Ramibrutinib for use in treatment of hidradenitis suppurativa

Abstract

The present disclosure relates to methods of treating and / or preventing such a disease or condition in a subject suffering from hidradenitis suppurativa comprising administering a therapeutically effective dose of LOU064. Also disclosed are medicaments, dosing regimens, pharmaceutical compositions, combinations, dosage forms, and kits for use in the disclosed uses and methods.

Description

[0001] This application is a divisional application of Chinese patent application 202380022664.5. The filing date of the original application is February 27, 2023, and the name of the invention is “Remibrutinib for use in the treatment of hidradenitis suppurativa”. Technical Field

[0002] The present invention relates to LOU064 or a pharmaceutically acceptable salt thereof for use in the effective and safe treatment of hidradenitis suppurativa (HS). Background Art

[0003] Hidradenitis suppurativa (HS), also known as acne inversa or Verneuil's disease, is a chronic, relapsing inflammatory disease characterized by deep nodules, sinus tracts, and abscesses that lead to fibrosis in the axillae, groin, breast folds, and anogenital area (Revuz and Jemec (2016) Dermatol Clin 34:1-5; Jemec GB. (2012) N Engl J Med 366:158-64). It is associated with severe pain and comorbidities, including metabolic, psychiatric, and autoimmune disorders, as well as an increased risk of skin cancer. (Revuz (2016); Shlyankevich et al. (2014) J Am Acad Dermatol 71:1144-50; Kohorst et al. (2015) J Am Acad Dermatol 73:S27-35; Wolkenstein et al. (2007) J Am Acad Dermatol 56:621-3). The average prevalence of HS by race / ethnicity is highest in African Americans (1.3%), lowest in Hispanics / Latinos (0.07%), and intermediate in Caucasians (0.75%) (Sachdeva et al. (2021) J. Cutan Med Surg.: 25(2):177-187).

[0004] The reported prevalence of HS varies from <1% to 4% of the population [Shlyankevich et al. (2014); Cosmatos et al. (2013) J Am Acad Dermatol 68:412-9; Davis et al. (2015) Skin Appendage Disord 1:65-73; Revuz et al. (2008) J Am Acad Dermatol 59:596-601; McMillan K. (2014) Am J Epidemiol 179:1477-83; Garg et al. (2017) J Am Acad Dermatol 77(1):118-122; Jemec et al. (1996) J Am Acad Dermatol 35:191-4]. However, the true prevalence of HS is difficult to determine because it is underdiagnosed, and estimates fluctuate depending on study design, population, and geographic location. [Miller et al. (2016) Dermatol Clin 34:7-16]. Although the National Institutes of Health (NIH) does not classify HS as a rare disease, experts generally agree that it affects <1% of the United States (US) population. [Cosmatos et al. (2013); Genetic and Rare Diseases Information Center. National Institutes of Health. Hidradenitis suppurativa. Available: / / rarediseases.info.nih.gov / diseases / 6658 / hidradenitis-suppurativa. Accessed March 20, 2017; Gulliver et al. (2016) Rev Endocr Metab Disord 17:343–51; Garg et al. 2007].

[0005] Current treatments for HS include topical and / or systemic antibiotics, hormonal interventions, retinoids, and, in selected cases, immunosuppressants, biologics (such as the tumor necrosis factor [TNF] inhibitor monoclonal antibody adalimumab, which is the only approved drug for HS and is usually used as a last resort before major surgical resection). [Gulliver et al. (2016); Zouboulis et al. (2015) J Eur Acad Dermatol Venereol 29:619-4414-16; Kimball et al. (2016) N Engl J Med 375:422-34]. Because the lesions are painful, patients often require analgesics and pain relief in addition to anti-inflammatory treatment.

[0006] However, symptom control and lesion resolution are inconsistent across treatments, and most treatments lack randomized controlled clinical trial results providing evidence-based data, with only adalimumab being approved. Although antibiotic therapy is used for long-term treatment lasting months or even years, it can lead to the recurrence of antibacterial resistance. Oral treatment with retinoids raises concerns about teratogenicity in sexually active, predominantly female populations. Furthermore, the effectiveness of inflammatory medications such as dapsone, fumarate, and cyclosporine is based on small case studies with mixed results, and these molecules are not used systematically. Due to these inconsistent results and the severity of HS disease, patients with HS more frequently utilize healthcare in high-cost settings (e.g., emergency departments and hospitalizations) than patients with other chronic inflammatory skin conditions. (Khalsa et al. (2016) J Am Acad Dermatol 73:609-14; Kirby et al. (2014) JAMA Dermatol 150:937-44).

[0007] The immunopathogenesis of HS is poorly understood, with a wide range of proposed and somewhat inconsistent mechanisms. Complement activation has been implicated in the pathogenesis of HS by increasing the concentration of the complement fragment C5a in the skin and blood of patients with HS (Kanni T. et al. Br J Dermatol. 2018;179(2):413–419). C5a is the primary chemoattractant for neutrophils, a prominent cell population in actively inflamed HS skin (Lima AL. et al. Br J Dermatol. 2016;174(3):514-520). Furthermore, increased levels of neutrophils that release neutrophil extracellular traps (NETs) in a process called NETosis have been demonstrated in both the blood and skin of patients with HS (Byrd AS et al., Sci transl Med. 2019: 11(508).eaav5908), as well as increased type I IFN responses and activation of plasmacytoid dendritic cells (pDCs). Other studies have suggested the involvement of the proinflammatory cytokines IL-17A and IFN-γ (Hotz C. et al.; J. Invest Dermatol. 2016: 136(9): 1768-1780; Vossen ARJV et al. Allergy. 2019, 74(3): 631-634), as well as keratinocyte-derived IL-6 and IL-1β. Additional transcriptomic studies have noted increased expression of immunoglobulin and plasma cell signature markers in HS (Hoffman LK. et al. PLoS One. 2018;13(9):e0203672), but a clear and comprehensive understanding of the immunopathogenic mechanisms involved in HS is lacking.

[0008] Gudjonsson et al. have deeply characterized the inflammatory response in HS using proteomic and transcriptomic approaches, as well as methods such as single-cell RNA sequencing or scRNAseq. Such studies revealed an immune response centered around IFN-γ, IL-36, and TNF, with a smaller contribution from IL-17A. Gudjonsson et al. further identified B cells and plasma cells, along with increased immunoglobulin production and complement activation, as participants in the pathogenesis of HS, with activation of the Bruton's tyrosine kinase (BTK) and spleen tyrosine kinase (SYK) pathways as central signaling networks in HS (JCI Insight. 2020; 5(19): e139930. https: / / doi.org / 10.1172 / jci.insight.139930).

[0009] The role of B cells in the pathogenesis of HS has also been suggested in previous reports (Van der Zee et al. 2012, 166:98-106; Musilova et al. J Invest Dermatol [Journal of Dermatological Research] 2020, 140:1091-1094). In addition, two recent studies have also emphasized the role of B cells in the pathogenesis of HS. One study demonstrated the anti-inflammatory effect of rituximab in HS explant cultures (Vossen et al., 2019, 181:314-23, and the other case study showed the successful treatment of HS by depleting B cells with rituximab (Takahashi et al., 2018, 45:e116-7). However, further studies are needed to determine whether targeting B cells can be an effective treatment.

[0010] BTK is a kinase that is essential for signaling through FcεRI in human mast cells and basophils. Because it is also crucial for B cell maturation, BTK has been pharmacologically targeted for the treatment of B cell malignancies. There are currently three FDA-approved BTK inhibitors (BTKi) in the United States. Ibrutinib (trade name Pharmacyclics, and AbbVie), acalabrutinib ( Acerta and AstraZeneca), and zanubrutinib ( BeiGene's (BeiGene) are both oral, covalent small molecule inhibitors of BTK.

[0011] In addition, many BTKi are being developed in clinical trials for the treatment of autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus. For example, acalabrutinib and zanubrutinib, as well as novel compounds ONO-4059 (tilutinib), HM71224 (peshetinib) and ABBV-105 (upadacitinib), are currently being tested for their efficacy in B-cell malignancies and / or autoimmune diseases such as rheumatoid arthritis (RA), Sjögren's syndrome (SjS) and systemic lupus erythematosus (SLE). In addition, ivotinib, tolebrutinib and fenacinib have entered Phase III studies in patients with multiple sclerosis (MS), obeticholic acid is being tested in Phase II studies and BIIB091 is being tested in Phase I studies for the treatment of MS.

[0012] Although it has been suggested that BTK inhibitors can be used to treat HS, there is currently no animal model for this disease, and BTK inhibitors have not been shown to treat human HS. In addition, due to the lack of selectivity of some early-developed BTK inhibitors (e.g., acalabrutinib, ibrutinib), those BTK inhibitors may not be suitable for non-malignant indications, especially for treatments that require long-term / long-term and safe use and / or indications in children or adolescent populations. The most common side effects of currently approved BTK inhibitors include nausea, diarrhea, rash, infection, cytopenia, bleeding, and arrhythmias. In particular, the long-term toxicity profile of ibrutinib (the first inhibitor) is well characterized and includes clinically significant incidences of arrhythmias, bleeding, infection, diarrhea, arthralgia, and hypertension. Acalabrutinib, the initial second-generation BTKi to receive approval from the U.S. Food and Drug Administration, demonstrated improved kinase selectivity for BTK, with commonly observed adverse reactions including infection, headache, and diarrhea (Hematology Am Soc Hematol Educ Program. 2020 Dec 4;2020(1):336–345).

[0013] Long-term safety data are not yet available for the BTK inhibitors currently in development, but the available safety data for fenacinib suggest that the biggest hurdle BTK inhibitors may face is whether side effects are acceptable during prolonged use. For example, a major event noted in the Phase IIa trial of fenacinib was a transient grade 3 elevation in ALT and / or AST in 8.3% and 6.3% of subjects in the higher-dose treatment group. Some side effects that have been observed with some BTKi may limit their use for the treatment or prevention of non-malignant indications, particularly when long-term administration is required. Furthermore, none of the FDA-approved BTK inhibitors are approved for use in children and adolescents. Therefore, until safety data are available in children, it remains unclear whether BTK inhibitors will be a viable option.

[0014] HS remains difficult to treat, with only one biologic therapy currently approved for its treatment (the anti-TNF agent adalimumab), and even with adalimumab, nearly 40% of patients experience a suboptimal treatment response. The disease is both physically and psychologically debilitating, so there is a clear unmet need for safe and effective long-term treatments for HS patients, particularly oral therapies. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 : Transcriptomic signature enrichment (genes overexpressed in lesional HS samples)

[0016] Figure 2: LOU signature in a (bulk) transcriptomic dataset of hidradenitis suppurativa (LOU064 suppressor gene)

[0017] Figure 3 : Simulation of BTK occupancy in the spleen at steady state.

[0018] Figure 4: (A) BTK occupancy trough during 24 hours of steady state. The graph shows the median prediction as dots and the vertical line shows the 95% prediction interval. (B) BTK occupancy mean during 24 hours of steady state. The graph shows the median prediction as dots and the vertical line shows the 95% prediction interval.

[0019] Figure 5 : Preferred particle size distribution of nano-LOU064. Summary of the Invention

[0020] The problem underlying the present invention is to provide a safe and effective treatment or prevention of HS. In particular, it is an object of the present invention to provide a safe and effective long-term treatment or prevention of HS.

[0021] Another object of the present invention is to provide improved treatment and / or prevention of HS.For example, one object of the present invention is to provide a treatment or prevention of HS that is more effective than anti-TNF therapy (e.g., adalimumab).

[0022] Therefore, disclosed herein are methods for preventing or treating HS, comprising administering to a subject in need thereof a therapeutically effective dose of a BTK inhibitor. In particular, BTK inhibitors (reversible or irreversible) that are selective for other structurally similar Tec family kinases (such as BMX, ITK, and TXK) can be used in the methods of the present invention. More particularly, BTK inhibitors that are selective for BTK over Tec (e.g., at least 10-fold, at least 20-fold, at least 30-fold BTK / tec selectivity) can be used in the methods of the present invention.

[0023] Also disclosed herein are methods of preventing or treating HS comprising administering a therapeutically effective dose of LOU064 to a subject in need thereof.

[0024] In addition, the present invention further provides a method for treating or preventing HS in a subject in need thereof, comprising administering to the subject a therapeutically effective dose of LOU064 or a pharmaceutically acceptable salt thereof and one or more therapeutic agents.

[0025] In another aspect of the present invention, the present invention provides a BTK inhibitor for use in the treatment and / or prevention of HS in a patient in need of such treatment and / or prevention.

[0026] In another aspect of the present invention, the present invention provides LOU064 for use in the treatment and / or prevention of HS in a patient in need of such treatment and / or prevention.

[0027] The present invention further relates to combinations of LOU064 and one or more additional therapeutic agents for use in treating or preventing HS in a patient in need of such treatment and / or prevention.

[0028] A further subject of the present invention is a process for the manufacture of a medicament for use in the above-mentioned treatment.

[0029] Further aspects, advantageous features and preferred embodiments of the invention, which are summarized in the following Examples E1 to E32, respectively, alone or in combination, contribute to solving the objects of the invention:

[0030] E1. A method of treating or preventing hidradenitis suppurativa (HS), comprising administering to a subject in need thereof a therapeutically effective dose of a BTK inhibitor, eg, a selective BTK inhibitor, eg, LOU064.

[0031] E2. The method of E1, wherein the therapeutically effective dose of LOU064 is about 50 mg to about 200 mg per day.

[0032] E3. The method of E2, wherein the therapeutically effective dose of LOU064 is about 25 mg twice daily to about 100 mg twice daily.

[0033] E4. The method according to E2, wherein the therapeutically effective dose of LOU064 is about 25 mg twice daily.

[0034] E5. The method of E2, wherein the therapeutically effective dose of LOU064 is about 100 mg twice daily.

[0035] E6. The method according to any one of the preceding embodiments, wherein LOU064 is administered short-term, eg, less than 6 months, preferably less than 3 months.

[0036] E7. The method of E6, wherein LOU064 is administered for up to 16 weeks, eg, 4, 12 or 16 weeks.

[0037] E8. The method of any one of embodiments E1 to E5, wherein LOU064 is administered chronically, eg, for more than 6 months, preferably more than one year.

[0038] E9. The method according to any one of the preceding embodiments, wherein LOU064 is administered as a monotherapy.

[0039] E10. The method according to any one of the preceding embodiments, wherein LOU064 is not concomitantly administered with a strong inhibitor of CYP3A.

[0040] E11. The method according to any one of the preceding embodiments, wherein LOU064 is not concomitantly administered with a strong inhibitor of CYP3A4.

[0041] E12. The method of any one of embodiments E1 to E8, wherein LOU064 is administered in combination therapy with one or more therapeutic agents.

[0042] E13. The method according to E12, wherein the patient is additionally treated with at least one topical medication and at least one antibacterial agent in combination with LOU064.

[0043] E14. The method according to any one of embodiments E1 to E11, wherein the patient has not been previously treated with systemic agents or local treatments for HS prior to treatment with LOU064.

[0044] E15. The method according to any one of the preceding embodiments, wherein the patient is selected based on at least one of the following criteria:

[0045] a) The patient has moderate to severe HS;

[0046] b) the patient had at least 3 inflammatory lesions prior to treatment with LOU064; or

[0047] c) the patient does not have extensive scarring due to HS (no more than 15 fistulas) prior to treatment with LOU064;

[0048] d) The patient has been clinically diagnosed with HS for at least 12 months;

[0049] e) The patient has at least two anatomical regions associated with HS lesions.

[0050] E16. The method according to any one of the preceding embodiments, wherein the patient achieves at least one of the following by week 16 of treatment:

[0051] a) Simplified HiSCR;

[0052] b) HiSCR clinical outcomes (HiSCR50, HiSCR75, or HiSCR90)

[0053] c) HS redness and swelling are reduced;

[0054] d) Reduced skin pain as measured by pain NRS; e.g. pain NRS 30

[0055] e) Reduction of itch as measured by the Itch NRS; e.g., Itch NRS 30

[0056] f) a decrease in the total number of HS inflammatory lesions or the number of different types of HS inflammatory lesions; for example, AN50, AN75, AN90, or AN100;

[0057] g) reduction in IHS4 score;

[0058] h) a reduction as measured by DLQI of ≤ 6; and / or

[0059] i) Improvement of DLQI.

[0060] E17. The method according to any one of the preceding embodiments, wherein when said method is used to treat a patient population with moderate to severe HS, at least 40% of said patients achieve at least one of the following by week 16 of treatment:

[0061] a) Simplified HiSCR;

[0062] b)HiSCR50;

[0063] c)HiSCR75

[0064] d)HiSCR90.

[0065] E18. The method of any one of embodiments E1 to E16, wherein when said method is used to treat a patient population with moderate to severe HS, at least 25% of said patients achieve an NRS30 response (e.g., a pain NRS30 or pruritus NRS30 response) by week 16 of treatment.

[0066] E19. The method according to any one of embodiments E1 to E16, wherein when said method is used to treat a patient population with moderate to severe HS, less than 15% of said patients experience HS red bumps during 16 weeks of treatment.

[0067] E20. The method according to any one of embodiments E1 to E16, wherein as early as one or two weeks after the first dose of LOU064, the patient has at least one of the following:

[0068] a) Pain reduction as measured by pain NRS, (e.g. pain NRS 30)

[0069] b) Reduction of pruritus as measured by the Itch NRS, (e.g., Skin Itch NRS 30)

[0070] b) a reduction in CRP, eg, at least 25%, as measured using a standard CRP assay.

[0071] E21. The method according to any one of the above embodiments, wherein the patient achieves a sustained response 3 months after the end of treatment as measured by inflammatory lesion counts, such as AN50, Hidradenitis Suppurativa Clinical Response (HiSCR) (e.g., sHiSCR, HiSCR50, HiSCR75, or HiSCR90), Numerical Rating Scale for Itch or Pain (NRS), Hidradenitis Suppurativa - Physician Global Assessment (HS-PGA), HS Severity Assessment (SASH), International HS Severity Scoring System (IHS4), or Dermatology Life Quality Index (DLQI).

[0072] E22. The method according to E21, wherein the patient achieves a sustained response 3 months after the end of treatment as measured by simplified HiSCR (sHiSCR), HiSCR50, HiSCR75 or HiSCR90.

[0073] E23. The method according to any one of the above embodiments, wherein the LOU064 is disposed in a pharmaceutical composition, wherein the pharmaceutical composition comprises one or more pharmaceutically acceptable carriers, each independently selected from a filler, a lubricant, a binder, a disintegrant, and a glidant.

[0074] E24. The method according to E23, wherein the pharmaceutical composition is in the form of a tablet or a capsule.

[0075] E25. The method of embodiment E23 or E24, wherein the pharmaceutical composition comprises nanoparticles of LOU064.

[0076] E26. The method according to E25, wherein the pharmaceutical composition comprises nanoparticles of LOU064 having an average particle size of between about 50 nm and about 750 nm as measured by PCS.

[0077] E27. The method of any one of embodiments E23 to E26, wherein the pharmaceutical composition comprises LOU064 and a binder in a weight ratio of about 2:1.

[0078] E28. The method of E27, wherein the pharmaceutical composition comprises LOU064, a binder, and a surfactant in a weight ratio of about 2:1:0.08.

[0079] E29. The method of any one of embodiments E23 to E26, wherein the pharmaceutical composition comprises LOU064 and a binder in a weight ratio of about 1:1.

[0080] E30. The method according to embodiment 29, wherein the pharmaceutical composition comprises LOU064, a binder, and a surfactant in a weight ratio of about 1:1:0.05.

[0081] E31. The method according to any one of embodiments E23 to E30, wherein the pharmaceutical composition comprises LOU064, polyvinylpyrrolidone-vinyl acetate copolymer as a binder and sodium lauryl sulfate as a surfactant.

[0082] E32. The method according to any one of the preceding embodiments, wherein LOU064 is an anhydrous free base in crystalline form characterized by an x-ray powder diffraction pattern when heated at a temperature of about 25°C and When measured at an x-ray wavelength λ of 100 nm, the diffraction pattern comprises one or more representative peaks, which, with respect to 2θ, are selected from the group consisting of: 7.8±0.2°2θ, 9.2±0.2°2θ, 12.0±0.2°2θ, 13.6±0.2°2θ, 15.6±0.2°2θ, 16.0±0.2°2θ, 17.8±0.2°2θ, 18.3±0.2°2θ, 19.4±0.2°2θ, 20. 2°2θ, 18.7±0.2°2θ, 19.2±0.2°2θ, 19.9±0.2°2θ, 22.1±0.2°2θ, 23.4±0.2°2θ, 23. 9±0.2°2θ, 24.8±0.2°2θ, 25.2±0.2°2θ, 25.5±0.2°2θ, 27.2±0.2°2θ, and 29.6±0.2°2θ. DETAILED DESCRIPTION

[0083] As used herein, Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase and a member of the TEC kinase family. BTK is expressed in selected cells of the adaptive and innate immune systems, including B cells, macrophages, mast cells / basophils, and platelets. BTK is essential for signaling through Fcε receptors (FcεR1 for IgE) and activating Fcγ receptors (FcγR for IgG), as well as B cell antigen receptors (BCRs), and BTK inhibitors. BTK inhibitors such as ibrutinib have been approved for the treatment of B cell malignancies (Hendriks et al. 2014). Recently, it has been shown that inhibition of BTK leads to inhibition of mast cell and basophil activation / degranulation in vitro and reduces wheal size in skin prick tests in patients with IgE-mediated allergies (Smiljkovic et al. 2017; Regan et al. 2017; Dispenza et al. 2018). Therefore, inhibition of BTK is an attractive therapeutic concept for the treatment of various autoimmune and chronic inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, chronic urticaria, atopic dermatitis, asthma, and primary Sjögren's syndrome (Tan et al. 2013; Whang and Chang 2014). Examples of BTK inhibitors include non-covalent, reversible BTK inhibitors such as fenacinib and covalent, irreversible BTK inhibitors such as ivotinib, tolebrutinib, rizarutinib, tilbutinib, branebrutinib, orelabrutinib, and remibrutinib (LOU064).

[0084] The term "comprising" encompasses "including" as well as "consisting of," eg, a composition "comprising" X may consist only of X or may include other materials, eg, X+Y.

[0085] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0086] The term "about" in relation to a numerical value x means, for example, + / - 10%. When used before a numerical range or a list of numbers, the term "about" applies to each number in the series, for example, the phrase "about 1-5" should be interpreted as "about 1 to about 5", or, for example, the phrase "about 1, 2, 3, 4" should be interpreted as "about 1, about 2, about 3, about 4, etc.".

[0087] As used herein, the term "salt" or "salts" refers to an acid addition salt or a base addition salt of a compound used in the method of the present invention. "Salt" particularly includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of the compound of the present invention and is generally not biologically or otherwise undesirable. In many cases, due to the presence of an amino group, the compound used in the method of the present invention is able to form acid salts and / or base salts. Examples of salts are those disclosed in WO 2015 / 079417, which are hereby incorporated by reference.

[0088] As used herein, the term "administering" with reference to a compound (eg, LOU064 or another agent) is used to refer to delivering the compound to a patient by any route, preferably by oral administration.

[0089] As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, and the like, and combinations thereof, as would be known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Printing Company, 1990, pp. 1289-1329). Except in the case where any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions / formulations is contemplated.

[0090] The term "therapeutically effective amount / dose" of a compound used in the methods of the present invention refers to that amount of the compound that will elicit a biological or medical response in a subject (e.g., reduction or inhibition of enzyme or protein activity, or improvement in symptoms of HS, alleviation of HS symptoms, slowing or delaying disease progression of HS, or prevention of HS).

[0091] The term "treatment" or "treat" is defined herein as the application or administration of LOU064 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising LOU064 or a pharmaceutically acceptable salt thereof, to a subject, or an isolated tissue or cell line from a subject, wherein the subject has a particular disease (e.g., HS), has symptoms associated with the disease (e.g., HS symptoms), or has a predisposition to develop the disease (if applicable), wherein the purpose is to cure the disease (if applicable), reduce the severity of the disease, alleviate, ameliorate one or more symptoms of the disease, ameliorate the disease, reduce or ameliorate any associated symptoms of the disease, or predispose to develop the disease. The term "treatment" or "treat" includes treating a subject suspected of having a disease as well as a subject who is ill or has been diagnosed with a disease or medical condition. In some aspects, the term "treat" refers to ameliorating a disease or disorder (i.e., slowing, arresting, or reducing the development or progression of a disease or at least one clinical symptom thereof). In another embodiment, "treat," "treating," or "treatment" refers to alleviating or improving at least one physical parameter, including those that cannot be discerned by the patient. In yet another embodiment, "treat," "treating," or "treatment" refers to modulating a disease or disorder physically (e.g., stabilization of discernible symptoms) or physiologically (e.g., stabilization of a physical parameter), or both. More specifically, the term "treating" disease HS refers to treating inflammatory lesions (in terms of quantity or quality or reducing their volume and size) in HS patients, and / or treating abscesses and inflammatory nodules and / or draining fistulas in HS patients, and / or reducing the amount of scarring and / or reducing functional limitations associated with scarring. Treating disease HS also refers to reducing pain, fatigue, and / or itching associated with HS, reducing pus release and reducing the odor associated with pus release, and / or improving the quality of life of HS patients and / or reducing work impairment.

[0092] As used herein, the terms "prevention," "prevent," and "preventing" of a disease or disorder (HS) refer to prophylactic treatment of the disease or disorder; or delaying and / or inhibiting the onset or progression of the disease or disorder. More specifically, the term "preventing" HS refers to preventing the development of red bumps and new lesions that may develop; preventing scarring and the functional limitations associated with scarring; and / or, in particular, preventing the need for surgical intervention for HS.

[0093] As used herein, the phrase "subject population" is used to refer to a group of subjects who would benefit biologically, medically, or in quality of life from such treatment.

[0094] As used herein, the term "subject" refers to an animal. Typically, the animal is a mammal. Subject also refers to, for example, primates (e.g., humans, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In preferred embodiments, the subject is a human. When referring to a human, the terms "subject" and "patient" are used interchangeably.

[0095] As used herein, the phrases "has not been previously treated for HS with systemic therapy" and "treatment-naive" refer to patients with HS who have not previously been treated for HS with systemic agents (e.g., methotrexate, cyclosporine), or with biologic agents (e.g., IL-12 and IL-23 blockers, such as ustekinumab and gosekumab), or with TNF-α inhibitors (e.g., adalimumab or infliximab), or with IL-17 blockers (e.g., secukinumab, eselkumab, and brolucizumab). Systemic agents (i.e., agents administered orally, by injection, etc.) differ from topical agents (e.g., topical medications and phototherapy) in that they have a systemic (whole-body) effect when delivered to the patient. In some embodiments of the disclosed methods, regimens, uses, kits, and pharmaceutical compositions, the patient has not previously been treated for HS with systemic therapy.

[0096] As used herein, the phrase "previously treated for HS with systemic agents" is intended to refer to patients who have previously undergone treatment with systemic agents for HS. Such patients include those previously treated with biologics (such as IL-12 and IL-23 blockers, such as ustekinumab and gosekumab), or with TNF-α inhibitors (such as infliximab), or with IL-17 blockers (such as secukinumab, acetylcholine, and brolumab), as well as those previously treated with non-biologics, such as systemic immunosuppressants or immunomodulators (e.g., cyclosporine, methotrexate, and cyclophosphamide), systemic therapies (including retinoids (such as isoretinoids), dapsone, metformin, and oral zinc therapy). In some embodiments of the present disclosure, the patient has previously been administered a systemic agent for HS. In some embodiments, the patient has previously been treated with a systemic agent for HS (e.g., methotrexate, cyclosporine), but the patient has not previously been treated with a systemic biologic (i.e., a drug produced by a living organism, such as an antibody, a receptor decoy, etc.) for HS (e.g., secukinumab, ustekinumab, acetylcholine, brolucrumab, TNFα inhibitors (etanercept, adalimumab, infliximab, remicade, etc.). In this case, the patient is referred to as "biologic-naive." In some embodiments, the patient is biologic-naive.

[0097] As used herein, "selection (selecting)" and "selected (selected)" about a patient are used to mean that based on (due to) a specific patient with predetermined criteria, a specific patient is specially selected from a larger patient group. Similarly, "selective treatment" refers to providing treatment to a patient with a specific disease, wherein this patient is specially selected from a larger patient group based on a specific patient with predetermined criteria. Similarly, "selective administration" refers to administering a drug to a patient, and the patient is specially selected from a larger patient group based on (due to) a specific patient with predetermined criteria. By selection, selective treatment and selective administration, it is meant that based on the patient's personal medical history (e.g., previous therapeutic intervention, such as previously treated with biological agents), biological characteristics (e.g., specific genetic markers), and / or performance (e.g., not meeting specific diagnostic criteria), personalized therapy is delivered to the patient, rather than simply delivering a standard treatment regimen based on the patient's membership in a larger group. With reference to treatment methods as used herein, selection does not refer to the accidental treatment of a patient with a specific criteria, but refers to the intentional selection of a patient to administer treatment based on a patient with a specific criteria. Thus, selective treatment / administration is distinguished from standard treatment / administration, which delivers a particular drug to all patients with a particular disease, regardless of their individual medical history, disease presentation, and / or biological characteristics. In some embodiments, patients are selected for treatment based on the HS they suffer from.

[0098] As used herein, the terms “a,” “an,” “the,” and similar terms used in the context of the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0099] As used herein, the term "pharmaceutical composition" refers to a product obtained by using, mixing or combining more than one active ingredient. It should be understood that pharmaceutical compositions as used herein include both fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of active ingredients, such as a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more combination partners, to a patient as a single entity or dosage form. In this context, the term refers to a fixed-dose combination in a unit dosage form (e.g., a capsule, tablet, or sachet). The terms "non-fixed combination" or "kit of parts" all mean that the active ingredients, such as a compound of the present disclosure and one or more combination partners and / or one or more adjuvants, are administered to a patient as separate entities simultaneously, synchronously, or sequentially without specific time limits, or independently co-administered, wherein such administration provides therapeutically effective levels of both compounds in the patient, particularly where these time intervals allow the combination partners to exhibit effective doses that act synergistically (e.g., additively or synergistically). The term "non-fixed combination" also applies to mixture therapies, such as the administration of three or more active ingredients. Thus, the term "non-fixed combination" specifically defines an administration, use, composition or formulation in which the compounds described herein can be administered independently of one another (i.e., simultaneously or at different time points). It will be understood that the term "non-fixed combination" also encompasses the use of a single agent with one or more fixed combination products, wherein each independent formulation has different amounts of these active ingredients. It will be further understood that the combination products described herein, as well as the term "non-fixed combination," encompass active ingredients (including the compounds described herein) wherein these combination partners are administered in completely separate pharmaceutical dosage forms or pharmaceutical formulations that are also marketed independently of one another. Instructions for use of the non-fixed combination are provided or may be provided in the packaging (e.g., leaflets, etc.) or other information provided to the physician and / or medical staff. The independent formulations or parts of the formulation, product or composition can then be administered simultaneously or chronologically staggered, i.e., the individual parts of the kit of parts can be administered at different time points and / or any part of the kit of parts can be administered at the same or different time intervals. In particular, the dosing intervals are selected such that the effect of the combined use of these moieties on the disease being treated is greater than / exceeds the effect obtained by using the compound of formula (I) or its pharmaceutically acceptable salt alone; therefore, the compounds used in the pharmaceutical combinations described herein have a combined activity. The ratio of the total amount of the compound of formula (I) or its pharmaceutically acceptable salt to the second agent to be administered as a pharmaceutical combination can be varied or adjusted to better meet the needs of a specific patient subgroup to be treated or the needs of an individual patient, which may be due to, for example, the patient's age, sex, weight, etc.

[0100] As used herein, the terms "co-administration" or "administered in combination" and the like are intended to encompass the administration of one or more compounds described herein together with a selected combination partner to a single subject (e.g., a patient or subject) in need thereof, and are intended to include treatment regimens in which these compounds are not necessarily administered by the same route of administration and / or are administered simultaneously.

[0101] LOU064

[0102] LOU064 (=N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, INN: remibrutinib) is a drug candidate disclosed in WO 2015 / 079417 A1 for the selective inhibition of Bruton's tyrosine kinase. This compound is a potent, highly selective, irreversible, covalent BTK inhibitor. Due to binding to the inactive conformation of BTK, LOU064 exhibits exquisite kinase selectivity and thus reduces kinase off-target binding, and due to covalent inhibition, the compound exhibits potent and sustained pharmacodynamic effects without the need for prolonged and high systemic compound exposure (Angst, D. et al., Discovery of LOU064 (Remibrutinib), a Potent and Highly Selective Covalent Inhibitor of Bruton's Tyrosine Kinase, J Med Chem. 2020 May 28;63(10):5102-5118).

[0103] LOU064 for use in the methods of the present invention is the free base, as represented by formula (I):

[0104]

[0105] In other embodiments, N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide is the free base of anhydrous crystalline Form A, as disclosed in WO2020 / 234779 (Example 1), which is hereby incorporated by reference.

[0106] LOU064, which has been previously suggested for the treatment of chronic spontaneous urticaria (CSU) (WO2020 / 234782A1) and Sjögren's syndrome (SjS) (WO2020 / 234781A1), is currently being tested in Phase II clinical studies for CSU and SjS.

[0107] In WO 2020 / 234782 A1, doses of 10 mg, 25 mg, and 100 mg are generally recommended to be administered bid to achieve maximum efficacy in CSU.

[0108] In a Phase 2b, randomized, double-blind, placebo-controlled trial, the efficacy and safety of LOU064 were evaluated in patients with at least moderately active chronic spontaneous urticaria (CSU) who were inadequately controlled on H1 antihistamines over a 12-week period. Patients received LOU064 10 mg once daily, 35 mg once daily, 100 mg once daily, 10 mg twice daily, 25 mg twice daily, 100 mg twice daily, or placebo (1:1:1:1:1:1:1 ratio). The 25 mg once daily regimen was found to be particularly effective compared to the other doses.

[0109] Therefore, a dose of 25 mg bid was selected for subsequent phase III clinical studies in CSU.

[0110] BTK occupancy in blood and / or tissue has been reported to be a suitable biomarker for dose selection in clinical studies such as the CSU and SjS studies (WO2020 / 234782 and WO2020 / 234781).

[0111] Furthermore, it has been reported that the BTK occupancy rate and duration of BTK occupancy are different in the blood and various tissues of female rats (WO2020 / 234781).

[0112] BTK occupancy in different tissues is relevant to efficacy and optimal dose selection in different indications. However, there is currently no consistent picture of all tissues relevant to HS indications, and therefore penetration of one or more tissues is required for the treatment or prevention of HS. As reported in rats, BTK occupancy and BTK occupancy half-life are different in blood and various tissues.

[0113] BTK occupancy half-life depends on turnover rate (the ability of BTK cells to regenerate). Such turnover rate is different in each tissue and is species-specific. BTK occupancy rate further depends on the PK / PD properties of the compound, which also depend on the species.

[0114] BTK inhibitors can act or intervene through three basic mechanisms or pathways:

[0115] 1) Reduce allergic / type I hypersensitivity reactions via FcεR1,

[0116] 2) Suppression of B cell autoreactivity and immune complexes in autoreactivity / inflammation or type 3 hypersensitivity reactions via FcγR and / or BCR,

[0117] 3) Inhibition of autoantibody secretion in autoantibody pathology or type 2 hypersensitivity reactions through BCR

[0118] Without being bound by theory, BTK inhibition is implicated in the latter two pathways, as HS is thought to be associated with B cell activity (Rumberger et al. 2020, Gudjonsson et al.) and through the presence of autoantibodies (Byrd et al. (2018), J. Dermatol. [British Journal of Dermatology]; 179(3):792-794, (2019), Camona-Rivera et al. (2021) J Invest Dermatol. [Journal of Dermatology Research] Oct 1:S0022-202X(21)02286-7.doi:10.1016 / j.jid.2021.07.187). B cells and plasma cells can be found in the tertiary lymphoid organs of diseased tissue. BTK conversion may be higher in B cells residing in tertiary lymphoid organs of HS lesions compared with cutaneous mast cells, and adequate target tissue penetration may be more difficult to achieve in HS compared with CSU due to fibrotic tissue remodeling and the formation of abscesses and fistulas.

[0119] On the other hand, CSU may be particularly dependent on the first pathway described above, as demonstrated by the activity of anti-IgE antibodies (via FcεR1), and therefore, clinical responses in HS may not be expected using any of the doses disclosed for CSU or other indications.

[0120] Thus, without being bound by any theory, an effective dose of LOU064 for treating or preventing HS is one that allows for higher tissue concentrations into inflamed, partially fibrotic HS lesions and potentially higher BTK turnover.

[0121] Pharmaceutical compositions for use in the methods of the invention

[0122] When combined with a pharmaceutically acceptable carrier, a BTK inhibitor, i.e., a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be used as a pharmaceutical composition. In addition to the compound of formula (I) or a pharmaceutically acceptable salt thereof, such a composition may also include a carrier, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials known in the art. The characteristics of the carrier depend on the route of administration. The pharmaceutical composition for use in the disclosed method may also contain other therapeutic agents for treating specific target disorders. For example, the pharmaceutical composition may also include an anti-inflammatory agent or an antipruritic agent. Such additional factors and / or agents may be included in the pharmaceutical composition to produce a synergistic effect with the compound of formula (I) or a pharmaceutically acceptable salt thereof, or to minimize the side effects caused by the compound of formula (I) or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the pharmaceutical composition for use in the disclosed method includes a compound of formula (I) or a pharmaceutically acceptable salt thereof, and its daily dose is about 50 mg to 200 mg, for example 25 mg bid or 100 mg bid.

[0123] Suitable compositions for oral administration include an effective amount of a compound of the present invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavorings, colorants, and preservatives to provide pharmaceutically refined and palatable formulations. Tablets may contain the active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for tablet manufacture. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).

[0124] The pharmaceutical compositions for use in the disclosed methods can be prepared in a conventional manner. In one embodiment, the pharmaceutical compositions are provided for oral administration. For example, these pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient and:

[0125] a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0126] b) lubricants, for example, silicon dioxide, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; in the case of tablets, also

[0127] c) binders, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if necessary

[0128] d) disintegrants, for example, starch, agar, alginic acid or its sodium salt or effervescent mixtures; and / or

[0129] e) Adsorbents, colorants, flavorings and sweeteners.

[0130] Thus, pharmaceutical compositions for use in the methods of the present invention comprise LOU064 and one or more pharmaceutically acceptable carriers, each independently selected from the group consisting of a filler, a lubricant, a binder, a disintegrant, and a glidant.

[0131] In another embodiment, suitable pharmaceutical compositions, LOU064 can be in any pharmaceutically acceptable form. It may be preferred that the pharmaceutical composition be in tablet or capsule form. Tablets may be film-coated or enteric-coated according to methods known in the art. It may also be preferred to include LOU064 in the pharmaceutical composition / formulation in the form of nano- or micro-particles.

[0132] If LOU064 is present in the form of nanoparticles in a pharmaceutical formulation, the average particle size may be less than 1000 nm. Preferably, the average particle size of LOU064 may be less than 500 nm, more preferably less than 250 nm.

[0133] In preferred embodiments, the average particle size of LOU064 may be between about 50 nm and about 1000 nm, or between about 50 nm and about 750 nm, or between about 60 nm and about 500 nm, or between about 70 nm and about 350 nm, or between about 100 nm and about 170 nm. More preferably, the average particle size of LOU064 may be between about 100 nm and about 350 nm, or between about 110 nm and about 200 nm, or between about 120 nm and about 180 nm, or between about 120 nm and about 160 nm. Preferably, the average particle size of LOU064 may be between about 150 nm and about 200 nm.

[0134] If LOU064 is present in the form of nanoparticles in a pharmaceutical formulation, oral administration is preferably at a dose of about 25 mg to about 100 mg twice daily, more preferably at a dose of about 100 mg twice daily.

[0135] If LOU064 is present in the form of micronized particles in the pharmaceutical formulation, the average particle size may be 1-5 μm or preferably 1.0-1.5 μm. Preferably, the average particle size of LOU064 may be 1.1 to 1.3 μm.

[0136] If LOU064 is present in the form of microparticles in the pharmaceutical formulation, oral administration is preferably at a dose of about 25 mg to about 100 mg twice daily, for example at a dose of about 25 mg twice daily.

[0137] In a preferred embodiment, the polydispersity index (PI) is between 0.01 and 0.5, more preferably between 0.1 and 0.2, in particular 0.12-0.14. The preferred particle size distribution is shown in Figure 5 .

[0138] The above average particle size is intensity-weighted. The average particle size can be determined by dynamic light scattering. Preferably, the average particle size is determined by photon correlation spectroscopy (PCS). In particular, the device "Zetasizer Nano ZS" version 7.13 from Malvern Panalytical Ltd., UK, can be used to determine the average particle size.

[0139] Preferably, the measurement is carried out using a 0.1 mM NaCl solution in purified water (1:10) as a wet dispersion method, with a decay index of 2-9, in particular 5. The measurement is preferably carried out at 25° C. Further preferred settings of the measuring system are as follows:

[0140] Cuvette: disposable quantitative cuvette

[0141] Counting rate (kcPs): 315

[0142] Duration: 60 seconds

[0143] Measuring position (mm): 4.65.

[0144] In one embodiment of the present invention, the LOU064 composition is formulated into a pharmaceutical composition suitable for oral administration to humans according to conventional procedures. Typically, the composition for oral administration is a capsule or tablet.

[0145] In one embodiment, the pharmaceutical composition / formulation of LOU064 may be formulated according to the formulations disclosed in U.S. Appl. No. 63 / 141558 or its family members (published PCT WO2022 / 162513), which are incorporated herein by reference.

[0146] According to the present invention, a suitable pharmaceutical composition for oral administration comprises LOU064 and a binder.

[0147] Suitable binders include polyvinyl pyrrolidone-vinyl acetate copolymer, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, methylcellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, polyethylene glycol, polyvinyl alcohol, shellac, polyvinyl alcohol-polyethylene glycol copolymer, polyethylene glycol-propylene glycol copolymer or a mixture thereof. Preferably, the binder is polyvinyl pyrrolidone-vinyl acetate copolymer.

[0148] The weight ratio of LOU064 to the binder may be about 3:1 to about 1:3; for example, about 3:1, about 2:1, about 1:1, preferably the weight ratio of LOU064 to the binder is about 2:1 or about 1:1.

[0149] Preferably, a suitable pharmaceutical composition for oral administration comprises LOU064, a binder, and a surfactant.

[0150] Suitable surfactants include sodium lauryl sulfate, potassium lauryl sulfate, ammonium lauryl sulfate, sodium lauryl ether sulfate, polysorbate, perfluorobutane sulfonate, dioctyl sulfosuccinate, or mixtures thereof. Preferably, the surfactant is sodium lauryl sulfate.

[0151] The weight ratio of LOU064, binder and surfactant is about 2:1:0.5, or about 2:1:0.1, or about 2:1:0.08, or about 2:1:0.05, or about 2:1:0.04, or about 2:1:0.03, or about 2:1:0.02. Preferably, the weight ratio of LOU064, binder and surfactant is about 2:1:0.08 or about 1:1:0.05.

[0152] In a particularly preferred embodiment, a pharmaceutical composition suitable for oral administration comprises LOU064, a binder, and a surfactant, wherein the binder is polyvinyl pyrrolidone-vinyl acetate copolymer (copovidone) and the surfactant is sodium lauryl sulfate (SLS), and wherein the weight ratio of LOU064, copovidone, and SLS is about 2:1:0.08. It is also particularly preferred that LOU064 is present in the pharmaceutical composition in the form of nanoparticles, preferably having an average particle size of between about 100 nm and about 200 nm as measured by PCS.

[0153] A method of treating or preventing HS using LOU064 or a pharmaceutically acceptable salt or crystalline form thereof.

[0154] Disclosed are methods of treating or preventing HS in a subject in need thereof using LOU064 or a pharmaceutically acceptable salt thereof, comprising administering to the subject a therapeutically effective dose of LOU064 or a pharmaceutically acceptable salt thereof. LOU064 or a pharmaceutically acceptable salt thereof for use in the disclosed methods can be used in vitro, ex vivo, or incorporated into a pharmaceutical composition and administered in vivo to treat a patient with HS (e.g., a human patient).

[0155] The appropriate dosage will vary depending on, for example, the specific pharmaceutically acceptable salt of LOU064, the specific polymorphic form of LOU064, the patient's weight, the mode of administration, the pharmaceutical composition, the nature and severity of the condition being treated, and the nature of the previous treatments the subject has undergone. Ultimately, the attending healthcare provider will determine the amount of LOU064 to treat each individual subject. In some embodiments, the attending healthcare provider can administer a low dose of LOU064 and observe the patient's response.

[0156] In one embodiment of the present disclosure, LOU064 or a pharmaceutically acceptable salt thereof is orally administered at a dose of about 50 mg to about 200 mg per day.

[0157] In one embodiment of the disclosure, LOU064 or a pharmaceutically acceptable salt thereof is orally administered at a dose of about 25 mg twice daily to about 100 mg twice daily, for example, about 25 mg twice daily (BID), about 50 mg BID, or about 100 mg BID.

[0158] In another embodiment, LOU064 is administered orally at a dose of about 25 mg twice daily.

[0159] In another embodiment, LOU064 is administered orally at a dose of about 100 mg twice daily.

[0160] The duration of therapy using the pharmaceutical compositions of the present disclosure will vary depending on the severity of the disease or disorder being treated and the condition and personal response of each individual subject. In some embodiments, LOU064 is administered to a subject short-term, e.g., up to 1 week, e.g., up to 2 weeks, e.g., up to 4 weeks, e.g., up to 12 weeks, e.g., up to 16 weeks, e.g., up to 24 weeks.

[0161] In some other embodiments, LOU064 is preferably administered to the subject chronically (e.g., LOU064 is used for an unlimited total duration, as long as the disease persists), e.g., for at least 6 months, e.g., for more than 1 year, 2 years, 3 years, 4 years, 10 years. LOU064 or a pharmaceutically acceptable salt thereof may be used for up to 5 years, 10 years, 15 years, 20 years, or for life. In preferred embodiments, treatment with LOU064 according to the present invention is chronic treatment.

[0162] HS is a chronic, inflammatory, scarring condition that primarily affects the intertriginous skin of the axilla, groin, inframammary, genital-anal, and perineal regions. It is also known as inverse acne. Three diagnostic criteria confirm the diagnosis of HS: typical lesions (deep, painful nodules [blind] boils in early primary lesions, or abscesses, sinus drainage, bridging scars, and "tombstone" open comedones in secondary lesions); typical distribution (axilla, groin, genital, perineal, and perianal regions, buttocks, and inframammary and intermammary regions); and chronicity and recurrence (Margesson and Danby (2014) Best Practices and Res. Clin. Ob. And Gyn 28:1013-1027). The body extent of HS can be categorized using Hurley's clinical staging, as shown in Table 1 below:

[0163]

[0164] Table 1: Hurley stages of HS. Indeed, patients with Hurley stage III may have exhausted stage III but still have active stage I or II disease.

[0165] HS is composed of follicular obstruction, ductal rupture, and secondary inflammation. Patients initially experience obstruction of the follicular duct, which over time leads to leakage and horizontal rupture into the dermis. When the hair follicle-pilosebaceous gland (FPSB) repair fails, follicular fragmentation stimulates three responses, initiating the HS disease process. The first is an inflammatory response triggered by the innate immune system, causing suppuration and tissue destruction, leading to a foreign body reaction and extensive scarring. The second response leads to epithelialized sinuses, which may develop from stem cells derived from FPSB units that survive the destruction caused by the inflammatory response. Third, in most cases, an invasive, hyperplastic gel mass is produced, which is composed of a gel containing inflammatory cells and is presumed to be a precursor to the aforementioned epithelialization elements. (See Margesson and Danby (2014)). As used herein, the phrase "slowing HS disease progression" refers to reducing the progression rate of any aspect of the HS disease process, particularly the inflammatory response. In some embodiments of the present disclosure, treatment with LOU064 slows HS disease progression.

[0166] Recurrence of HS in patients includes the development of papules, pustules or inflamed nodules, pain and itching, abscesses, drainage and any combination thereof. As used herein, "HS red bumps" (etc.) are defined as an increase of at least 25% in abscess and inflamed nodule counts (AN) relative to baseline, with a minimum increase of two ANs.

[0167] In some embodiments of the present disclosure, treatment with LOU064 according to the disclosed methods prevents HS redness and swelling, reduces the severity of HS redness and swelling, and / or reduces the frequency of HS redness and swelling. In some embodiments, when treating a HS patient population according to the disclosed methods, less than 5%, less than 10%, less than 15%, or less than 20% experience redness and swelling during the first 16 weeks of treatment.

[0168] As used herein, the phrase "reducing the severity of HS redness and swelling" and the like means reducing the intensity of HS redness and swelling, such as reducing the number and / or size of abscesses and / or inflammatory nodules, reducing the intensity of specific redness and swelling components (e.g., reducing the number, size, thickness, etc. of abscesses and / or inflammatory nodules, reducing the degree of skin irritation (itching, pain), etc.), and / or reducing the duration of the presence of redness and swelling (or its components).

[0169] As used herein, the phrase "reducing the frequency of HS lumps" and the like means reducing the incidence of HS lumps, for example, reducing the incidence of abscesses and / or inflammatory nodules. By reducing the frequency of HS lumps, patients will experience fewer recurrences of HS. The incidence of lumps can be assessed by monitoring patients over time to determine whether the prevalence of lumps is decreasing.

[0170] As used herein, the phrase "preventing HS red bumps" means eliminating future HS red bumps and / or red bump components.

[0171] The effectiveness of HS treatment can be assessed using various known methods and tools for measuring HS disease status and / or HS clinical response. Some examples include, for example, Hurley staging, severity assessment scoring system (SAHS), Sartorius score, modified Sartorius score, HS physician global assessment (HS-PGA) score, visual analog scale (VAS) or numeric rating scale (NRS) for assessing skin-related pain or pruritus, Dermatology Life Quality Index (DLQI), HS clinical response based on the sum of abscesses and inflammatory nodules (HiSCR: HiSCR50, HiSCR75 or HiSCR90), simplified HiSCR, EuroQuol-5D (EQ5D), hospital focus The depression and anxiety scale, healthcare resource utilization, hidradenitis suppurativa severity index (HSSI), work productivity index (WPI), inflamed body surface area (BSA), inverse acne severity index (AISI), etc. (see, for example, Deckers and Prens (2016) Drugs 76:215-229; Sartorius et al. (2009) Br. J. Dermatol 161:831-39; Chiricozzi et al. (2015) Wounds 27(10):258-264). In some embodiments, the effectiveness of the methods of the present invention disclosed herein can be assessed by: HS Physician's Global Assessment (HS-PGA), Severity Assessment Score (SAHS), Numeric Rating Scale (NRS) (itch or pain), Dermatology Life Quality Index (DLQI), HS Clinical Response based on the sum of abscesses and inflammatory nodules (HiSCR, i.e., HiSCR50, HiSCR75, or HiSCR90), and / or simplified HiSCR. Preferably, the effectiveness of HS treatment as disclosed herein can be assessed by: HS Clinical Response based on the sum of abscesses and inflammatory nodules (HiSCR, i.e., HiSCR50, HiSCR75, or HiSCR90), and / or simplified HiSCR.

[0172] In some embodiments, HS patients respond to HS treatment and achieve HiSCR. In some embodiments, when treating a HS patient population according to the disclosed methods, by week 16, at least 30%, at least 40%, at least 50%, at least 60%, or at least 70% achieve at least one of the following:

[0173] -HiSCR50;

[0174] -HiSCR75;

[0175] -HiSCR90; or

[0176] - Simplified HiSCR (sHiSCR); preferably 2HiSCR.

[0177] In other embodiments, the effectiveness of a HS treatment as disclosed herein can be measured by the difference between the response rate of treated patients (i.e., patients who achieve a HiSCR response (HiSCR, i.e., HiSCR50, HiSCR75, HiSCR90, or sHiSCR response) to HS treatment with a compound of the invention) and the response rate of placebo-treated patients by week 16 of treatment. In some embodiments, the difference in response rate, as measured by HiSCR (HiSCR50, HiSCR75, HiSCR90, or sHiSCR), is at least 15%, at least 25%, at least 30%, or at least 35%.

[0178] For treatment response, preferred scoring systems are HiSCR (HiSCR50, HiSCR75 or HiSCR90), simplified HiSCR, pain or pruritus NRS (e.g., pain NRS30 or pruritus NRS30), severity assessment scoring system (SAHS), HS-PGA, inflammatory lesion count (count of abscesses, inflammatory nodules and / or draining fistulas), ISH4 and DLQI.

[0179] Hidradenitis suppurativa clinical response (HiSCR) is a measure of clinical response to HS treatment. The HiSCR50 response to treatment (compared to baseline) is as follows: 1) at least a 50% reduction (AN50) in abscesses and inflammatory nodules, and 2) no increase in the number of abscesses, and 3) no increase in the number of draining fistulas.

[0180] In some embodiments, the HS patient responds to HS treatment and achieves a HiSCR50.

[0181] In some embodiments, when treating a HS patient population according to the disclosed methods, at least 40%, at least 50%, at least 60%, or at least 70% achieve HiSCR50 by week 16 of treatment.

[0182] As used herein, "simplified HiSCR" or "sHiSCR" refers to a modified HiSCR that does not include abscess count (relative to baseline) when assessing lesion progression. In preferred embodiments, HS patients respond to HS treatment and achieve a simplified HiSCR. In some embodiments, when treating a HS patient population according to the disclosed methods, at least 40%, at least 50%, at least 60%, or at least 70% achieve a simplified HiSCR by week 16 of treatment.

[0183] HiSCR75 responses to treatment (compared to baseline) were as follows: 1) a reduction of at least 75% in abscesses and inflammatory nodules, and 2) no increase in the number of abscesses, and 3) no increase in the number of draining fistulas.

[0184] HiSCR90 responses to treatment (compared to baseline) were as follows: 1) at least a 90% reduction in abscesses and inflammatory nodules, and 2) no increase in the number of abscesses, and 3) no increase in the number of draining fistulas.

[0185] In preferred embodiments, the HS patient responds to HS treatment and achieves HiSCR75 or HiSCR90.

[0186] In some embodiments, when treating a HS patient population according to the disclosed methods, at least 40%, at least 50%, at least 60%, or at least 70% achieve HiSCR75 by week 16 of treatment.

[0187] In some embodiments, when treating a HS patient population according to the disclosed methods, at least 40%, at least 50%, at least 60%, or at least 70% achieve HiSCR90 by week 16 of treatment.

[0188] Pain can be assessed using a numeric rating scale (NRS). In some embodiments, HS patients respond to HS treatment and achieve an improved pain NRS. Pain NRS30 is defined as a reduction of at least 30% in pain compared to baseline and a decrease of at least 1 unit in the Patient Global Assessment (PGA) of cutaneous pain in patients with a baseline score of 3 or higher. In some embodiments, HS patients respond to HS treatment and achieve NRS30. In some embodiments, when treating a HS patient population according to the disclosed methods, by week 16 of treatment, at least 25%, at least 30%, at least 40%, at least 50%, or at least 60% achieve NRS30. In a preferred aspect of this embodiment, when treating a HS patient population according to the disclosed methods, by week 16 of treatment, at least 30% achieve NRS30. In some embodiments, in response to treatment according to the claimed methods, the patient experiences a reduction in pain (as measured by VAS or NRS, preferably NRS) as early as 1 or 2 weeks after the initial administration.

[0189] The severity assessment scoring system (SAHS) is described in Hassam et al. JAMA Dermatol (2018), 154(3):330-335. The severity of HS can be assessed using the SAHS score, which measures the number of affected areas (left axilla, right axilla, left inframammary, right inframammary, intermammary or chest, abdomen, mons pubis, left groin, right groin, genitalia, perianal or perineum, left gluteal, right gluteal, etc. [e.g., neck, behind the ear]), the number of inflammatory and / or painful lesions other than fistulas (ILOFs), and the number of fistulas. These physician-rated items are completed using two patient-reported items: patients are asked about the number of new boils or red bumps from existing boils that have broken out in the past 4 weeks and the current severity of pain in the most symptomatic lesion during daily activities (e.g., sitting, moving, or working) on ​​a numerical rating scale (NRS). The SAHS score is a composite score of all the information collected above. Mild HS is defined as a SASH score of 4 or less. Moderate HS is defined as a SASH score of 5 to 8, and severe HS is defined as a SASH score of 9 or higher.

[0190] In some embodiments, HS patients respond to HS treatment by achieving an improved SAHS score. In some embodiments, HS patients respond to HS treatment by achieving a decrease in SAHS score of at least one point compared to baseline. In other embodiments, HS patients respond to HS treatment by achieving a decrease in SAHS score of at least two points or at least three points compared to baseline. Preferably, prior to treatment with LOU064, the SAHS score at baseline is at least 4.

[0191] The International Hidradenitis Suppurativa Severity Score (IHS4) is a clinically validated tool for dynamically assessing the severity of HS that can be used in clinical trials or in real-world settings (Zouboulis et al. (2017); Br. J. Dermatol. [British Journal of Dermatology]; 177(5):1401-9.). According to this tool, the severity of HS is assessed by summing the individual HS lesions according to the following scheme:

[0192] Number of tuberculosis × 1 +

[0193] Number of abscesses × 2+

[0194] Number of drainage tunnels (fistulas / sinuses) × 4

[0195] The severity of HS is then defined as:

[0196] Mild HS: ≤ 3 points

[0197] Moderate HS: 4–10 points

[0198] Severe HS: ≥11 points

[0199] HS lesions are defined as follows: A nodule (inflammatory nodule) is a raised, three-dimensional, round, infiltrative lesion >10 mm in diameter. An abscess is a tender, fluctuating mass >10 mm in diameter with a surrounding erythematous area; the abscess contains pus in the center. A drainage tract is a raised, tender, fluctuating longitudinal mass of variable length and depth that terminates at the skin surface and sometimes exudes fluid. Fistulas and sinuses are examples of tracts.

[0200] In some embodiments, the HS patient achieves an improved (ie, reduced) IHS4 score.

[0201] In some embodiments, HS patients respond to HS treatment by achieving a decrease of at least two points in the IHS4 score compared to baseline. In other embodiments, HS patients respond to HS treatment by achieving a decrease of at least three points or a decrease of at least four points in the IHS4 score compared to baseline.

[0202] The DLQI is the most established instrument for measuring the quality of life in dermatology. It consists of questions about how the skin condition has affected different aspects of your feelings and activities of daily living over the past week. Each question is scored from 0 (not at all) to 3 (very much). The maximum score is 30, with 0–1 being considered no impact on the patient's life, 2–5 a little impact, 6–10 a moderate impact, 11–20 a very great impact, and 21–30 an extreme impact. (See Finlay and Khan (1994) Clin Exp Dermatol 19:210–16). In some embodiments, patients with HS respond to HS treatment with an improved DLQI.

[0203] In certain embodiments, in response to the treatment according to the claimed method, as measured by standard CRP assay or high sensitivity CRP (hsCRP) assay, the patient experiences a reduction in CRP as early as 1 or 2 weeks after initial administration. As used herein, "C-reactive protein" and "CRP" refer to serum C-reactive protein, a plasma protein generally used as an indicator for the acute phase response to inflammation. The CRP level in plasma can be given with any concentration, such as mg / dl, nmol / L. CRP levels can be measured by a variety of standard assays, such as radial immune diffusion, electroimmunoassay, immunoturbidimetry, ELISA, turbidimetry, fluorescence polarization immunoassay and laser turbidimetry. CRP test can be tested using standard CRP test or high sensitivity CRP (hs-CRP) test (that is, using laser turbidimetry to measure the high sensitivity test of low-level CRP in sample). Kits for measuring CRP levels are available commercially from various companies, such as Calbiotech, Inc., Cayman Chemical, Roche Diagnostics Corporation, Abazyme, DADE Behring, Abnova Corporation, Aniara Corporation, Bio-Quant Inc., Siemens Healthcare Diagnostics, and the like.

[0204] The Sartorius HS score (also known as the HS score or HSS) is derived by counting the affected areas, nodules, and sinus tracts in HS patients. (Sartorius et al. (2003) Br J Dermatol [British Journal of Dermatology] 149:211–13). The modified Sartorius HS score is a revised version of the original HSS that was slightly simplified to make it more practical, for example, by including fewer specific lesions in the score and changing the number of points given for each parameter (Sartorius et al. (2009) Br. J Dermatol. [British Journal of Dermatology] 161:831-839). In some embodiments, HS patients respond to HS treatment, achieving an improved modified Sartorius HS.

[0205] The HS Physician's Global Assessment (HS-PGA) is a 6-point rating scale (scores range from 0 to 5) based on the number of HS lesions (i.e., abscesses, draining fistulas, inflammatory nodules, and non-inflammatory nodules). (Kimball AB, Kerdel F, Adams D, et al. Adalimumab for the treatment of moderate to severe hidradenitis suppurativa: a parallel randomized trial. Ann Intern Med 2012;157:846–855). In some embodiments, patients with HS respond to HS treatment by achieving an improved HS-PGA. In some embodiments, patients with HS respond to HS treatment by achieving a decrease in HS-PGA score of at least 2 points compared to baseline. Preferably, the HS-PGA score at baseline is at least 3 prior to treatment with LOU064.

[0206] In some embodiments, when a population of HS patients is treated according to the disclosed methods, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of patients who respond to treatment by week 16 (e.g., patients who achieve a HiSCR (e.g., HiSCR50; HiSCR75 or HiSCR90) or a simplified HiSCR by week 16) have a sustained response 3 months after the end of treatment, or 6 months after the end of treatment, or 12 months after the end of treatment. In another aspect of this embodiment, at least 40% or at least 50% of patients who respond to treatment by week 16 (e.g., patients who achieve a HiSCR (e.g., HiSCR50; HiSCR75 or HiSCR90) or a simplified HiSCR by week 16) have a sustained response 3 months after the end of treatment. Preferably, at least 70% of patients who respond to treatment by week 16 (e.g., patients who achieve a HiSCR (e.g., HiSCR50; HiSCR75 or HiSCR90) or a simplified HiSCR by week 16) have a sustained response 3 months after the end of treatment. As used herein, the term "sustained" means that the outcome or goal (e.g., pain reduction, inflammation reduction) is substantially maintained over a given time.

[0207] Lesion-associated pruritus can be assessed using a patient survey. Patients are asked to rate lesion-associated pruritus on a scale from 0 (no itch) to 10 (worse itch possible). In some embodiments, when treating a HS patient population according to the disclosed methods, the pruritus score improves by at least 2 points, preferably at least 3 points. Furthermore, when compared to the placebo group, the difference between the treatment group and the placebo group is at least 1 point.

[0208] Lesion-associated pruritus can also be assessed using the Numerical Rating Scale (NRS) for pruritus. The vast majority of HS patients report pruritus (Fernandez et al. (2021) Itch and pain by lesion morphology in hidradenitis suppurativa patients. Int J Dermatol.; 60(2): e56-e59). The NRS is a segmented numerical version of the visual analog scale (VAS), in which respondents select an integer (0-10 integers on an 11-point scale) that best reflects the intensity of their skin disease-associated pruritus (Nguyen et al. (2021). J Eur Acad Dermatol Venereol. 2021 Jan; 35(1): 50-61). In some embodiments, HS patients respond to HS treatment and achieve an improved skin NRS. An itch NRS of 30 is defined as a reduction of at least 30% in skin pruritus compared to baseline. In some embodiments, HS patients respond to HS treatment by achieving a Skin NRS of 30. In some embodiments, when treating a population of HS patients according to the disclosed methods, at least 25%, at least 30%, at least 40%, at least 50%, or at least 60% achieve a Skin NRS of 30 by week 16 of treatment. In a preferred aspect of this embodiment, when treating a population of HS patients according to the disclosed methods, at least 30% achieve a Skin NRS of 30 by week 16 of treatment. In some embodiments, in response to treatment according to the claimed methods, the patient experiences a reduction in skin pruritus (as measured by Skin NRS) as early as 1 or 2 weeks after the initial administration.

[0209] Odor caused by lesion drainage can be assessed using a patient survey. Patients are asked to rate the odor caused by lesion drainage on a scale of 1 (no odor), 2 (little odor), 3 (moderate odor), to 4 (lots of odor). In some embodiments, when treating a HS patient population according to the disclosed methods, the itch score improves by at least 1 point, preferably at least 2 points. Furthermore, when compared to the placebo group, the difference between the treatment group and the placebo group is at least 1 point.

[0210] The impact of HS on the ability to perform work can be assessed using a patient survey. Patients are asked to rate the extent to which HS affects their ability to perform work on a scale from 1 (not at all), 2 (a little), 3 (moderately), 4 (a lot), to 5 (unable to perform any work). In some embodiments, when treating a HS patient population according to the disclosed methods, the pruritus score improves by at least 1 point, preferably by at least 2 points. Furthermore, when compared to the placebo group, the difference between the treatment group and the placebo group is at least 1 point.

[0211] Security:

[0212] The short-term safety of LOU064 has been demonstrated in Phase I clinical studies with single doses up to 600 mg and further with 100 mg bid for up to 18 days. However, there are no available data on long-term safety (i.e., beyond 52 weeks) at this time.

[0213] Given the dose-limiting side effects observed with the covalent irreversible BTK inhibitors ivotinib and tolebrutinib, ivotinib has shown dose-limiting liver enzyme elevations at a dose of 75 mg bid and tolebrutinib has shown dose-limiting diarrhea in Phase II clinical studies (Becker A. et al., 2019, Clin Transl Sci; 13, 325-336; Montalban X. et al., 2019, N Engl J Med; 380(25): 2406-17, Smith PF et al., 2019, ACTRIMS Forum, February 28, 2019, P072), it is encouraging that no meaningful increase in the incidence of these adverse events was seen even with LOU064 at a higher dose of 100 mg bid for an extended period of time (up to 52 weeks). In particular, LOU064 at a dose of 100 mg bid did not induce any dose-limiting liver enzyme elevations or other off-target effects over an extended period of time (up to 52 weeks). Therefore, LOU064 is suitable for long-term treatment.

[0214] Thus, an object of the invention is LOU064 for use in the methods described, wherein the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lipase do not change by more than 10% by week 12, week 24, or week 52 of treatment compared to the baseline levels at the start of therapy.

[0215] Therefore, it is particularly surprising that LOU064 not only effectively treats HS but also has a better safety profile compared to other BTK inhibitors, particularly compared to acalabrutinib, especially when maintained over an extended period of time. For example, the currently approved BTK inhibitors primarily for the treatment of hematological malignancies (ibrutinib, acalabrutinib, and zanubrutinib) have known safety hurdles. Major safety hurdles include infection, effects on platelet function (risk of bleeding), and cytopenias. Other safety concerns for one or more approved BTKi include arrhythmias (atrial fibrillation and flutter) and heart failure and hypertension for ibrutinib only.

[0216] Therefore, in a preferred embodiment of the present invention, LOU064 or a pharmaceutically acceptable salt thereof for use in treating HS is used for long-term treatment. The term long-term treatment indicates that LOU064 or a pharmaceutically acceptable salt thereof is used for an extended period of time. For example, LOU064 or a pharmaceutically acceptable salt thereof can be safely used for more than 6 months, 10 months, 1 year, 2 years, 3 years, 4 years, or 10 years. LOU064 or a pharmaceutically acceptable salt thereof may be used for up to 2 years, 5 years, 10 years, 15 years, 20 years, or for life.

[0217] In one embodiment, LOU064 is not only effective in treating HS, but also has a safety profile that includes one or more of the following features:

[0218] - No clinically relevant increased risk of infection,

[0219] - No clinically relevant increase in severe bleeding,

[0220] - No clinically relevant liver enzyme elevations; long-term treatment is permitted.

[0221] combination:

[0222] The pharmaceutical compositions for use in the disclosed methods may also contain other therapeutic agents for treating specific targeted disorders. For example, the pharmaceutical compositions may also include anti-inflammatory agents. Such additional factors and / or agents may be included in the pharmaceutical compositions to produce a synergistic effect with LOU064 described herein.

[0223] During the treatment of HS, various therapies may be beneficially combined with LOU064.

[0224] Thus, LOU064 can be administered simultaneously with one or more other therapeutic agents or before or after the therapeutic agent. LOU064 for use in the methods of the invention can be administered separately by the same or different routes of administration as the other agents, or administered together in the same pharmaceutical composition.

[0225] In one embodiment, the present invention relates to a method for treating or preventing HS in a subject, comprising administering to the subject a therapeutically effective dose of LOU064 and at least one other therapeutic agent as a combined preparation for simultaneous, separate, or sequential use in therapy. Optionally, the pharmaceutical composition for use in the methods of the invention may comprise a pharmaceutically acceptable excipient as described above.

[0226] Products provided as combined preparations for use in the methods of the invention include compositions comprising LOU064 and one or more other therapeutic agents together in the same pharmaceutical composition, or LOU064 and one or more other therapeutic agents in separate forms (e.g., in the form of a kit).

[0227] In one embodiment, the present invention provides a kit for use in the methods of the present invention, the kit comprising two or more separate pharmaceutical compositions, at least one of which comprises LOU064 or a pharmaceutically acceptable salt thereof. In one embodiment, the kit comprises a device for separately retaining the compositions (e.g., a container, a separate bottle, or a separate foil packet). An example of such a kit is a blister pack, such as is typically used for packaging tablets, capsules, and the like.

[0228] The kits of the invention can be used for administering different dosage forms (e.g., oral and parenteral), for administering separate compositions at different dosage intervals or for titrating separate compositions against each other. To aid compliance, the kits of the invention typically comprise instructions for administration.

[0229] In the combination therapies of the present invention, LOU064 and the other therapeutic agent can be manufactured and / or formulated by the same or different manufacturers. In addition, LOU064 and the other therapeutic agent can be used together to form a combination therapy: (i) before the combination product is released to the physician (for example, in the case of a kit containing a compound for use in the methods of the present invention and the other therapeutic agent); (ii) shortly before administration, by the physician himself (or under the guidance of the physician); (iii) in the patient himself, for example, during the sequential administration of LOU064 and the other therapeutic agent.

[0230] Thus, the present invention provides the use of LOU064 or a pharmaceutically acceptable salt thereof for treating or preventing HS, wherein the medicament is prepared for administration with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating or preventing HS, wherein the medicament is LOU064 or a pharmaceutically acceptable salt thereof.

[0231] The present invention also provides LOU064, or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing HS, wherein the compound is prepared for administration with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating or preventing HS, wherein the other therapeutic agent is prepared for administration with LOU064, or a pharmaceutically acceptable salt thereof.

[0232] The present invention also provides LOU064, or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing HS, wherein the compound is administered with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating or preventing HS, wherein the other therapeutic agent is administered with LOU064, or a pharmaceutically acceptable salt thereof.

[0233] The present invention also provides the use of LOU064, or a pharmaceutically acceptable salt thereof, for treating and / or preventing HS in a patient in need of such treatment and / or prevention, wherein the patient has previously (e.g., within 24 hours) been treated with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating or preventing HS in a patient in need thereof, wherein the patient has previously (e.g., within 24 hours) been treated with LOU064, or a pharmaceutically acceptable salt thereof.

[0234] Such combination therapies include topical therapies (creams [nonsteroidal or steroidal], lotions, antimicrobials), systemic therapies (eg, use of biologics, antibiotics, or chemicals), antimicrobials, photodynamic therapy, and surgical intervention (laser, drainage or incision, excision).

[0235] Examples of oral antibiotics are tetracycline, clindamycin, and rifampicin.

[0236] Non-limiting examples of topical HS agents for use with LOU064 include benzoyl peroxide, topical steroid creams, topical antibiotics in the aminoglycoside group, such as clindamycin, gentamicin, and erythromycin, resorcinol creams, iodine washes, and chlorhexidine.

[0237] Non-limiting examples of HS agents for use in systemic therapy with LOU064 include IL-17 antagonists (eselgizumab, brolucizumab, secukinumab, CJM112), as well as IL17A / F antagonists (such as bimelezumab) or IL17C antagonists (such as MOR106), tumor necrosis factor-α (TNF-α) blockers (such as (etanercept), (adalimumab), (infliximab) and (golimumab)), interleukin-12 / 23 blockers (eg (ustekinumab), tasocitinib, and briginumab), IL-23 blockers (such as goserekumab, tetracycline, and risankizumab), p19 inhibitors, PDE4 inhibitors (such as apremilast or or others such as roflumilast), complement pathway inhibitors such as factor B inhibitors (e.g., compounds disclosed in WO2015 / 009616 or LNP023 (also known as 4-((2S,4S)-4-ethoxy-1-((5-methoxy-7-methyl)-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid)), C5a inhibitors such as IFX-001 or vilobelimab or CCX1 68 (also known as avaxomevapine) or BDB001), IL-1 antagonists (canakinumab, gevuzumab, rilonacept, anakinra, or bermedizumab), or bispecific antibodies (such as MAS825 or rugilumab (IL-1b and IL-1a)), inflammasome inhibitors (such as NLRP3 and NLRP5 inhibitors), CXCR1 / 2 inhibitors, IL-18 antagonists, IL-6 antagonists, IL-36 antagonists, CD20 antagonists, CTLA4 antagonists, IL-8 antagonists, B cell depleting agents (particularly CD20 antagonists such as rituximab), as well as BAFF-R (such as ipilimumab) and CD40 antagonists (such as iscalimab (CFZ533)), IL-21 antagonists, IL-22 antagonists, IL-36 or IL-36R antagonists, GCSF inhibitors, VEGF antagonists, CXCL antagonists, MK-2 inhibitors (such as zunsemetinib), IRAK4 inhibitors or IRAK4 degraders (such as SAR44656), LTA4H inhibitors, S1P inhibitors, BTK inhibitors, SYK inhibitors (such as fotantinib), MMP antagonists, and defensin antagonists (e.g., receptor decoys, antagonistic antibodies, etc.), as well as broad-spectrum oral JAK inhibitors (pan-JAKi) or more specific TYK2 or JAK 1. JAK2 or JAK3 inhibitors (more specific / selective JAK / TYK inhibitors include, for example, allosteric inhibitors (such as deucrayacitinib) or catalytic inhibitors).

[0238] Additional HS agents for use in combination with LOU064 during HS treatment include retinoids (such as acitretin (e.g., ) and isotretinoin), immune system suppressants (e.g., rapamycin, T-cell blockers [e.g., (alefacept) and [efalizumab]), cyclosporine, methotrexate, mycophenolate mofetil, mycophenolic acid, leflunomide, tacrolimus, etc.), hydroxyurea (e.g., ), sulfasalazine, 6-thioguanine, fumarate esters (e.g., dimethyl fumarate and ester fumarate), azathioprine, colchicine, cis-retinoic acid, steroids, corticosteroids, certolizumab, mometasone, rosiglitazone, pioglitazone, crystalline botulinum toxin, triamcinolone, IFX-1 (InflaRx), LY-3041658 (Eli Lilly and Company), Lilly), TE-2232 (Immunwork), NSAIDs, COX inhibitors, prescription narcotics, ketoprofen, codeine, gabapentin, pregabalin fentanyl, antibiotics (topical, oral, IV) (e.g., clindamycin, rifampin, tetracycline, sarecycline, doxycycline, minocycline, lymecycline, trimethoprim-sulfamethoxazole, erythromycin, ceftriaxone, moxifloxacin, metronidazole, alone or in combination), corticosteroids (injectable or oral), antiandrogens / hormone therapy (oral contraceptives, spironolactone, finasteride, dutasteride, progesterone IUD, cyproconazole acetate, ethinyl estradiol, gestodene, norgestimate, desogestrel, drospirenone, spironolactone), triamcinolone, MEDI8968, hydroxychloroquine, dapsone, metformin, adapalene, azelaic acid, and zinc.

[0239] Preferred combinations for use in the disclosed kits, methods and uses include a PDE4i and a JAKi, and an antibiotic (all oral).

[0240] Examples of JAK inhibitors for combined use are BMS986165, INCB054707, ruxolitinib, abrocitinib, tofacitinib and baricitinib. Other examples of JAK inhibitors are compounds disclosed in WO 2017 / 089985, WO 2018 / 055550 and WO 2018 / 055551.

[0241] Those skilled in the art will be able to discern appropriate dosages of the above-mentioned HS agents for co-delivery with LOU064.

[0242] When administered with CYP3A inhibitors, especially strong CYP3A inhibitors, such as strong CYP3A4 inhibitors, it is expected that LOU064 oral drug exposure may increase several-fold. Similarly, strong inducers of CYP4A (such as CYP3A4) can significantly reduce exposure and lead to reduced efficacy of LOU064. These properties of LOU064 are relevant not only to the treatment of HS, but also to any BTK-induced condition. Strong CYP3A inhibitors or CYP3A inducers are defined according to the FDA 2020 guidance. Therefore, a strong CYP3A inhibitor (such as a CYP3A4 inhibitor) is an inhibitor that, when co-administered with LOU064, results in an increase in the area under the curve (AUC) of more than 5-fold or a decrease in clearance of more than 80% compared to administration of LOU064 alone. A strong CYP3A inducer (eg, a strong CYP3A4 inducer) is one that reduces the AUC by 80% or more (eg, by 85%, 90%, 95%) following co-administration with LOU064 compared to administration of LOU064 alone.

[0243] Concomitant administration of strong CYP3A inhibitors and / or inducers (e.g., strong CYP3A4 inhibitors and / or inducers) may result in substantial changes in LOU064 drug exposure and should be avoided. Strong CYP3A4 inhibitors include drugs selected from the group consisting of boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir / ritonavir, darunavir / ritonavir, elvitegravir / ritonavir, idelalisib, indinavir, indinavir / ritonavir, itraconazole, ketoconazole, LCL161, lopinavir / ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, saquinavir / ritonavir, telaprevir, telithromycin, tipranavir / ritonavir, troleandomycin, dasabuvir sodium (Viekirapack), and / or voriconazole. CYP3A4 inhibitors may also contain grapefruit juice.

[0244] Thus, in another preferred embodiment, LOU064 is not concomitantly administered with strong inhibitors and / or inducers of CYP3A4 (eg, as defined above).

[0245] It was further found that LOU064 can be co-administered with oral contraceptives (such as ethinylestradiol or levonorgestrel) without significantly affecting the exposure and efficacy of the oral contraceptives. Therefore, in a preferred embodiment, LOU064 is co-administered with an oral contraceptive.

[0246] As a covalent, irreversible BTK inhibitor, LOU064 acts through irreversible inhibition of BTK, which is offset by de novo protein synthesis. Thus, without wishing to be bound by any theory, it is believed that while the reconstitution of the B cell pool after B cell depletion may take several months, restoration of B cell function following BTK inhibition can be achieved shortly after discontinuation, particularly within days. Thus, if necessary, the therapy can be discontinued quickly, providing clinicians and patients with easier and faster response capabilities in the event of unforeseen circumstances.

[0247] Especially in light of the COVID-19 pandemic, patients with B cell depletion are at increased risk of infection. Furthermore, the lack of a fully functional adaptive immune response may lead to a more severe course of the disease.

[0248] However, because LOU064 does not lead to depletion of the B cell pool, cessation of therapy results in rapid restoration of full B cell function. This allows patients and treating physicians to respond quickly to infectious diseases or vaccination needs, particularly with live and attenuated vaccines.

[0249] According to the present invention, LOU064 can be administered during an infection (e.g., during a COVID-19 infection). Thus, LOU064 administration can continue during an infection (e.g., during a COVID-19 infection).

[0250] Preferably, administration of LOU064 is delayed in patients with an active infection (e.g., COVID-19) until the infection resolves.

[0251] Thus, one embodiment of the present invention relates to LOU064 for use in the treatment of HS, wherein patients are treated for acute infection or previous infection with COVID-19.

[0252] In additional embodiments, LOU064 treatment is continued during COVID-19 infection.

[0253] In a preferred embodiment, LOU064 treatment is interrupted during COVID-19 infection and continued after the infection is overcome.

[0254] Still other embodiments of the present invention relate to LOU064 for use in treating HS, wherein the patient is vaccinated during LOU064 therapy. Alternatively, the patient can be vaccinated with a non-live vaccine during LOU064 therapy. In one embodiment, the patient is vaccinated with a quadrivalent influenza vaccine, a PPV-23 vaccine, or a KLH neoantigen vaccine during LOU064 therapy (e.g., 15 days after the start of LOU064 therapy). In one aspect of this embodiment, the patient receiving the quadrivalent influenza vaccine achieves a response defined as a >4-fold increase in anti-hemagglutinin antibody titer compared to baseline 28 days after vaccination. In another aspect of this embodiment, the patient receiving the PPV-23 vaccine achieves a >2-fold increase in IgG titer 28 days after vaccination compared to baseline. In yet another embodiment, the patient receiving the KLH neoantigen vaccine achieves a T cell-dependent antibody response 28 days after vaccination, as measured by anti-KLH IgG and IgM titers.

[0255] Another embodiment of the present invention relates to LOU064 for use in the treatment of HS, wherein LOU064 treatment is discontinued due to vaccination, in particular wherein LOU064 treatment is discontinued 5-10 days (e.g., 7 or 8 days), preferably 6 weeks prior to vaccination and continued after vaccination, for example 5-20 days, preferably 5-10 days, or more preferably 10-15 days after vaccination. In alternative embodiments, vaccination is vaccination with a live and / or attenuated vaccine. In a specific aspect of this embodiment, after discontinuation of LOU064 treatment (e.g., 5-10 days or 7 or 8 days after discontinuation of LOU064 treatment), the patient is vaccinated with a quadrivalent influenza vaccine, a PPV-23 vaccine, or a KLH neoantigen vaccine. In one aspect of this embodiment, the patient receiving the quadrivalent influenza vaccine achieves a response defined as a >4-fold increase in anti-hemagglutinin antibody titer compared to baseline 28 days after vaccination. In another aspect of this embodiment, patients receiving the PPV-23 vaccine achieved a >2-fold increase in IgG titers compared to baseline 28 days after vaccination. In yet another embodiment, patients receiving the KLH neoantigen vaccine achieved a T cell-dependent antibody response, as measured by anti-KLH IgG and IgM titers, 28 days after vaccination. LOU064 treatment was then continued starting on day 29 after vaccination.

[0256] LOU064 or a pharmaceutically acceptable salt thereof is conveniently administered orally. The duration of oral therapy using the pharmaceutical compositions of the present disclosure will vary depending on the severity of the disease being treated and the condition and personal response of each individual patient. A healthcare provider will use the pharmaceutical compositions of the present disclosure to determine the appropriate duration of oral therapy and the timing of administration of such therapy. In some embodiments, HS patients are treated according to the claimed methods for at least 16 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, or at least 52 weeks. In some embodiments, HS in patients is treated for an extended period of time.

[0257] In one embodiment, the pharmaceutical compositions of the present invention for use in preventing or treating HS can be provided in a unit dose of about 25 mg to about 100 mg of one or more active ingredients for a subject weighing approximately 50-70 kg. The therapeutically effective dose of the compound or pharmaceutical composition will depend on the subject's species, weight, age, and individual condition, as well as the severity of the contrast-induced nephrotic disorder. A physician, clinician, or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient necessary to prevent, treat, or inhibit the progression of the disorder or disease.

[0258] A preferred formulation is a capsule or tablet composition comprising about 25 mg to about 100 mg of LOU064 and one or more excipients independently selected from fillers, disintegrants, binders, and optionally lubricants and glidants. In a preferred embodiment, the capsule or tablet composition comprises about 25 mg of LOU064 or a pharmaceutically acceptable salt thereof and one or more excipients independently selected from fillers, disintegrants, binders, and optionally lubricants and glidants. In another embodiment, the capsule or tablet composition comprises about 50 mg of LOU064 or about 100 mg of LOU064 and one or more excipients independently selected from fillers, disintegrants, binders, and optionally lubricants and glidants.

[0259] Disclosed herein are methods for treating hidradenitis suppurativa (HS), comprising orally administering to a patient in need thereof a daily dose of about 50 mg to about 200 mg of LOU064, or a pharmaceutically acceptable salt thereof. The dose can be administered to the patient on a once-daily or twice-daily schedule. In another embodiment, the method comprises orally administering to a patient in need thereof a dose of about 25 mg to about 100 mg of LOU064 twice daily (BID). In a preferred aspect of this embodiment, the method comprises orally administering to the patient a dose of about 25 mg of LOU064 twice daily (BID). In another preferred aspect of this embodiment, the method comprises orally administering to the patient a dose of about 100 mg of LOU064 twice daily (BID).

[0260] In preferred embodiments of the disclosed methods, uses, and kits, the patient achieves a sustained response after one year of treatment as measured by the (Simplified) Hidradenitis Suppurativa Clinical Response (HiSCR), HiSCR50, HiSCR75, HiSCR90, Numerical Rating Scale (NRS), Hidradenitis Suppurativa - Physician Global Assessment (HS-PGA), or Dermatology Life Quality Index (DLQI), HS Severity Assessment (SASH), or International HS Severity Scoring System (IHS4).

[0261] In preferred embodiments of the disclosed methods, uses, and kits, the patient has previously been treated for HS with a systemic agent prior to treatment with LOU064 as disclosed herein. In preferred embodiments of the disclosed methods, uses, and kits, the systemic agent is selected from the group consisting of a topical treatment, an antibiotic, an immune system suppressant, a TNF-α inhibitor, an IL-1 antagonist, and combinations thereof.

[0262] In some embodiments of the disclosed methods, uses, and kits, the patient has not been previously treated for HS with systemic agents or local therapies (ie, the patient is treatment-naive or biologic-naive) prior to treatment with LOU064 as disclosed herein.

[0263] In one embodiment of the disclosed methods, uses, and kits, LOU064 (or a pharmaceutically acceptable salt thereof) as described herein is administered in combination with at least one of an antibiotic, a JAK inhibitor, a TYK2 inhibitor, a PDE4 inhibitor, or an immunosuppressant.

[0264] In preferred embodiments of the disclosed methods, uses, and kits, the dose of LOU064 as described herein is about 25 mg to about 100 mg BID. In other preferred embodiments of the disclosed methods, uses, and kits, the dose of LOU064 is about 25 mg BID or 100 mg BID.

[0265] In preferred embodiments of the disclosed methods, uses, and kits, the patient has moderate to severe HS.

[0266] As used herein, the phrase "moderate to severe" refers to HS disease in which patients have ≥3 active inflammatory lesions [i.e., deep inflammatory lesions such as abscesses and / or inflammatory nodules], no more than 15 fistulas, and HS lesions involving at least two anatomical regions.

[0267] In preferred embodiments of the disclosed methods, uses, and kits, the patient is an adult. In some embodiments of the disclosed methods, uses, and kits, the HS patient is an adult with moderate to severe HS disease.

[0268] In some embodiments of the disclosed methods, uses, and kits, the patient is an adolescent patient (age>12 years). In some embodiments, the patient is an adolescent patient with moderate to severe HS.

[0269] In some embodiments of the disclosed methods, uses, and kits, the patient has been diagnosed with HS for at least one year.

[0270] In some embodiments of the disclosed methods, uses, and kits, the patient does not have extensive scarring due to HS (ie, <20 fistulas, draining or non-draining, preferably no more than 15 fistulas).

[0271] In some embodiments of the disclosed methods, uses, and kits, the patient previously had an inadequate response to conventional systemic HS therapy.

[0272] In preferred embodiments of the disclosed methods, uses and kits, the patient has an HS-PGA score of ≥3 prior to treatment with LOU064.

[0273] In preferred embodiments of the disclosed methods, uses and kits, the patient achieves a (simplified) HiSCR by week 16 of treatment.

[0274] In preferred embodiments of the disclosed methods, uses, and kits, the patient achieves an NRS30 (eg, a pain NRS30 or a pruritus NRS30) by week 16 of treatment.

[0275] In preferred embodiments of the disclosed methods, uses, and kits, the patient has a reduction in HS redness and swelling by week 16 of treatment.

[0276] In preferred embodiments of the disclosed methods, uses and kits, the patient achieves a reduction of ≤ 6 as measured by the DLQI by week 16 of treatment.

[0277] In preferred embodiments, when the disclosed methods, uses or kits are used to treat a patient population with moderate to severe HS, at least 40% of said patients achieve HiSCR (sHiSCR, HiSCR50, HiSCR75 or HiSCR90) by week 16 of treatment in response to said administering step.

[0278] In another preferred embodiment, when the disclosed methods, uses or kits are used to treat a patient population with moderate to severe HS, the difference between the responder rate by week 16 of treatment (e.g., patients who achieve a HiSCR response (sHiSCR, HiSCR50, HiSCR75 or HiSCR90 response) to HS treatment) and the responder rate of placebo-treated patients is at least 15%, at least 25%, or at least 30%.

[0279] In preferred embodiments of the disclosed methods, uses and kits, the patient's modified Sartorius score is reduced after 16 weeks of treatment.

[0280] In preferred embodiments of the disclosed methods, uses and kits, the patient's DLQI improves after 16 weeks of treatment.

[0281] In preferred embodiments, when the disclosed methods, uses or kits are used to treat a patient population with moderate to severe HS, at least 25% (and preferably at least 30%) of said patients achieve an NRS30 response in response to said administering step by week 16 of treatment.

[0282] In preferred embodiments, when the disclosed methods, uses or kits are used to treat a patient population with moderate to severe HS, less than 15% of said patients experience HS red bumps over a 16-week treatment period in response to said administering step.

[0283] In preferred embodiments of the disclosed methods, uses and kits, the patient is additionally treated with at least one topical medication and at least one antimicrobial agent in combination with LOU064 as described herein.

[0284] In preferred embodiments of the disclosed methods, uses, and kits, the patient is treated with LOU064 as described herein for at least 16 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, or at least 52 weeks. Most preferably, the patient is treated for at least 16 weeks.

[0285] In preferred embodiments of the disclosed methods, uses and kits, the patient has reduced pain (as measured by VAS or NRS, preferably NRS) as early as one or two weeks after the first dose of LOU064.

[0286] In preferred embodiments of the disclosed methods, uses, and kits, the patient's skin pruritus is reduced (as measured by NRS) as early as one or two weeks after the first dose of LOU064. For example, the patient achieves a skin pruritus NRS of 30 after 1 or 2 weeks after the first dose of LOU064.

[0287] In preferred embodiments of the disclosed methods, uses, and kits, the patient's CRP is reduced (by about 25% to about 30%) as early as one or two weeks after the first dose of LOU064 (as measured using a standard CRP assay).

[0288] In a preferred embodiment of the present disclosure, LOU064 is an anhydrous crystalline Form A of the free base as disclosed in WO2020 / 234779 (Example 1). In one aspect of this embodiment, LOU064 Form A is in a substantially pure phase.

[0289] Overview

[0290] The details of one or more embodiments of the present disclosure are set forth in the specification sheet attached above. Preferred methods and materials are now described, but any methods and materials similar or equivalent to those described herein may also be used for the practice or testing of the present disclosure. Other features, objects, and advantages of the present disclosure will be clear from the specification sheet and according to the claims. In this specification sheet and the appended claims, the singular form includes plural referents unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those of ordinary skill in the art to which the present disclosure belongs. All patents and publications cited in this specification sheet are incorporated by reference. The following examples are provided to more fully illustrate the preferred embodiments of the present disclosure. These examples should never be interpreted as limiting the scope of the disclosed subject matter as defined by the appended claims.

[0291] Examples

[0292] abbreviation

[0293] AE adverse effects

[0294] bid or BID twice a day

[0295] qd once a day

[0296] ECG electrocardiogram

[0297] PK pharmacokinetics

[0298] PD pharmacodynamics

[0299] po (by mouth = oral)

[0300] Example 1: LOU064 signature in the hidradenitis suppurativa transcriptomics dataset (genes downregulated by LOU064)

[0301] Figure 1: Gene expression was measured in skin from healthy donors and in lesional and non-lesional skin from HS patients using Affymetrix GeneChip HG-U133 Plus 2 (GSE148027). We found that BTK expression (as measured by probe 205504_at) was significantly upregulated in lesional (but not non-lesional) skin compared to healthy controls.

[0302] Figure 2 Figure 2 shows the LOU signature (LOU064-suppressed genes) in a (large) transcriptomic dataset of hidradenitis suppurativa. The LOU064 signature was generated by stimulating whole blood with IgM and then treating it with LOU064. The transcriptomic profiles of these samples were measured using Ampliseq. We defined the 52 genes that we found to be significantly downregulated (FDR < 0.05) by LOU064 compared to stimulation alone as the "LOU signature."

[0303] A large amount of transcriptomic data was measured by Affy chips (Carlos A. Penno et al., J. Invest. Dermatol. 2020, Vol. 140, No. 21, 2421-2432.e10) - 49 of the 52 signature marker genes were also present in this data and were targeted by a total of 106 probes (each gene may be targeted by multiple probes). These 106 probes were used for signature enrichment using an algorithm called GSVA (Sonja Hanzelmann et al. BMC Bioinformatics 2013, 14(7) - https: / / doi.org / 10.1186 / 1471-2105-14-7), which calculates the enrichment of these 106 probes compared to all other measured probes for each sample (General method for genomic enrichment: Aravind Subramanian et al. PNAS 2005, 102(43) 15545-15550). The results are shown in Figure 1 The Wilcoxon test was used to show significantly different enrichment of signatures between healthy and diseased HS samples (p ~ 2.7e-7).

[0304] The data demonstrate upregulation of LOU064-suppressed genes (LOU064 signature) in hidradenitis lesions.

[0305] Example 2: Dosage Rationale

[0306] Assuming that there are no relevant interspecies differences in conversion and drug efficacy, the translational PK / PD model simulation described below is used to predict the human peripheral tissue occupancy of remibrutinib (e.g., spleen and lymph nodes). The PK / PD model focuses on B cells, which, as mentioned above, are reported to be the relevant major target of BTK inhibition in HS. In addition to the circulating fraction, B cells typically reside in lymph nodes and spleen. In HS, B cells are also present in the so-called "tertiary lymphoid organs" in HS lesion tissues, similar to the key lymph nodes and germinal center characteristics. Compared with circulating B cells in peripheral blood, it is believed that B cells residing in the spleen, lymph nodes or tertiary lymphoid organs in HS lesions exhibit faster BTK conversion. Translational PK / PD model simulations guide dose selection for the treatment of HS with LOU064.

[0307] Predicting BTK occupancy using a translational PK / PD model of LOU064

[0308] Due to the pharmacological properties of LOU064 (irreversible binding), BTK occupancy in blood is not an informative biomarker for dose selection. Full occupancy is achieved even at low doses before pharmacological activity is demonstrated by other biomarkers (CD63, CD203c, skin prick test). Occupancy in tissues may be more representative of the expected efficacy of LOU064.

[0309] Target

[0310] The objectives of this analysis were to characterize the pharmacokinetics (PK) of LOU064 in healthy volunteers and to simulate BTK occupancy in human spleen / tissue across a range of doses and dosing schedules (BID vs. QD) using a previously developed translational target occupancy model.

[0311] data

[0312] Pharmacokinetic data from a phase I clinical study reported by Kaul et al. (2021) were used for the current analysis, including 102 patients.

[0313] method

[0314] A two-step approach was used to develop a translational targeted occupancy model to simulate BTK occupancy in the spleen / tissue.

[0315] In the first step, a population PK model was developed to describe the LOU064 PK data from the Phase I clinical study reported by Kaul et al. (2021). In the second step, the parameter estimates from the population PK model were used in a BTK occupancy model to predict BTK occupancy in the blood and spleen / tissue. Finally, the BTK occupancy model was used to predict BTK occupancy in the spleen / tissue at different doses and different dosing schedules (QD, BID).

[0316] result

[0317] A population PK model was developed to describe the interim PK from a Phase I clinical study reported by Kaul et al. (2021). To account for changes in clearance after repeated dosing of doses below 50 mg (lower steady-state clearance on day 12 compared to day 1, with no difference at higher doses), clearance was modeled as a function of exponential time decay for doses below 50 mg and constant clearance for doses above 50 mg. Overall, the resulting population model described the PK data reasonably well.

[0318] The PK parameter estimates were used to translate the BTK occupancy model to simulate BTK occupancy at steady state. BTK occupancy simulations showed that BID dosing was more effective than QD dosing at the same dose, achieving higher BTK occupancy (trough or mean over a 24-hour interval).

[0319] The steady-state BTK occupancy at trough and mean over a 24-hour period for the 10 mg, 35 mg, 100 mg once daily and 10 mg, 25 mg, and 100 mg twice daily dosing regimens for selected dose numbers for the QD and BID regimens are shown in Figure 4A (trough BTK occupancy during the steady-state 24-hour period) and Figure 4B (Average of BTK occupancy during the 24-hour steady state.) Both figures show that daily doses up to 200 mg (100 mg BID) may be required to achieve BTK trough occupancy > 80% in peripheral target tissues.

[0320] Simulations were performed to compare different dosing regimens. A comparison of spleen BTK occupancy over time for steady-state simulations at 100 mg BID versus 100 mg QD is shown in Figure 3 The plot shows higher and less variable occupancy with BID dosing compared to QD dosing, as expected from first principles.

[0321] in conclusion:

[0322] The model predicts that significantly higher overall BTK occupancy can be achieved with the bid dosing regimen. While the 25 mg bid dosing regimen predicts a BTK trough occupancy of approximately 70%-95% in human tissues, the 100 mg bid dosing regimen is predicted to achieve ≥90% BTK trough occupancy.

[0323] Example 3: Clinical trial design

[0324] Blinding of subjects and investigators allowed unbiased assessment of subjective readouts, such as lesion counts or overall HS-PGA scores for HS, as well as adverse events.

[0325] A randomized, subject and investigator double-blind, placebo-controlled, multicenter, parallel-group study was conducted to evaluate the efficacy, safety, and tolerability of several active therapeutic compounds, such as LOU064 (remibrutinib), in subjects with moderate to severe hidradenitis suppurativa (HS). Following the screening period, the treatment period was 16 weeks, followed by approximately 4 weeks of safety follow-up. Subjects were given 25 mg BID po of LOU064, 100 mg BID po, or placebo BID po. Approximately 70 subjects were randomized, 60 to receive the active (30 will receive 100 mg bid, 30 to receive 25 mg bid), and 10 to receive placebo.

[0326] The primary objective is to demonstrate preliminary efficacy of LOU064 compared to placebo in HS subjects after 16 weeks of treatment. Following the 16-week treatment period, a 4-week follow-up period will be conducted to observe whether the sustainability of this effect is maintained or improved after 16 weeks of treatment.

[0327] Solution Summary

[0328] Primary Objective(s): The primary objective of this study is to evaluate the efficacy of remibrutinib compared with placebo in patients with moderate to severe inflammatory HS by comparing the proportion of patients who achieved a clinical response defined by the Simplified Hidradenitis Suppurativa Clinical Response (HiSCR) after 16 weeks of treatment.

[0329] Secondary objectives: To assess the safety and tolerability of remibrutinib in patients with moderate to severe hidradenitis suppurativa (HS) by: (i) number and severity of AEs, and (ii) physical examination, vital signs, safety laboratory measurements, and ECG at baseline and repeatedly until the study completion visit

[0330] Study Design: This is a non-confirmatory, randomized, subject- and investigator-blind, placebo-controlled, multicenter, parallel-group study to evaluate the efficacy, safety, and tolerability of remibrutinib in subjects with moderate to severe hidradenitis suppurativa. For remibrutinib, the maximum duration of participation of any subject in a single cohort shall not exceed 25 weeks and will include a 35-day screening period, a 16-week treatment period, and will end with a 4-week safety follow-up. LOU064 (remibrutinib), 100 mg bidpo or 25 mg bidpo, or placebo will be administered from Day 1 (Week 1) to Day 113 (Week 17). Subjects will be randomized in a 3:3:1 ratio to the remibrutinib treatment group or its corresponding placebo group.

[0331] Population: Adult male and female participants aged 18 to 65 years with moderate to severe hidradenitis suppurativa and a diagnosis of recurrent inflammatory lesions at least 12 months prior to screening.

[0332] Key inclusion criteria: Male and female subjects aged 18 to 65 years (inclusive) with a clinical diagnosis of HS at least 12 months prior to screening; minimum body weight at screening of 50 kg (inclusive); patients with moderate to severe HS as assessed at screening (pre-dose on Day 1):

[0333] - A total of at least 3 inflammatory lesions, i.e., abscesses and / or inflammatory nodules, and

[0334] - No more than 15 fistulas, and

[0335] -HS lesions need to involve at least two anatomical regions

[0336] Key exclusion criteria:

[0337] - Use of other study drugs at screening, or within 30 days or 5 half-lives of randomization (whichever is longer); or longer if required by local regulations;

[0338] - Females who are physiologically capable of becoming pregnant unless they are using highly effective contraception during dosing and for at least 2 weeks after the last dose of remibrutinib

[0339] - Significant bleeding risk or coagulopathy such as:

[0340] o History of gastrointestinal bleeding, such as that associated with nonsteroidal anti-inflammatory drug (NSAID) use, that is clinically relevant:

[0341] o Use of anticoagulants [e.g., warfarin or novel oral anticoagulants (NOACs)] within 2 weeks prior to randomization

[0342] o International Normalized Ratio (INR) greater than 1.5 at screening

[0343] o Use of antiplatelet drugs within two weeks prior to randomization [including dual antiplatelet therapy (e.g., acetylsalicylic acid + clopidogrel)]

[0344] Note: Monotherapy with acetylsalicylic acid (up to 100 mg / day) or clopidogrel is not excluded.

[0345] o Major surgery within 8 weeks prior to screening or planned surgery during study treatment.

[0346] Key efficacy assessments:

[0347] - Simplified and crude Hidradenitis Suppurativa Clinical Response (HiSCR) rates

[0348] -International Hidradenitis Suppurativa Severity Scoring System (IHS4)

[0349] -Hidradenitis suppurativa - Physician's Global Assessment (HS-PGA) score and responder rate

[0350] -HS inflammatory lesion count

[0351] - Severity Assessment of Hidradenitis Suppurativa (SAHS)

[0352] Key safety assessments:

[0353] - Number and severity of adverse events (CTCAE v5.0 grading)

[0354] -Physical examination, including vital signs, safety laboratory measurements, and ECG

[0355] Other assessments:

[0356] -PK

[0357] - Skin Itch NRS (Group D)

[0358] - Patient-reported outcomes included the Numerical Rating Scale (NRS) for Skin Pain, the Dermatology Life Quality Index (DLQI), and the Patient Global Assessment (PGA).

[0359] Target

[0360]

[0361]

[0362] Additional references for clinical evaluation:

[0363] A simplified HiSCR was chosen as the primary endpoint. The original HiSCR (Kimball et al. 2016 N Engl J Med 375:422-34) used in a Phase 3 clinical trial with adalimumab has been validated. The simplified HiSCR is defined as a 50% reduction in the total number of abscesses plus inflammatory nodules without an increase in draining fistulas. However, in contrast to the original HiSCR, an increase in abscesses was allowed to constitute a clinical response if the previous conditions were met.

[0364] Inflammatory lesions of HS will be counted as individual lesions in typical anatomical areas (inflammatory nodules, abscesses, and draining fistulas). In addition to the counts, a global assessment scale (Hidradenitis Suppurativa - Physician Global Assessment or HS-PGA) and a composite score (Hidradenitis Suppurativa Severity Assessment Score or SAHS) will be used. Abscesses and nodules will also be presented as AN counts.

[0365] HS-PGA (Hidradenitis suppurativa-Physician Global Assessment): This score will be used as an exploratory objective to assess HS and was used and described in Kimball AB, Kerdel F, Adams D, et al. (2012) Adalimumab for the treatment of moderate to severe Hidradenitis suppurativa: a parallel randomized trial. Ann Intern Med;157:846-55.

[0366] The SAHS score is a composite score (Hessam S, Scholl L, Sand M et al. (2018) A Novel Severity Assessment Scoring System for Hidradenitis Suppurativa. JAMA Dermatol; 154(3):330-335.) and will be derived from the information collected for inflammatory lesion counts, fistula counts, and NRS pain. In addition, the anatomical region and the number of new or inflamed existing boils will be collected in both cohorts.

[0367] Several patient-reported outcomes will be used, including the Dermatology Life Quality Index (DLQI). Finally, as skin-related pain is the most important symptom from the participant's perspective, a numerical rating scale (NRS) for pain will be included.

[0368] Other patient-reported outcomes (PROs) will include the Dermatology Life Quality Index (DLQI) as a dermatology-related quality of life (QoL) tool (with validated scores available in many countries and languages). It will also include a patient global assessment.

[0369] Skin pain - NRS (Numerical Rating Scale for Pain): The NRS for skin-related pain was used in the adalimumab study (Kimball et al. (2016) N Engl J Med 375:422-34) and is used as a measure of skin or HS-related pain, which is one of the greatest burdens experienced by patients (Matusiak et al. (2017) J Am Acad Dermatol; 76:670-5). The mean and worst value (in the last 24 hours) of HS-related pain will be recorded.

[0370] Since pruritus is now recognized as a symptom in patients with HS, the skin itch NRS was also included (Nguyen et al. 2021, Fernandez et al. 2021).

[0371] Example 5: 100 mg film-coated tablets

[0372] Preferred pharmaceutical compositions (film-coated tablets) are described below.

[0373]

[0374] 1,2 Remove during processing

[0375] Example 6: 50 mg film-coated tablets

[0376] Preferred pharmaceutical compositions (film-coated tablets) are described below.

[0377]

[0378]

[0379] 1,2 Remove during processing

[0380] Example 7: 25 mg film-coated tablets

[0381] Preferred pharmaceutical compositions (film-coated tablets) are described below.

[0382]

[0383]

[0384] 1,2 Remove during processing

[0385] Example 8: Security of LOU064

[0386] The safety of LOU064 has been tested in Phase I and II pharmacokinetic and clinical pharmacology studies in healthy subjects, as well as in Phase II / III clinical studies in patients with indications other than MS, specifically chronic spontaneous urticaria (CSU) and Sjögren's syndrome (SjS).

[0387] Short-term safety of LOU064 in a Phase I clinical study

[0388] LOU064 was administered as a single dose or multiple doses for up to 18 days, covering a dose range from 0.5 mg to 600 mg for up to 18 days, and further demonstrated short-term safety in a Phase I clinical study at 100 and 200 mg bid for up to 12 days (Kaul, M. et al. (2021). Remibrutinib (LOU064): A selective potent oral BTK inhibitor with promising clinical safety and pharmacodynamics in a randomized phase I trial. Clinical and Translational Science. 10.1111 / cts.13005).

[0389] Summary of Safety from the Phase 2b (Extension) Study in CSU Subjects (Interim Results)

[0390] The long-term safety and tolerability of LOU064 were evaluated in a 52-week open-label extension study in eligible subjects with CSU enrolled in the Phase 2b study at a dose of 100 mg bid.

[0391] Based on an interim analysis of 100 subjects who received at least one dose of LOU064 and had a median exposure of 17.86 weeks (range: 2.9 weeks to 44.7), no safety signals were observed. At the time of cutoff, 93 subjects (93%) were ongoing and 7 subjects had discontinued from the study; no discontinuations were due to adverse events. Table 4 presents the safety summary data observed in the Phase 2b study as of the interim analysis cutoff date.

[0392] Table 4 Interim Analysis of the Open-Label Extension Study: Death, Other Serious or Clinically Significant Adverse Events, or Related Discontinuations (Safety Set)

[0393]

[0394] Interim analysis ended August 31, 2020

[0395] Fifty-eight subjects (58%) experienced at least one treatment-emergent AE. Most AEs were not serious, did not lead to treatment discontinuation, and were mild in severity. The most frequently affected SOC was infections and infestations (14%), followed by skin and subcutaneous tissue disorders (13%), with no trends for specific adverse events. The most common adverse events with preferred terms (≥2%) were headache (6%), diarrhea (4%), dizziness (3%), and gastroenteritis (3%); no bleeding events (defined as events under the broad SMQ Bleeding, with PTs including platelet aggregation abnormalities, platelet aggregation decreased, platelet aggregation inhibition, platelet function disorders, platelet function test abnormalities, and platelet toxicity) or events under the SOC Blood and lymphatic system disorders were reported. Three SAEs were reported: ovarian cyst, chest pain, and appendicitis; none were considered related to study drug.

[0396] Conclusions of the Phase 2b Study and Corresponding Open-Label Extension Study

[0397] In summary, no safety findings were observed across all doses evaluated in the Phase 2b study. Furthermore, in the corresponding CSU extension study, open-label, using LOU064 100 mg twice daily, no safety signals were observed among the 100 subjects enrolled as of August 31, 2020. The proposed highest dose of LOU064, 100 mg twice daily, was considered well tolerated and had a favorable safety profile.

[0398] Summary of the safety of the Phase 2b study (extension phase) in CSU subjects (interim results / with 35.14 weeks Summary of patients with median exposure

[0399] In the above 52-week open-label extension study, the long-term safety and tolerability of LOU064 in eligible subjects with CSU who participated in the Phase 2b study at a dose of 100 mg bid were evaluated. A new interim analysis was conducted on patients (N=183) with a median exposure of 35.14 weeks, and the results were compared with the safety results in the randomized, double-blind, placebo-controlled Ph2b core study in adult patients with CSU who received up to 12 weeks (wk) of (1:1:1:1:1:1:1) remibrutinib 10 mg qd (once daily), 35 mg qd, 100 mg qd, 10 mg bid (twice daily), 25 mg bid or 100 mg bid or placebo (NCT03926611). (Table 5)

[0400] During long-term exposure in ES (median 35.14 weeks, N = 183), the proportion of patients experiencing at least one adverse effect (AE) with remibrutinib treatment (57.4% [n = 105]) was similar to that in CS (presented with any dose of remibrutinib) (58.1% [n = 155]; median 12.14 weeks, N = 267). In ES, there were 4 serious adverse effects (SAEs), 6 AEs leading to treatment discontinuation, and no deaths. The incidence of AEs reported by major organ class (SOC) was similar in ES and CS: infections and infestations (23.0% and 24.0%), followed by skin / subcutaneous tissue disorders (17.5% and 16.9%) (Table 5). The incidence of AEs reported by preferred term was comparable in ES and CS, with headache being the most common (6.6% and 9.7%). The incidence of AESIs in ES, such as infection (23%), bleeding (4.4%), and cytopenias (0.5%), was consistent with that in CS. Newly occurring significant transaminase elevations were single in both ES (isolated ALT > 3xULN, normalized within 4 weeks, 1 patient discontinued early for personal reasons) and CS (1 patient with ALT > 5xULN, treatment normalized). Analysis of laboratory parameters revealed no significant safety concerns, and no clinically meaningful changes in vital signs were observed. No significant ECG findings or QT > 500ms were noted in any patient.

[0401] Table 5: Safety profile of remibrutinib (LOU064) in the Phase 2b core and extension studies (safety set)

[0402]

[0403]

[0404] in conclusion

[0405] Remibrutinib demonstrated a favorable safety profile across the dose range, and no new safety signals were observed with longer-term exposure to the 100 mg bid dose for up to 52 weeks in patients with CSU.

[0406] Example 9: Evaluation of the Modulation of Immune Responses to Three Different Types of Vaccines by Concomitant and Interrupted Administration of Remibrutinib in Healthy Subjects

[0407] Objectives and relevant endpoints

[0408]

[0409]

[0410] Study Design

[0411] Overall design

[0412] This randomized, double-blind, placebo-controlled study has a parallel group design. Considering the estimated withdrawal rate of up to 20%, approximately 90 healthy women and male participants with non-fertile potential are randomly assigned to any one of the three treatment groups to achieve a minimum of 72 evaluable completers. The study will include a 28-day screening phase, a 43-day treatment phase, and then the study is completed and evaluated within two weeks after the last study drug is used (the 57th day). A safety follow-up call is carried out approximately 30 days (the 73rd day) after the last study drug is used. Participants live from -1 day to the 1st day and the 14th to 17th day. In general, the longest study duration for each participant is approximately 85 days.

[0413] Evaluation of concomitant and discontinued remibrutinib treatment for influenza / 23 and impact.

[0414] Study implementation

[0415] Screening and baseline

[0416] Participants who meet eligibility criteria at screening will be allowed to undergo baseline assessments on Day -1. All baseline safety assessments must be obtained before the first dose. At baseline, participants will be randomly assigned to one of the three treatment groups described below.

[0417] treat

[0418] All participants received study drug (remibrutinib 100 mg or placebo twice daily) from day 1 to day 42 and returned to the clinic for an end-of-treatment visit on day 43. All participants also received quadrivalent influenza vaccine, PPV-23 vaccine, and KLH neoantigen vaccine on day 15. Vaccinations were to be administered 3 hours after study drug administration.

[0419] Study medication was administered to participants by clinic staff during clinic visits and during the residency period (Days -1 to 1 and 14-17). After discharge from the clinic visit during the treatment period, study medication was provided to participants along with a medication diary for self-administration at home.

[0420] Safety assessments will include physical examination, ECG, vital signs, standard clinical laboratory evaluations (hematology, blood chemistry, urinalysis), adverse event and serious adverse event monitoring.

[0421] Multiple blood samples will be drawn from all participants on Days 8, 15, and 36 to assess the pharmacokinetics of remibrutinib.

[0422] Group A (concomitant remibrutinib treatment):

[0423] Participants will receive placebo (bid) from Days 1-7, followed by treatment with remibrutinib (100 mg bid) on Study Days 8-15 to achieve PK / PD steady-state prior to the three vaccine administrations on Day 15. Participants will continue to receive remibrutinib (100 mg bid) until Day 42.

[0424] Group B (interruption of remibrutinib treatment):

[0425] Participants will be treated with remibrutinib 100 mg bid from days 1-7 to achieve PK / PD steady-state conditions, followed by placebo (bid) from days 8-28, and all three vaccines will be administered on day 15. Treatment with remibrutinib 100 mg bid will be reinitiated from days 29 to 42.

[0426] Group C (placebo):

[0427] Participants in Group C will receive placebo (bid) from Days 1-42 and will receive the three vaccines under placebo conditions on Day 15.

[0428] Key inclusion criteria

[0429] · Must provide signed informed consent before participating in the study.

[0430] Healthy or mildly obese but otherwise healthy male and female participants of non-reproductive potential aged 18 to 55 years (inclusive).

[0431] • Participants should be in good health as determined by medical history, physical examination, vital signs, ECG, and laboratory tests indicated at the Screening and Baseline Visits.

[0432] Vital signs (systolic and diastolic blood pressure and pulse rate) will be assessed in the seated position and again (when required by the assessment schedule) in the standing position at Screening and Baseline. Seated vital signs (after 3 minutes in the seated position) must be within the following ranges:

[0433] Tympanic membrane temperature of 35.0°C to 37.5°C.

[0434] Systolic blood pressure (SBP) between 90 and 139 mmHg, inclusive.

[0435] Diastolic blood pressure (DBP) between 50 and 89 mmHg inclusive.

[0436] Pulse rates between 45 and 90 bpm (inclusive).

[0437] Participants had to weigh at least 50 kg to participate in the study, and their body mass index (BMI) had to be within the range of 18 to 34.9 kg / m2.

[0438] Participants must be willing to remain at the clinical center as required by the protocol and adhere to the requirements / instructions outlined in the ICF.

[0439] ·Ability to read, speak and understand the local language in order to understand and comply with study requirements.

[0440] Key exclusion criteria

[0441] 1. Use of other study drugs within 5 half-lives or 30 days (whichever is longer) before the first dose.

[0442] 2. Current evidence or past history of clinically significant ECG abnormalities or family history (grandparents, parents, and siblings) of long QT syndrome or other cardiac conduction abnormalities, history of additional risk factors for torsade de pointes (TdP) (e.g., heart failure, hypokalemia), and / or known history or current clinically significant arrhythmias. Abnormal ECG is defined as PR > 220 msec, QRS complex > 120 msec, QTcF > 450 msec in males and females, or any other morphological changes other than early repolarization, nonspecific ST or T wave changes.

[0443] 3. History or presence of malignancy in any organ system (except localized basal cell carcinoma of the skin or in situ cervical cancer) that has been treated or untreated within the past 5 years (regardless of whether there is evidence of local recurrence or metastasis).

[0444] 4. History or presence of any clinically significant disease in any major system organ class (including but not limited to cardiovascular, pulmonary, metabolic, hepatic, renal, hematological, endocrine, neurological, or psychiatric disease that has not resolved within two weeks prior to the initial dose)

[0445] 5. Hypersensitivity reaction to remibrutinib or drugs from the same compound class or their excipients.

[0446] 6. Any contraindications to the use of Pneumovax 23, influenza, or KLH vaccines, including any acute infection, fever, or hypersensitivity reaction or known hypersensitivity reaction to any relevant component of the vaccine to be administered in this study (e.g., egg or shellfish / KLH).

[0447] 7. History of 2022-2023 seasonal influenza vaccination or known clinical diagnosis of influenza infection during the 2022-2023 influenza season prior to recruitment.

[0448] 8. History of previous exposure or immunization with KLH.

Claims

1. A pharmaceutical composition comprising LOU064 for use in treating hidradenitis suppurativa (HS) in a patient in need of such treatment.

2. The pharmaceutical composition of claim 1, wherein LOU064 is administered daily at a dose of about 50 mg to about 200 mg (wherein, The term "about" indicates a variation of + / - 10%).

3. The pharmaceutical composition of claim 2, wherein LOU064 is administered at a dose of about 25 mg twice daily to about 100 mg twice daily (wherein, The term "about" indicates a variation of + / - 10%).

4. The pharmaceutical composition of claim 2, wherein LOU064 is administered at a dose of about 100 mg twice daily (wherein, The term "about" indicates a variation of + / - 10%).

5. The pharmaceutical composition of claim 2, wherein LOU064 is administered at a dose of about 25 mg twice daily (wherein, The term "about" indicates a variation of + / - 10%).

6. The pharmaceutical composition of any one of claims 1-5, wherein LOU064 is administered for less than 3 months.

7. The pharmaceutical composition according to any one of claims 1 to 5, wherein LOU064 is administered for up to 16 weeks.

8. The pharmaceutical composition of any one of claims 1-5, wherein LOU064 is administered for more than 6 months.

9. The pharmaceutical composition according to any one of claims 1 to 5, which is administered as a monotherapy.

10. The pharmaceutical composition according to any one of claims 1 to 5, which is not administered simultaneously with a strong inhibitor of CYP3A.

11. The pharmaceutical composition according to any one of claims 1 to 5, which is not administered simultaneously with a strong inhibitor of CYP3A4.

12. The pharmaceutical composition of any one of claims 1-5, which is administered in combination with one or more second therapeutic agents.

13. The pharmaceutical composition of any one of claims 1-5, wherein the patient has not been previously treated for HS with a systemic or topical therapeutic agent prior to treatment with LOU064.

14. The pharmaceutical composition according to any one of claims 1 to 5, wherein the patient is selected according to at least one of the following criteria: a) The patient suffers from moderate to severe HS; b) prior to treatment with said LOU064, said patient had at least 3 inflammatory lesions; or c) prior to treatment with LOU064, the patient had fewer than 15 fistulas as a result of HS, without extensive scarring; d) the patient has a clinical diagnosis of HS for at least 12 months; e) The patient has at least two anatomical sites associated with HS lesions.

15. The pharmaceutical composition according to any one of claims 1 to 5, wherein the patient achieves at least one of the following by week 16 of treatment: a) Simplified HiSCR; b) HS erythema reduction; c) pain reduction as measured by pain NRS; d) reduced skin pruritus as measured by the pruritus NRS; f) a decrease in the number of HS inflammatory lesions overall or of various types; g) reduction in IHS4 score; h) a reduction of ≤ 6 as measured by the DLQI; and / or i) DLQI improvement.

16. The pharmaceutical composition of any one of claims 1-5, wherein when using the pharmaceutical composition to treat a patient population suffering from moderate to severe HS, at least 40% of the patients achieve at least one of the following by week 16: a)HiSCR50; b)HiSCR75; c)HiSCR90; or d) Simplified HiSCR.

17. The pharmaceutical composition according to any one of claims 1 to 5, wherein by week 16 of treatment, at least 25% of the patients achieve an NRS 30 response; or less than 15% of the patients develop HS erythema.

18. The pharmaceutical composition of any one of claims 1-5, wherein the patient has at least one of the following one or two weeks after the first administration of LOU064: a) pain reduction as measured by the pain NRS; b) reduced skin pruritus as measured by the pruritus NRS; c) At least a 25% reduction in CRP as measured using a standard CRP assay.

19. The pharmaceutical composition of any one of claims 1 to 5, wherein the patient achieves a sustained response 3 months after the end of the treatment as measured by the number of inflammatory lesions, Hidradenitis Suppurativa Clinical Response (HiSCR), Numerical Rating Scale for Itch or Pain (NRS), Hidradenitis Suppurativa-Physician Global Assessment (HS-PGA), HS Severity Assessment (SASH), International HS Severity Scoring System (IHS4), or Dermatology Life Quality Index (DLQI).

20. The pharmaceutical composition of claim 19, wherein the patient achieves a sustained response 3 months after the end of treatment as measured by simplified HiSCR (sHiSCR), HiSCR50, HiSCR75 or HiSCR90.

21. The pharmaceutical composition of any one of claims 1-5, wherein LOU064 is formulated in a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, each independently selected from a filler, a lubricant, a binder, a disintegrant, and a glidant.

22. The pharmaceutical composition according to claim 21, wherein the pharmaceutical composition is in the form of a tablet or a capsule.

23. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition comprises nanoscale particles of LOU064.

24. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition comprises nanoscale particles of LOU064 having an average particle size of about 50 nm to about 750 nm as determined by PCS (wherein, The term "about" indicates a variation of + / - 10%).

25. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition comprises LOU064 and a binder in a weight ratio of about 2:1 (wherein The term "about" indicates a variation of + / - 10%).

26. The pharmaceutical composition of claim 25, wherein the pharmaceutical composition comprises LOU064, a binder, and a surfactant in a weight ratio of about 2:1:0.08 (wherein, The term "about" indicates a variation of + / - 10%).

27. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition comprises LOU064 and a binder in a ratio of about 1:1 by weight (wherein, The term "about" indicates a variation of + / - 10%).

28. The pharmaceutical composition of claim 27, wherein the pharmaceutical composition comprises LOU064, a binder, and a surfactant in a weight ratio of about 1:1:0.05 (wherein The term "about" indicates a variation of + / - 10%).

29. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition comprises LOU064, polyvinyl pyrrolidone-vinyl acetate copolymer as a binder, and sodium lauryl sulfate as a surfactant.

30. The pharmaceutical composition according to any one of claims 1 to 5, wherein LOU064 is a crystalline form of anhydrous free base, characterized in that The X-ray powder diffraction pattern is as follows: When the X-ray wavelength λ is measured, the diffraction pattern includes a range selected from 7.8±0.2°2θ, 9.2±0.2°2θ, 12.0±0.2°2θ, 13.6±0.2°2θ, 15.6±0.2°2θ, 16.0±0.2°2θ, 17.8±0.2°2θ, 18.3±0.2°2θ, 18.7±0.2°2θ, 19.2±0.2°2θ, 19. and 29.6±0.2°2θ (wherein the term "about" indicates a variation of + / - 10%).

31. A composition comprising a therapeutically effective amount of LOU064 and one or more therapeutic agents for treating hidradenitis suppurativa (HS) in a patient in need of such treatment.

32. The composition of claim 31 , wherein the one or more therapeutic agents are topical agents or antiseptics.

Images