Ruxolitinib for use in the treatment of hidradenitis suppurativa

Abstract

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

Description

Technical Field

[0001] 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

[0002] Hidradenitis suppurativa (HS) (also called inverse acne or Verneuil's disease) is a chronic, relapsing, inflammatory disease characterized by deep nodules, fistulas, and abscesses that cause fibrosis in the axillae, groin, breast-fold, and anogenital areas (Revuz and Jemec (2016) Dermatol Clin 34:1-5; Jemec GB. (2012) N Engl J Med 366:158-64). It is associated with significant pain and comorbidities, including metabolic diseases, mental diseases, and autoimmune diseases, 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 HS prevalence rate among different ethnic groups was highest in the African American population (1.3%), lowest in the Hispanic / Latino population (0.07%), and intermediate among white populations (0.75%) (Sachdeva et al. (2021) J. Cutan Med Surg.:25(2):177-187).

[0003] The reported prevalence of HS varies from <1% to 4% in 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, HS is underdiagnosed, and the true prevalence is difficult to confirm because estimates vary depending on study design, population, and geographical location [Miller et al. (2016) Dermatol Clin 34:7-16]. The National Institutes of Health (NIH) does not classify HS as a rare disease, but experts generally believe that the prevalence of this disease is <1% of the US population [Cosmatos et al. (2013); Genetic and Rare Diseases Information Center. National Institutes of Health. Hidradenitis suppurativa. Available at: / / 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].

[0004] Current treatments for HS consist of topical and / or systemic antibiotics, hormonal interventions, retinoids, and, if selected, immunosuppressants, biologic agents such as the tumor necrosis factor [TNF] inhibitor monoclonal antibody adalimumab, the only approved drug for HS, and often, as a last resort, major surgical excision [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]. Since the lesions are painful, patients frequently require analgesics and painkillers in addition to anti-inflammatory treatment.

[0005] However, symptom control and lesion resolution are inconsistent across treatment modalities, and randomized controlled clinical trial results providing evidence-based data are lacking for most treatments, with only adalimumab being approved. Antibiotic therapy is used for long-term treatment over months and even years, but it can lead to a recurrence of antibacterial resistance. Oral treatment with retinoids raises concerns about teratogenicity in a predominantly sexually active female population. Furthermore, the effectiveness of anti-inflammatory drugs such as dapsone, fumarates, and cyclosporine is based on a few case studies with variable results, and these molecules are not used systematically. Due to these inconsistent results and the severity of HS disease, HS patients utilize healthcare in high-cost settings (e.g., emergency care and inpatient treatment) more frequently than patients with other chronic inflammatory skin diseases (Khalsa et al. (2016) J Am Acad Dermatol 73:609-14; Kirby et al. (2014) JAMA Dermatol 150:937-44).

[0006] The immunopathogenicity of HS has been scarcely elucidated, and widely and somewhat inconsistent pathogenic mechanisms have been proposed. Complement activation has been implicated in the pathogenesis of HS by the high concentrations of the complement fragment C5a in the skin and blood of HS patients (Kanni T. et al. Br J Dermatol. 2018;179(2):413-419). C5a is a major chemoattractant for neutrophils, a prominent cell population in the 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 HS patients, along with an increased type I IFN response and activation of plasmacytoid dendritic cells (pDCs) (Byrd AS et al., Sci transl Med. 2019:11(508).eaav5908). Other studies have suggested the involvement of the inflammatory 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. Further transcriptome studies have shown increased expression of immunoglobulin and plasma cell signatures in HS (Hoffman LK. Et al. PLoS One. 2018;13(9):e0203672), but a clear and comprehensive view of the immunopathogenic mechanisms involved in HS is lacking.

[0007] Gudjonsson et al. characterized the inflammatory response in hidradenitis suppurativa (HS) using proteomic and transcriptomic approaches and techniques such as single-cell RNA sequencing or scRNAseq. Such studies revealed an immune response concentrated on IFN-γ, IL-36, and TNF, with a lesser contribution by IL-17A. Gudjonsson et al. further identified B cells and plasma cells as contributing factors in HS pathogenesis, along with activation of the Bruton tyrosine kinase (BTK) and spleen tyrosine kinase (SYK) pathways as central signaling networks in HS, and an associated increase in immunoglobulin production and complement activation (JCI Insight. 2020;5(19):e139930. https: / / doi.org / 10.1172 / jci.insight.139930).

[0008] The role of B cells in HS pathogenesis has also been shown in previous reports (Van der Zee et al. 2012, 166:98 - 106; Musilova et al. J Invest Dermatol 2020, 140:1091 - 1094). Furthermore, the role of B cells in HS pathogenesis has been emphasized by two recent studies, one demonstrating the anti-inflammatory effect of rituximab in HS explant cultures (Vossen et al., 2019, 181:314 - 23), and the other case study showing the success of treating HS using B cell depletion with rituximab (Takahashi et al., 2018, 45:e116 - 7). However, further research is needed to determine whether targeting B cells can be an effective treatment.

[0009] BTK is an essential kinase for FcεRI-mediated signaling in human mast cells and basophils. It is also important for B cell maturation, and thus BTK has been pharmacologically targeted for the treatment of B cell malignancies. There are currently three FDA-approved BTK inhibitors (BTKis) in the United States. Ibrutinib (trade name Imbruvica®; Pharmacyclics, and AbbVie), acalabrutinib (Calquence®; Acerta and AstraZeneca), and zanubrutinib (Brukinsa®; BeiGene) are all oral, covalent small molecule inhibitors of BTK.

[0010] Furthermore, many BTKis in development are 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 the novel compounds ONO-4059 (tirabrutinib), HM71224 (poseltinib), 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). Additionally, evobrutinib, trebrutinib, and fenebrutinib have entered phase III trials in patients with multiple sclerosis (MS), oralerabrutinib has been tested in phase II trials, and BIIB091 has been tested for efficacy in the treatment of MS in phase I trials.

[0011] Despite the suggestion that BTK inhibitors may be useful in the treatment of HS, there is no existing animal model for this disease, and BTK inhibitors have not yet been shown to treat HS in humans. Furthermore, due to the lack of selectivity of some of the more previously developed BTK inhibitors (e.g., acalabrutinib, ibrutinib), those BTK inhibitors may not be suitable for the treatment of non-malignant indications, particularly for indications that require long-term / chronic and safe use, and / or in pediatric or adolescent populations. The most common side effects of currently approved BTK inhibitors include nausea, diarrhea, rash, infections, cytopenia, bleeding, and arrhythmias. In particular, the long-term toxicity profile of ibrutinib, a first-in-class inhibitor, has been well characterized and includes clinically significant incidences of arrhythmias, bleeding, infections, diarrhea, arthralgia, and hypertension. Acalabrutinib, an early second-generation BTKi that received approval from the US Food and Drug Administration, demonstrates improved kinase selectivity for BTK but is associated with commonly observed adverse reactions including infections, headache, and diarrhea (Hematology Am Soc Hematol Educ Program. 2020 Dec 4;2020(1):336-345).

[0012] Long-term safety data are not available for currently developing BTK inhibitors, but the available safety data for fenebrutinib may suggest that the biggest hurdle that BTK inhibitors may face is whether the side effects during chronic use are tolerable. For example, the prominent major events in the Phase IIa trial of fenebrutinib were transient grade 3 increases in ALT and / or AST in 8.3% and 6.3% of the subjects in the high-dose treatment arm. Some of the side effects already observed for some BTKis may limit their use for treating or preventing non-malignant indications, especially when long-term administration may be required. Furthermore, none of the BTK inhibitors approved by the FDA are approved in pediatric and adolescent populations. Therefore, until safety data in children become available, it is unclear whether BTK inhibitors are a viable option.

[0013] HS remains difficult to treat, and the only biological therapy currently approved for its treatment is the anti-TNF agent adalimumab, but even adalimumab has a suboptimal treatment response in approximately 40% of patients. This disease is physically and mentally debilitating, and there is an obvious unmet need to provide a safe and effective long-term treatment, particularly an oral treatment, for HS patients.

Brief Description of the Drawings

[0014]

Figure 1

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Figure 4-1

Figure 4-2

Figure 5

[0015] The underlying problem of the present invention is to provide a safe and effective treatment or prevention of HS. In particular, an object of the present invention is to provide a safe and effective long-term treatment or prevention of HS.

[0016] Also, an object of the present invention is to provide an improved treatment and / or prevention of HS. For example, an object of the present invention is to provide a treatment or prevention of HS that is more effective than anti-TNF treatment, such as adalimumab.

[0017] Accordingly, a method for preventing or treating HS, comprising administering a therapeutically effective dose of a BTK inhibitor to a subject in need thereof, is disclosed herein. Particularly useful in the methods of the present invention are BTK inhibitors (reversible or irreversible) that are selective for other structurally similar Tec family kinases such as BMX, ITK, and TXK. Particularly useful according to the present invention are 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).

[0018] A method for preventing or treating HS, comprising administering a therapeutically effective dose of LOU064 to a subject in need thereof, is also disclosed herein.

[0019] Furthermore, the present invention further provides a method for treating or preventing HS in a subject in need thereof, the method comprising administering to the subject a therapeutically effective dose of LOU064 or a pharmaceutically acceptable salt thereof, together with one or more therapeutic agents.

[0020] In another aspect of the invention, the present invention provides a BTK inhibitor for use in such treatment and / or prevention in a patient in need of treatment and / or prevention of HS.

[0021] In another aspect of the invention, the present invention provides LOU064 for use in such treatment and / or prevention in a patient in need of treatment and / or prevention of HS.

[0022] The present invention further relates to a combination of LOU064 and one or more additional therapeutic agents for use in such treatment or prevention in a patient in need of treatment and / or prevention of HS.

[0023] A further subject of the present invention is a method for the manufacture of a medicament for use in the treatment described above.

[0024] The further aspects, advantageous features and preferred embodiments of the present invention, summarized in the following embodiments E1 to E32, each alone or in combination, serve to solve the object of the present invention:

[0025] E1. A method for treating or preventing hidradenitis suppurativa (HS), the method comprising administering to a subject in need thereof a therapeutically effective dose of a BTK inhibitor, such as a selective BTK inhibitor, such as LOU064.

[0026] E2. The method according to E1, wherein the therapeutically effective dose of LOU064 is from about 50 mg to about 200 mg per day.

[0027] E3. The method according to E2, wherein the therapeutically effective dose of LOU064 is from about 25 mg twice a day to about 100 mg twice a day.

[0028] The method according to E2, wherein a therapeutically effective dose of LOU064 is about 25 mg twice a day.

[0029] The method according to E2, wherein a therapeutically effective dose of LOU064 is about 100 mg twice a day.

[0030] E6. The method according to any one of the preceding embodiments, wherein LOU064 is administered for a short period, for example, less than 6 months, preferably less than 3 months.

[0031] E7. The method according to E6, wherein LOU064 is administered for a maximum of 16 weeks, for example, for 4, 12, or 16 weeks.

[0032] E8. The method according to any one of embodiments E1 - E5, wherein LOU064 is administered for long - term use, for example, more than 6 months, preferably more than 1 year.

[0033] E9. The method according to any one of the preceding embodiments, wherein LOU064 is administered as monotherapy.

[0034] E10. The method according to any one of the preceding embodiments, wherein LOU064 is not administered simultaneously with a strong inhibitor of CYP3A.

[0035] E11. The method according to any one of the preceding embodiments, wherein LOU064 is not administered simultaneously with a strong inhibitor of CYP3A4.

[0036] E12. The method according to any one of embodiments E1 - E8, wherein LOU064 is administered in combination therapy with one or more therapeutic agents.

[0037] E13. The method according to E12, wherein the patient is further treated with at least one topical agent and at least one disinfectant in combination with LOU064.

[0038] The method according to any one of embodiments E1 to E11, wherein the patient has not been previously treated with a systemic agent or a topical treatment agent for HS before treatment with E14.LOU064.

[0039] E15. The patient is selected according to at least one of the following criteria: a) The patient has moderate to severe HS; b) Before treatment with LOU064, the patient has at least 3 inflammatory lesions; or c) Before treatment with LOU064, the patient does not have scarring of the extensive fistula with a range of 15 or less as a result of HS); d) The patient has a clinical diagnosis of HS for at least 12 months; e) The patient has at least 2 anatomical sites involved in HS lesions, the method according to any of the above embodiments.

[0040] E16. By the 16th week of treatment, the patient has the following: a) Simplified HiSCR; b) HiSCR clinical outcome (HiSCR50, HiSCR75 or HiSCR90) c) Reduction of HS erythema; d) Pain NRS; for example, reduction of skin pain as measured by pain NRS30 e) Pruritus NRS; for example, reduction of pruritus as measured by pruritus NRS30 f) Overall or various types of HS inflammatory lesion variables; for example, reduction of AN50, AN75, AN90 or AN100; g) Reduction of IHS4 score; h) A reduction of ≤6 when measured by DLQI; and / or i) Improvement of DLQI The method according to any of the above embodiments, achieving at least one of the above.

[0041] E17. When treating a population of patients with moderate to severe HS using the above method, at least 40% of the patients have the following by the 16th week of treatment: a) Simplified HiSCR; b) HiSCR50; c) HiSCR75 d) HiSCR90 The method according to any of the above embodiments, achieving at least one of the above.

[0042] E18. When treating a population of patients with moderate to severe HS using the method, at least 25% of the patients achieve an NRS30 response (e.g., pain NRS30 or itching NRS30 response) by the 16th week of treatment. The method according to any of embodiments E1 - E16.

[0043] E19. When treating a population of patients with moderate to severe HS using the method, less than 15% of the patients develop HS erythema during 16 weeks of treatment. The method according to any of embodiments E1 - E16.

[0044] E20. Approximately one or two weeks after the first administration of LOU064, the patient has at least one of the following: a) Reduction in pain as measured by the pain NRS (e.g., pain NRS30) b) Reduction in itching as measured by the itching NRS (e.g., skin itching NRS30) b) A decrease in CRP of at least 25%, for example, as measured using a standard CRP assay The method according to any of embodiments E1 - E16.

[0045] E21. When measured by an inflammatory variable such as AN50, Hidradenitis suppurativa clinical response (HiSCR) (e.g., sHiSCR, HiSCR50, HiSCR75, or HiSCR90), itching or pain numerical rating scale (NRS), Hidradenitis suppurativa - physician global assessment (HS - PGA), HS severity assessment (SASH), International HS severity score system (IHS4), or Dermatology Life Quality Index (DLQI), the patient achieves a sustained response three months after the end of treatment. The method according to any of the above embodiments.

[0046] E22. The method according to E21, wherein when measured by simplified HiSCR (sHiSCR), HiSCR50, HiSCR75 or HiSCR90, the patient achieves a sustained response 3 months after the end of treatment.

[0047] E23. The method according to any of the above embodiments, wherein LOU064 is disposed in a pharmaceutical composition, and the pharmaceutical composition comprises one or more pharmaceutically acceptable carriers, each of which is independently selected from fillers, lubricants, binders, disintegrants and glidants.

[0048] E24. The method according to E23, wherein the pharmaceutical composition is in the form of a tablet or capsule.

[0049] E25. The method according to embodiment E23 or E24, wherein the pharmaceutical composition comprises nanosized particles of LOU064.

[0050] E26. The method according to E25, wherein the pharmaceutical composition comprises nanosized particles of LOU064 having an average particle size of about 50 nm to about 750 nm as measured by PCS.

[0051] E27. The method according to any one of embodiments E23 to E26, wherein the pharmaceutical composition comprises LOU064 and a binder in a weight ratio of about 2:1.

[0052] E28. The method according to E27, wherein the pharmaceutical composition comprises LOU064, a binder and a surfactant in a weight ratio of about 2:1:0.08.

[0053] E29. The method according to any one of embodiments E23 to E26, wherein the pharmaceutical composition comprises LOU064 and a binder in a weight ratio of about 1:1.

[0054] 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.

[0055] 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.

[0056] E32. The method according to any of the preceding embodiments, wherein LOU064 is in a crystalline form of the anhydrous free base characterized by an X-ray powder diffraction pattern comprising one or more representative peaks with respect to 2θ 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, 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, when measured at a temperature of about 25 °C and an X-ray wavelength, λ, of 1.5405 Å.

Mode for Carrying Out the Invention

[0057] 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 signal transduction via Fcε receptors (FcεR1 in the case of IgE) and activating Fcγ receptors (FcγR in the case of IgG), as well as the B cell antigen receptor (BCR) and BTK inhibitors. BTK inhibitors such as ibrutinib are approved for the treatment of B cell malignancies (Hendriks et al 2014). Recently, inhibition of BTK has been demonstrated to result in inhibition of mast cell and basophil activation / degranulation in vitro and a decrease in wheal size in skin prick tests in patients suffering from IgE-mediated allergy (Smiljkovic et al 2017; Regan et al 2017; Dispenza et al 2018). Thus, inhibition of BTK is an attractive therapeutic concept for treating 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 fenebrutinib, as well as non-covalent, irreversible inhibitors of BTK such as evobrutinib, trebrutinib, rilzabrutinib, tirabrutinib, branebrutinib, orelabrutinib, and remibrutinib (LOU064).

[0058] The term "comprising" encompasses "including" as well as "consisting of"; for example, a composition "comprising" X may consist solely of X or may include something additional, e.g., X + Y.

[0059] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that, in view of a reasonable benefit / risk ratio and within the scope of reasonable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction, or other problems or complications.

[0060] The term "about" in relation to a numerical value x means, for example, + / - 10%. When used before a numerical range or list of numerical values, the term "about" applies to each numerical value in the series. For example, the phrase "about 1 - 5" should be interpreted as "about 1 - 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.".

[0061] As used herein, the term "salt" or "salts" refers to acid addition salts or base addition salts of a compound for use in the methods of the present invention. Particularly included as "salts" are "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effects and properties of the compounds of the present invention and are typically not biologically or otherwise harmful. In many cases, the compounds for use in the methods of the present invention are capable of forming acid salts and / or base salts due to the presence of amino groups. Examples of salts are those disclosed in WO 2015 / 079417 pamphlet, which is incorporated herein by reference.

[0062] As used herein, the term "administer" in relation to a compound, such as LOU064, or another agent, is used to refer to the delivery of that compound to a patient by any route, preferably oral administration.

[0063] As used herein, the term "pharmaceutically acceptable carrier" includes any solvent, dispersion medium, coating, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal agents), isotonic agent, absorption delaying agent, salt, preservative, drug stabilizer, binder, excipient, disintegrant, lubricant, sweetening agent, flavoring agent, dye, and the like and combinations thereof, as known to those of ordinary skill in the art (e.g., see Remington’s Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). The use of any conventional carrier in a therapeutic or pharmaceutical composition / formulation is contemplated, provided it is not incompatible with the active ingredient.

[0064] The term "therapeutically effective amount / dose" of a compound for use in the methods of the present invention refers to that amount of the compound that induces a biological or medical response in a subject, e.g., decreases or inhibits enzyme or protein activity, or improves the symptoms of HS, alleviates the HS pathology, slows or delays the disease progression of HS, or prevents HS.

[0065] The term "treatment" or "treating" 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 to tissue or cell line isolated from a subject, where the subject has a particular disease (e.g., HS), a symptom associated with the disease (e.g., a symptom of HS), or a tendency to develop the disease (if applicable), and the purpose is to cure one or more symptoms of the disease (if applicable), reduce the severity, relieve and improve such symptoms, improve the disease, reduce or improve any associated symptoms of the disease or the tendency to develop the disease. The term "treatment" or "treating" includes treating a subject suspected of having a disease as well as a subject diagnosed as being ill or suffering from a disease or medical condition. In one aspect, the term "treating" refers to improving a disease or disorder (i.e., slowing or stopping or reducing the manifestation or progression of at least one of the disease or its clinical symptoms). In another embodiment, "treating", "treatment" or "treat" refers to reducing or improving at least one physical parameter that may not be recognizable by the patient. In yet another embodiment, "treating", "treatment" or "treat" refers to modulating the disease or disorder, either physically (e.g., stabilization of recognizable symptoms), physiologically (e.g., stabilization of physical parameters), or both. More specifically, the term "treating" the disease HS refers to treating inflammatory lesions in HS patients (reducing them in number or quality or in their volume and size), and / or treating abscesses and inflammatory nodules and / or draining fistulas in HS patients, and / or reducing the amount of scarring, and / or alleviating the functional restrictions associated with the scarring. Treating the disease HS also refers to reducing pain, malaise and / or itching associated with HS, reducing pus discharge and the odor associated with pus discharge, and / or improving the quality of life for HS patients, and / or reducing work disability.

[0066] As used herein, the terms “prevent,” “preventing,” and “prevention” of a disease or disorder (HS) refer to prophylactic treatment of the disease or disorder; or delaying and / or suppressing the manifestation or progression of the disease or disorder. More specifically, the term “preventing” a disease HS refers to preventing the appearance of HS erythema and / or new lesions; preventing scarring and preventing functional restrictions associated with scarring, and / or in particular, preventing surgical intervention for HS.

[0067] As used herein, the phrase “population of subjects” is used to mean a group of subjects who may benefit biologically, medically, or in terms of quality of life from such treatment.

[0068] As used herein, the term “subject” refers to an animal. Typically, the animal is a mammal. The subject also refers to, for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In a preferred embodiment, the subject is a human. The term “subject” is used synonymously with “patient” when it refers to a human.

[0069] As used herein, the phrases "not previously treated with systemic therapy for HS" and "treatment-naive" refer to HS patients who have not previously been treated with systemic agents for HS, such as methotrexate, cyclosporine, or biologic agents (e.g., IL-12 and IL-23 blockers such as ustekinumab and guselkumab or TNF-α inhibitors such as adalimumab or infliximab, or IL-17 blockers such as secukinumab, ixekizumab, and brodalumab). Systemic agents (i.e., agents administered orally, by injection, etc.) differ from topical agents (e.g., topical medications and phototherapy) in that systemic agents have a systemic (whole body) effect when delivered to the patient. In certain embodiments of the disclosed methods, regimens, uses, kits, and pharmaceutical compositions, the patient has not previously been administered systemic therapy for HS.

[0070] As used herein, the phrase "previously treated with a systemic agent for HS" is used to mean a patient who has previously received HS treatment with a systemic agent. Such patients include patients previously treated with biologics, such as IL-12 and IL-23 blockers, such as ustekinumab and guselkumab, or TNF-α inhibitors, such as infliximab, or IL-17 blockers, such as secukinumab, ixekizumab, and brodalumab, and patients previously treated with non-biologics, such as systemic immunosuppressive or immunomodulatory agents (such as cyclosporine, methotrexate, and cyclophosphamide), retinoids (such as isotretinoin), dapsone, metformin, and oral zinc treatment. In certain embodiments of the disclosure, the patient has previously been administered a systemic agent for HS. In certain embodiments, the patient has previously been administered a systemic agent for HS (such as methotrexate, cyclosporine), but the patient has not previously been administered a systemic biologic agent (i.e., a drug produced by a living organism, such as an antibody, receptor decoy, etc.) (such as secukinumab, ustekinumab, ixekizumab, brodalumab, TNF α inhibitors (etanercept, adalimumab, infliximab remicade, etc.). In this case, the patient is referred to as "biologic-naive". In certain embodiments, the patient is biologic-naive.

[0071] As used herein, "selecting" and "selected" with respect to a patient are used to mean that a particular patient is specifically selected from a larger group of patients based on (by) a particular patient having a predetermined criterion. Similarly, "selectively treating" refers to providing treatment to a patient having a particular disease, where the patient is specifically selected from a larger group of patients based on a particular patient having a predetermined criterion. Similarly, "selectively administering" refers to administering a drug to a patient specifically selected from a larger group of patients based on (by) a particular patient having a predetermined criterion. Selecting, selectively treating, and selectively administering do not mean that a standard treatment plan is delivered based only on the patient being a member of a larger group, but rather that an individualized treatment based on the patient's history (e.g., past therapeutic interventions, e.g., past treatment with biologics), biology (e.g., specific gene markers), and / or symptoms (e.g., not meeting certain diagnostic criteria) is delivered to the patient. With respect to the methods of treatment used herein, selecting does not refer to the accidental treatment of a patient having a particular criterion, but rather to a deliberate selection to administer treatment to a patient based on a particular patient having a particular criterion. Thus, selective treatment / administration is different from a standard treatment / administration that delivers a particular drug to all patients having a particular disease, regardless of the patient's history, disease symptoms, and / or biology. In one embodiment, the patient is selected for treatment based on having HS.

[0072] As used herein, the terms "a", "an", "the" and similar terms used in connection with the present invention (in particular, with respect to the claims) shall be construed to include both the singular and the plural unless specifically indicated otherwise herein or clearly contradicted by the context.

[0073] As used herein, the term "pharmaceutical combination" means a product obtained by the use, mixing or combination of two or more active ingredients. It should be understood that the pharmaceutical combinations as used herein include both fixed combinations and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredient, for example, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more combination partners are administered to a patient simultaneously as a single entity or dosage form. In such cases, the term refers to a fixed-dose combination in one unit dosage form (e.g., capsule, tablet, or sachet). The terms "non-fixed combination" or "kit of parts" both mean that the active ingredient, for example, the compounds of the present disclosure and one or more combination partners and / or one or more adjuvants are administered or co-administered to a patient as separate entities, either simultaneously, concurrently or sequentially, without a specific time limit, and such administration, in particular when these time intervals enable the combination partners to exhibit a combined effect, e.g., an additive or synergistic effect, provides therapeutically effective levels of the two compounds in the patient's body. The term "non-fixed combination" also applies to cocktail therapies, e.g., the administration of three or more active ingredients. Thus, the term "non-fixed combination" defines, in particular, the administration, use, composition or formulation in the sense that the compounds described herein can be administered independently of each other, i.e., simultaneously or at different times. The term "non-fixed combination" should also be understood to include the use of a single agent together with one or more fixed combination products of independent formulations each containing different amounts of the active ingredient. The combination products described herein as well as the term "non-fixed combination" include the active ingredients (including the compounds described herein), and it should be further understood that the combination partners are administered as completely separate pharmaceutical dosage forms or pharmaceutical formulations that are also sold independently of each other.Instructions for use of the unfixed combination may be provided in the packaging, such as a leaflet, or other information provided to physicians and / or medical staff, or may be provided. In that case, the independent pharmaceutical or parts of the pharmaceutical, product, or composition may be administered simultaneously or at different times, i.e., the individual parts of the kit of parts may each be administered at different times and / or at equal or different time intervals for any part of the kit of parts. In particular, the time interval of administration is selected such that the effect on the disease treated by the combined use of the parts is greater / higher than the effect obtained by the use of only the compound of formula (I) or a pharmaceutically acceptable salt thereof; thus, the compounds used in the pharmaceutical combinations described herein are co-active. The ratio of the total amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the second agent administered as a pharmaceutical combination may be varied or adjusted to suit the needs of the particular patient subpopulation being treated or the needs of an individual patient obtained, for example, by the patient's age, sex, weight, etc.

[0074] As used herein, terms such as "co-administration" or "combined administration" mean 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 the compounds are not necessarily administered by the same route of administration and / or simultaneously.

[0075] LOU064 LOU064 (=N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, INN: Remibrutinib) is disclosed in WO 2015 / 079417 A1 pamphlet as a drug candidate for the selective inhibition of Bruton's tyrosine kinase. This compound is a potent, highly selective, irreversible covalent BTK inhibitor. Due to its binding to the inactive conformation of BTK, LOU064 exhibits excellent kinase selectivity and thus reduces kinase off-target binding. Through covalent inhibition, the compound shows potent and sustained pharmacodynamic effects without the need for long-term 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).

[0076] LOU064 for use in the method of the present invention has the formula (I): [Chemical formula] and is the free base represented by

[0077] In other embodiments, N-(3-(6-amino-5-(2-(N-methylacrylamide)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide is the anhydrous crystalline form A of the free base, as disclosed in WO 2020 / 234779 A1 pamphlet (Example 1), which is incorporated herein by reference.

[0078] LOU064, which has already been proposed for use in the treatment of chronic spontaneous urticaria (CSU) (International Publication No. WO 2020 / 234782 A1) and Sjögren's syndrome (SjS) (International Publication No. WO 2020 / 234781 A1), is currently being tested in a Phase 2 clinical trial for CSU and SjS.

[0079] In International Publication No. WO 2020 / 234782 A1, it was generally suggested that twice-daily (b.i.d.) administration at doses of 10 mg, 25 mg, and 100 mg achieved maximum efficacy in CSU.

[0080] In a Phase 2b, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of LOU064 over 12 weeks in patients with at least moderately active chronic spontaneous urticaria (CSU) who had inadequate control with H1-antihistamines, patients were administered LOU064 10 mg q.d. (once daily), 35 mg q.d., 100 mg q.d., 10 mg b.i.d. (twice daily), 25 mg b.i.d., 100 mg b.i.d., or placebo (in a 1:1:1:1:1:1:1 ratio). The 25 mg b.i.d. regimen was found to be particularly effective compared to the other doses.

[0081] Therefore, the 25 mg b.i.d. dose was selected for subsequent Phase III clinical trials for CSU.

[0082] BTK occupancy in blood and / or tissue has been reported to be a suitable biomarker for selecting doses for clinical trials such as CSU and SjS trials (International Publication No. WO 2020 / 234782 and International Publication No. WO 2020 / 234781).

[0083] Furthermore, it has been reported that BTK occupancy and the persistence of BTK occupancy differ in the blood and various tissues of female rats (International Publication No. WO 2020 / 234781).

[0084] The BTK occupancy in different tissues is related to the efficacy and optimal dose selection in different indications. However, there is currently no consistent overall picture for all tissues related to the HS indication, and thus for the tissues that need to be penetrated to treat or prevent HS. As reported in rats, the BTK occupancy and BTK occupancy half-life are different in blood and various tissues.

[0085] The BTK occupancy half-life depends on the turnover rate (the ability of BTK cells to regenerate). Such turnover rates vary by tissue and are species-specific. The BTK occupancy further depends on the PK / PD properties of the compound, which are also species-dependent.

[0086] BTK inhibitors can act or intervene through three basic mechanisms of action or pathways: 1) Reduction of allergic / I-type hypersensitivity via FcεR1, 2) Inhibition of B-cell autoreactivity and immune complexes in autoreactive / inflammatory or type 3 hypersensitivity via FcγR and / or BCR, 3) Inhibition of autoantibody secretion in autoimmune diseases or type 2 hypersensitivity via BCR.

[0087] Although not related to the theory, BTK inhibition is related to the latter two pathways, which is because it has been suggested that HS is related to B cell activity (Rumberger et al. 2020, Gudjonsson et al.) and due to the presence of autoantibodies (Byrd et al (2018), J.Dermatol.; 179(3):792-794, (2019), Camona-Rivera et al. (2021) J Invest Dermatol. Oct 1:S0022-202X(21)02286-7.doi:10.1016 / j.jid.2021.07.187). B cells and plasma cells are found in the tertiary lymphoid organs in the diseased tissue. BTK turnover is potentially higher in B cells located in the tertiary lymphoid organs of HS lesions compared to dermal mast cells, and sufficient target tissue penetration may be more difficult to achieve in HS compared to CSU due to the remodeling of fibrous tissue and the presence of abscesses and fistula tracts.

[0088] On the other hand, CSU is likely to particularly depend on the first-mentioned pathway as demonstrated by the activity of anti-IgE antibodies (via FcεR1), and thus the clinical response in HS may not be predicted using CSU doses or any doses disclosed for other indications.

[0089] Therefore, without being restricted by any theory, an effective dose of LOU064 for the treatment or prevention of HS is a dose that allows for a potentially higher BTK turnover and a higher tissue concentration in the inflamed and partially fibrotic HS lesions.

[0090] Pharmaceutical composition for use in the method of the present invention A BTK inhibitor, i.e., a compound of formula (I), or a pharmaceutically acceptable salt thereof, can be used as a pharmaceutical composition when combined with a pharmaceutically acceptable carrier. Such a composition can contain, in addition to the compound of formula (I) or a pharmaceutically acceptable salt thereof, a carrier, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials known in the art. The properties of the carrier depend on the route of administration. The pharmaceutical composition for use in the disclosed methods can also contain additional therapeutic agents for the treatment of a particular targeted disorder. For example, the pharmaceutical composition can also include an anti-inflammatory agent or an antipruritic agent. Such additional factors and / or agents can 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 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 methods contains the compound of formula (I) or a pharmaceutically acceptable salt thereof in a daily dose of about 50 mg to 200 mg, for example, 25 mg bid, or 100 mg bid.

[0091] Suitable compositions for oral administration include the active ingredient in the form of tablets, troches, 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 the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents to provide pharmaceutically elegant and palatable formulations. Tablets may contain the active ingredient admixed with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, time delay materials such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin or olive oil.

[0092] Pharmaceutical compositions for use in the disclosed methods can be manufactured by conventional methods. In one embodiment, the pharmaceutical composition is provided for oral administration. For example, the pharmaceutical composition may contain a) diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants such as silica, talcum, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; and further for tablets c) a binder, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; optionally d) a disintegrant, such as starch, agar, alginic acid or its sodium salt, or a foaming mixture; and / or e) an absorbent, a colorant, a flavor and a sweetener It is a tablet or gelatin capsule containing the active ingredient together with them.

[0093] Therefore, the pharmaceutical composition for use in the method of the present invention comprises LOU064 and one or more pharmaceutically acceptable carriers, each of which is independently selected from a filler, a lubricant, a binder, a disintegrant and a glidant.

[0094] In another embodiment, the suitable pharmaceutical composition, LOU064, may be present in any pharmaceutically acceptable form. The pharmaceutical composition would preferably be in the form of a tablet or a capsule. The tablet can be film-coated or enteric-coated according to methods known in the art. It would also be preferred to include LOU064 in the pharmaceutical composition / formulation as nano-sized or micro-sized particles.

[0095] When LOU064 is present in the pharmaceutical formulation in the form of nano-sized particles, the average particle size can be less than 1000 nm. Preferably, the average particle size of LOU064 can be less than 500 nm, more preferably less than 250 nm.

[0096] In a preferred embodiment, the average particle size of LOU064 can be from about 50 nm to about 1000 nm, or from about 50 nm to about 750 nm, or from about 60 nm to about 500 nm, or from about 70 nm to about 350 nm, or from about 100 nm to about 170 nm, more preferably, the average particle size of LOU064 can be from about 100 nm to about 350 nm, or from about 110 nm to about 200 nm, or from about 120 nm to about 180 nm or from about 120 nm to about 160 nm, preferably, the average particle size of LOU064 can be from about 150 nm to about 200 nm.

[0097] When LOU064 is present in a pharmaceutical formulation in the form of nano-sized particles, oral administration is preferably at a dose of about 25 mg to about 100 mg twice a day, more preferably at a dose of about 100 mg twice a day.

[0098] When LOU064 is present in a pharmaceutical formulation in the form of micro-sized particles, the average particle size can be 1 - 5 μm or preferably 1.0 - 1.5 μm. Preferably, the average particle size of LOU064 can be 1.1 - 1.3 μm.

[0099] When LOU064 is present in a pharmaceutical formulation in the form of micro-sized particles, oral administration is preferably at a dose of about 25 mg to about 100 mg twice a day, for example, at a dose of about 25 mg twice a day.

[0100] In a preferred embodiment, the polydispersity index (PI) is 0.01 - 0.5, more preferably 0.1 - 0.2, and particularly 0.12 - 0.14. A preferred particle size distribution is shown in Figure 5.

[0101] The above average particle size is weighted by intensity. 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, to determine the average particle size, a device "Zetasizer Nano ZS", Version 7.13, manufactured by Malvern Panalytical Ltd. (UK) can be used.

[0102] Preferably, the measurement is carried out as a wet dispersion method using a 0.1 mM NaCl solution (1:10) in purified water, where the attenuator index is 2 - 9, and particularly 5. The measurement is preferably carried out at 25°C. Further preferred settings of the measurement system are as follows: Cell: Disposable sizing cuvette Count rate (kcPs): 315 Duration: 60 seconds Measurement position (mm): 4.65.

[0103] In one embodiment of the present invention, the LOU064 composition is formulated according to routine procedures as a pharmaceutical composition adapted for oral administration to humans. Typically, the composition for oral administration is in the form of capsules or tablets.

[0104] In one embodiment, the pharmaceutical composition / formulation for LOU064 is formulated according to the formulations disclosed in U.S. Provisional Patent Application No. 63 / 141558 or its family members (International Publication No. 2022 / 162513 Pamphlet), which are incorporated herein by reference.

[0105] According to the present invention, a suitable pharmaceutical composition for oral administration comprises LOU064 and a binder.

[0106] Suitable binders include polyvinylpyrrolidone-vinyl acetate copolymer, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose, carboxymethyl cellulose, methylcellulose, hydroxyethyl cellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose, polyethylene glycol, polyvinyl alcohol, shellac, polyvinyl alcohol-polyethylene glycol copolymer, polyethylene-propylene glycol copolymer, or mixtures thereof. Preferably, the binder is polyvinylpyrrolidone-vinyl acetate copolymer.

[0107] The weight ratio of LOU064 to the binder can be about 3:1 to about 1:3; for example, about 3:1, about 2:1, about 1:1, and preferably, the weight ratio of LOU064 to the binder is about 2:1 or about 1:1.

[0108] Preferably, a suitable pharmaceutical composition for oral administration comprises LOU064, a binder, and a surfactant.

[0109] 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.

[0110] The weight ratios of LOU064, the binder, and the surfactant are 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 ratios of LOU064, the binder, and the surfactant are about 2:1:0.08 or about 1:1:0.05.

[0111] In a particularly preferred embodiment, a suitable pharmaceutical composition for oral administration comprises LOU064, a binder, and a surfactant, wherein the binder is polyvinylpyrrolidone-vinyl acetate copolymer (copovidone), the surfactant is sodium lauryl sulfate (SLS), and the weight ratio of LOU064, copovidone, and SLS is about 2:1:0.08. It is even more particularly preferred that LOU064 is present in this pharmaceutical composition in the form of nano-sized particles having an average particle size of about 100 nm to about 200 nm as measured by PCS.

[0112] A method for treating or preventing HS using LOU064 or a pharmaceutically acceptable salt thereof, or a crystalline form thereof. A method for use in treating or preventing HS in a subject in need thereof, and LOU064 or a pharmaceutically acceptable salt thereof are disclosed, which comprises 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 method can be used in vitro, ex vivo or incorporated into a pharmaceutical composition and can be administered in vivo to treat HS patients (e.g., human patients).

[0113] The appropriate dosage will vary, for example, depending on the specific pharmaceutically acceptable salt of LOU064, the specific polymorphic form of LOU064, the weight of the patient, the method of administration, the pharmaceutical composition, and the nature and severity of the condition being treated, as well as the nature of past treatments the subject has received. Ultimately, the attending medical personnel will determine the amount of LOU064 to treat each individual subject. In certain embodiments, the attending medical personnel may administer a low dose of LOU064 and observe the subject's response.

[0114] In one embodiment of the present disclosure, LOU064 or a pharmaceutically acceptable salt thereof is orally administered at a dosage of about 50 mg to about 200 mg per day.

[0115] In one embodiment of the present disclosure, LOU064 or a pharmaceutically acceptable salt thereof is orally administered at a dosage of about 25 mg twice a day to about 100 mg twice a day, for example, about 25 mg twice a day (BID), about 50 mg BID or about 100 mg BID.

[0116] In another embodiment, LOU064 is orally administered at a dosage of about 25 mg twice a day.

[0117] In another embodiment, LOU064 is orally administered at a dosage of about 100 mg twice a day.

[0118] The treatment period using the pharmaceutical composition of the present disclosure will vary depending on the severity of the disease or disorder being treated and the condition and individual response of each individual subject. In certain embodiments, the subject is administered LOU064 for a short period of time, for example, up to 1 week, for example, up to 2 weeks, for example, up to 4 weeks, for example, up to 12 weeks, for example, up to 16 weeks, for example, up to 24 weeks.

[0119] In certain other embodiments, the subject is preferably administered LOU064 over a long period of time (e.g., LOU064 is used indefinitely for the entire period over which the disease exists to justify its use, e.g., for at least 6 months, e.g., for 1 year, 2 years, 3 years, 4 years, over 10 years. LOU064 or a pharmaceutically acceptable salt thereof can be used for up to 5 years, 10 years, 15 years, 20 years or for life. In a preferred embodiment, the treatment with LOU064 according to the present invention is a chronic treatment.

[0120] HS is a chronic, inflammatory, scarring condition that primarily affects the skin intertriginous areas of the body's axillae, groin, inframammary, anogenital, and perineum. It is also known as inverse acne. Three diagnostic criteria establish the diagnosis of HS: typical lesions (deep, painful nodules [hidden] masses in initial primary lesions, or abscesses, sinus tracts, bridging scars, and "gravestone" open comedones in secondary lesions); typical topography (axillae, groin, genitalia, perineum and perianal area, buttocks, and inframammary and intermammary areas; and chronicity and recurrence (Margesson and Danby (2014) Best Practices and Res.Clin.Ob.And Gyn 28:1013-1027). The physical extent of HS can be classified using the Hurley clinical staging classification shown in Table 1 below:

[0121]

Table 1

[0122] HS consists of follicular comedones, duct rupture, and secondary inflammation. The patient first develops a blockage of the follicular duct, which over time leads to duct leakage and horizontal rupture into the dermis. When repair of the follicle-pilosebaceous (FPSB) unit fails, the follicular fragments stimulate three reactions that initiate the HS disease course. The first reaction is an inflammatory response triggered by the innate immune system, which causes suppuration and tissue destruction, resulting in a foreign body reaction and extensive scarring. The second reaction results in an epithelium-lined cavity, which can arise from stem cells in the surviving FPSB units that have been disrupted by the inflammatory response. Thirdly, an invasive proliferative gelatinous mass consisting of a gel containing inflammatory cells occurs in most cases and is hypothesized to be the precursor of the epithelium-lined elements described above (see Margesson and Danby (2014)). As used herein, the phrase "retarding the progression of the HS disease" means retarding any of the aspects of the HS disease course described above, particularly reducing the rate of progression of the inflammatory response. In certain embodiments of the present disclosure, treatment with LOU064 retards the progression of the HS disease.

[0123] Recurrence of HS in a patient includes the occurrence of papules, pustules or inflammatory nodules, pain and pruritus, abscesses, drainage, and any combination thereof. As used herein, "HS erythema" (etc.) is defined as at least a 25% increase in the number of abscesses and inflammatory nodules (AN) with a minimum increase of two AN compared to baseline.

[0124] In certain embodiments of the present disclosure, treatment according to the disclosed method with LOU064 prevents HS erythema, reduces the severity of HS erythema, and / or reduces the frequency of HS erythema. In certain embodiments, when a population of HS patients is treated according to the disclosed method, less than 5%, less than 10%, less than 15%, or less than 20% develop erythema during the first 16 weeks of treatment.

[0125] As used herein, phrases such as "reducing the severity of HS erythema" mean reducing the intensity of HS erythema, e.g., reducing the number and / or size of abscesses and / or inflammatory nodules, reducing the intensity of specific erythema 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 amount of time that erythema (or its components) persists.

[0126] As used herein, phrases such as "reducing the frequency of HS erythema" mean reducing the incidence of HS erythema, e.g., reducing the incidence of abscesses and / or inflammatory nodules. By reducing the frequency of HS erythema, the patient experiences fewer HS recurrences. The incidence of erythema can be evaluated by monitoring the patient over time to determine whether the prevalence of erythema has decreased.

[0127] As used herein, the phrase "preventing HS erythema" means eliminating future HS erythema and / or erythema components.

[0128] The effectiveness of HS treatment can be evaluated using various known methods and means for measuring HS disease states and / or HS clinical responses. 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 numerical rating scale (NRS) for evaluating skin-related pain or skin itching, 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 anxiety and depression scale, healthcare resource utilization, hidradenitis suppurativa severity index (HSSI), work productivity index (WPI), body surface area (BSA), acne inversa 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 certain embodiments, the effectiveness of the methods of the invention disclosed herein can be evaluated by HS Physician Global Assessment (HS-PGA), severity assessment scoring score (SAHS), score numerical rating scale (NRS) (itching 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 the HS treatment disclosed herein can be evaluated by HS clinical response based on the sum of abscesses and inflammatory nodules (HiSCR, i.e., HiSCR50, HiSCR75 or HiSCR90), and / or simplified HiSCR.

[0129] In certain embodiments, HS patients achieve HiSCR in response to HS treatment. In certain embodiments, when a population of HS patients is treated according to the disclosed methods, at least 30%, at least 40%, at least 50%, at least 60% or at least 70% achieve at least one of the following by week 16: - HiSCR50; - HiSCR75; - HiSCR90; or - Simplified HiSCR (sHiSCR); preferably, 2HiSCR of the above.

[0130] In other embodiments, the efficacy of the HS treatment disclosed herein is measured by the difference between the proportion of responders (i.e., patients who achieve a HiSCR response (HiSCR, i.e., HiSCR50, HiSCR75, HiSCR90 or sHiSCR response) to HS treatment with the compounds of the invention) in treated patients by week 16 of treatment and the proportion of responders in placebo-treated patients. In certain embodiments, this difference in the proportion of responders as measured by HiSCR (HiSCR50, HiSCR75, HiSCR90 or sHiSCR) is at least 15%, at least 25%, at least 30% or at least 35%.

[0131] Preferred scoring systems for treatment response 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 variables (number of abscesses, inflammatory nodules, and / or draining fistulas), ISH4 and DLQI.

[0132] The Hidradenitis Suppurativa Clinical Response (HiSCR) is a measure of the clinical response to HS treatment. The HiSCR50 response to treatment (compared to baseline) is as follows: 1) at least a 50% decrease in abscesses and inflammatory nodules (AN50), and 2) no increase in the number of abscesses, and 3) no increase in the number of draining fistulas.

[0133] In certain embodiments, an HS patient achieves HiSCR50 in response to HS treatment.

[0134] In certain embodiments, when a population of HS patients is treated according to the disclosed method, at least 40%, at least 50%, at least 60%, or at least 70% achieve HiSCR50 by week 16 of treatment.

[0135] 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, an HS patient achieves simplified HiSCR in response to HS treatment. In certain embodiments, when a population of HS patients is treated according to the disclosed method, at least 40%, at least 50%, at least 60%, or at least 70% achieve simplified HiSCR by week 16 of treatment.

[0136] The HiSCR75 response to treatment (compared to baseline) is as follows: 1) at least a 75% decrease in abscesses and inflammatory nodules, and 2) no increase in the number of abscesses, and 3) no increase in the number of draining fistulas.

[0137] The HiSCR90 response to treatment (compared to baseline) is as follows: 1) at least a 90% decrease in abscesses and inflammatory nodules, and 2) no increase in the number of abscesses, and 3) no increase in the number of draining fistulas.

[0138] In preferred embodiments, an HS patient achieves HiSCR75 or HiSCR90 in response to HS treatment.

[0139] In certain embodiments, when a population of HS patients is treated 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.

[0140] In certain embodiments, when a population of HS patients is treated 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.

[0141] Pain can be evaluated using a Numerical Rating Scale (NRS). In certain embodiments, HS patients achieve an improved pain NRS in response to HS treatment. Pain NRS30 is defined as at least a 30% reduction in pain and at least a 1 unit decrease from baseline in the Patient Global Assessment (PGA) of cutaneous pain in patients with a baseline score of 3 or greater. In certain embodiments, HS patients achieve NRS30 in response to HS treatment. In certain embodiments, when a population of HS patients is treated according to the disclosed methods, at least 25%, at least 30%, at least 40%, at least 50%, or at least 60% achieve NRS30 by week 16 of treatment. In a preferred aspect of this embodiment, when a population of HS patients is treated according to the disclosed methods, at least 30% achieve NRS30 by week 16 of treatment. In certain embodiments, in response to treatment according to the claimed methods, patients experience pain reduction at about 1 or 2 weeks after the first administration, as measured preferably by VAS or NRS, and preferably by NRS.

[0142] 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 evaluated by the SAHS score, and the following items are examined: the number of lesion areas (left axilla, right axilla, left inframammary, right inframammary, intermammary or chest, abdomen, mons pubis, left groin, right groin, genitalia, perianal or perineum, left buttock, right buttock, and others [e.g., neck, posterior auricle]), the number of inflammatory and / or painful lesions other than fistulas (ILOF), and the number of fistulas. These items evaluated by a physician are completed by two items reported by the patient: the patient is asked about the number of new nodules or the number of existing nodules that have spread during the past four weeks, and the patient is asked to evaluate the current severity (NRS) of the pain of the most symptomatic lesion during the patient's daily activities (e.g., sitting, moving, or working) on a numerical rating scale. The SAHS score is a composite score of all the collected information above. Mild cases of HS are defined by a SAHS score of 4 or less. Moderate HS is defined by a SASH score of 5-8, and severe cases of HS are defined by a SASH of 9 or more.

[0143] In certain embodiments, HS patients achieve an improved SAHS score in response to HS treatment. In certain embodiments, HS patients achieve at least a 1-point decrease from baseline in the SAHS score in response to HS treatment. In other embodiments, HS patients achieve at least a 2-point decrease or at least a 3-point decrease from baseline in the SAHS score in response to HS treatment. Preferably, the SAHS score was at least 4 at baseline prior to treatment with LOU064.

[0144] The International Hidradenitis Suppurativa Severity Score System (IHS4) is a clinically established tool for the dynamic assessment of HS severity that can be used in clinical trials or real-life settings (Zouboulis et al. (2017); Br. J. Dermatol.; 177(5):1401-9.). The severity of HS according to this tool is evaluated by summing individual HS lesions according to this scheme: Number of nodules × 1 + Number of abscesses × 2 + Number of drainage tracts (fistulas / sinuses) × 4

[0145] Next, the severity of HS is defined as follows: Mild HS: ≤ 3 points Moderate HS: 4 - 10 points Severe HS: ≥ 11 points

[0146] The definition of HS lesions is as follows: Nodules (inflammatory nodules) are raised, three-dimensional, circular, infiltrated lesions with a diameter > 10 mm. Abscesses are soft but fluctuant tumors with a diameter > 10 mm, surrounded by an erythematous area; the center of the abscess contains pus. Drainage tracts are raised, soft but fluctuant longitudinal tumors of variable length and depth, terminating at the skin surface and may leak fluid. Fistulas and sinuses are examples of drainage tracts.

[0147] In certain embodiments, HS patients achieve an improved IHS4 score (i.e., a decrease).

[0148] In certain embodiments, HS patients achieve at least a 2-point decrease from baseline in the IHS4 score in response to HS treatment. In other embodiments, HS patients achieve at least a 3-point decrease or at least a 4-point decrease from baseline in the IHS4 score in response to HS treatment.

[0149] The DLQI is the most established measure of dermatological quality of life. It consists of questions regarding skin disease for feelings and various aspects of daily life activities during the previous week. Each question is scored from 0 (not at all) to 3 (very much so). The maximum score is a total of 30 points, where 0 - 1 is considered to have no impact on the patient's life, 2 - 5 is small, 6 - 10 is moderate, 11 - 20 is very large, and 21 - 30 is extremely large (see Finlay and Khan (1994) Clin Exp Dermatol 19:210 - 16). In certain embodiments, HS patients achieve an improved DLQI in response to HS treatment.

[0150] In certain embodiments, in response to treatment according to the claimed method, the patient experiences a decrease in CRP as measured by a standard CRP assay or a high - sensitivity CRP (hsCRP) assay, approximately one or two weeks after the first administration. As used herein, "C - reactive protein" and "CRP" refer to serum C - reactive protein, a plasma protein commonly used as an indicator of the acute - phase response to inflammation. The level of CRP in plasma can be expressed at any concentration, for example, mg / dl, nmol / L. The level of CRP can be measured by various standard assays, such as radial immunodiffusion, electroimmunoassay, immunoturbidimetry, ELISA, nephelometry, fluorescence polarization immunoassay, and laser nephelometry. The test for CRP can use a standard CRP test or a high - sensitivity CRP (hs - CRP) test (i.e., a high - sensitivity test capable of measuring low levels of CRP in a sample using laser nephelometry). Kits for detecting the level of CRP can be purchased 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, etc.

[0151] The Sartorius HS score (also called the HS score or HSS) is assigned by counting lesion areas, nodules, and fistulas in HS patients (Sartorius et al. (2003) Br J Dermatol 149:211-13). The modified Sartorius HS score is a modified version of the original HSS by making some simplifications to make it more practical, such as including fewer specific lesions in the score, changing the number of points given for each parameter, etc. (Sartorius et al. (2009) Br.J Dermatol.161:831-839). In certain embodiments, HS patients achieve a modified Sartorius HS that is improved in response to HS treatment.

[0152] The HS Physician Global Assessment (HS-PGA) is a 6-point 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 certain embodiments, HS patients achieve an improved HS-PGA in response to HS treatment. In certain embodiments, HS patients achieve at least a 2-point decrease from baseline in the HS-PGA score in response to HS treatment. Preferably, the HS-PGA score was at least 3 at baseline prior to treatment with LOU064.

[0153] In certain 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 the patients who responded to treatment by week 16 (e.g., patients who achieved HiSCR (e.g., HiSCR50; HiSCR75 or HiSCR90) or simplified HiSCR by week 16) maintained their response 3 months after the end of treatment, 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 the patients who responded to treatment by week 16 (e.g., patients who achieved HiSCR (e.g., HiSCR50; HiSCR75 or HiSCR90) or simplified HiSCR by week 16) maintained their response 3 months after the end of treatment. Preferably, at least 70% of the patients who responded to treatment by week 16 (e.g., patients who achieved HiSCR (e.g., HiSCR50; HiSCR75 or HiSCR90) or simplified HiSCR by week 16) maintained their response 3 months after the end of treatment. As used herein, the term "maintained" means that an outcome or goal (e.g., pain reduction, inflammation reduction) is substantially maintained over a given period of time.

[0154] Lesion-related pruritus can be evaluated by patient surveys. Patients are asked to rate lesion-related pruritus on a scale of 0 (no pruritus) to 10 (worst imaginable pruritus). In certain embodiments, when a population of HS patients is treated according to the disclosed methods, the pruritus score is improved by at least 2 points, preferably at least 3 points. Further, when compared to the placebo group, the difference between the treatment group and the placebo group is at least 1 point.

[0155] Lesion-related pruritus can also be evaluated by a pruritus numerical scale (NRS). Pruritus is reported by the majority of HS patients (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 a visual analog scale (VAS) where respondents select an integer (an integer from 0 to 10 on an 11-point scale) that best reflects the intensity of their skin disease-related pruritus (Nguyen et al.,(2021),.J Eur Acad Dermatol Venereol.2021 Jan;35(1):50-61). In certain embodiments, HS patients achieve an improved skin NRS in response to HS treatment. Pruritus NRS30 is defined as at least a 30% reduction in skin pruritus from baseline. In certain embodiments, HS patients achieve skin NRS30 in response to HS treatment. In certain embodiments, when a population of HS patients is treated according to the disclosed method, at least 25%, at least 30%, at least 40%, at least 50%, or at least 60% achieve skin NRS30 by week 16 of treatment. In a preferred aspect of this embodiment, when a population of HS patients is treated according to the disclosed method, at least 30% achieve skin NRS30 by week 16 of treatment. In certain embodiments, in response to treatment according to the claimed method, the patient experiences a reduction in skin pruritus as measured by skin NRS, at about 1 or 2 weeks after the first administration.

[0156] The odor caused by the purulence of the lesion can be evaluated by patient surveys. Patients are asked to rate the odor caused by the purulence of the lesion on a scale of 1 (no odor), 2 (slight odor), 3 (moderate odor), to 4 (considerable odor). In certain embodiments, when a population of HS patients is treated according to the disclosed method, the pruritus score is improved by at least 1 point, preferably at least 2 points. Further, when compared to the placebo group, the difference between the treatment group and the placebo group is at least 1 point.

[0157] The impact of HS on the ability to complete work can be evaluated by patient surveys. Patients are asked to rate how much HS affects their ability to complete work on a scale of 1 (none), 2 (slight), 3 (moderately), 4 (greatly), to 5 (unable to work at all). In certain embodiments, when a population of HS patients is treated according to the disclosed method, the pruritus score is improved by at least 1 point, preferably at least 2 points. Further, when compared to the placebo group, the difference between the treatment group and the placebo group is at least 1 point.

[0158] Safety The short-term safety of single doses of up to 600 mg and further up to 100 mg b.i.d. of LOU064 for up to 18 days was demonstrated in a Phase I clinical trial. However, data regarding long-term (i.e., greater than 52 weeks) safety are not available at this time.

[0159] Considering the dose-limiting side effects observed with the covalently irreversible BTK inhibitors ibrutinib and acalabrutinib, ibrutinib already showed dose-limiting elevation of liver enzymes at a dose of 75 mg b.i.d. in phase II clinical trials, and acalabrutinib showed dose-limiting diarrhea (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 P.F. et al., 2019, ACTRIMS Forum, Feb 28, 2019, P072), and it is promising that no significant increase in the occurrence of these adverse events was seen with LOU064 even at the high dose of 100 mg b.i.d. over a long period (up to 52 weeks). In particular, LOU064 does not induce any dose-limiting elevation of liver enzymes and other off-target effects at a dose of 100 mg b.i.d. over a long period (up to 52 weeks). Therefore, LOU064 is suitable for long-term treatment.

[0160] Accordingly, one object of the present invention is LOU064 for use in the methods described herein, where, up to 12 weeks, 24 weeks or 52 weeks of treatment, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lipase do not change by more than 10% compared to the baseline levels at the start of treatment.

[0161] Accordingly, LOU064 not only effectively treats HS, but in particular, when treatment is maintained over a long period, it was particularly surprising that it also has a better safety profile compared to other BTK inhibitors, particularly compared to acalabrutinib. For example, the BTK inhibitors currently approved mainly for the treatment of hematological malignancies (ibrutinib, acalabrutinib, and zanubrutinib) have known safety impairments. The major safety impairments include infections, effects on platelet function (risk of bleeding), and cytopenias. Other safety concerns for one or more of the approved BTKis include cardiac arrhythmias (atrial fibrillation and flutter) and, for ibrutinib only, heart failure and hypertension.

[0162] Accordingly, in a preferred embodiment of the 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 over a long period. For example, LOU064 or a pharmaceutically acceptable salt thereof can be safely used over 6 months, 10 months, 1 year, 2 years, 3 years, 4 years, over 10 years. LOU064 or a pharmaceutically acceptable salt thereof can be used for up to 2 years, 5 years, 10 years, 15 years, 20 years or for life.

[0163] In one embodiment, LOU064 not only effectively treats HS, but also has the following characteristics: - No clinically relevant increase in the risk of infections, - No clinically relevant increase in major bleeding, - No clinically relevant increase in liver enzymes and has a safety profile that includes one or more of the above; enabling such long-term treatment.

[0164] Combination: The pharmaceutical composition for use in the disclosed method may also contain additional therapeutic agents for the treatment of a particular targeted disorder. For example, the pharmaceutical composition may also include an anti-inflammatory agent. Such additional factors and / or agents may be included in the pharmaceutical composition to produce a synergistic effect with LOU064 described herein.

[0165] Various therapies can be beneficially combined with LOU064 during the treatment of HS.

[0166] Accordingly, LOU064 can be administered simultaneously with, before, or after one or more other therapeutic agents. LOU064 for use in the methods of the present invention can be administered separately by the same or different routes of administration, or together in the same pharmaceutical composition with other agents.

[0167] In one embodiment, the present invention relates to a method of 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 formulation for simultaneous, separate, or sequential use in a therapy. Optionally, the pharmaceutical composition for use in the methods of the present invention may contain pharmaceutically acceptable excipients as described above.

[0168] The product provided as a combined formulation for use in the methods of the present invention comprises LOU064 and other therapeutic agents together in the same pharmaceutical composition, or comprises compositions containing LOU064 and other therapeutic agents in separate forms, for example in the form of a kit.

[0169] In one embodiment, the present invention provides a kit for use in the methods of the present invention, comprising two or more separate pharmaceutical compositions, at least one of which contains LOU064 or a pharmaceutically acceptable salt thereof. In one embodiment, the kit includes means for separately holding the compositions, such as a container, a divided vial, or a disassembled foil packet. An example of such a kit is a blister pack, as typically used for packaging tablets, capsules, etc.

[0170] The kits of the present invention can be used to administer separate compositions at different dosing intervals or to titrate separate compositions relative to each other, for example, to administer different dosage forms, such as oral and parenteral. To assist with medication compliance, the kits of the present invention typically include dosing instructions.

[0171] In the combination therapy of the present invention, LOU064 and other therapeutic agents can be manufactured and / or formulated by the same or different manufacturers. Further, LOU064 and other therapeutic agents can be combined into a combination therapy (i) prior to the presentation of the combination product to the physician (e.g., in the case of a kit containing a compound and other therapeutic agents for use in the methods of the present invention); (ii) by the physician himself (or under the guidance of the physician) immediately prior to administration; or (iii) by the patient himself during the sequential administration of, for example, LOU064 and other therapeutic agents.

[0172] Accordingly, the present invention provides the use of LOU064 or a pharmaceutically acceptable salt thereof for treating or preventing HS, wherein the agent is prepared for administration together with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating or preventing HS, wherein the agent is LOU064 or a pharmaceutically acceptable salt thereof to be administered.

[0173] 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 together 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 together with LOU064 or a pharmaceutically acceptable salt thereof.

[0174] 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 together 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 together with LOU064 or a pharmaceutically acceptable salt thereof.

[0175] 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 treatment and / or prevention of HS, where the patient has been previously treated (e.g., within 24 hours) 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, where the patient has been previously treated (e.g., within 24 hours) with LOU064 or a pharmaceutically acceptable salt thereof.

[0176] Such combination therapies include topical therapies (creams [non-steroidal or steroidal], washes, antiseptics), systemic therapies (e.g., by biologics, antibiotics, or chemicals), antiseptics, photodynamic therapy, and surgical interventions (laser, drainage or incision, excision).

[0177] Examples of oral antibiotics are tetracycline and clindamycin and rifampicin.

[0178] Non-limiting examples of topical HS agents for use with LOU064 include benzoyl peroxide, topical steroid creams, aminoglycoside topical antibiotics such as clindamycin, gentamicin, and erythromycin, resorcinol cream, iodine scrub, and chlorhexidine.

[0179] Non-limiting examples of HS agents for use in systemic therapy for use with LOU064 include IL-17 antagonists (ixekizumab, brodalumab, secukinumab CJM112), similarly IL17A / F antagonists (such as bimekizumab) or IL17C antagonists (such as MOR106), tumor necrosis factor-α (TNF-α) blockers (Enbrel® (etanercept), Humira® (adalimumab), Remicade® (infliximab), and Simponi® (golimumab), etc.), interleukin 12 / 23 blockers (Stelara® (ustekinumab), tasocitinib, and briakinumab, etc.), IL-23 blockers (such as guselkumab, tildrakizumab, and risankizumab), p19 inhibitors, PDE4 inhibitors, such as apremilast or Otezla® or others such as roflumilast, complement pathway inhibitors, such as factor B inhibitors (for example, the compounds disclosed in WO 2015 / 009616 pamphlet, or 4-((2S,LNP023, also known as (4S)-4-ethoxy-1-((5-methoxy-7-methyl)-1H-indol-4-yl)methyl)piperidin-2-yl)benzoic acid, C5a inhibitors (such as CCX168, also known as IFX-001 or vilobelimab or Avacopan, or BDB001), IL-1 antagonists (canakinumab, gevokizumab, rilonacept, anakinra, or belmeki mab), or bispecific antibodies, such as MAS825 or rutikizumab (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 (in particular, CD20 antagonists, such as rituximab, and BAFF-R, such as ianamalumab, and CD40 antagonists, such as isaklimab (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 fostamatinib, MMP antagonists, and defensin antagonists (such as receptor decoys, antagonist antibodies, etc.), and broad-spectrum oral JAK inhibitors (pan-JAKi) or more specific TYK2 or JAK 1, JAK2 or JAK 3 inhibitors (more specific / selective JAK / TYK inhibitors include, for example, allosteric inhibitors, such as deucrayacitinib, or catalytic inhibitors).

[0180] For use in combination with LOU064 in the treatment of HS, additional HS agents include retinoids such as acitretin (e.g., Soriatane®) and isotretinoin, immunosuppressants (e.g., rapamycin, T-cell blockers [e.g., Amevive® (alefacept) and Raptiva® (efalizumab)], cyclosporine, methotrexate, mycophenolate mofetil, mycophenolic acid, leflunomide, tacrolimus, etc.), hydroxyurea (e.g., Hydrea®), sulfasalazine, 6-thioguanine, fumarates (e.g., dimethyl fumarate and fumaric acid esters), azathioprine, colchicine, alitretinoin, steroids, corticosteroids, certolizumab, mometasone, rosiglitazone, pioglitazone, botulinum toxin, triamcinolone, IFX-1 (InflaRx), LY-3041658 (Eli Lilly), TE-2232 (Immunwork), NSAIDs, COX inhibitors, prescription narcotics, ketoprofen, codeine, gabapentin, pregabalin, fentanyl, antibiotics (topical, oral, intravenous (IV)) (e.g., clindamycin, rifampin, tetracycline, sarecycline, doxycycline, minocycline, lymecycline, trimethoprim-sulfamethoxazole, erythromycin, ceftriaxone, moxifloxacin, metronidazole, separately or in combination), corticosteroids (injectable or oral), anti-androgen / hormone therapy (oral contraceptives, spironolactone, finasteride, dutasteride, progesterone IUD, cyproterone acetate, ethinyl estradiol, gestoden, norgestimate, desogestrel, drospirenone, spironolactone), triamcinolone acetonide, MEDI8968, hydroxychloroquine, dapsone, metformin, adapalene, azelaic acid, and zinc.

[0181] Preferred combinations for use in the disclosed kits, methods, and uses include PDE4i and JAKi, and antibiotics (all for oral use).

[0182] Examples of JAK inhibitors for use in combination are BMS986165, INCB054707, ruxolitinib, abrocitinib, tofacitinib and baricitinib. Other examples of JAK inhibitors are the compounds disclosed in WO 2017 / 089985 pamphlet, WO 2018 / 055550 pamphlet and WO 2018 / 055551 pamphlet.

[0183] One of ordinary skill in the art will be able to understand the appropriate dosage of the above HS agents for co-delivery with LOU064.

[0184] It is expected that LOU064 oral drug exposure can be increased several-fold when administered with a CYP3A inhibitor, particularly a strong CYP3A inhibitor, such as a strong CYP3A4 inhibitor. Similarly, a strong inducer of CYP4A, such as CYP3A4, can significantly reduce exposure and result in a decrease in the efficacy of LOU064. These properties of LOU064 are relevant not only for the treatment of HS, but also for the treatment and / or prevention of any BTK-mediated condition. A strong CYP3A inhibitor or CYP3A inducer is defined according to the FDA 2020 guidelines. Thus, a strong CYP3A inhibitor (e.g., a CYP3A4 inhibitor) is an inhibitor that 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 after co-administration with LOU064. A strong CYP3A inducer (e.g., a strong CYP3A4 inducer) is an inducer that decreases the AUC by 80% or more (e.g., by 85%, by 90%, by 95%) compared to administration of LOU064 alone after co-administration with LOU064.

[0185] Concomitant administration with a potent CYP3A inhibitor and / or inducer, such as a potent CYP3A4 inhibitor and / or inducer, may likely cause a large change in LOU064 drug exposure and should be avoided. Drugs selected as potent CYP3A4 inhibitors include boceprevir, clarithromycin, cobicistat, conivaptan, darunavir / 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, Viekira pack or / and voriconazole. CYP3A4 inhibitors may also be included in grapefruit juice.

[0186] Accordingly, in another preferred embodiment, LOU064 is not co-administered with a potent inhibitor and / or inducer of CYP3A4, as defined above herein, for example.

[0187] It has further been found that LOU064 can be co-administered with oral contraceptives such as ethinyl estradiol or levonorgestrel without a major impact on their exposure and efficacy. Accordingly, in a preferred embodiment, LOU064 is co-administered with an oral contraceptive.

[0188] As a covalent irreversible BTK inhibitor, LOU064 acts by irreversible inhibition of BTK that is counteracted by de novo protein synthesis. Thus, while not wishing to be bound by any theory, it is thought that reconstitution of the B cell pool after B cell depletion may take several months, but recovery of B cell function after BTK inhibition can be achieved immediately after discontinuation, particularly within a few days. Thus, if necessary, this treatment can be rapidly discontinued, thereby giving the clinician and patient a greater ability to respond more easily and quickly in the event of an unexpected situation.

[0189] Particularly, considering the COVID-19 pandemic, patients with B cell depletion have a higher risk of infection. Furthermore, the absence of a fully functional adaptive immune response is likely to lead to a more severe course.

[0190] However, since LOU064 does not cause depletion of the B cell pool, cessation of treatment leads to a rapid recovery of full B cell function. This gives patients and treating physicians the possibility to respond rapidly to requirements for infection or vaccination, particularly vaccination with live and attenuated vaccines.

[0191] According to the invention, LOU064 can be administered during infection, for example during COVID-19 infection. Thus, LOU064 administration can be continued during infection, for example during COVID-19 infection.

[0192] Preferably, LOU064 administration is delayed in patients with active infection, such as COVID-19, until the infection has resolved.

[0193] Thus, one embodiment of the invention relates to LOU064 for use in the treatment of HS, in which patients acutely infected with or previously infected with COVID-19 are treated.

[0194] In a further embodiment, LOU064 treatment is continued during COVID-19 infection.

[0195] In a preferred embodiment, LOU064 treatment is interrupted during COVID-19 infection and continued after the infection has been overcome.

[0196] Still other embodiments of the present invention relate to LOU064 for use in the treatment of HS, wherein a patient is vaccinated during LOU064 treatment. Alternatively, a patient may be vaccinated during LOU064 treatment with a non-live vaccine. In one embodiment, a patient is vaccinated with a quadrivalent influenza vaccine, a PPV-23 vaccine or a KLH neoantigen vaccine during LOU064 treatment (e.g., at 15 days after initiation of LOU064 treatment). In one aspect of this embodiment, a patient administered the quadrivalent influenza vaccine achieves a response as defined by a >4-fold increase in anti-hemagglutinin antibody titer at 28 days after vaccination compared to baseline. In another aspect of this embodiment, a patient administered the PPV-23 vaccine achieves a >2-fold increase in IgG titer at 28 days after vaccination compared to baseline. In yet another embodiment, a patient administered the KLH neoantigen vaccine achieves a T cell-dependent antibody response as measured by anti-KLH IgG and IgM titers at 28 days after vaccination.

[0197] Another embodiment of the present invention is that LOU064 treatment is discontinued for vaccination, in particular, LOU064 treatment is discontinued 5 to 10 days before vaccination, for example 7 or 8 days before, preferably 6 weeks before, and after vaccination, for example, 5 to 20 days after vaccination, preferably 5 to 10 days after, or most preferably 10 to 15 days after, and then continued. LOU064 is for use in the treatment of HS. In an alternative embodiment, the vaccination is a vaccination with a live vaccine and / or an attenuated vaccine. In a particular aspect of this embodiment, the patient is vaccinated with a quadrivalent influenza vaccine, a PPV-23 vaccine or a KLH neoantigen vaccine after discontinuing LOU064 treatment (for example, 5 to 10 days or 7 or 8 days after discontinuing LOU064 treatment). In one aspect of this embodiment, a patient administered a quadrivalent influenza vaccine achieves a response as defined by a >4-fold increase in anti-hemagglutinin antibody titer at 28 days after vaccination compared to baseline. In another aspect of this embodiment, a patient administered a PPV-23 vaccine achieves a >2-fold increase at 28 days after vaccination compared to the IgG titer baseline. In yet another embodiment, a patient administered a KLH neoantigen vaccine achieves a T cell-dependent antibody response as measured by anti-KLH IgG and IgM titers at 28 days after vaccination. Thereafter, LOU064 treatment is started and continued 29 days after vaccination.

[0198] LOU064 or a pharmaceutically acceptable salt thereof is conveniently administered orally. The duration of oral treatment using the pharmaceutical compositions of the present disclosure will vary depending on the disease and condition being treated, the severity thereof, and the individual response of each patient. Healthcare providers will determine the appropriate duration of oral treatment and the timing of administration of the treatment using the pharmaceutical compositions of the present disclosure. In certain embodiments, the patient is treated for HS according to the claimed method for at least 16 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks, at least 52 weeks. In certain embodiments, the patient is treated for HS in chronic use.

[0199] In one embodiment, the pharmaceutical composition of the present invention for use in the prevention or treatment of HS may have a unit dose of the active ingredient of about 25 mg to about 100 mg for a subject of about 50 to 70 kg. The therapeutically effective dosage of the compound and the pharmaceutical composition depends on the species, body weight, age and individual condition of the subject, and the severity of contrast-induced nephropathy. A physician, clinician or veterinarian of ordinary skill can readily determine the respective effective amounts of the active ingredient necessary to prevent, treat or inhibit the progression of the disorder or disease.

[0200] Preferred formulations are capsule or tablet compositions comprising from 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 yet 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.

[0201] Disclosed herein is a method of treating hidradenitis suppurativa (HS) comprising orally administering to a patient in need thereof a dose of from about 50 mg to about 200 mg of LOU064, or a pharmaceutically acceptable salt thereof, once daily. Said dose can be administered to the patient according to either a once-daily dosing schedule or a twice-daily dosing schedule. In another embodiment, the method comprises orally administering to a patient in need thereof a dose of from 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 said 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 said patient a dose of about 100 mg of LOU064 twice daily (BID).

[0202] In a preferred embodiment of the disclosed methods, uses and kits, the patient achieves a sustained response one year after treatment as measured by (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 Score System (IHS4).

[0203] In a preferred embodiment of the disclosed methods, uses and kits, prior to treatment with LOU064 as disclosed herein, the patient has been previously treated with systemic agents for HS. In a preferred embodiment of the disclosed methods, uses and kits, the systemic agents are selected from the group consisting of topical treatments, antibiotics, immunosuppressants, TNF - α inhibitors, IL - 1 antagonists, and combinations thereof.

[0204] In certain embodiments of the disclosed methods, uses and kits, prior to treatment with LOU064 as described herein, the patient has not been previously treated with systemic agents or topical treatment agents for HS (i.e., the patient is treatment - naive or biologic - treatment - naive).

[0205] 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.

[0206] In a preferred embodiment of the disclosed methods, uses and kits, the dosage of LOU064 as described herein is from about 25 mg to about 100 mg BID. In other preferred embodiments of the disclosed methods, uses and kits, the dosage of LOU064 is about 25 mg BID or 100 mg BID.

[0207] In a preferred embodiment of the disclosed methods, uses and kits, the patient has moderate to severe HS.

[0208] As used herein, the phrase "moderate to severe" refers to HS disease in a patient having at least two anatomical sites involved with inflammatory lesions of activity ≧3 [i.e., deep inflammatory lesions such as abscesses and / or inflammatory nodules], at most 15 fistulas, and HS lesions.

[0209] In a preferred embodiment of the disclosed methods, uses, and kits, the patient is an adult. In certain embodiments of the disclosed methods, uses, and kits, the HS patient is an adult suffering from moderate to severe HS disease.

[0210] In certain embodiments of the disclosed methods, uses, and kits, the patient is an adolescent patient (12 years of age or older). In certain embodiments, the patient is an adolescent patient suffering from moderate to severe HS.

[0211] In certain embodiments of the disclosed methods, uses, and kits, the patient has been diagnosed with HS for at least one year.

[0212] In certain embodiments of the disclosed methods, uses, and kits, the patient does not have extensive scarring as a result of HS (i.e., <20 fistulas, draining or non-draining, preferably at most 15 fistulas).

[0213] In certain embodiments of the disclosed methods, uses, and kits, the patient has previously had an inadequate response to conventional systemic HS treatments.

[0214] In a preferred embodiment of the disclosed methods, uses, and kits, prior to treatment with LOU064, the patient has an HS-PGA score of ≧3.

[0215] In a preferred embodiment of the disclosed methods, uses, and kits, the patient achieves (simplified) HiSCR by week 16 of treatment.

[0216] In a preferred embodiment of the disclosed methods, uses, and kits, the patient achieves NRS30 (e.g., pain NRS30 or pruritus NRS30) by week 16 of treatment.

[0217] In a preferred embodiment of the disclosed methods, uses, and kits, the patient has a reduction in HS erythema by week 16 of treatment.

[0218] In a preferred embodiment of the disclosed methods, uses, and kits, the patient achieves a reduction of ≤6 as measured by DLQI by week 16 of treatment.

[0219] In a preferred embodiment, when treating a population of patients with moderate to severe HS using the disclosed methods, uses, or kits, at least 40% of said patients achieve HiSCR (sHiSCR, HiSCR50, HiSCR75, or HiSCR90) by week 16 of treatment in response to said administration step.

[0220] In another preferred embodiment, when treating a population of patients with moderate to severe HS using the disclosed methods, uses, or kits, the difference between the proportion of responders (e.g., patients who achieve a HiSCR response (sHiSCR, HiSCR50, HiSCR75, or HiSCR90 response) to HS treatment) and the proportion of responders in placebo-treated patients is at least 15%, at least 25%, or at least 30% by week 16 of treatment.

[0221] In a preferred embodiment of the disclosed methods, uses, and kits, the patient has a decrease in the modified Sartorius score by week 16 of treatment.

[0222] In a preferred embodiment of the disclosed methods, uses, and kits, the patient has an improvement in DLQI by week 16 of treatment.

[0223] In a preferred embodiment, when treating a population of patients with moderate to severe HS using the disclosed method, use or kit, at least 25% (preferably at least 30%) of said patients achieve NRS30 by week 16 of treatment in response to said administration step.

[0224] In a preferred embodiment, when treating a population of patients with moderate to severe HS using the disclosed method, use or kit, less than 15% of said patients develop HS erythema during 16 weeks of treatment in response to said administration step.

[0225] In a preferred embodiment of the disclosed method, use and kit, the patient is further treated with at least one topical agent and at least one antiseptic in combination with LOU064 described herein.

[0226] In a preferred embodiment of the disclosed method, use and kit, the patient is treated with LOU064 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.

[0227] In a preferred embodiment of the disclosed method, use and kit, the patient has a reduction in pain as measured by VAS or NRS, preferably NRS, about 1 or 2 weeks after the first administration of LOU064.

[0228] In a preferred embodiment of the disclosed method, use and kit, the patient has a reduction in skin pruritus as measured by NRS about 1 or 2 weeks after the first administration of LOU064. For example, the patient achieves a skin pruritus NRS30 1 or 2 weeks after the first administration of LOU064.

[0229] In a preferred embodiment of the disclosed method, use, and kit, the patient has a decrease in CRP (a decrease of about 25% to about 30%) as measured using a standard CRP assay about one or two weeks after the first administration of LOU064.

[0230] In a preferred embodiment of the present disclosure, LOU064 is the free base anhydrous crystalline Form A as disclosed in International Publication No. WO 2020 / 234779 (Example 1). In one aspect of this embodiment, LOU064 Form A is in a substantially pure phase.

[0231] General Details of one or more embodiments of the present disclosure are set forth in the foregoing accompanying description. Any methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present disclosure, but the preferred methods and materials are described herein. Other features, objects, and advantages of the present disclosure will be apparent from this specification and the claims. In this specification and the appended claims, the singular forms include the plural unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference. The following examples are presented to illustrate more particularly preferred embodiments of the present disclosure.

Examples

[0232] Abbreviations AE Adverse effect b.i.d. or BID Twice a day q.d. Once a day ECG Electrocardiogram PK Pharmacokinetics PD Pharmacodynamics p.o. Oral (from the mouth = oral)

[0233] Example 1: LOU064 Signature (Genes Downregulated by LOU064) in the Transcriptome Dataset of Hidradenitis Suppurativa Figure 1: Gene expression was measured using Affymetrix GeneChip HG-U133 Plus 2 in skin from healthy donors and in lesional and non-lesional skin from HS patients (GSE148027). The inventors found that BTK expression (measured by probe 205504_at) was significantly upregulated in lesional (not non-lesional) skin compared to healthy controls.

[0234] Figure 2 represents the LOU signature (LOU064 repressed genes) in the (bulk) transcriptome dataset of hidradenitis suppurativa. The LOU064 signature was generated by stimulating whole blood with IgM, followed by treatment with LOU064. The transcriptome profiles of these samples were measured using Ampliseq. Fifty-two genes that the inventors found to be significantly downregulated by LOU064 (FDR < 0.05) compared to stimulation only were defined as the "LOU signature".

[0235] Bulk transcriptomics data were measured by Affy chips (Carlos A. Penno et al., J. Invest. Dermatol. 2020, Vol 140, Issue 21, 2421 - 2432.e10) - 49 of the 52 signature genes were also present in this data and targeted by a total of 106 probes (each gene can be targeted by multiple probes). These 106 probes were used for signature enrichment by 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 on gene set enrichment: Aravind Subramanian et al. PNAS 2005, 102(43)15545 - 15550). The results are visualized in Figure 1. The Wilcoxon test was used to show significantly different signature enrichment between healthy and lesional HS samples (p ~ 2.7e - 7).

[0236] The data demonstrate up - regulation of the LOU064 - repressing gene (LOU064 signature) in hidradenitis lesions.

[0237] Example 2: Dosage basis Using the translational PK / PD model simulation described below, the human peripheral tissue occupancy (e.g., spleen and lymph nodes) of remibrutinib was predicted assuming no relevant interspecies differences in turnover and efficacy. The PK / PD model was focused on B cells, which have been reported to be the main relevant target of BTK inhibition in HS, as described above. B cells are typically present in the lymph nodes and spleen in addition to the circulating fraction. In HS, B cells are also present in so-called "tertiary lymphoid organs" in HS lesion tissues, which are similar in characteristics to primary lymph nodes and germinal centers. B cells present in the spleen, lymph nodes, or tertiary lymphoid organs in HS lesions are thought to exhibit a faster BTK turnover compared to circulating B cells in peripheral blood. The translational PK / PD model simulation led to the dose selection for the treatment of HS by LOU064.

[0238] Prediction of BTK occupancy using the translational PK / PD model for LOU064 The BTK occupancy in blood is not a useful biomarker for dose selection due to the pharmacologic properties (irreversible binding) of LOU064. It reaches complete occupancy even at low doses before pharmacologic activity is indicated by other biomarkers (CD63, CD203c, skin prick test). The occupancy in tissues may be more representative of the predicted efficacy of LOU064.

[0239] Objective The objective of this analysis was to characterize the pharmacokinetics (PK) of LOU064 in healthy volunteers and to simulate the BTK occupancy in human spleen / tissues across a range of doses and dosing schedules (twice daily (B.I.D) vs once daily (QD)) using a previously developed translational target occupancy model.

[0240] Data Pharmacokinetic data from a Phase I clinical trial reported by Kaul et al. (2021) were used in this analysis, including 102 patients.

[0241] Method A translational target occupancy model for simulating BTK occupancy in the spleen / tissue was developed using a two-step approach.

[0242] In the first step, a population PK model was established to explain the LOU064 PK data from a Phase I clinical trial reported by Kaul et al. (2021). In the second step, parameter estimates from the population PK model were used in the BTK occupancy model to predict BTK occupancy in blood and spleen / tissue. Finally, the BTK occupancy model was used to predict BTK occupancy in the spleen / tissue for different doses and different dosing schedules (once daily (QD), twice daily (B.I.D.)).

[0243] Results A population PK model was developed to explain the intermediate PK from a Phase I clinical trial reported by Kaul et al. (2021). Clearance was modeled as an exponentially decaying function of time for doses less than 50 mg and a constant function of clearance for doses greater than 50 mg to account for changes in clearance after repeated dosing at doses less than 50 mg (lower clearance at steady state on day 12 compared to day 1 when there was no difference at higher doses). Generally, the resulting population model explained the PK data to some extent.

[0244] PK parameter estimates were used in the translational BTK occupancy model to simulate BTK occupancy at steady state. The BTK occupancy simulations showed that twice-daily (B.I.D.) dosing was more effective than once-daily (QD) dosing of the same dose in achieving higher BTK occupancy (at trough or averaged over a 24-hour interval).

[0245] For the dosing frequencies selected in once-daily (QD) and twice-daily (B.I.D.) regimens, the trough and mean steady-state BTK occupancy over a 24-hour period are shown in Figure 4A (24-hour trough of BTK occupancy at steady state) and Figure 4B (24-hour mean of BTK occupancy at steady state), respectively, for once-daily 10 mg, 35 mg, 100 mg and twice-daily 10 mg, 25 mg and 100 mg dosing schedules. Both figures show that a maximum once-daily dose of 200 mg (100 mg twice-daily (B.I.D.)) may be required to achieve a trough BTK occupancy ≥ 80% in peripheral target tissues.

[0246] Simulations were performed to compare different dosing schedules. A comparison of the simulated splenic BTK occupancy at steady state over time for 100 mg twice-daily (B.I.D.) versus 100 mg once-daily (QD) is shown in Figure 3. The graph shows that, as expected from the basic principles, the occupancy from twice-daily (B.I.D.) dosing is higher and less variable compared to once-daily (QD) dosing.

[0247] Conclusion: The model predicted that a significantly higher overall BTK occupancy could be achieved using a b.i.d. dosing schedule. A trough BTK occupancy of approximately 70 - 95% is predicted in human tissues for the 25 mg b.i.d. dosing schedule, while the 100 mg b.i.d. dosing schedule is predicted to achieve a trough BTK occupancy of ≥ 90%.

[0248] Example 3: Clinical Trial Design Blinding of subjects and investigators allows for an unbiased assessment of variables in HS or the overall HS-PGA score, as well as subjective readouts such as adverse events.

[0249] Randomization, subject and investigator blinding, placebo control, multi - center and parallel - group comparison trials are conducted to evaluate the efficacy, safety and tolerability of several active treatment compounds, such as LOU064 (remibrutinib), in subjects with moderate to severe hidradenitis suppurativa (HS). After the screening period, the treatment period is 16 weeks, followed by a safety follow - up of about 4 weeks. Subjects are administered LOU064 at 25 mg BID p.o., 100 mg BID p.o., or placebo BID p.o. Approximately 70 subjects are randomly divided, 60 receive active drug (30 receive 100 mg bid and 30 receive 25 mg bid), and 10 receive placebo.

[0250] The primary objective is to demonstrate the preliminary efficacy of treatment with LOU064 in HS subjects after 16 weeks of treatment compared to placebo. After the 16 - week treatment period, a 4 - week follow - up period is included to observe whether the effect persists or increases after 16 weeks of treatment.

[0251] Summary of the protocol Primary objective: The primary objective of this trial is to evaluate the efficacy of remibrutinib compared to placebo in patients with moderate to severe inflammatory HS by comparing the proportion of patients who achieve a clinical response defined by the Hidradenitis Suppurativa Clinical Response (HiSCR) after 16 weeks of treatment.

[0252] Secondary objectives: Repeatedly from baseline until the end - of - study visit, to evaluate the safety and tolerability of remibrutinib in patients with moderate to severe hidradenitis suppurativa (HS) by (i) the number and severity of AEs and (ii) physical examinations, vital signs, safety laboratory measurements and ECG.

[0253] Study Design: This is an open-label, randomized, subject- and investigator-blinded, placebo-controlled, multi-center, parallel-group comparative trial to evaluate the efficacy, safety, and tolerability of ruxolitinib in subjects with moderate to severe hidradenitis suppurativa. The maximum duration of participation for any subject in a single cohort should not exceed 25 weeks for ruxolitinib, consisting of a 35-day screening period, a 16-week treatment period, and ending with a 4-week safety follow-up. LOU064 (ruxolitinib), 100 mg b.i.d. p.o. or 25 mg b.i.d. p.o. or placebo is included from Day 1 (Week 1) to Day 113 (Week 17). Subjects are randomly assigned in a 3:3:1 ratio to either the ruxolitinib treatment arm or its corresponding placebo.

[0254] Population: Adult male and female participants, 18 to 65 years of age, presenting with moderate to severe hidradenitis suppurativa diagnosed with recurrent inflammatory lesions for at least 12 months prior to screening.

[0255] Major Eligibility Criteria: Male and female subjects, 18 to 65 years of age (including endpoints), with clinically diagnosed HS for at least 12 months prior to screening; minimum body weight of 50 kg (including endpoints) at screening; patients with moderate to severe HS according to the assessment at screening (prior to dosing on Day 1): - At least 3 inflammatory lesions in total, i.e., abscesses and / or inflammatory nodules, and - Fistulas of 15 or less, and - At least 2 anatomical sites that need to be involved in HS lesions.

[0256] Major Exclusion Criteria: - Use of other investigational drugs within the longer of the time at screening, or within 30 days or 5 half-lives of randomization, whichever is longer; or within a longer time if required by local regulations; - Physiologically fertile women, except when using a highly effective contraceptive method during and for at least 2 weeks after the last dose of ruxolitinib - A significant bleeding risk or coagulation disorder, such as: · A history of clinically relevant gastrointestinal bleeding related to the use of, for example, non-steroidal anti-inflammatory drugs (NSAIDs): · Use of anticoagulants [e.g., warfarin or novel oral anticoagulants (NOACs)] within 2 weeks before randomization · International Normalized Ratio (INR) greater than 1.5 at screening · Use of antiplatelet drugs [including dual antiplatelet therapy (e.g., acetylsalicylic acid + clopidogrel)] within 2 weeks before randomization Note: Monotherapy with acetylsalicylic acid (up to 100 mg / day) or clopidogrel is not excluded. · Major surgery within 8 weeks before screening or surgery scheduled during the trial treatment period.

[0257] Primary efficacy evaluations: - Simplified and original Hidradenitis suppurativa clinical response (HiSCR) rate - International Hidradenitis Suppurativa Severity Score System (IHS4) - Hidradenitis suppurativa - Physician Global Assessment (HS-PGA) score and proportion of responders - HS inflammatory variables - Severity Assessment of Hidradenitis Suppurativa (SAHS)

[0258] Primary safety evaluations: - Number and severity of adverse events (CTCAE v5.0 grading) - Physical examinations including vital signs, safety laboratory measurements, and ECG

[0259] Other evaluations: - PK - Skin Pruritus NRS (cohort D) - Patient-reported outcomes including Skin Pain Numerical Rating Scale (NRS), Dermatology Life Quality Index (DLQI), and Patient Global Assessment (PGA).

[0260]

Table 2

[0261]

Table 3

[0262]

Table 4

[0263] Further reference to clinical evaluation: · The simplified HiSCR was selected as the primary endpoint. The original HiSCR (Kimball et al 2016 N Engl J Med 375:422-34) used in the phase 3 clinical trial conducted with adalimumab has been validated. The simplified HiSCR does not include an increase in draining fistulas and is defined as a 50% decrease in the total number of abscesses and inflammatory nodules. However, in contrast to the original HiSCR, an increase in abscesses is allowed to constitute a clinical response if the previous criteria are met. · The inflammatory lesions of HS will be counted as individual lesions (inflammatory nodules, abscesses, and draining fistulas) in typical anatomical sites. In addition to counting, a global assessment scale (hidradenitis suppurativa - physician global assessment or HS-PGA) as well as a composite score (severity assessment of hidradenitis suppurativa score or SAHS) will be used. Abscesses and nodules will also be presented as the AN number. · HS-PGA (hidradenitis suppurativa - physician global assessment): The score was used and described for exploratory purposes to evaluate HS 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. · 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 is obtained from the information collected on inflammatory variables, number of fistulas, and NRS pain. Additionally, anatomical site and new or extended existing tumors will be collected in both cohorts. · Several patient-reported outcomes, including the Dermatology Life Quality Index (DLQI), will be used. Finally, from the perspective of the subject, skin-related pain is the most important symptom, and a Numerical Rating Scale (NRS) for pain is included. · Other patient-reported outcomes (PRO) will include the Dermatology Life Quality Index (DLQI) as a validated score for dermatology-related quality of life (QoL) measures available in many countries and languages. It will also include a global patient assessment. · Skin pain - NRS (Numerical Rating Scale for pain): The NRS for skin-related pain is used in the adalimumab trial (Kimball et al. (2016) N Engl J Med 375:422-34) and will be used as skin or HS-related pain, one of the major burdens for patients (Matusiak et al (2017) J Am Acad Dermatol;76:670-5). HS-related pain will be recorded on average over the previous 24 hours and at the worst point (over the previous 24 hours). · When pruritus is recognized here as a symptom in HS patients, a Skin Pruritus NRS was included (Nguyen et al 2021, Fernandez et al 2021).

[0264] Example 5: 100 mg film-coated tablets The following shows a preferred pharmaceutical composition (film-coated tablets).

[0265]

Table 5

[0266] Example 6: 50 mg Film-Coated Tablets The following shows preferred pharmaceutical compositions (film-coated tablets).

[0267] [Table 6]

[0268] Example 7: 25 mg Film-Coated Tablets The following shows preferred pharmaceutical compositions (film-coated tablets).

[0269] [Table 7]

[0270] Example 8: Safety of LOU064 The safety of LOU064 was tested in Phase I and Phase II pharmacokinetic and clinical pharmacology healthy subject trials and Phase II / Phase III clinical trials conducted in patients with indications other than MS, particularly patients suffering from chronic spontaneous urticaria (CSU) and Sjögren's syndrome (SjS).

[0271] Short-Term Safety of LOU064 in Phase I Clinical Trials As a single dose, or as multiple doses over up to 18 days covering a dose range of 0.5 mg to 600 mg, and further, the short-term safety of LOU064 at 100 and 200 mg twice daily (b.i.d.) for up to 12 days was demonstrated in a Phase I clinical trial (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).

[0272] Summary of safety (interim results) in the Phase 2b trial (extension period) in CSU subjects In a 52-week open-label continuous dosing trial to evaluate the long-term safety and tolerability of LOU064 in eligible subjects with CSU who participated in the Phase 2b trial, the dose used was 100 mg twice daily (b.i.d.).

[0273] Safety signals were not observed based on an interim analysis of 100 subjects who received at least one dose of LOU064 at a median exposure of 17.86 weeks (range: 2.9 weeks to 44.7). At the cutoff time point, 93 subjects (93%) were continuing and 7 subjects had discontinued the trial; none of the discontinuations were due to adverse events. Table 4 shows a summary of the safety observed in the Phase 2b trial up to the cutoff date for the interim analysis.

[0274]

Table 8

[0275] Fifty-eight subjects (58%) had at least one AE that occurred during treatment. Most of the AEs were not severe and did not lead to treatment discontinuation, with mild severity. The SOCs with the highest frequency of occurrence were infections and parasitic diseases (14%), followed by skin and subcutaneous tissue disorders (13%), and there was no tendency for specific adverse events. The most commonly seen adverse event preferred terms (≥2%) were headache (6%), diarrhea (4%), dizziness (3%), and gastroenteritis (3%); bleeding events (defined as events under PT including bleeding SMQ broad area and platelet aggregation abnormalities, decreased platelet aggregation, platelet aggregation inhibition, platelet dysfunction, abnormal platelet function tests, and platelet toxicity) or events under the SOC blood and lymphatic system disorders were not reported. Three SAEs: ovarian cyst, chest pain, and appendicitis were reported; none were considered related to the investigational drug.

[0276] Conclusions from the Phase 2b trial and corresponding open-label extension trial Overall, there were no findings regarding safety in the Phase 2b trial across all doses evaluated. Additionally, in the corresponding CSU extension trial using LOU064 100 mg twice daily (b.i.d.) in an open-label manner, no safety signals were observed in the 100 subjects enrolled as of 31-Aug-2020. The highest dose of 100 mg LOU064 twice daily (b.i.d.) provided was considered well-tolerated and had a favorable safety profile.

[0277] Summary of safety in the Phase 2b (extension) trial in CSU subjects (patients with median exposure of 35.14 weeks) In the above 52-week open-label continuous dosing study to evaluate the long-term safety and tolerability of LOU064 in eligible subjects with CSU who participated in the Phase 2b trial at a dose of 100 mg twice daily (b.i.d.), a new interim analysis was conducted in patients (N = 183) with a median exposure of 35.14 weeks, and the results were compared with the safety results in a randomized double-blind, placebo-controlled Ph2b core trial in adult patients with CSU who were given lenvatinib 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 for up to 12 weeks (wks) (NCT03926611) (Table 5).

[0278] In the long-term exposure of ES (median 35.14 weeks, N = 183), the proportion of patients with at least one adverse event (AE) was similar to that in CS for lenvatinib treatment (57.4% [n = 105]) (shown by any lenvatinib dose) (58.1% [n = 155]; median 12.14 weeks, N = 267). In ES, there were 4 serious adverse events (SAEs) and 6 AEs leading to treatment discontinuation and death. The occurrence of AEs by organ-based major classification (SOC) reported in ES and CS was similar: infections and infestations (23.0% and 24.0%), followed by skin / subcutaneous tissue disorders (17.5% and 16.9%) (Table 5). The occurrence of AEs reported by preferred term was equivalent in ES and CS, with headache (6.6% and 9.7%) being the most frequent. The occurrence of AESIs in ES such as infections (23%), bleeding (4.4%), and cytopenia (0.5%) was consistent with CS. There was 1 newly occurring significant increase in aminotransferase in both ES (isolated ALT > 3×ULN, normalized within 4 weeks in 1 patient who discontinued early for personal reasons) and CS (ALT > 5×ULN in 1 patient, normalized with treatment). Analysis of laboratory parameters showed no significant safety concerns, and no clinically significant changes in vital signs were observed. There were no significant ECG findings or QTs > 500 ms shown in any patient.

[0279]

Table 9

[0280]

Table 10

[0281] Conclusion Ramucirumab demonstrated a favorable safety profile across the full dose range, and no new safety signals were observed over the longer-term exposure to the 100 mg bid dose for up to 52 weeks in patients with CSU.

[0282] Example 9: Evaluation of the Modulation of the Immune Response to Three Different Types of Vaccines by the Concurrent and Intermittent Administration of Ramucirumab in Healthy Subjects

[0283]

Table 11

[0284] Study Design Overall Design This randomized, double-blind, placebo-controlled trial has a parallel-group comparison design. Approximately 90 healthy female and male participants of childbearing potential will be randomly assigned to one of three treatment groups to achieve a minimum of 72 evaluable completers, taking into account an estimated discontinuation rate of up to 20%. The study will consist of a 28-day screening period, a 43-day treatment period, and then a study completion assessment (Day 57) within 2 weeks after the last study drug administration. A safety follow-up call will be made approximately 30 days after the last study drug administration (Day 73). Participants will be resident on Days -1, 1, and 14 - 17. Overall, the maximum study period for each participant will be approximately 85 days.

[0285] Evaluate the simultaneous and intermittent treatment scenarios of Remibrutinib for influenza / the impact of Pneumovax (registered trademark) 23 and Immucothel (registered trademark) against placebo.

[0286] Conduct of the trial Screening and baseline Participants who meet the eligibility criteria at screening will undergo baseline evaluation on Day - 1. All baseline safety evaluation results must be available prior to the first dose. At baseline, participants will be randomly assigned to one of the three treatment groups described below.

[0287] Treatment All participants will be administered the investigational drug (Remibrutinib 100 mg or placebo twice a day (b.i.d.)) from Day 1 to Day 42 and will return to the clinic on Day 43 for the end of the treatment visit. All participants will also be administered a quadrivalent influenza vaccine, PPV - 23 vaccine, and KLH neoantigen vaccine on Day 15. Vaccination should be performed 3 hours after the investigational drug administration.

[0288] During the clinical visit and residence (from Day - 1 to Days 1 and 14 - 17), participants will be administered the investigational drug by the study staff at the clinic. At the time of discharge from the clinical visit during the treatment period, the investigational drug will be given to the participants for self - administration at home along with a medication diary.

[0289] Safety evaluations include physical examination, ECG, vital signs, standard clinical laboratory evaluations (hematology, blood chemistry, urine tests), adverse event, and serious adverse event monitoring.

[0290] Multiple blood samples were obtained from all participants on Days 8, 15, and 36 to evaluate Remibrutinib pharmacokinetics.

[0291] Group A (simultaneous Remibrutinib treatment): Participants will be administered placebo (twice a day (b.i.d.)) from Day 1 to Day 7 to achieve PK / PD steady state before administration of the three vaccines on Day 15, and then treatment with lenvatinib (100 mg twice a day (b.i.d.)) from Day 8 to Day 15 of the trial. Participants will continue to receive lenvatinib (100 mg twice a day (b.i.d.)) until Day 42.

[0292] Group B (intermittent lenvatinib treatment): Participants will be treated with 100 mg of lenvatinib twice a day (b.i.d.) from Day 1 to Day 7 to achieve PK / PD steady state conditions, and then placebo (twice a day (b.i.d.)) will be administered from Day 8 to Day 28, and three vaccines will be administered on Day 15. Treatment with 100 mg of lenvatinib twice a day (b.i.d.) will resume from Day 29 to Day 42.

[0293] Group C (placebo): Participants in Group C will be administered placebo (b.i.d.) from Day 1 to Day 42 and will be inoculated with three vaccines on Day 15 under placebo conditions.

[0294] Main eligibility criteria · Signed informed consent must be obtained before participating in the trial. · Healthy, or overweight with mild obesity or otherwise healthy, male and non-pregnant female participants aged 18 - 55 years (including endpoints). · Participants should be in good health as determined by medical history, screening, physical examination, vital signs, ECG, and clinical tests at the time of screening and baseline visit. · At screening and baseline, vital signs (maximum and minimum blood pressure and pulse rate) are evaluated sitting and again standing (if required by the assessment schedule). Sitting vital signs (after sitting for 3 minutes) should be within the following ranges: · Tympanic body temperature of 35.0 - 37.5 °C. · Maximum blood pressure (SBP) of 90 - 139 mmHg (including endpoints). · Minimum diastolic blood pressure (DBP) of 50 to 89 mmHg (including endpoints). · Heart rate of 45 to 90 bpm (including endpoints). · Participants must weigh at least 50 kg and have a body mass index (BMI) within the range of 18 to 34.9 kg / m2 to participate in the study. · Participants must be willing to stay at the clinical site when required by the protocol and comply with the requirements / instructions outlined in the ICF. · Be able to read, speak, and understand the local language to understand and comply with the study requirements.

[0295] Major exclusion criteria 1. Use of other investigational drugs within either half-life or within 30 days prior to the first dose, whichever is longer. 2. Current evidence or history of clinically significant ECG abnormalities or family history (grandparents, parents, and siblings) of QT prolongation syndrome or other abnormalities in cardiac conduction, history of additional risk factors for torsades de pointes (TdP) (e.g., heart failure, hypokalemia), and / or known medical history or current clinically significant arrhythmias. Abnormal ECG defined as PR > 220 msec, QRS complex > 120 msec, QTcF > 450 msec for both men and women, or any other morphological changes other than early repolarization, non-specific S-T or T wave changes. 3. History or presence of any treated or untreated malignant tumor (other than localized basal cell carcinoma of the skin or carcinoma in situ of the cervix) in any organ system within the past 5 years, regardless of evidence of local recurrence or metastasis. 4. History or presence of any clinically significant disease in any major organ classification (including but not limited to cardiovascular, pulmonary, metabolic, hepatic, renal, hematological, endocrine, nervous, or psychiatric disorders) that has not resolved within 2 weeks prior to the first dose. 5. Hypersensitivity to lenvatinib or drugs from the same compound class or its excipients. 6. Any contraindications to the use of Pneumovax 23, influenza, or KLH vaccines, including any acute infection, fever, or hypersensitivity reaction or known hypersensitivity to any of the vaccine's associated components (e.g., chicken eggs or crustaceans / KLH) administered in this trial. 7. Vaccination history with the seasonal influenza vaccine for the 2022 - 2023 season or a known clinical diagnosis of influenza infection during the 2022 - 2023 influenza season prior to enrollment. 8. History of past exposure or immunization with KLH. The invention described in the original claims of the present application is appended below. [1] A BTK inhibitor, such as a selective BTK inhibitor, such as LOU064, for use in the treatment and / or prevention of HS. [2] LOU064 for use as described in [1], wherein LOU064 is administered at a dose of about 50 mg to about 200 mg per day. [3] LOU064 for use as described in [2], wherein LOU064 is administered at a dose of about 25 mg twice a day to about 100 mg twice a day. [4] LOU064 for use as described in [2], wherein LOU064 is administered at a dose of about 100 mg twice a day. [5] LOU064 for use as described in [2], wherein LOU064 is administered at a dose of about 25 mg twice a day. [6] LOU064 for use as described in any of [1] to [5], wherein LOU064 is administered for a short period, such as less than 6 months, preferably less than 3 months. [7] LOU064 for use as described in [6], wherein LOU064 is administered for a maximum of 16 weeks, such as for 4, 12, or 16 weeks. [8] LOU064 for use as described in any of [1] to [5], wherein LOU064 is administered for long-term use; such as for chronic use for more than 6 months, more than 1 year. [9] LOU064 for use as described in any of [1] to [8], wherein LOU064 is administered as monotherapy.

[10] LOU064 for use as described in any of [1] to [9], wherein LOU064 is not administered simultaneously with a strong inhibitor of CYP3A.

[11] LOU064 for use as described in any of [1] to

[10] , wherein LOU064 is not administered simultaneously with a strong inhibitor of CYP3A4.

[12] LOU064 for use as described in any of [1] to [8], wherein LOU064 or a pharmaceutical composition containing the same is administered in combination with one or more second therapeutic agents.

[13] A combination comprising a therapeutically effective dose of LOU064 and one or more therapeutic agents for use in such treatment and / or prevention in a patient in need of treatment and / or prevention of HS.

[14] LOU064 for use as described in

[13] , wherein the patient is further treated with at least one topical agent and at least one disinfectant in combination with LOU064.

[15] LOU064 for use according to any of [1] to

[11] , wherein the patient has not been previously treated with a systemic agent or a topical therapeutic agent for HS prior to treatment with the LOU064.

[16] The patient is selected according to at least one of the following criteria: a) The patient has moderate to severe HS; b) Prior to treatment with the LOU064, the patient has at least three inflammatory lesions; or c) Prior to treatment with the LOU064, the patient does not have extensive scarring of fistulas with a size of 15 or less as a result of HS); d) The patient has a clinical diagnosis of HS for at least 12 months; e) The patient has at least two anatomical sites involved in HS lesions, LOU064 for use according to any of [1] to

[15] .

[17] By the 16th week of treatment, the patient has the following: a) Simplified HiSCR; b) Reduction of HS erythema; c) Reduction of pain as measured by the pain NRS, for example, pain reduction as measured by pain NRS30; d) Reduction of pruritus as measured by the pruritus NRS, for example, reduction of skin pruritus as measured by skin pruritus NRS30 f) Reduction of overall or various types of HS inflammatory lesion variables, such as AN50, AN75, AN90 or AN100; g) Reduction of the IHS4 score; h) Reduction of ≤6 as measured by DLQI; and / or i) Improvement of DLQI LOU064 for use according to any of [1] to

[16] , achieving at least one of the above.

[18] When treating a population of patients with moderate to severe HS using the method, at least 40% of the patients achieve at least one of the following by the 16th week: a) HiSCR50; b) HiSCR75; c) HiSCR90; or d) Simplified HiSCR LOU064 for use according to any of [1] to

[17] .

[19] By the 16th week of treatment, at least 25% of the patients achieve an NRS30 response (for example, a pain NRS30 or skin pruritus NRS30 response); or less than 15% of the patients develop HS erythema, LOU064 for use according to any of [1] to

[17] .

[20] At about one or two weeks after the first administration of the LOU064, the patient has the following: a) Reduction of pain as measured by the pain NRS, for example, the patient achieves pain NRS30, b) Reduction of skin itching as measured by the itching NRS; for example, the patient achieves a skin itching NRS of 30 c) Decrease in CRP as measured using a standard CRP assay, a decrease of at least 25% LOU064 for use according to any of [1] to

[17] , having at least one of the above.

[21] When the patient is measured by an inflammatory variable such as AN50, hidradenitis suppurativa clinical response (HiSCR) (e.g., sHiSCR, HiSCR50, HiSCR75 or HiSCR90), itching or pain numerical rating scale (NRS), hidradenitis suppurativa - physician global assessment (HS - PGA), HS severity assessment (SASH), international HS severity score system (IHS4) or dermatology life quality index (DLQI), LOU064 for use according to any of [1] to

[20] , achieving a sustained response 3 months after the end of the treatment.

[22] When the patient is measured by simplified HiSCR (sHiSCR), HiSCR50, HiSCR75 or HiSCR90, LOU064 for use according to

[21] , achieving a sustained response 3 months after the end of the treatment.

[23] LOU064 is disposed in a pharmaceutical composition, the pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, each independently selected from fillers, lubricants, binders, disintegrants and glidants, LOU064 for use according to any of [1] to

[22] .

[24] The pharmaceutical composition is in tablet or capsule form, LOU064 for use according to

[23] .

[25] The pharmaceutical composition contains nano - sized particles of LOU064, LOU064 for use according to

[23] or

[24] .

[26] The pharmaceutical composition contains nano - sized particles of LOU064 having an average particle size of about 50 nm to about 750 nm as measured by PCS, LOU064 for use according to

[25] .

[27] The pharmaceutical composition contains LOU064 and a binder in a weight ratio of about 2:1, LOU064 for use according to any of

[23] to

[26] .

[28] The pharmaceutical composition contains LOU064, a binder and a surfactant in a weight ratio of about 2:1:0.08, LOU064 for use according to

[27] .

[29] LOU064 for use according to any one of

[23] to

[26] , wherein the pharmaceutical composition comprises LOU064 and a binder in a weight ratio of about 1:1.

[30] LOU064 for use according to

[29] , wherein the pharmaceutical composition comprises LOU064, a binder and a surfactant in a weight ratio of about 1:1:0.05.

[31] LOU064 for use according to any one of

[23] to

[30] , wherein the pharmaceutical composition comprises LOU064, a polyvinylpyrrolidone-vinyl acetate copolymer as a binder, and sodium lauryl sulfate as a surfactant.

[32] LOU064 is in a crystalline form of the anhydrous free base characterized by an X-ray powder diffraction pattern comprising one or more representative peaks for 2θ 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, 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 when measured at a temperature of about 25 °C and an X-ray wavelength, λ, of 1.5405 Å. LOU064 for use according to any one of [1] to

[31] .

Claims

1. A pharmaceutical composition comprising LOU064 for use in the treatment of hidradenitis suppurativa (HS) in patients in need thereof.

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

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

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

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

6. The pharmaceutical composition according to any one of claims 1 to 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 a maximum of 16 weeks.

8. The pharmaceutical composition according to any one of claims 1 to 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 monotherapy.

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

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

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

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

14. The patient is selected according to at least one of the following criteria: a) The patient has moderate to severe HS; b) The patient has at least three inflammatory lesions before treatment with LOU064; or c) The patient does not have extensive scarring of fistulas of 15 or less as a result of HS before treatment with LOU064); d) The patient has a clinical diagnosis of HS for at least 12 months; e) The patient has at least two anatomical sites involved in HS lesions, the pharmaceutical composition according to any one of claims 1 to 5.

15. By the 16th week of treatment, the patient has the following: a) Simplified HiSCR; b) Reduction of HS erythema; c) Reduction of pain as measured by the pain NRS; d) Reduction of skin itching as measured by the itching NRS f) Reduction of the total or various types of HS inflammatory lesion numbers; g) Reduction of the IHS4 score; h) A reduction of ≤ 6 as measured by DLQI; and / or i) Improvement of DLQI The pharmaceutical composition according to any one of claims 1 to 5, which achieves at least one of the above.

16. When treating a population of patients with moderate to severe HS using the pharmaceutical composition, at least 40% of the patients have, by the 16th week, the following: a) HiSCR50; b) HiSCR75; c) HiSCR90; or d) Simplified HiSCR The pharmaceutical composition according to any one of claims 1 to 5, which achieves at least one of the above.

17. By the 16th week of treatment, at least 25% of the patients achieve an NRS30 response; or less than 15% of the patients develop HS erythema. The pharmaceutical composition according to any one of claims 1 to 5.

18. One week or two weeks after the first administration of LOU064, the patient has at least one of the following: a) Reduction in pain as measured by the pain NRS, b) Reduction in skin itching as measured by the itching NRS, c) At least a 25% decrease in CRP as measured using a standard CRP assay The pharmaceutical composition according to any one of claims 1 to 5.

19. When the patient is measured by inflammatory variables, hidradenitis suppurativa clinical response (HiSCR), itching or pain numerical evaluation scale (NRS), hidradenitis suppurativa - physician global assessment (HS - PGA), HS severity assessment (SASH), international HS severity score system (IHS4) or dermatology quality of life index (DLQI), a sustained response is achieved 3 months after the end of the treatment. The pharmaceutical composition according to any one of claims 1 to 5.

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

21. LOU064 is disposed in the pharmaceutical composition, and the pharmaceutical composition includes one or more pharmaceutically acceptable carriers, each of which is independently selected from a filler, a lubricant, a binder, a disintegrant, and a glidant. The pharmaceutical composition according to any one of claims 1 to 5.

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 according to claim 21, wherein the pharmaceutical composition includes nano-sized particles of LOU064.

24. The pharmaceutical composition according to claim 23, wherein the pharmaceutical composition includes nano-sized particles of LOU064 having an average particle size of about 50 nm to about 750 nm as measured by PCS (wherein the term "about" means a change of + / −10%).

25. The pharmaceutical composition according to claim 21, wherein the pharmaceutical composition includes LOU064 and a binder in a weight ratio of about 2:1 (wherein the term "about" means a change of + / −10%).

26. The pharmaceutical composition according to claim 25, wherein the pharmaceutical composition includes LOU064, a binder, and a surfactant in a weight ratio of about 2:1:0.08 (wherein the term "about" means a change of + / −10%).

27. The pharmaceutical composition according to claim 21, wherein the pharmaceutical composition includes LOU064 and a binder in a weight ratio of about 1:1 (wherein the term "about" means a change of + / −10%).

28. The pharmaceutical composition according to claim 27, wherein the pharmaceutical composition includes LOU064, a binder, and a surfactant in a weight ratio of about 1:1:0.05 (wherein the term "about" means a change of + / −10%).

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

30. The anhydrous free base crystalline form characterized by an X-ray powder diffraction pattern comprising one or more representative peaks for 2θ 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, 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 when measured at a temperature of about 25 °C and an X-ray wavelength, λ, of 1.5405 Å (where the term "about" means a variation of + / − 10%), the pharmaceutical composition according to any one of claims 1 to 5.

31. A combination comprising a therapeutically effective dose of LOU064 and one or more therapeutic agents for use in the treatment of hidradenitis suppurativa (HS) in a patient in need thereof.

32. The combination according to claim 31, wherein the one or more therapeutic agents are topical agents or disinfectants.

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