative analgesic use for HS-related skin pain relative to patients who were untreated at one or more of 16 weeks, 28 weeks, 36 weeks, 52 weeks, and 104 weeks.

[0106] IV. Pharmaceutical Compositions and Routes of Administration

[0107] Upadacitinib can be administered to human patients either by itself or in the form of a pharmaceutical composition, wherein upadacitinib is mixed with a biologically suitable carrier or excipient in a dose for treating or ameliorating a disease or condition as described herein. Mixtures of these compounds can also be administered to patients either in the form of a simple mixture or in the form of a suitable formulated pharmaceutical composition.

[0108] The pharmaceutical compositions of the present disclosure can be prepared in a manner known per se, for example, by means of conventional mixing, dissolving, granulating, sugar coating, grinding, emulsifying, encapsulating, entrapping, or lyophilizing methods.

[0109] Thus, one or more physiologically acceptable carriers including excipients and auxiliaries can be used to formulate the pharmaceutical compositions used according to the present disclosure in a conventional manner, and the excipients and auxiliaries facilitate the processing of the active compounds into pharmaceutically usable preparations. Appropriate formulation depends on the chosen route of administration.

[0110] Examples

[0111] Examples 1 and 2 demonstrate that the JAK1 inhibitor upadacitinib is effective and safe for the treatment of hidradenitis suppurativa (HS) in human patients, especially those with moderate to severe chronic HS.

[0112] Example 1. Safety and Efficacy of Upadacitinib in Subjects with Moderate to Severe Chronic Hidradenitis Suppurativa (HS) Figure 1

[0113] The study was a Phase 2, 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 hidradenitis suppurativa (HS).Study Design The study design of this clinical trial is shown.

[0114] Objectives and Efficacy Endpoints

[0115] The duration of the study was 57 weeks, including an approximately 35-day screening period, followed by a 48-week double-blind treatment period, and a 30-day visit after the last dose of the study drug. As shown below, subjects were randomly assigned in a 2:1 ratio to one of 2 groups:

[0116] ● Upadacitinib 30 mg once daily (QD) (N = 40): Upadacitinib 30 mg was orally administered daily from the baseline visit through Period 1 and Period 2.

[0117] ● Placebo (N = 20): A placebo of upadacitinib was taken from the baseline visit until the 12-week visit (Period 1). At Week 12, subjects were switched to blinded upadacitinib 15 mg QD until Period 2.

[0118] Primary Endpoint

[0119] 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 evaluated based on the achievement of HiSCR after 12 weeks of treatment.

[0120] Secondary Endpoints

[0121] The primary endpoint was the hidradenitis suppurativa clinical response (HiSCR) at Week 12, where HiSCR was defined as at least a 50% reduction in the total abscess and inflammatory nodule (AN) count relative to baseline, where the abscess count did not increase relative to baseline and the draining fistula count did not increase relative to baseline.

[0122] Additional Endpoints

[0123] The secondary endpoint was the pain assessment scale (NRS30) at Week 12: Among subjects with a baseline NRS ≥ 3, at Week 12, in the patient's overall skin pain assessment (PGA skin pain), a reduction of at least 30% and at least 1 unit relative to baseline was achieved in the NRS30.

[0124] Table 1. Endpoint Analysis Strategy

[0125] The following additional efficacy endpoints were evaluated:

[0126] 1. Experiencing erythema, defined as at least a 25% increase in the AN count relative to baseline, with a minimum increase of 2%

[0127] 2. The Dermatology Life Quality Index (DLQI) changed from baseline

[0128] 3. The Hidradenitis Suppurativa Symptom Assessment (HSSA) changed from baseline

[0129] 4. HS-related swelling based on HSSA assessment changed from baseline

[0130] 5. HS-related odor based on HSSA assessment changed from baseline

[0131] 6. HS-related worst drainage based on HSSA assessment changed from baseline

[0132] For the primary and secondary endpoints, upadacitinib was compared with placebo using three different analysis strategies, as summarized in Table 1 below:

[0133] Main Methods for Handling Missing Data

[0134]

[0135]

[0136] a Historical placebo rates for HiSCR (25%) and NRS30 (22.5%): Assume that placebo subjects met the same eligibility criteria from previous adalimumab HS studies (Pioneer I and Pioneer II).

[0137] For additional endpoints, upadacitinib was compared with historical reference values for placebo, and upadacitinib subjects were compared with placebo subjects in the trial.

[0138] Study Population and Number of Enrolled Subjects

[0139] For categorical variables, the primary method for handling missing data was non-responder imputation [NRI] combined with multiple imputation [MI]. For continuous variables, missing data were handled by mixed-effects model repeated measures (MMRM). Missing data for long-term efficacy in Period 2 were handled based on observed cases (OC).

[0140] Table 2. Subject Distribution in Period 1

[0141] A total of 68 subjects were randomly assigned (21 in PBO and 47 in UPA 30 mg). A total of 60 (88.2%) subjects completed the study drug in Period 1 (Table 2). Demographics and baseline characteristics were generally balanced between treatment groups (Table 3). The subject distribution in the ongoing Period 2 is presented in Table 4.

[0142] Table 3. Main Demographics and Disease Characteristics

[0143]

[0144] Table 4. Subject Distribution in Period 2

[0145]

[0146]

[0147] Efficacy

[0148]

[0149] Note: Subjects who were randomly assigned to placebo in Period 1 and did not continue into Period 2 were excluded from this summary.

[0150] Primary and Secondary Endpoints

[0151] HiSCR (NRI-C) at Week 12

[0152] The study met the primary endpoint and demonstrated the superiority of UPA 30 mg over the historical placebo rate (one-sided p-value = 0.018). Results from the primary and secondary endpoints are summarized in Table 5. Results from the additional endpoints selected are provided in Table 6.

[0153] Table 5. Primary and Secondary Endpoints (NRI-C) :

[0154] ● Compared with the historical placebo rate of 25%, the percentage of subjects treated with UPA 30 mg who achieved a HiSCR response at Week 12 was statistically significantly higher (38.3%).

[0155] ● Sensitivity analysis of upadacitinib subjects versus synthetic placebo subjects who were combined with placebo in the trial showed similar results in favor of UPA 30 mg (38.3% versus 29.2% in placebo, one-sided p-value = 0.142).

[0156] ● Sensitivity analysis of upadacitinib subjects versus placebo subjects in the trial only showed similar results in favor of UPA 30 mg (38.3% versus 23.8% in placebo, one-sided p-value

[0157] = 0.087).

[0158] Table 6. Selected Additional Endpoints

[0159]

[0160] * One-sided p-value ≤ 0.05.

[0161] Efficacy over Time

[0162]

[0163]

[0164] *p-value ≤ 0.05.

[0165] Figure 2

[0166] The response rates and 95% confidence intervals (CIs) of HiSCR and pain NRS30 using NRI-C at each visit during Period 1 for the following 3 groups of subjects are presented in Figure 3 and Figure 2 as follows: UPA 30 mg; synthetic placebo subjects combined with the placebo in the trial; placebo subjects in the trial only. Specifically, Figure 3 shows the response rate and 95% CI (NRI-C) of HiSCR at the Period 1 visit, and Figure 4 shows the response rate and 95% CI (NRI-C) of pain NRS30 at the Period 1 visit. The response rates and 95% CIs of HiSCR based on OC at each visit up to the cut-off date are presented in Table 7. Summary of Overall and Stratified Data for HiSCR at Week 12 wherein UPA 30 mg and the placebo in the trial were used during Period 1, and then UPA 15 mg was used until the cut-off date during Period 2. Table 7 is a summary of the overall and stratified data for HiSCR at Week 12.

[0167] Safety

[0168]

[0169] Example 2. Safety and Efficacy of Upadacitinib in Subjects with Moderate to Severe Chronic Hidradenitis Suppurativa (HS) - Post-Hoc Analysis

[0170] Treatment-emergent adverse events (TEAEs), adverse events of special 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.

[0171] Those skilled in the art will recognize or be able to ascertain using only routine experimentation many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims. The contents of all references, patents, and published patent applications cited in this application are incorporated herein by reference.

[0172] Figure 5A Figure 5B

[0173] In the study of Example 1, a post hoc efficacy assessment was conducted up to week 40. This analysis included the proportion of patients with ≥75% and ≥90% reduction in AN count compared to baseline without an increase in the abscess or draining fistula count (HiSCR 75 and HiSCR 90, respectively), and the proportion of patients achieving ≥55% reduction in the International HS Severity Scoring System endpoint (IHS4-55), which dynamically assesses inflammatory nodules, abscesses, and draining channels.

[0174] As described above, the Phase 2 study met the primary endpoint, and the preliminary analysis showed that the proportion of patients with moderate to severe HS treated with upadacitinib 30 mg achieving HiSCR at week 12 was statistically significantly higher compared to the pre-specified adult historical placebo rate. Specifically, compared to the pre-specified single historical placebo rate, the proportion of patients receiving upadacitinib 30 mg achieving HiSCR at week 12 (primary endpoint) was statistically significantly higher (upadacitinib 30 mg, 38.3%; historical placebo, 25.0%; difference = 13.3% [95% CI, -0.6 to 27.2]; one-sided P = 0.018)( Table 8. Proportion of Patients Treated with Upadacitinib Who Achieved HiSCR and NRS30 at Week 12 Compared to Synthetic Placebo Plus Placebo in the Trial ). At week 12, a higher proportion of patients receiving UPA 30 mg achieved HiSCR 75 (21.3%, nominal P <.001) and HiSCR 90 (8.5%, nominal P =.015) compared to those receiving placebo; and no patients in the placebo group achieved HiSCR75 or HiSCR90.

[0175] A similar trend was observed when comparing the effect of upadacitinib on HiSCR to placebo in the trial, where the proportion of patients receiving upadacitinib 30 mg achieving HiSCR was numerically higher (adjusted difference = 14.7%; nominal P = 0.087). Similar results were also observed in the supplementary analysis when comparing the effect of upadacitinib to the combined effect of synthetic placebo plus placebo in the trial (Table 8).

[0176] For NRS30, the proportion of patients receiving upadacitinib 30 mg achieving this endpoint was higher compared to the pre-specified historical placebo rate. Specifically, among patients with baseline NRS ≥3, the proportion of patients receiving upadacitinib 30 mg achieving NRS30 at week 12 was numerically higher compared to the pre-specified single historical placebo rate (secondary endpoint; upadacitinib 30 mg, 36.4% vs. historical placebo, 22.5%; difference = 13.9%; nominal P = 0.028)( Figure 6A)。The proportion of patients who achieved NRS30 at week 12 was numerically higher in patients receiving upadacitinib 30 mg compared to those receiving placebo in the trial (upadacitinib 30 mg, 36.4% vs placebo in the trial, 33.3%; adjusted difference = 2.2%, nominal P = 0.421), or when compared to the combined synthetic placebo plus placebo in the trial (Table 8).

[0177] Figure 6B Table 9. Upadacitinib Achieved Higher Clinical Efficacy in Patients with Moderate to Severe Hidradenitis Suppurativa

[0178]

[0179] The achievement of HiSCR with upadacitinib 30 mg at week 12 continued to improve or was maintained through week 40 ( Subgroup Analysis and Figure 7A and Table 9). Among 21 patients randomized to placebo, 19 (90.5%) switched to receive upadacitinib 15 mg; within the first 4 weeks of the blinded extension period, the proportion of these patients achieving HiSCR increased and this proportion of patients was maintained through week 40, indicating a trend of improvement from baseline similar to that observed in patients receiving upadacitinib 30 mg. Achievement of HiSCR at week 12 with upadacitinib 30 mg was independent of baseline Herrey stage or prior TNF-α inhibitor exposure and was maintained through week 40. At week 40 (OC), HiSCR, HiSCR 75, and HiSCR 90 were achieved by 75.9% and 31.0% of patients receiving UPA 30 mg (n = 29), respectively, and by 71.4%, 50.0%, and 28.6% of patients switched to UPA 15 mg (n = 14), respectively (Table 9). Considering that patients on placebo treatment did not achieve HiSCR, these higher HiSCR efficacy levels more clearly distinguished responders. Response to upadacitinib was durable, with increasing proportions of patients achieving HiSCR 75 and HiSCR 90 through week 40.

[0180] Analysis using IHS4 - 55 was consistent with those reported for HiSCR. Specifically, at week 40, 72.4% of patients receiving UPA 30 mg and 85.7% of patients switched to UPA 15 mg achieved IHS4 - 55 for the draining sinus tract (Table 9). Compared to 19.0% of patients in the placebo group achieving IHS4 - 55 at week 12, 40.4% of patients in the UPA30mg group achieved IHS4 - 55 (nominal P =.020 vs placebo). For the OC analysis, the proportion of patients receiving UPA 30 mg achieving these benchmarks was slightly higher at week 12 (Table 9).

[0181] Figure 7B

[0182]

[0183] Conclusions

[0184] In the subgroup analysis, patients receiving upadacitinib 30 mg had a higher proportion achieving HiSCR compared to patients receiving placebo in the trial, both in patients with prior inadequate response to TNF-α inhibitor therapy (upadacitinib, 41.7%; placebo, 16.7%; nominal P = 0.115) and in patients who had not received TNF-α inhibitor therapy (upadacitinib, 37.1%, placebo, 26.7%; nominal P = 0.228). ​ ) The HiSCR response rate with upadacitinib 30 mg treatment was similar between Hurley stage subgroups and was similar to the response rate observed in the overall population. ​ )

[0185] ​

[0186] Overall, the study met the primary endpoint. The preliminary analysis showed that patients with moderate to severe HS treated with upadacitinib 30 mg had a statistically significantly higher proportion achieving HiSCR at week 12 compared to the pre-specified adult historical placebo rate. The proportion of patients achieving HiSCR with upadacitinib 30 mg treatment further improved or was maintained up to week 40, demonstrating the durability of response to upadacitinib. For patients who switched from placebo to upadacitinib 15 mg at week 12, a similar proportion of patients in the 15 mg upadacitinib group achieved HiSCR at week 40 compared to those who received upadacitinib 30 mg from baseline, although the study was not designed to compare the efficacy of upadacitinib 15 mg with upadacitinib 30 mg. The findings from this Phase 2 study demonstrated that treatment with upadacitinib improved persistent lesions and pain control in adults with moderate to severe HS. In summary, upadacitinib can provide a higher level of clinical efficacy across HS lesion types, including sinus tracts, to address the unmet needs of patients with moderate to severe HS.

Claims

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

2. The method according to claim 1, wherein the patient is an adult.

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

4. The method according to any one of claims 1 to 3, wherein, relative to the number of inflammatory lesions (AN count) before the start of treatment, at 12 weeks after the first daily administration, the AN count has decreased by at least 50%.

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

6. The method according to any one of claims 1 to 5, wherein the patient achieves a hidradenitis suppurativa clinical response 50 (HiSCR50) at 12 weeks after the first daily administration.

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

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

9. The method according to any one of claims 1 to 8, wherein the patient has no response or intolerance to anti-TNF therapy.

10. The method according to any one of claims 1 to 9, wherein the patient has a total AN count equal to or greater than 5 before the start of the treatment.

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

12. The method according to any one of claims 1 to 11, wherein the patient experiences a reduction in erythema within the 12th week, defined as an increase in the AN count of at least 25% relative to baseline, with a minimum increase of 2%.

13. The method according to any one of claims 1 to 12, wherein at 12 weeks after the first daily administration, one or more of the following are achieved relative to patients not receiving the treatment: The dermatology life quality index (DLQI) is improved compared to baseline; The hidradenitis suppurativa symptom assessment (HSSA) is improved compared to baseline; HS-related swelling based on the HSSA assessment is improved compared to baseline; HS-related odor based on the HSSA assessment is improved compared to baseline; HS-related worst drainage based on the HSSA assessment is improved compared to baseline.

14. A method for treating human patients suffering from moderate to severe hidradenitis suppurativa (HS), wherein the patient has no response or intolerance to anti-TNF therapy, the method comprising orally administering 30 mg of upadacitinib to the patient once daily.

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

16. The method according to claim 14, wherein the patient is an adult.

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

18. The method according to any one of claims 1 to 2 or 14 to 17, wherein Hidradenitis suppurativa clinical response 50 (HiSCR 50) is achieved at week 16.

19. The method according to any one of claims 1 to 2 or 14 to 18, wherein Hidradenitis suppurativa clinical response 75 (HiSCR 75) is achieved at week 16.

20. The method according to any one of claims 1 to 2 or 14 to 19, wherein Hidradenitis suppurativa clinical response 90 (HiSCR 90) is achieved at week 16.

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

22. The method according to any one of claims 1 to 2 or 14 to 21, wherein the drain fistula count in the patient is reduced relative to the drain fistula count before the start of treatment.

23. The method according to any one of claims 1 to 2 or 14 to 22, wherein at week 2, a numeric rating scale 30 (NRS30) is achieved in the patient's overall HS-related skin pain assessment, and wherein before the start of the treatment, the patient has an NRS of ≥3.

24. The method according to any one of claims 1 to 2 or 14 to 23, wherein a reduction in the experience of erythema is achieved relative to patients not receiving the treatment.

25. The method according to any one of claims 1 to 2 or 14 to 24, wherein at week 16, one or more of the following are achieved relative to patients not receiving the treatment: The dermatology life quality index (DLQI) is improved relative to baseline; The hidradenitis suppurativa symptom assessment (HSSA) is improved relative to baseline; The international hidradenitis suppurativa severity scoring system score is improved relative to baseline; The HS-related odor based on the HSSA assessment is improved relative to baseline; The hidradenitis suppurativa impact assessment (HSIA) is improved relative to baseline.

26. The method according to any one of claims 1 to 2 or 14 to 25, wherein the patient achieves "much improved" or "very much improved" on the overall patient global change impression (overall PGIC).

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

28. The method according to any one of claims 1 to 2 or 14 to 27, wherein the patient achieves an improvement in the Euro-QoL 5-dimension 5-level health state (EQ-5D-5L) relative to baseline.

29. The method according to any one of claims 1 to 2 or 14 to 28, wherein the patient achieves an improvement in work productivity and impairment (WPAI) relative to baseline.

30. The method according to any one of claims 1 to 2 or 14 to 29, wherein the treatment provides a reduction in the incidence of disease progression.

31. The method according to any one of claims 1 to 2 or 14 to 30, wherein the treatment provides a reduction in the cumulative analgesic use for HS-related skin pain relative to patients who did not receive the treatment at one or more of 16 weeks, 28 weeks, 36 weeks, 52 weeks, and 104 weeks.

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

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