Remibrutinib for use in treatment of hidradenitis suppurativa

Abstract

To provide methods for treating and / or preventing Hidradenitis Suppurativa (HS) in a subject having such disease or condition.SOLUTION: A BTK inhibitor, for use in treating and / or preventing HS, for example a selective BTK inhibitor, for example LOU064, is provided. Medicaments, dosing regimens, pharmaceutical compositions, combinations, dosage forms, and kits for use in the disclosed uses and methods are also provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention provides LOU064 for use in the effective and safe treatment of hidradenitis suppurativa (HS). or a pharmaceutically acceptable salt thereof. [Background technology]

[0002] Hidradenitis suppurativa (HS), also known as acne inversa or Bernoulli's disease, is a condition that affects the axilla, groin, and Deep fibrosis causing fibrosis in the breast-fold and anogenital area It is a chronic, recurrent, inflammatory disease characterized by superficial nodules, fistulas, and abscesses. (Revuz and Jemec(2016)Dermatol Clin 34:1 -5;Jemec GB.(2012)N Engl J Med 366:158-6 4) It is associated with increased risk of metabolic, psychiatric, and autoimmune diseases, as well as skin cancer. It is associated with significant pain and comorbidities, including: (Revuz (2016); Shly ankevich et al.(2014)J Am Acad Dermatol 71:1144-50;Kohorst et al (2015) J Am Acad Dermatol 73:S27-35;Wolkenstein et al.(20 07)J Am Acad Dermatol 56:621-3). Different races / ethnicities The average prevalence of HS among the general population is highest in the African American population (1.3%), It was lowest among Hispanics / Hispanics (0.07%) and intermediate among the White population. (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% of the population. [Shlyank evich et al.(2014);Cosmatos et al.(2013) J Am Acad Dermatol 68:412-9;Davis et al. (2015)Skin Appendage Disord 1:65-73;Revu z 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 Derma tol,77(1):118-122;Jemec et al.(1996)J Am Acad Dermatol 35:191-4]. However, HS is underdiagnosed. Estimates vary by study design, population, and geographic location, so the true incidence is unknown. , and it is difficult to confirm [Miller et al. (2016) Dermatol Clin 34:7-16. National Institutes of Health The National Institutes of Health (NIH) has not classified HS as a rare disease. However, experts generally believe the prevalence of this disease to be <1% of the United States (US) population. Cosmatos et al. (2013); Genetic and Ra re Diseases Information Center.National Institutes of Health.Hydradenitis suppur ativa.Available at: / / rarediseases.info.n ih.gov / diseases / 6658 / hidradenitis-suppur ativa.Accessed March 20, 2017;Gulliver et al.(2016)Rev Endocr Metab Disord 17:343 -51;Garg et al. 2007].

[0004] Current treatments for HS include topical and / or systemic antibiotics, hormonal interventions, and retinoids. and, in selected cases, immunosuppressants, biologics, e.g., anti-cancer drugs, which are the only approved drugs for HS. Tumor necrosis factor [TNF] inhibitor monoclonal antibody adalimumab, and often the final The procedure consists of major surgical resection [Gulliver et al. (2016); Zouboulis et al. (2015) J Eur Acad Dermato l Venereol 29:619-4414-16;Kimball et al. (2016) N Engl J Med 375:422-34]. The lesions were painful. Therefore, patients frequently require pain medications and analgesics in addition to anti-inflammatory treatment.

[0005] However, symptom control and lesion resolution are inconsistent across treatments and evidence is lacking. Randomized controlled clinical trial results providing data based on Only adalimumab is approved for this treatment. Antibiotic therapy may be required for several months and even Although used for long-term treatment over several years, antibiotic therapy has led to a resurgence of antimicrobial resistance. Oral retinoid treatment has been shown to have teratogenic effects in sexually active, primarily female, populations. Furthermore, the availability of anti-inflammatory drugs such as dapsone, fumarate, and cyclosporine Efficacy is based on small case studies with variable results, and these molecules are not systematically Because of these inconsistent results and the severity of HS disease, Patients with chronic inflammatory skin diseases are more frequently diagnosed in high-cost settings (e.g., ambulances) than patients with other chronic inflammatory skin diseases. Emergency care and inpatient care) (Khalsa et al. (2016) J Am Acad Dermatol 73:609-14;Kirby et al (2014) JAMA Dermatol 150:937-44).

[0006] The immunopathogenesis of HS is poorly understood, with widespread and somewhat discordant pathogenic mechanisms. Complement activation is thought to be responsible for the elevated levels of the complement fragment C5a in the skin and blood of HS patients. It is believed that depending on the concentration, it may be involved in the onset of HS (Kanni T. et al.Br J Dermatol.2018;179(2):413-419). C5a is actively It is a major chemoattractant for neutrophils, a prominent cell population in inflamed HS skin. (Lima AL.et al.Br J Dermatol.2016;174(3 ):514-520). Furthermore, neutrophil cells in a process called NETosis Increased levels of neutrophils releasing extracellular traps (NETs) are associated with increased type I IFN responses and In both the blood and skin of HS patients, along with activation of plasmacytoid dendritic cells (pDCs), It has been demonstrated that (Byrd AS et al., Sci transl Med. 2 019:11(508).eaav5908). Other studies have shown that the inflammatory cytokine IL- 17A and IFN-γ (Hotz C. et al.; J. Invest Dermat ol.,2016:136(9):1768-1780;Vossen ARJV et al.Allergy.2019,74(3):631-634), and keratinosa These results suggest the involvement of IL-6 and IL-1β derived from the thyroid gland. Studies have shown increased expression of immunoglobulin and plasma cell signatures in HS ( Hoffman LK.Et al.PLoS One.2018;13(9):e02 03672), a clear and comprehensive view of the immunopathogenic mechanisms involved in HS is lacking. are.

[0007] Gudjonsson et al., using proteomic and transcriptomic techniques and single-cell Using techniques such as RNA sequencing or scRNAseq, we have been able to characterize the role of HS in deep-seated disease. The inflammatory response was characterized. Such studies focused on IFN-γ, IL-36, and TNF. The study revealed a more mediated immune response, with a smaller contribution from IL-17A. Son et al. further demonstrated that the Bruton type β receptor is a central signaling network in HS. Along with BTK and SYK pathway activation, H together with an associated increase in immunoglobulin production and complement activation as contributing factors in S pathogenesis. B cells and plasma cells were identified (JCI Insight.2020;5(19): e139930.https: / / doi.org / 10.1172 / jci.insi ght.139930).

[0008] The role of B cells in the development of HS has also been suggested in previous reports (Van de r Zee et al.2012,166:98-106;Musilova et al. al.J Invest Dermatol 2020,140:1091-1094) Furthermore, the role of B cells in HS pathogenesis has also been highlighted by two recent studies: One demonstrated the anti-inflammatory effect of rituximab in HS explant cultures (Voss en et al.,2019,181:314-23), while the other case study was Showing the success of treating HS using B cell depletion with mab (Takahashi et al. l.,2018,45:e116-7). However, further research is needed to target B cells. These studies are needed to determine whether or not facilitating the treatment of rheumatoid arthritis can be an effective treatment.

[0009] BTK mediates FcεRI-mediated signaling in human mast cells and basophils. BTK is an essential kinase for B cell maturation. , which are being pharmacologically targeted for the treatment of B-cell malignancies. There are currently three There are FDA-approved BTK inhibitors (BTKis). uvica®; Pharmacyclics, and AbbVie), Acalab Rutinib (Calquence®; Acerta and AstraZeneca ), and zanubrutinib (Brukinsa®; BeiGene) are all It is an oral covalent small molecule inhibitor of TK.

[0010] Additionally, many BTKis in development are being developed to treat rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus. It is currently in clinical trials for the treatment of autoimmune diseases such as rheumatoid arthritis. nib and zanubrutinib, as well as the novel compound ONO-4059 (tirabrutinib), HM 71224 (posertinib) and ABBV-105 (upadacitinib) are candidates for the treatment of B-cell malignancies. tumors and / or autoimmune diseases, such as rheumatoid arthritis (RA), Sjögren's syndrome (SJ are currently being tested for their efficacy in systemic lupus erythematosus (SLE) and systemic lupus erythematosus (SLE). Furthermore, evobrutinib, trebrutinib, and fenebrutinib are being used in the treatment of multiple sclerosis. orelabrutinib is currently in Phase II trials in patients with multiple sclerosis (MS). BIIB091 has been studied in Phase 1 trials for efficacy in treating MS. It was tested in a clinical trial.

[0011] Despite suggestions that BTK inhibitors may be useful in the treatment of HS, the clinical significance of this disease remains unclear. There are no existing animal models, and BTK inhibitors have not yet been shown to treat HS in humans. Furthermore, some earlier developed BTK inhibitors (e.g., acalabra Due to the lack of selectivity of these BTK inhibitors (e.g., ibrutinib, ibrutinib), these inhibitors are not suitable for long-term / For the treatment of indications requiring chronic and safe use, and / or for pediatric or adolescent Currently approved BTK inhibitors may not be suitable for non-malignant indications in the adolescent population. The most common side effects of inhibitors include nausea, diarrhea, rash, infection, cytopenia, bleeding, and In particular, the first-in-class inhibitor ibrutinib The long-term toxicity profile is well characterized and includes arrhythmias, bleeding, infections, diarrhea, and arthralgia. and clinically significant incidence of hypertension. Early second-generation BTK approved by the Drug Administration Acalabrutinib, a vasopressin-dependent inhibitor of BTK, demonstrates improved kinase selectivity over BTK. Commonly observed adverse reactions include infections, headache, and diarrhea (Hematolog y Am Soc Hematol Educ Program.2020 Dec 4 ;2020(1):336-345).

[0012] Long-term safety data are not available for BTK inhibitors currently under development, but phenobarbital The available safety data for brutinib is the biggest obstacle BTK inhibitors may face. This may suggest whether side effects during chronic use are tolerable. The primary event noted in the Phase IIa study of fenebrutinib was a complication of the high-dose treatment arm. Transient grade 3 increases in ALT and / or AST in 8.3% and 6.3% of patients, respectively Some of the side effects already observed with some BTKs, especially in the long term, restrict their use to treating or preventing non-malignant indications, if administration may be required. Furthermore, none of the FDA-approved BTK inhibitors have been shown to be effective in children and adolescents. Therefore, until safety data in children are available, It is unclear whether BTK inhibitors are a viable option.

[0013] HS remains difficult to treat, and the only drugs currently approved for its treatment are One biologic treatment is the anti-TNF agent adalimumab, but even with adalimumab, the therapeutic response is poor. The disease is physically and mentally debilitating. This has the clear objective of providing a safe and effective long-term treatment, particularly an oral treatment, for HS patients. There are significant unmet needs. [Brief explanation of the drawings]

[0014] [Figure 1]Transcriptomic signature enrichment (genes overexpressed in diseased HS samples). [Figure 2] LOU signature (LOU064-repressed genes) in the hidradenitis suppurativa (bulk) transcriptome dataset. [Figure 3] Simulation of splenic BTK occupancy at steady state. [Figure 4-1] Figure 4A: BTK occupancy trough at steady state over 24 hours. Graph showing median predictions as points and vertical lines indicating 95% prediction intervals. Figure 4B: BTK occupancy average at steady state over 24 hours. Graph showing median predictions as points and vertical lines indicating 95% prediction intervals. [Figure 4-2] (As mentioned above.) [Figure 5] Favorable particle size distribution of nano-sized LOU064. Summary of the Invention

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

[0016] It is also an object of the present invention to provide improved treatment and / or prevention of HS. For example, it is an object of the present invention to provide a method for treating or preventing HS that is more effective than anti-TNF treatments, such as adalimumab. The aim is to provide prevention.

[0017] Therefore, a method for preventing or treating HS may include administering a therapeutically effective dose of a BTK inhibitor. Disclosed herein are methods comprising administering an agent to a subject in need thereof. Particularly useful in the methods of the present invention are other structurally similar proteins such as BMX, ITK, and TXK. BTK inhibitors (reversible or irreversible) that are selective for Tec family kinases Particularly useful according to the present invention are antibodies that are selective for BTK over Tec (e.g., , at least 10-fold, at least 20-fold, at least 30-fold BTK / tec selectivity)B It is a TK inhibitor.

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

[0019] Additionally, the present invention further provides a method for treating or preventing HS in a subject in need thereof. a therapeutically effective dose of LOU064 or a pharmaceutically acceptable salt thereof in combination with one or more and administering to said subject a therapeutic agent as described above.

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

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

[0022] The present invention further provides a method for treating and / or preventing HS in a patient in need thereof. LOU064 in combination with one or more further therapeutic agents for use in the treatment or prophylaxis Regarding.

[0023] A further subject of the present invention is a method for the manufacture of a medicament for use in the above-mentioned treatments. be.

[0024] Further aspects, advantageous features and preferred embodiments of the present invention are summarized in the following embodiments E1 to E32. The preferred embodiments, each alone or in combination, contribute to solving the object of the present invention. stand:

[0025] E1. A method for treating or preventing hidradenitis suppurativa (HS), comprising administering a therapeutically effective dose of A BTK inhibitor, e.g., a selective BTK inhibitor, e.g., LOU064, is administered to a patient in need thereof. The method comprises administering to a subject

[0026] E2. The therapeutically effective dose of LOU064 is about 50 mg to about 200 mg daily. The method described in E1.

[0027] E3. Therapeutically effective doses of LOU064 range from approximately 25 mg twice daily to approximately 100 mg twice daily. The method according to E2, wherein the amount of

[0028] E4. The therapeutically effective dose of LOU064 is approximately 25 mg twice daily, as described in E2 How to do it.

[0029] E5. A therapeutically effective dose of LOU064 is approximately 100 mg twice daily, as described in E2. How to post.

[0030] E6.LOU064 is administered over a short period of time, e.g., less than 6 months, preferably less than 3 months. 12. The method of any one of the preceding embodiments, wherein the patient is administered

[0031] E7.LOU064 is administered for up to 16 weeks, e.g., 4, 12, or 16 weeks. The method according to E6,

[0032] E8.LOU064 is suitable for chronic use over a long period of time, e.g., more than 6 months, preferably more than 1 year. The method of any one of embodiments E1 to E5, wherein the administration is for the purpose of

[0033] E9. Any one of the preceding embodiments, wherein LOU064 is administered as monotherapy The method described below.

[0034] E10.LOU064 should not be administered concomitantly with strong CYP3A inhibitors. 10. The method of any one of embodiments.

[0035] E11. LOU064 should not be administered concurrently with a strong inhibitor of CYP3A4, 10. The method of any one of embodiments.

[0036] E12. An implementation in which LOU064 is administered in combination therapy with one or more therapeutic agents. The method of any one of embodiments E1 to E8.

[0037] E13. The patient is taking at least one topical medication and at least one The method of claim E12, further treated with at least one disinfectant.

[0038] E14. Prior to treatment with LOU064, the patient is taking systemic or topical medications for HS. The method of any one of embodiments E1-E11, wherein the patient has not been previously treated with the drug.

[0039] E15. Patients are 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 prior to treatment with LOU064; or c) Prior to treatment with LOU064, patients had extensive fistulas of 15 or fewer as a result of HS. no circumferential scarring); d) the patient has a clinical diagnosis of HS for at least 12 months; e) Patients have at least two anatomical sites involved in HS lesions, 10. The method of any one of the above aspects.

[0040] E16. The patient, by week 16 of treatment, has: a) Simplified HiSCR; b) HiSCR clinical results (HiSCR50, HiSCR75 or HiSCR90) c) reduction of HS erythema; d) Reduction of cutaneous pain as measured by the Pain NRS; e.g., Pain NRS30 e) reduction in itch as measured by the Pruritus NRS; e.g., Pruritus NRS30 f) HS inflammatory lesion counts for all or various types; e.g., AN50, AN75, AN9 0 or a decrease in AN100; g) reduction in IHS4 score; h) a decrease of ≦6 as measured by DLQI; and / or i) Improvement of DLQI 3. The method according to any of the preceding embodiments, wherein the method achieves at least one of the following:

[0041] E17. The method is used to treat a population of patients with moderate to severe HS. In this case, at least 40% of the patients have one of the following by week 16 of treatment: a) Simplified HiSCR; b) HiSCR50; c) HiSCR75 d) HiSCR90 3. The method according to any of the preceding embodiments, wherein the method achieves at least one of the following:

[0042] E18. The method is used to treat a population of patients with moderate to severe HS. In this case, at least 25% of the patients will achieve an NRS30 response (e.g., pain relief) by week 16 of treatment. Any of embodiments E1 to E16, wherein the patient achieves a pain NRS30 or itch NRS30 response. The method described.

[0043] E19. The method is used to treat a population of patients with moderate to severe HS. In embodiments E1-E, fewer than 15% of the patients develop HS erythema during 16 weeks of treatment. The method according to any one of E16.

[0044] E20. If the patient receives, approximately one or two weeks after the first dose of LOU064, one of the following: a) Reduction in pain as measured by the Pain NRS, (e.g., Pain NRS30) b) reduction in pruritus as measured by the Pruritus NRS, (e.g., Skin Pruritus NRS30) b) A decrease in CRP, e.g., of at least 25%, as measured using a standard CRP assay Small The method of any of embodiments E1-E16, having at least one of:

[0045] E21. The patient is evaluated for inflammatory lesion counts, e.g., AN50, hidradenitis suppurativa clinical response (HiSC), R) (e.g., sHiSCR, HiSCR50, HiSCR75, or HiSCR90) , pruritus or pain numerical rating scale (NRS), hidradenitis suppurativa - physician global rating (HS-PG) A), HS severity assessment (SASH), International HS Severity Scoring System (IHS4) or Sustained improvement 3 months after the end of treatment as measured by the Dermatology Life Quality Index (DLQI) 3. The method of any of the above embodiments, wherein the reaction is effected.

[0046] E22. The patient is a patient with simplified HiSCR (sHiSCR), HiSCR50, HiSC Achieved a sustained response 3 months after the end of treatment as measured by R75 or HiSCR90 The method according to E21,

[0047] E23.LOU064 is disposed in a pharmaceutical composition, said pharmaceutical composition comprising one or more drugs and a physiologically acceptable carrier, which may each independently comprise a filler, a lubricant, a binder, , a disintegrant and a glidant.

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

[0049] E25. Embodiment E23 or E26, wherein the pharmaceutical composition comprises nano-sized particles of LOU064. 24. The method according to claim 24.

[0050] E26. The pharmaceutical composition has an average wavelength of about 50 nm to about 750 nm as measured by PCS. The method of E25, comprising nano-sized particles of LOU064 having a particle size.

[0051] E27. A pharmaceutical composition comprising LOU064 and a binder in a weight ratio of about 2:1. The method of any one of aspects E23 to E26.

[0052] E28. A pharmaceutical composition comprising LOU064, a binder, and The method of E27, comprising a surfactant.

[0053] E29. A pharmaceutical composition comprising LOU064 and a binder in a weight ratio of about 1:1. The method of any one of aspects E23 to E26.

[0054] E30. A pharmaceutical composition comprising LOU064, a binder, and 30. The method of embodiment 29, comprising a surfactant.

[0055] E31. Pharmaceutical compositions comprising LOU064, polyvinylpyrrolidone-acetic acid as a binder Embodiment E comprising a vinyl acid copolymer and sodium lauryl sulfate as a surfactant. 23 to E30.

[0056] E32.LOU064 was measured at a temperature of approximately 25°C and an X-ray wavelength, λ, of 1.5405 Å. When the angle is 12.0±0.2°2θ, 7.8±0.2°2θ, 9.2±0.2°2θ, 12.0±0.2°2θ, 3.6±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, 2 3.9±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 The X-ray powder diffraction pattern is characterized by one or more representative peaks at selected 2θ. 10. The method of any of the preceding embodiments, wherein the crystalline form of the anhydrous free base is . DETAILED DESCRIPTION OF THE INVENTION

[0057] As used herein, Bruton's tyrosine kinase (BTK) refers to a cytoplasmic tyrosine kinase. BTK is a member of the mitochondrial kinase and TEC kinase families. Selected members of the adaptive and innate immune system, including macrophages, mast cells / basophils, and platelets BTK is expressed in cells. It binds to the Fcε receptor (FcεR1 for IgE) and activates Fcγ receptors (FcγR in the case of IgG), and B cell antigen receptors (BCR) and B BTK inhibitors such as ibrutinib are essential for signal transduction via BTK inhibitors. The agent is approved for the treatment of B-cell malignancies (Hendriks et al. 2014). Recently, inhibition of BTK has been shown to inhibit mast cell and basophil activation / desgranulation in vitro. Inhibition of granules and swelling in skin prick tests by patients with IgE-mediated allergies. It has been demonstrated that this treatment results in a reduction in blemish size (Smiljkovic et al. 2017). 17;Regan et al. 2017;Dispenza et al. 2018) Therefore, inhibition of BTK may be beneficial in treating rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus. various skin conditions, including chronic urticaria, atopic dermatitis, asthma, and primary Sjögren's syndrome This is an attractive therapeutic concept for treating various autoimmune and chronic inflammatory diseases (Tan et al. 2013;Whang and Chang 2014). BTK inhibitors Examples include non-covalent, reversible BTK inhibitors such as fenebrutinib, and evo Brutinib, trebrutinib, rilzabrutinib, tirabrutinib, branebrutinib, Non-covalent binding of BTK, such as orelabrutinib and remibrutinib (LOU064), Irreversible inhibitors are included.

[0058] The term "comprising" is used interchangeably with "including" and and "consisting of," e.g., "comprises" X. The "ising" composition may consist of only X or may contain something additional. It may be, for example, X+Y.

[0059] As used herein, the term "pharmaceutically acceptable" means a compound that is Use of a substance that is not likely to cause excessive toxicity, irritation, or allergies, within the bounds of sound medical judgment, consistent with the benefit / risk ratio. Can be used in contact with human and animal tissues without adverse reactions or other problems or complications. "Drugs" refers to compounds, materials, compositions, and / or dosage forms suitable for administering a drug to a patient.

[0060] The term "about" in relation to a numerical value x means, for example, + / - 10%. When used before a list of numbers, the term "about" applies to each number in the series and For example, the phrase "about 1 to 5" should be interpreted as "about 1 to about 5"; or For example, the phrase "about 1, 2, 3, 4" should be interpreted as "about 1, about 2, about 3, about 4, etc." should be interpreted.

[0061] As used herein, the term "salt" or "salts" The term refers to an acid addition salt or a base addition salt of a compound for use in the method of the present invention. The term "salt" particularly includes "pharmaceutically acceptable salts." The term "salts" refers to compounds that retain the biological effectiveness and properties of the compounds of the present invention and are typically biologically In most cases, the term "salt" refers to a salt that is not harmful chemically or otherwise harmful. The compounds of formula (I) are capable of forming acid and / or base salts due to the presence of amino groups. Examples of salts are described in WO 2015 / 079417, which is incorporated herein by reference. This is what is disclosed in Fret.

[0062] As used herein, a compound, e.g., LOU064, or another agent may be used in conjunction with The term "administering" refers to the administration of a compound to a patient by any route, preferably oral administration. is used to refer to the delivery of compounds.

[0063] As used herein, the term "pharmaceutically acceptable carrier" means a compound that is As is known (e.g., Remington's Pharmaceuticals Sciences,18th Ed.Mack Printing Company,1 990, pp. 1289-1329), any solvent, dispersion medium, coating, boundary Surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungals), isotonic agents, absorption delaying agents, salts , preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, etc. Except insofar as any conventional carrier is incompatible with the active ingredient, it is not intended to be limiting. Its use in pharmaceutical compositions / formulations is envisaged.

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

[0065] The term "treatment" or "treating" refers to a subject or tissue or tissue isolated from a subject. or a cell line, The application or administration of a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof is referred to herein as defined, where the subject is a patient with a particular disease (e.g., HS), a symptom associated with the disease (e.g., symptoms of HS) or predisposition to developing the disease (if applicable), and the purpose is to: To cure one or more symptoms of a disease (if applicable), reduce its severity, or alleviating or improving symptoms such as, or improving the disease, any associated symptoms of the disease, or "Treatment" or "treating" refers to the reduction or amelioration of the tendency to develop a condition. The term refers to subjects suspected of having a disease as well as subjects who are ill or suffering from a disease or condition. In some embodiments, "treating" includes treating a subject diagnosed with a disease. The term "ameliorate" refers to ameliorating a disease or disorder (i.e., reducing at least the severity of the disease or its clinical symptoms). "Slowing, stopping, or reducing the onset or progression of any one of these." In another embodiment, "treat," "treating," or "treatment" refers to the Alleviate or improve at least one physical parameter, including those that may not be discernible. In yet another embodiment, "treat," "treating," or "treatment" refers to Treatment can be physical (e.g., stabilization of discernible symptoms), physiological (e.g., physical pain), or both. More specifically, it refers to modulating a disease or disorder through: The term "treating" the disease HS refers to treating inflammatory lesions in HS patients. (reducing in number or quality or in their volume and size), and / or To treat abscesses and inflammatory nodules and / or draining fistulas in HS patients; and / or is intended to reduce the amount of scarring and / or alleviate the functional limitations associated with scarring. Treating the disease HS also reduces the pain, fatigue, and / or itching associated with HS. reducing pus discharge and odors associated with pus discharge; and / or or to improve the quality of life and / or work disability for HS patients. It refers to reducing harm.

[0066] As used herein, "prevention," "preventing," or "preventing" a disease or disorder (HS) is defined as a condition that is caused by a disease or disorder (HS). The term "preventing" refers to the prophylactic treatment of a disease or disorder; or the prevention of a disease or disorder. It refers to delaying and / or inhibiting the onset or progression of disease H. The term "preventing" HS refers to preventing HS erythema and / or new lesions from appearing. to prevent scarring and the functional limitations associated with scarring, and / or to, in particular, refers to preventing surgical intervention for S.

[0067] As used herein, the phrase "population of subjects" refers to a group of subjects who have received treatment from such a treatment. A group of subjects who may benefit biologically, medically, or in quality of life is used to mean

[0068] As used herein, the term "subject" refers to an animal. The subject may also be, for example, a primate (e.g., a human, male or female). , cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. A subject is a human. The term "subject" when referring to a human is the same as "patient." It is used in a proper way.

[0069] As used herein, "not previously treated with systemic therapy for HS" and the term "treatment-naive" refers to patients who have not received systemic medications for HS, such as methotrexate. , cyclosporine, or biologic agents (e.g., IL-12 and IL-23 blockers, e.g., UTIs) sutekinumab and guselkumab or TNF-α inhibitors, e.g., adalimumab or inflammasome inhibitors liximab, or IL-17 blockers, such as secukinumab, ixekizumab, and brodalumab This refers to HS patients who have not been previously treated with systemic agents (i.e., oral, injectable). Drugs given by injection or other means are systemic (total) when delivered to a patient. The disclosed method differs from topical agents (e.g., topical medications and phototherapy) in that it has a therapeutic effect on the body. In certain embodiments of the methods, regimens, uses, kits, and pharmaceutical compositions, the patient is have not previously received systemic treatment for S.

[0070] As used herein, "previously treated with a systemic agent for HS" means The term is used to refer to patients who have previously been treated for HS with systemic agents. Such patients may be treated with biologics, such as IL-12 and IL-23 blockers, e.g., Ustilago ssp. Tekinumab and guselkumab or TNF-α inhibitors, such as infliximab, or I Previous treatment with L-17 blockers, e.g., secukinumab, ixekizumab, and brodalumab and patients receiving non-biologic agents, such as systemic immunosuppressants or immunomodulators (e.g., cyclosporine). thrombin, methotrexate and cyclophosphamide), retinoids (isotretinoin Previously treated with systemic therapy, including dapsone, metformin, and oral zinc therapy In certain embodiments of the present disclosure, the patient may have previously received a systemic medication for HS. In one embodiment, the patient is receiving a systemic medication for HS (e.g., methotrexate). Although the patient had previously received steroids (e.g., cyclosporine, cyclosporine), he had not received any systemic antibiotics for HS. Pharmaceuticals (i.e., drugs produced by living organisms, e.g., antibodies, receptor decoys, etc.) (e.g., For example, secukinumab, ustekinumab, ixekizumab, brodalumab, TNF-α inhibitors If you have previously received anticoagulants (etanercept, adalimumab, infliximab, etc.) In this case, the patient is referred to as "biologic-naive." The patient was biologic treatment naive.

[0071] As used herein, "select" and "selected" in reference to a patient are A particular patient may have a greater chance of receiving a treatment based on the particular patient having certain criteria. Similarly, "selective treatment" is used to mean specifically selected from a group of "To provide treatment" refers to providing treatment to a patient with a particular disease, where the patient is The treatment is specifically selected from a larger group of patients based on a particular patient having certain criteria. Similarly, "selectively administering" refers to administering to a particular patient based on (or by) certain criteria. ), refers to administering a drug to a patient who is specifically selected from a larger group of patients. To selectively treat, selectively treat, and selectively administer means to treat a patient who is a member of a larger group. Rather than delivering a standard treatment plan based solely on the patient's medical history (e.g. previous therapeutic interventions, e.g., previous treatment with biologics), biology (e.g., specific genetic Individuals based on genetic markers, and / or symptoms (e.g., failure to meet specific diagnostic criteria) As used herein, the term "method of treatment" refers to the delivery of a second treatment to a patient. Therefore, selection does not refer to the chance treatment of patients with specific criteria, but rather to the specific It refers to the careful selection of patients to administer treatment based on their criteria. Therefore, selective treatment / administration is not based on the patient's medical history, disease symptoms, and / or biology. , differs from standard treatment / administration, which delivers a specific drug to all patients with a specific disease. In one embodiment, patients are selected for treatment based on having HS.

[0072] As used herein, the term "compound" refers to the use of the present invention (particularly in connection with the claims). The terms "a," "an," "the," and similar terms used herein are intended to refer to the same or similar entities as specifically set forth herein. includes both the singular and the plural unless otherwise specified or clearly contradicted by the context should be interpreted as follows.

[0073] The term "pharmaceutical combination" as used herein means a combination of two or more active ingredients. This specification means the product obtained from using or mixing or combining the same. Pharmaceutical combinations as used herein are defined as fixed combinations of active ingredients and fixed It should be understood that the term "fixed combination" includes both fixed combinations and non-fixed combinations. The term "combination" refers to the administration of an active ingredient, e.g., a compound of formula (I) or its A pharmaceutically acceptable salt and one or more combination partners may be administered as a single entity or dosage form. In such cases, the term refers to a single unit dosage form. refers to a fixed dose combination in a single unit (e.g., capsule, tablet, or sachet). "non-fixed combination" or "kit of parts" " refers to the active ingredients, e.g., a compound of the present disclosure and one or more combination parts. The toner and / or one or more auxiliaries may be mixed simultaneously, in parallel or sequentially without any specific time limit. is meant to be administered to a patient independently as separate entities or co-administered, either as a single entity or as a single entity. Such administration is particularly important if these time intervals are such that the combination partners exert a joint effect, e.g. The therapeutic effectiveness of the two compounds in the patient is enhanced when the two compounds are capable of exhibiting additive or synergistic effects. The term "unfixed combination" refers to cocktail therapy, e.g. Therefore, the term "non-fixed combination" also applies to the administration of three or more active ingredients. " refers to the compounds described herein that are present independently of each other, i.e., simultaneously or may be administered at different times, particularly to define the administration, use, composition or formulation. The term "non-fixed combination" refers to single drugs containing different amounts of the active ingredients in them. Use together with one or more fixed combination products with each individual formulation containing It should be understood that the combination products and and the term "non-fixed combination" refers to combinations of active ingredients (compounds described herein) The combination partners are completely separate products that are also sold independently of each other. It should further be understood that the compound may be administered as a pharmaceutical dosage form or pharmaceutical preparation. If the instructions for use of the combination are not provided on the packaging, e.g. a leaflet, or by a doctor and / or is or may be provided in other information provided to medical staff, The formulations or parts of the formulation, product or composition may be administered simultaneously or at staggered times. i.e., each individual part of the kit of parts can be The parts may be administered at different times and / or at equal or different time intervals. In particular, the time interval between administrations should be determined based on the efficacy of the combined use of the parts for the treatment of the disease. The effect is obtained by using only the compound of formula (I) or a pharmaceutically acceptable salt thereof. and therefore, the pharmaceutical combinations described herein are selected to have greater / higher efficacy. The compounds used in this study are synergistically active against a second drug administered as a pharmaceutical combination. The proportion of the total amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to be administered is determined based on the specific the needs of a subpopulation of patients, or a single patient, which may be based, for example, on patient age, sex, weight, etc. It can be modified or adjusted to better suit the needs of the user.

[0074] As used herein, terms such as "co-administration" or "administration in combination" mean , one or more compounds described herein, together with selected combination partners, administration to a single subject (e.g., a patient or subject) in need thereof. This means that the compounds are not necessarily administered by the same route of administration and / or at the same time. It is intended to include treatment regimens other than those listed above.

[0075] LOU064 LOU064 (=N-(3-(6-amino-5-(2-(N-methylacrylamide) Ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclo Propyl-2-fluorobenzamide (INN: remibrutinib) is a Bruton's tyrosine kinase inhibitor. WO 2015 / 079417 A as a drug candidate for selective inhibition of steroid kinases This compound is a potent, highly selective, irreversible covalent BT LOU064 is a BTK inhibitor. Due to its binding to the inactive conformation of BTK, Covalent inhibition of kinases, thus reducing kinase off-target binding This allows the compound to have potent and sustained pharmacodynamic effects without the need for prolonged, high systemic compound exposure. (Angst, D. et al., Discovery of LOU064 (Remibrutinib), a Potent and Highly Selec tive Covalent Inhibitor of Bruton's Tyro sine Kinase,J Med Chem.2020 May 28;63(10 ):5102-5118).

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

[0077] In another embodiment, N-(3-(6-amino-5-(2-(N-methylacrylamide) (Iodo)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4- Cyclopropyl-2-fluorobenzamide is disclosed in International Publication No. 2003 / 002299, which is incorporated herein by reference. As disclosed in the pamphlet of Japanese Patent Publication No. 2020 / 234779 (Example 1), The anhydrous crystalline form A of

[0078] Chronic spontaneous urticaria (CSU) (International Publication No. 2020 / 234782 A1 Pamphlet Rett) and Sjögren's syndrome (SjS) (International Publication No. WO 2020 / 234781 A1 LOU064, which has already been proposed for use in the treatment of CS It is currently being tested in phase 2 clinical trials for U and SjS.

[0079] In the pamphlet of International Publication No. 2020 / 234782 A1, 10 mg, 25 m Doses of 100 mg and 100 mg given twice daily (bid) were associated with the greatest efficacy in CSU. It was generally suggested that achieving sexual maturity was the key.

[0080] H1-antihistamines with at least moderately active chronic spontaneous urticaria (CSU) Efficacy of LOU064 over 12 weeks in patients inadequately controlled with anticoagulants In a Phase 2b, randomized, double-blind, placebo-controlled study evaluating efficacy and safety, LOU064 10 mg qd (once a day), 35 mg qd, 100 mg qd, 10 mg bid (twice daily), 25 mg bid, 100 mg g bid or placebo (1:1:1:1:1:1:1:1 ratio). The 5 mg bid regimen was found to be particularly effective compared with other doses .

[0081] Therefore, a dose of 25 mg bid was recommended for subsequent Phase III studies of CSU. were selected for clinical trials.

[0082] BTK occupancy in blood and / or tissues is measured in clinical trials such as CSU and SjS studies. It has been reported that IFN-γ is a suitable biomarker for selecting the dose for Brochure No. 2020 / 234782 and Brochure No. 2020 / 234781 Let).

[0083] Furthermore, BTK occupancy and persistence of BTK occupancy were significantly increased in the blood and various tissues of female rats. It has been reported that the results differ depending on the patient (International Publication No. WO 2020 / 234781). .

[0084] BTK occupancy in different tissues may influence efficacy in different indications and optimal dose selection. However, all tissues relevant to HS indications and therefore to the treatment or management of HS are There is currently no consensus on the tissues that need to be infiltrated to prevent infection. As reported in the study, BTK occupancy and BTK half-life were observed in blood and various It varies in organizations.

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

[0086] BTK inhibitors may act or intervene through three basic mechanisms or pathways of action: 1) Attenuation of FcεR1-mediated allergic / type I hypersensitivity, 2) B cell autoreactivity / inflammation or type 3 hypersensitivity via FcγR and / or BCR Inhibition of cell autoreactivity and immune complexes, 3) Inhibition of autoantibody secretion in BCR-mediated autoantibody pathology or type 2 hypersensitivity.

[0087] Without being bound by theory, BTK inhibition is associated with the latter two pathways, which may HS is associated with B cell activity (Rumberger et al. 2020, Gudjonsson et al.) and the presence of autoantibodies. This is because (Byrd et al (2018), J. Dermatol.; 179 ( 3):792-794, (2019),Camona-Rivera et al.(2 021)J Invest Dermatol.Oct 1:S0022-202X(2 1)02286-7.doi:10.1016 / j.jid.2021.07.187) B cells and plasma cells are found in tertiary lymphoid organs in diseased tissue. BTK turnover -potentially in B cells located in tertiary lymphoid organs in HS lesions compared with cutaneous mast cells High and sufficient target tissue penetration is achieved by fibrous tissue remodeling and the removal of abscesses and fistulas (f istula tract), which is more difficult to achieve at HS compared to CSU. It can be difficult.

[0088] On the other hand, CSU is a marker of immune response, as demonstrated by the activity of anti-IgE antibodies (mediated by FcεR1). This is likely to be particularly dependent on the pathway first described above, and therefore may be a clinically relevant factor in HS. Responses are not predicted with the CSU dose or any doses disclosed for other indications. This sometimes happens.

[0089] Therefore, without being bound by any theory, the therapeutic or prophylactic effects of HS The effective dose of LOU064 for this purpose is potentially higher BTK turnover, which reduces inflammation. This dose allows for higher tissue concentrations in the resulting partially fibrotic HS lesions.

[0090] Pharmaceutical compositions for use in the methods of the present invention BTK inhibitors, i.e., compounds of formula (I), or pharmaceutically acceptable salts thereof, are available from the pharmaceutical When combined with a physiologically acceptable carrier, it can be used as a pharmaceutical composition. The compositions may contain, in addition to the compound of formula (I) or a pharmaceutically acceptable salt thereof, carriers, various diluents, agents, bulking agents, salts, buffers, stabilizers, solubilizers, and other materials known in the art. The characteristics of the carrier will depend on the route of administration. The pharmaceutical composition 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 or antipruritic agent. The agent may produce a synergistic effect with the compound of formula (I) or a pharmaceutically acceptable salt thereof, or minimizes the side effects caused by the compound of formula (I) or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the disclosed method The pharmaceutical composition for use in the method may be administered in a daily dose of about 50 mg to 200 mg, e.g., 2 5 mg bid, or 100 mg bid of the compound of formula (I) or a pharmaceutically acceptable salt thereof Contains salt.

[0091] Suitable compositions for oral administration include tablets, lozenges, aqueous or oily suspensions, dispersible powders, and the like. tablets or granules, emulsions, hard or soft capsules, or syrups or elixirs Compositions intended for oral administration contain an effective amount of a compound of the present invention in the form of a pharmaceutical preparation. It may be prepared according to any method known in the art for the manufacture of compositions, and such Such compositions may contain sweeteners, flavoring agents, and / or other additives to provide a pharmaceutically elegant and palatable formulation. The tablet may contain one or more agents selected from the group consisting of an anti-inflammatory agent, a coloring agent, and a preservative. The active ingredient may be in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients include, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, inert diluents such as calcium or sodium phosphate; granulating and disintegrating agents, e.g., thiamin; starch, or alginic acid; binders, such as starch, gelatin or acacia and lubricants, such as magnesium stearate, stearic acid, or talc. The agent is uncoated or coated to delay disintegration and absorption in the gastrointestinal tract, thereby , coated by known techniques to provide sustained activity over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate Oral formulations may be prepared by dissolving the active ingredient in an inert solid diluent, such as calcium carbonate. as hard gelatin capsules mixed with sodium, calcium phosphate or kaolin; The active ingredient is dissolved in water or an oil medium, such as peanut oil, liquid paraffin, or olive oil. It may be provided as a soft gelatin capsule mixed with oil.

[0092] Pharmaceutical compositions for use in the disclosed methods can be prepared in conventional manner. In embodiments, the pharmaceutical composition is provided for oral administration. For example, the pharmaceutical composition comprises: a) diluents, such as lactose, dextrose, sucrose, mannitol, sol Vitol, cellulose and / or glycine; b) lubricants, such as silica, talcum, stearic acid, its magnesium or calcium ammonium salts and / or polyethylene glycol; and for tablets c) binders, such as magnesium aluminum silicate, starch paste, gelatin Chin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or or polyvinylpyrrolidone; as needed d) disintegrating agents, such as starch, agar, alginic acid or its sodium salt, or granules; foaming mixture; and / or e) Absorbents, colorants, flavors and sweeteners It is a tablet or gelatin capsule containing the active ingredient together with

[0093] Thus, the pharmaceutical composition for use in the methods of the present invention comprises LOU064 and 1 and one or more pharmaceutically acceptable carriers, each of which may independently comprise a filler, a lubricant, It is selected from binders, disintegrants and glidants.

[0094] In another embodiment, a suitable pharmaceutical composition, LOU064, can be administered in any pharmaceutically acceptable form. The pharmaceutical composition may be in the form of a tablet or capsule. Tablets may be film coated or enteric coated according to methods known in the art. It can be incorporated into pharmaceutical compositions / formulations as nano- or micro-sized particles. It may also be preferable to include OU064.

[0095] When LOU064 is present in the pharmaceutical formulation in the form of nano-sized particles, the average particle size is 1 Preferably, the average particle size of LOU064 is less than 500 nm. More preferably, it may be less than 250 nm.

[0096] In a preferred embodiment, the average particle size of LOU064 is from about 50 nm to about 1000 nm. , or about 50 nm to about 750 nm, or about 60 nm to about 500 nm, or about 70 nm to about 350 nm, or about 100 nm to about 170 nm, more preferably LOU064 The average particle size is about 100 nm to about 350 nm, or about 110 nm to about 200 nm, or about It may be 120 nm to about 180 nm or about 120 nm to about 160 nm, and preferably LO The average particle size of U064 can be from about 150 nm to about 200 nm.

[0097] When LOU064 is present in the pharmaceutical formulation in the form of nano-sized particles, oral administration is preferred. Preferably, the dose is about 25 mg to about 100 mg twice a day, more preferably about 1 mg twice a day. The dose is 00mg.

[0098] When LOU064 is present in the pharmaceutical formulation in the form of micro-sized particles, the average particle size is , 1 to 5 μm, or preferably 1.0 to 1.5 μm. Preferably, LOU06 The average particle size of 4 can be 1.1 to 1.3 μm.

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

[0100] In a preferred embodiment, the polydispersity index (PI) is 0.01 to 0.5, more preferably is 0.1 to 0.2, particularly 0.12 to 0.14. A preferred particle size distribution is shown in FIG. will be done.

[0101] The average particle size above is intensity weighted. The average particle size is determined by dynamic light scattering. Preferably, the average particle size is determined by photon correlation spectroscopy (PCS). To determine the average particle size, Malvern Panalytical Ltd. (UK) )'s device "Zetasizer Nano ZS", Version 7.13 It can be used.

[0102] Preferably, the measurement is performed by wet analysis using a 0.1 mM NaCl solution in purified water (1:10). This is done as a diffusion method, where the attenuator index is 2 to 9, in particular 5. The measurement is preferably carried out at 25°C. The preferred configuration is: Cell: Disposable sizing cuvette Counting rate (kcPs): 315 Duration: 60 seconds Measurement position (mm): 4.65.

[0103] In one embodiment of the present invention, the LOU064 composition is adapted for oral administration to humans. The pharmaceutical compositions are formulated in accordance with routine procedures. The composition is a capsule or a tablet.

[0104] In one embodiment, pharmaceutical compositions / formulations for LOU064 are described herein by reference. No. 63 / 141,558 or family members thereof, which are incorporated by reference herein. (International Publication No. WO 2022 / 162513) It will be transformed.

[0105] According to the present invention, a suitable pharmaceutical composition for oral administration comprises LOU064 and a binder. nothing.

[0106] Suitable binders include polyvinylpyrrolidone-vinyl acetate copolymer, polyvinyl Ibuprofen, Hydroxypropylcellulose, Hydroxypropylmethylcellulose, Hypromellose, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose cellulose, carboxyethyl cellulose, carboxymethyl hydroxyethyl cellulose , polyethylene glycol, polyvinyl alcohol, shellac, polyvinyl alcohol- Polyethylene glycol copolymer, polyethylene-propylene glycol copolymer, or a mixture thereof. Preferably, the binder is polyvinylpyrrolidone- It is a vinyl acetate copolymer.

[0107] The weight ratio of LOU064 to binder is 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 and 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. Contains sexually active agents.

[0109] Suitable surfactants include sodium lauryl sulfate, potassium lauryl sulfate, lauryl sulfate, Ammonium lauryl sulfate, sodium lauryl ether sulfate, polysorbate, perfluoro butanesulfonate, dioctyl sulfosuccinate, or a mixture thereof. Preferably, the surfactant is sodium lauryl sulfate.

[0110] The weight ratio of LOU064, binder and surfactant is about 2:1:0.5, or about 2: 1:0.1, or about 2:1:0.08, or about 2:1:0.05, or about 2:1:0.0 4, or about 2:1:0.03, or about 2:1:0.02. Preferably, LOU06 4. The weight ratio of binder to surfactant is about 2:1:0.08 or about 1:1:0.05 is.

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

[0112] Treatment of HS with LOU064 or its pharmaceutically acceptable salts or crystalline forms thereof Or methods of prevention. For use in treating or preventing HS in a subject in need thereof, and LOU064 or a pharmaceutically acceptable salt thereof are disclosed herein as therapeutic The method includes administering to a subject an effective dose of LOU064 or a pharmaceutically acceptable salt thereof. LOU064 or a pharmaceutically acceptable salt thereof for use in the disclosed methods may be administered intravenously or intramuscularly. It can be used in vitro, ex vivo, or incorporated into pharmaceutical compositions, and administered to HS patients (e.g. The compounds may be administered in vivo to treat a patient (eg, a human patient).

[0113] Suitable dosages can be determined, for example, by administering a particular pharmaceutically acceptable salt of LOU064, LOU064 The specific polymorphic form of the compound, the patient's weight, the method of administration, the pharmaceutical composition, and the nature and function of the condition being treated. The severity of the condition will vary depending on the nature of the previous treatments the subject has received. The attending healthcare professional will determine the amount of LOU064 with which to treat each individual subject. In one embodiment, the attending healthcare professional administers a low dose of LOU064 and the subject The reaction can be observed.

[0114] In one embodiment of the present disclosure, LOU064 or a pharmaceutically acceptable salt thereof is administered at a dose of about 100 mg / day. It is administered orally in doses of 50 mg to approximately 200 mg.

[0115] In one embodiment of the present disclosure, LOU064 or a pharmaceutically acceptable salt thereof is administered twice a day. Approximately 25 mg twice a day to approximately 100 mg twice a day, e.g., approximately 25 mg twice a day (BID), approximately 5 It is administered orally at a dose of 0 mg BID or about 100 mg BID.

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

[0117] In another embodiment, LOU064 is administered orally at a dose of about 100 mg twice daily. do.

[0118] The duration of treatment using the pharmaceutical compositions of the present disclosure will depend on the severity of the disease or disorder being treated and the individual It will vary depending on the condition and personal response of each individual subject. , the subject may be administered for a short period of time, e.g., up to 1 week, e.g., up to 2 weeks, e.g., up to 4 weeks, For example, LOU for up to 12 weeks, for example, for up to 16 weeks, for example, for up to 24 weeks He is given 064.

[0119] In certain other embodiments, the subject preferably receives LOU064 for an extended period of time. administered (e.g., LOU064) for as long as the disease is present to justify its use. For example, for at least 6 months, for example, 1 year, 2 years, 3 years, 4 years, 10 years or more LOU064 or its pharmaceutically acceptable salts may be used indefinitely for the entire duration of the study. It may be used for 5 years, 10 years, 15 years, 20 years, or for life. In some embodiments, treatment with LOU064 according to the present invention is a chronic treatment.

[0120] HS primarily affects the skin in the axillary, groin, submammary, anogenital, and perineal areas of the body. It is a chronic inflammatory scarring condition affecting the skin. It is also called acne inversa. The diagnostic criteria establish the diagnosis of HS: typical lesions (deep, painful ulcers in the initial primary lesion) Nodules (occult) or abscesses, draining sinuses, bridging scars, and "tombstone" openings in secondary lesions comedones); typical topography (axillary, groin, genital, perineal and perianal areas, buttocks) and infra- and intermammary areas; and chronic and recurrent (Margesson and Danby(2014)Best Practices and Res.Clin. Ob. And Gyn 28:1013-1027). The physical severity of HS is shown in the table below. The Hurley clinical staging system, shown in Figure 1, can be used to classify the disease:

[0121] [Table 1]

[0122] HS consists of follicular plugging, ductal disruption, and secondary inflammation. Patients first experience a blocked follicular duct. This causes ductal leakage and horizontal tears into the dermis over time. If repair of the pilosebaceous gland (FPSB) fails, hair follicle fragments may form, initiating the HS disease process. The first response is the inflammatory response triggered by the innate immune system. , causing suppuration and tissue destruction, resulting in a foreign body reaction and extensive scarring. This results in an epithelial-lined sinus, which survives the destruction caused by the inflammatory response. Third, they may arise from stem cells derived from the damaged FPSB units. In most cases, an invasive proliferative gelatinous mass occurs, covered by the epithelium described above. It is hypothesized that this is a precursor of the elements mentioned above (Margesson and Danby (2014) As used herein, the phrase "slowing HS disease progression" means , slowing the rate of progression of any of the above-mentioned aspects of the HS disease process, particularly the inflammatory response. In certain embodiments of the present disclosure, treatment with LOU064 slows HS disease progression. Delay the line.

[0123] Recurrence of HS in patients may be characterized by papules, pustules or inflammatory nodules, pain and itching, abscesses, pus drainage, and any combination thereof. As used herein, "HS erythema" (etc.) are abscess and inflammatory nodule counts with minimal increase in the two ANs compared to baseline Defined as at least a 25% increase in (AN).

[0124] In certain embodiments of the present disclosure, treatment according to the disclosed methods with LOU064 is Preventing S erythema, reducing the severity of HS erythema, and / or reducing the frequency of HS erythema In one embodiment, when a population of HS patients is treated according to the disclosed methods, Less than 5%, less than 10%, less than 15%, or less than 20% experienced erythema during the first 16 weeks of treatment. arise.

[0125] As used herein, phrases such as "reducing the severity of HS erythema" mean , reducing the intensity of HS erythema, e.g., the number and / or number of abscesses and / or inflammatory nodules; or reducing the size, intensity of certain erythema components (e.g. , reducing the number, size, thickness, etc. of abscesses and / or inflammatory nodules, skin irritation (itching) (reduction of the degree of rash, pain, etc.), and / or persistence of erythema (or its components). This means reducing the amount of time spent

[0126] As used herein, phrases such as "reducing the frequency of HS erythema" refer to: Reducing the incidence of HS erythema, e.g., reducing the incidence of abscesses and / or inflammatory nodules By reducing the frequency of HS flares, patients will experience fewer The incidence of erythema was monitored over time, and the incidence of erythema decreased. This can be evaluated by determining whether

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

[0128] The effectiveness of HS treatment can be assessed by various known methods and methods for measuring HS pathology and / or HS clinical response. Some examples include the Hurley staging system. , Severity Assessment Scoring System (SAHS), Sartorius score, modified Sa rtorius score, HS Physician Global Assessment (HS-PGA) score, skin-related pain or Visual analog scale (VAS) or numeric rating scale (N) to assess skin pruritus RS), Dermatology Life Quality Index (DLQI), HS clinical score based on the sum of abscesses and inflammatory nodules. Bed reaction (HiSCR: HiSCR50, HiSCR75 or HiSCR90), simplified H iSCR, EuroQuol-5D (EQ5D), Hospital Anxiety and Depression Scale, Medical Resource Utilization , Hidradenitis Suppurativa Severity Index (HSSI), Work Productivity Index (WPI), Inflammed Body Surface Area (B Acne Severity Index (SA), and Acne Inverse Severity Index (AISI) (e.g., Deckers and Prens(2016)Drugs 76:215-229;Sartori us et al.(2009)Br.J.Dermatol 161:831-39; Chiricozzi et al. (2015) Wounds 27(10):258 In one embodiment, the efficacy of the methods of the present invention disclosed herein is HS Physician Global Assessment (HS-PGA), Severity Assessment Scoring Score (SAHS), Numerical Rating Scale (NRS) score (itch or pain), Dermatology Quality of Life Index (DL QI), HS clinical response (HiSCR, i.e., Hi SCR50, HiSCR75 or HiSCR90), and / or simplified HiSCR Preferably, the effectiveness of the HS treatments disclosed herein can be assessed by the following: abscess and HS clinical response based on the sum of inflammatory nodules (HiSCR, i.e., HiSCR50, Hi can be assessed by HiSCR75 or HiSCR90), and / or simplified HiSCR. do.

[0129] In one embodiment, the HS patient achieves HiSCR in response to the HS treatment. In embodiments, a population of HS patients treated according to the disclosed methods may experience at least At least 30%, at least 40%, at least 50%, at least 60% or at least 7 0% had the following by week 16: -HiSCR50; -HiSCR75; -HiSCR90; or - Simplified HiSCR (sHiSCR); preferably, 2HiSCR Achieve at least one of the following.

[0130] In other embodiments, the efficacy of the HS treatments disclosed herein continues through week 16 of treatment. The proportion of responders (i.e., H) in treated patients at In response to S treatment, HiSCR response (HiSCR, i.e., HiSCR50, HiSCR Patients achieving a 75, HiSCR90 or sHiSCR response) and placebo-treated patients In some embodiments, the difference between the percentage of patients who respond to the treatment and the percentage of patients who respond to the treatment can be measured. HiSCR (HiSCR50, HiSCR75, HiSCR90 or sHiSCR) This difference in the proportion of responders measured by , at least 30% or at least 35%.

[0131] The preferred scoring system for treatment response is HiSCR (HiSCR50, HiSCR75 or HiSCR90), simplified HiSCR, pain or pruritus NRS (e.g. For example, pain NRS30 or skin pruritus NRS30), severity assessment scoring system (SA HS), HS-PGA, number of inflammatory lesions (number of abscesses, inflammatory nodules, and / or draining fistulas), I SH4 and DLQI.

[0132] The Hidradenitis Suppurativa Clinical Response (HiSCR) is a measure of clinical response to HS treatment. The HiSCR50 response to treatment (compared to baseline) was: ) at least a 50% reduction in abscesses and inflammatory nodules (AN50), and 2) an increase in the number of abscesses none, and 3) no increase in the number of draining fistulas.

[0133] In one embodiment, the HS patient achieves HiSCR50 in response to the HS treatment.

[0134] In one embodiment, 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% are cured Achieve HiSCR50 by week 16 of treatment.

[0135] As used herein, "simplified HiSCR" or "sHiSCR" refers to a method for detecting a lesion. Refers to the modified HiSCR that does not include abscess counts relative to baseline when assessing progression In a preferred embodiment, the HS patient achieves simplified HiSCR in response to HS treatment. In one embodiment, a population of HS patients is treated according to the disclosed methods. In this case, at least 40%, at least 50%, at least 60%, or at least 70% , achieving simplified HiSCR by week 16 of treatment.

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

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

[0138] In a preferred embodiment, the HS patient has HiSCR75 or Hi Achieve SCR90.

[0139] In one embodiment, 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% are cured Achieve HiSCR75 by week 16 of treatment.

[0140] In one embodiment, 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% are cured Achieve HiSCR90 by week 16 of treatment.

[0141] Pain may be assessed using a numeric rating scale (NRS). HS patients achieve improved pain NRS in response to HS treatment. Pain NRS30 is at least 30% reduction in pain and baseline score of 3 or greater A small decrease from baseline in the Patient Global Assessment (PGA) of cutaneous pain was observed In one embodiment, the HS patient is treated with HS. In one embodiment, a population of HS patients responds to the disclosed At least 25%, at least 30%, at least 40% when treated according to the method , at least 50%, or at least 60% achieve NRS30 by week 16 of treatment In a preferred aspect of this embodiment, a population of HS patients is treated according to the disclosed methods. When treated with CIRR, at least 30% achieve an NRS30 by week 16 of treatment. In certain embodiments, in response to treatment according to the claimed methods, the patient receives When measured by VAS or NRS, preferably NRS, about one or two weeks after , resulting in pain relief.

[0142] The severity assessment scoring system (SAHS) was developed by Hassam et al. A Dermatol (2018), 154(3):330-335. The severity of HS can be assessed by the SAHS score, which examines the following: Number of affected areas (left axilla, right axilla, left submammary, right submammary, intermammary or chest, abdomen, pubic area) Mons, left groin, right groin, genitals, perianal or perineal area, left buttock, right buttock, and other [ e.g., neck, postauricular]), number of inflammatory and / or painful lesions other than fistulas (ILOF) These physician-assessed items were compared with the two patient-reported items. The questionnaire was completed by: Patients were asked to report the number of new tumors or the spread of existing tumors during the past 4 weeks. The patient was asked about the number of tumors and whether they were present during daily activities (e.g., sitting, moving, or working). To assess the current severity of pain in the most symptomatic lesion on a numerical rating scale (NRS). The SAHS score is a composite score of all the above collected information. Mild cases of S are defined by an SAHS score of 4 or less. Moderate S is defined by an SAHS score of 5-8. Severe cases of HS are defined by a SASH score of 9 or more. will be done.

[0143] In one embodiment, the HS patient has an improved SAHS score in response to the HS treatment. In one embodiment, the HS patient achieves a SAHS score of 0.05 in response to the HS treatment. In other embodiments, at least a 1 point reduction from baseline is achieved. HS patients are expected to respond to HS treatment by achieving an improvement in SAHS score of at least 2 from baseline. Achieve a point reduction or at least a 3-point reduction in SAHS score. A score of at least 4 was present at baseline before treatment with LOU064.

[0144] The International Hidradenitis Suppurativa Severity Scoring System (IHS4) has been used in clinical trials or real-life conditions. The Zou is a clinically established tool for dynamically assessing HS severity that can be used boulis et al.(2017);Br.J.Dermatol.;177(5 ):1401-9.) The severity of HS according to this measure is determined by the individual H according to this scheme. S is assessed by summing the lesions: Number of nodules × 1+ Number of abscesses x 2+ Number of drainage channels (fistulas / sinuses) x 4

[0145] The severity of HS is then defined as: Mild HS: ≦3 points Moderate HS: 4 to 10 points Severe HS: ≥ 11 points

[0146] The definition of HS lesions is as follows: nodules (inflammatory nodules) >10 mm in diameter; Abscesses are raised, three-dimensional, round, infiltrated lesions with a globular structure. A soft, fluctuant mass, >10 mm in diameter, containing pus in the center of the abscess The drainage tract is a raised, soft, fluctuant longitudinal mass of variable length and depth. They may terminate at the skin surface and leak fluid. Fistulas and sinuses are examples of drainage channels. .

[0147] In one embodiment, the HS patient has an improved (i.e., lowered) IHS4 score. Achieve.

[0148] In one embodiment, the HS patient responds to the HS treatment by improving the baseline IHS4 score. In another embodiment, patients with HS achieve a reduction of at least 2 points from baseline. Response to HS treatment is associated with an increase in IHS4 score of at least 3 points from baseline Achieve a reduction in saturation or at least a 4-point reduction.

[0149] The DLQI is the most established dermatological quality of life measure. It measures the It consists of questions about skin conditions related to emotions and various aspects of daily life activities. Scores are given from 0 (not at all) to 3 (very much). A total of 30 points are awarded. A score is calculated based on the patient's life, where 0-1 indicates no impact, and 2-5 indicates minimal impact. 6-10 is moderate impact, 11-20 is very large, and 21-30 is extremely large impact. (Finlay and Khan (1994) Clin Exp Der In one embodiment, the HS patient is treated with Achieve improved DLQI in response to treatment.

[0150] In certain embodiments, in response to treatment according to the claimed methods, the patient may experience a decrease in blood cholesterol levels after the first dose. Approximately one or two weeks after administration, standard CRP assay or high-sensitivity CRP (hsCRP) assay As used herein, "c-reactive protein" refers to a reduction in CRP as measured by a CRP assay. "C-reactive protein" and "CRP" are serum C-reactive protein, i.e., a protein that responds to inflammation. CRP in plasma is a plasma protein commonly used as an indicator of the acute phase response to blood clots. The level of CRP can be expressed as any concentration, e.g., mg / dl, nmol / L. Bell has performed a variety of standard assays, e.g., radial immunodiffusion, electroimmunoassay, immunoassay, Immunoturbidimetry, ELISA, turbidimetry, fluorescence polarization immunoassay, and laser nephelometry Tests for CRP can be performed using standard CRP tests or high-sensitivity CRP ( hs-CRP) test (i.e., using laser nephelometry to detect low levels of CRP in a sample) A highly sensitive test capable of measuring CRP can be used to detect CRP levels. The kits are available from various companies, such as Calbiotech, Inc., Cayman Ch. chemical, Roche Diagnostics Corporation, Aba zyme, DADE Behring, Abnova Corporation, Ani ara Corporation, Bio-Quant Inc., Siemens H It can be purchased from Healthcare Diagnostics, etc.

[0151] The Sartorius HS score (also called the HS score or HSS) is a measure of the risk of HS patients. It is calculated by counting the lesion area, nodules, and fistulas in the patient (Sartor ius et al. (2003) Br J Dermatol 149:211-13 The modified Sartorius HS score has some simplifications that make it more practical to use, e.g. For example, fewer specific lesions may be included in the score, and points may be awarded for each parameter. This is a modified version of the original HSS by changing the number of rius et al.(2009)Br.J Dermatol.161:831-8 39). In one embodiment, HS patients have improved modified SAR in response to HS treatment. Achieve torius HS.

[0152] The HS Physician Global Assessment (HS-PGA) is a holistic assessment of HS lesions (i.e., abscesses, draining fistulas, inflammatory A 6-point rating scale (scores range from 0 to 5) based on the number of nodules (inflammatory nodules, and non-inflammatory nodules) (Kimball AB, Kerdel F, Adams D et al Adalimumab for the treatment of moderators ate to severe hidradenitis suppurativa:a parallel randomized trial.Ann Intern Me In one embodiment, the HS patient is treated with In one embodiment, HS patients achieve improved HS-PGA in response to the treatment. An increase in HS-PGA score of at least 2 points from baseline in response to HS treatment Preferably, the HS-PGA score is, prior to treatment with LOU064, was at least 3 at baseline.

[0153] In one embodiment, when a population of HS patients is treated according to the disclosed methods, Patients who responded to treatment by week 16 (e.g., HiSCR by week 16 (e.g., HiS Patients who achieve CR50; HiSCR75 or HiSCR90) or simplified HiSCR At least 40%, at least 50%, at least 60%, at least 70%, At least 80% or at least 90% are still alive 3 months after the end of treatment or 6 months after the end of treatment In another aspect of this embodiment, the response was sustained 12 months after the end of treatment or 12 months after the end of treatment. Patients who responded to treatment by week 16 (e.g., HiSCR by week 16 (e.g., HiSCR50; HiSCR75 or HiSCR90) or simplified HiSCR At least 40% of patients (those who complete the treatment) or at least 50% of patients 3 months after the end of treatment Preferably, patients who responded to treatment by week 16 (e.g., week 16) HiSCR (e.g., HiSCR50; HiSCR75; or HiSCR90) At least 70% of patients achieving a CR or simplified HiSCR were at least 70% 3 months after the end of treatment. As used herein, the term "sustained" refers to an outcome. or the goal (e.g., pain relief, inflammation reduction) is substantially maintained over a given period of time. This means that...

[0154] Lesion-associated pruritus can be assessed by patient survey. Patients are asked to rate lesion-associated pruritus from 0 (no pruritus) to 1 (no pruritus). Patients are asked to rate the itching sensation on a scale of 10 (no itching) to 10 (worse itching than one could imagine). When a population of HS patients is treated according to the disclosed methods, the pruritus score is The improvement is at least 2 points, preferably at least 3 points. When compared with the placebo group, the difference between the treatment and placebo groups is at least 1 point.

[0155] Lesion-related pruritus can also be assessed by the Pruritus Numerical Scale (NRS). reported by the majority of HS patients (Fernandez et al. (2021) I tch and pain by lesion morphology in hid radenitis suppurativa patients.Int J Der matol.;60(2):e56-e59). The NRS allows respondents to assess their skin disease-related Subjects were asked to select the integer (0 to 10 on an 11-point scale) that best reflected the intensity of the itch. It is a segmented numeric version of the visual analog scale (VAS) (Nguy en et al.(2021),.J Eur Acad Dermatol Ven ereol.2021 Jan;35(1):50-61). In one embodiment, H S patients achieve improved skin NRS in response to HS treatment. Pruritus NRS30 is In some embodiments, the reduction in skin irritation is defined as at least a 30% reduction in skin irritation from the skin line. In one embodiment, the HS patient achieves a skin NRS30 in response to HS treatment. and a population of HS patients treated according to the disclosed methods shows at least 25% At least 30%, at least 40%, at least 50%, or at least 60% are cured Achieve a 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 methods, at least 30% experience a reduction in the severity of the disease after treatment. In one embodiment, the claimed subject In response to standard treatment, patients reported a significant improvement in skin NRS scores as early as one or two weeks after the first dose. This results in a reduction in skin itching as measured by

[0156] The odor caused by the drainage of the lesion can be assessed by patient survey. The odor caused by the drainage of the lesion was rated as 1 (no odor), 2 (slight odor), or 3 (moderate odor). Participants are asked to rate the odor on a scale of 4 (slight odor) to 4 (extreme odor). Thus, when a population of HS patients is treated according to the disclosed methods, the pruritus scores are at least Both the placebo group and the control group will improve by 1 point, preferably by at least 2 points. When compared, the difference between the treatment and placebo groups is at least 1 point.

[0157] The impact of HS on the ability to complete tasks can be assessed by patient surveys. Patients were asked to rate the extent to which HS affected their ability to complete tasks on a scale from 1 (not at all) to 2 ( 3 (a little), 4 (moderately), 5 (a lot) to 6 (completely unable to work) In one embodiment, a population of HS patients is treated according to the disclosed methods. If the pruritus score is improved by at least 1 point, preferably by at least 2 points, Furthermore, when compared with the placebo group, the difference between the treatment and placebo groups is at least is also worth 1 point.

[0158] safety Up to 600 mg single dose and up to 100 mg bi for up to 18 days d. The short-term safety of LOU064 was demonstrated in a Phase I clinical trial. However, data related to long-term safety (i.e., beyond 52 weeks) are not currently available. .

[0159] Dose-limiting effects observed with the covalent irreversible BTK inhibitors evobrutinib and trebrutinib Considering the limited side effects, evobrutinib was administered at a dose of 75 mg bi- d. dose already showed dose-limiting liver enzyme elevations, and trebrutinib 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 PFet al.,2 019,ACTRIMS Forum,Feb 28,2019,P072), these A significant increase in the incidence of adverse events was observed with 100 mg bilirubin over a long period (up to 52 weeks). It is encouraging that this was not seen with LOU064 even at high doses of .d. U064 is effective at a dose of 100 mg bid for extended periods (up to 52 weeks). It does not induce any dose-limiting liver enzyme elevations or other off-target effects. U064 is suitable for long-term treatment.

[0160] Therefore, one object of the present invention is to provide LOU064 for use in the methods described. wherein the alanine aminotransferase is administered for up to 12 weeks, up to 24 weeks, or up to 52 weeks of treatment. ALT, aspartate aminotransferase (AST), and The levels of riboflavin did not change by more than 10% compared with the baseline level at the start of treatment. do not have.

[0161] Therefore, LOU064 not only effectively treats HS, but also has the potential to significantly improve long-term survival, particularly in patients with HS. When maintained over a prolonged period, the efficacy of acalabrutinib is particularly strong compared to other BTK inhibitors. It was particularly surprising that it also had a better safety profile compared to other drugs. Additionally, BTK inhibitors currently approved for the treatment of hematological malignancies (ibrutinib, acanthosis nigricans) Labrutinib, and zanubrutinib) have known safety issues. These include infections, effects on platelet function (risk of bleeding), and cytopenias. Other safety concerns with one or more of the approved BTKs include cardiac arrest and arrhythmias (atrial fibrillation and flutter) and, for ibrutinib only, heart failure and hypertension. can be done.

[0162] Therefore, in a preferred embodiment of the present invention, a method for treating HS is provided. LOU064 or a pharmaceutically acceptable salt thereof is used for long-term treatment. The term "prolonged use" refers to the use of LOU064 or a pharmaceutically acceptable salt thereof over an extended period of time. For example, LOU064 or a pharmaceutically acceptable salt thereof may be administered for 6 months, 10 months, or May be used safely for months, 1 year, 2 years, 3 years, 4 years, or over 10 years. U064 or its pharmaceutically acceptable salts are administered for up to 2, 5, 10, or 15 years. , 20 years or for life.

[0163] In one embodiment, LOU064 not only effectively treats HS but also has the following characteristics: Signs: - no clinically relevant increase in risk of infection, - No clinically relevant increase in major bleeding, - No clinically relevant elevations in liver enzymes and have a safety profile that includes one or more of the following: .

[0164] combination: Pharmaceutical compositions for use in the disclosed methods include those for the treatment of specific targeted disorders. For example, the pharmaceutical composition may also include an anti-inflammatory agent. These additional factors and / or agents may produce a synergistic effect with LOU064 as described herein. To achieve this, it may be included in a pharmaceutical composition.

[0165] A variety of therapies may be beneficially combined with LOU064 in the treatment of HS.

[0166] Thus, LOU064 may be administered simultaneously with, before, or after one or more other therapeutic agents. LOU064 for use in the methods of the present invention may be administered in the same or different doses. They may be administered separately by route of administration or together in the same pharmaceutical composition as other drugs.

[0167] In one embodiment, the present invention provides a method for treating or preventing HS in a subject, comprising: , as a combined preparation for simultaneous, separate or sequential use in therapy; Administering a therapeutically effective dose of LOU064 and at least one other therapeutic agent to the subject. Optionally, the pharmaceutical composition for use in the method of the present invention comprises the steps of: The composition may contain pharmaceutically acceptable excipients so as to be

[0168] Products provided as combined preparations for use in the methods of the present invention may be used in combination with other pharmaceuticals containing the same pharmaceutical agent. LOU064 and other therapeutic agents may be included together in a pharmaceutical composition or in separate forms, e.g., a kit. The present invention also includes compositions containing LOU064 and other therapeutic agents in the form of a pharmaceutical composition.

[0169] In one embodiment, the present invention provides a pharmaceutical composition comprising two or more separate pharmaceutical compositions, at least one of which one containing LOU064 or a pharmaceutically acceptable salt thereof). In one embodiment, the kit comprises a container, a divided It includes a means for separately holding the compositions, such as a bottle or a disassembled foil packet. An example of such a kit is a packaging material, such as is typically used for packaging tablets, capsules and the like. It's a lister pack.

[0170] The kit of the present invention may be used to administer the separate compositions at different dosing intervals or to administer the separate compositions. For example, to administer different oral and parenteral dosage forms, To aid in compliance, the kits of the invention typically include administration instructions. nothing.

[0171] In the combination therapy of the present invention, LOU064 and the other therapeutic agent may be from the same or different manufacturers. Additionally, LOU064 and other therapeutic agents may be manufactured and / or formulated by i) Prior to release of a combination product to a physician (e.g., a compound for use in a method of the invention) and kits containing other therapeutic agents; (ii) by the physician (or under the physician's direction) immediately prior to administration. (iii) by the patient themselves, for example, during continuous administration of LOU064 and other therapeutic agents, They may be combined into a combination therapy.

[0172] Thus, the present invention provides a method for treating or preventing HS using LOU064 or a pharmaceutical formulation thereof. and the use of a salt thereof which is acceptable for the treatment of a rhodium-containing ... 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 compound thereof for use in a method for treating or preventing HS. Pharmaceutically acceptable salts are provided, wherein the compounds are suitable for administration with another therapeutic agent. The present invention also provides other therapeutic agents for use in methods of treating or preventing HS. wherein the other therapeutic agent is administered together with LOU064 or a pharmaceutically acceptable salt thereof. It is prepared to be given.

[0174] The present invention also provides LOU064 or a compound thereof for use in a method for treating or preventing HS. Pharmaceutically acceptable salts are provided wherein the compound is administered in conjunction with another therapeutic agent. The present invention also provides additional therapeutic agents for use in methods of treating or preventing HS, and the other therapeutic agent is administered together with LOU064 or a pharmaceutically acceptable salt thereof.

[0175] The present invention also provides a method for treating and / or preventing HS in a patient in need thereof. and / or preventing the use of LOU064 or a pharmaceutically acceptable salt thereof, Here, the patient has been previously treated (e.g., within 24 hours) with another therapeutic agent. Ming also describes the use of other therapeutic agents to treat or prevent HS in patients in need thereof. wherein the patient has not previously received LOU064 or a pharmaceutically acceptable salt thereof (e.g., If so, they are treated within 24 hours.

[0176] Such combination treatments include topical treatments (creams [non-steroidal or steroidal], cleaning agents, disinfectants), systemic treatment (e.g., with biologicals, antibiotics, or chemicals), digestive These include toxic drugs, photodynamic therapy, and surgical intervention (laser, drainage or incision, excision).

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

[0178] Non-limiting examples of topical HS agents for use with LOU064 include benzo peroxide. topical steroid creams, topical aminoglycoside antibiotics, e.g., Clinda Mycobacterium erythromycin, gentamicin, and erythromycin, resorcinol cream, iodine supplements Club, and chlorhexidine.

[0179] Non-limiting examples of HS agents used in systemic therapy for use with LOU064 include: IL-17 antagonists (ixekizumab, brodalumab, secukinumab CJM1 12), as well as IL17A / F antagonists (e.g., bimekizumab) or IL17C antagonists. agonists (e.g., MOR106), tumor necrosis factor-α (TNF-α) blockers (Enbre l® (etanercept), Humira® (adalimumab), Re micade® (infliximab) and Simponi® (golpidem) temafibrate), interleukin 12 / 23 blockers (Stelara® (U) sutekinumab), tasocitinib, and briakinumab), IL-23 blockers (gcel p19 inhibitors, PDE4 inhibitors, e.g., cumab, tildrakizumab, and risankizumab For example, apremilast or Otezla®, or other such drugs such as roflumilast others), complement pathway inhibitors, such as factor B inhibitors (e.g., WO 2015 / 00961 The compounds disclosed in Pamphlet No. 6, or 4-((2S,4S)-4-ethoxy-1- ((5-methoxy-7-methyl)-1H-indol-4-yl)methyl)piperidine- 2-yl)benzoic acid (also known as LNP023), C5a inhibitor (IFX-00 1 or CCX168, also known as vilobelimab or Avacopan, or BDB001, etc.), IL-1 antagonists (canakinumab, gevokizumab, rilonase puto, anakinra, or bermekimab), or bispecific antibodies, such as MAS825 or rutikizumab (IL-1b and IL-1a), an inflammasome inhibitor, e.g. NLRP3 and NLRP5 inhibitors, CXCR1 / 2 inhibitors, IL-18 antagonists, IL-6 antagonist, IL-36 antagonist, CD20 antagonist, CTL A4 antagonists, IL-8 antagonists, B cell depletors (especially CD20 antagonists) rituximab, and BAFF-R, such as ianalumab, and CD40 antagonists, such as iscalimab (CFZ533), IL-21 antagonists, IL-22 antagonist, IL-36 or IL-36R antagonist, GCSF inhibitor agents, VEGF antagonists, CXCL antagonists, MK-2 inhibitors, e.g., Zunse Metinib, IRAK4 inhibitors or IRAK4 degraders (SAR44656, etc.), LTA4 H inhibitors, S1P inhibitors, BTK inhibitors, SYK inhibitors, e.g., fostamatinib, MM P antagonists, and defensin antagonists (e.g., receptor decoys, antagonists) and oral broad-spectrum JAK inhibitors (pan-JAKi) or more specific TY JAK2 or JAK 1, JAK2 or JAK 3 inhibitors (more specific / selective) Selective JAK / TYK inhibitors include, for example, allosteric inhibitors, such as Duclase vasitinib (deucrayacitinib) or catalytic inhibitors).

[0180] As an additional HS agent for use in combination with LOU064 in the treatment of HS retinoids, such as acitretin (e.g., Soriatane®) and Isotretinoin, immune system suppressants (e.g., rapamycin), T-cell blockers [e.g., Am evive® (alefacept) and Raptiva® [efali izumab]) cyclosporine, methotrexate, mycophenolate mofetil, mycofe hydroxyurea (e.g., Hydre a (registered trademark), sulfasalazine, 6-thioguanine, fumarate (e.g., fumarate dimethyl fumarate and fumarate), azathioprine, colchicine, alitretinoin, Steroids, corticosteroids, certolizumab, mometasone, rosiglitazone, pioglitazone Glitazones, botulinum toxin, triamcinolone, IFX-1 (InflaRx), LY -3041658(Eli Lilly), TE-2232(Immunwork), N SAIDs, COX inhibitors, prescription narcotics, ketoprofen, codeine, gabapentin, Pregabalin, gentanyl, antibiotics (topical, oral, IV) )) (e.g., clindamycin, rifampin, tetracycline, sarecycline, Doxycycline, minocycline, lymecycline, trimethoprim-sulfamethoxazole Sasol, erythromycin, ceftriaxone, moxifloxacin, metronidazole corticosteroids (injectable or oral), antiandrogens hormone therapy (oral contraceptives, spironolactone, finasteride, dutasteride, Progesterone IUD, cyproterone acetate, ethinyl estradiol, gestodene, Lugestimate, desogestrel, drospirenone, spironolactone), triamcinolone Lonacetonide, MEDI8968, hydroxychloroquine, dapsone, metformin, These include adapalene, azelaic acid and zinc.

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

[0182] Examples of JAK inhibitors for use in combination are BMS986165, INCB05 4707, ruxolitinib, abrocitinib, tofacitinib, and baricitinib. Other examples of JAK inhibitors are described in WO 2017 / 089985, WO 2017 / 089985, WO 2017 / 089986, WO 2017 / 089987, WO 2017 / 089988, WO 2017 / 089989 ... Brochure No. 2018 / 055550 and International Publication No. 2018 / 055551 The compounds disclosed in Fret.

[0183] Those skilled in the art will understand the appropriate dosages of the above HS agents for co-delivery with LOU064. It will be possible to do this.

[0184] LOU064 oral drug exposure is associated with CYP3A inhibitors, particularly strong CYP3A inhibitors, e.g. For example, it is expected that the effects may be increased several-fold when administered with a strong CYP3A4 inhibitor. Similarly, strong inducers of CYP4A, such as CYP3A4, significantly decrease exposure. These properties of LOU064 may result in reduced efficacy of LOU064. and / or prophylaxis for any BTK-mediated pathology, as well as for the treatment of Strong CYP3A inhibitors or inducers should be administered in accordance with the FDA 2020 guidelines. Therefore, a strong CYP3A inhibitor (e.g., a CYP3A4 inhibitor) , greater than five-fold increase in area under the curve after co-administration with LOU064 compared to LOU064 administration alone Inhibitors that result in an increase in AUC or a reduction in clearance by more than 80%. YP3A inducers (e.g., strong CYP3A4 inducers) may increase L Compared to administration of OU064 alone, the AUC should be increased by 80% or more (e.g., by 85%, 90% It is an inducer that reduces the level of ATP by 95% (by 95%).

[0185] Strong CYP3A inhibitors and / or inducers, e.g., strong CYP3A4 inhibitors and / or Co-administration with an inducer may potentially cause significant changes in LOU064 drug exposure, Strong CYP3A4 inhibitors include boceprevir and clarithromycin. mycobacterium, cobicistat, conivaptan, danoprevir / ritonavir, darunavir / ritonavir Idelalisib, Elvitegravir / Ritonavir, Idelalisib, Indinavir, Indinavir / ritonavir, itraconazole, ketoconazole, LCL161, lopinavir / ritonavir vir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, Quinavir, saquinavir / ritonavir, telaprevir, telithromycin, tipranavir / Ritonavir, troleandomycin, Viekira pack and / or voriconazole CYP3A4 inhibitors are also found in grapefruit juice. It may be included.

[0186] Thus, in another preferred embodiment, LOU064 is, for example, a Concomitant administration of strong inhibitors and / or inducers of CYP3A4, as defined above It will not be done.

[0187] LOU064 significantly improved the efficacy and safety of ethinyl estra- It has further been found that the compound can be co-administered with oral contraceptives such as diazepam or levonorgestrel. Therefore, in a preferred embodiment, LOU064 is co-administered with an oral contraceptive. will be done.

[0188] As a covalent irreversible BTK inhibitor, LOU064 inhibits the production of BTK by de novo protein synthesis. It acts by irreversible inhibition of BTK, which is counteracted by the Although we do not wish to be limited by this, reconstitution of the B cell pool after B cell depletion can take several months. Although recovery of B cell function after BTK inhibition can take time, recovery is achieved soon after cessation, typically within a few days. Therefore, if necessary, this therapy can be stopped quickly. , thereby providing clinicians and patients with easier and faster diagnostics when unexpected situations arise. Gives faster reaction times.

[0189] Especially in light of the COVID-19 pandemic, B cell depleted patients may be more susceptible to infections. Furthermore, the absence of a fully functional adaptive immune response is associated with a more severe illness. It is highly likely to lead to overuse.

[0190] However, LOU064 does not result in depletion of the B cell pool, making it possible to discontinue treatment. Inhibition leads to rapid restoration of full B-cell function. This allows patients and treating physicians to Infection or vaccination requirements, in particular with live and attenuated vaccines Gives the possibility to respond quickly.

[0191] According to the present invention, LOU064 is administered during an infection, e.g., during a COVID-19 infection. Therefore, LOU064 administration should be continued during infection, e.g., COVID-19 infection. It can be done.

[0192] Preferably, LOU064 administration is continued for an active infection, e.g., COV, until the infection is resolved. Delayed in patients with ID-19.

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

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

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

[0196] Yet another embodiment of the present invention is a vaccine comprising a patient vaccinated during LOU064 treatment. Alternatively, the patient may be vaccinated against HS with a non-live vaccine. In one embodiment, patients may be vaccinated during LOU064 treatment. During LOU064 treatment (e.g., 15 days after starting LOU064 treatment), The vaccines administered are the flu vaccine, PPV-23 vaccine, or KLH neoantigen vaccine. In one embodiment, patients receiving the quadrivalent influenza vaccine have a baseline A >4-fold increase in antihemagglutinin antibody titers at 28 days post-vaccination compared with In another aspect of this embodiment, PPV-23 achieves a response as defined by Patients receiving the vaccine had a significantly higher IgG 28 days after vaccination compared to baseline In yet another embodiment, the KLH neoantigen vaccine achieves a >2-fold increase in titer. Patients receiving the vaccine will be assessed by anti-KLH IgG and IgM titers 28 days after vaccination. Achieve a T cell dependent antibody response when measured.

[0197] Another embodiment of the present invention is when LOU064 treatment is discontinued for vaccination, particularly LOU064 treatment is administered 5 to 10 days, for example 7 or 8 days, prior to vaccination, preferably , should be stopped 6 weeks before vaccination, preferably 5 to 20 days after vaccination. For the treatment of HS, the treatment is continued after 5 to 10 days, or most preferably after 10 to 15 days. In an alternative embodiment, vaccination is with a live Vaccination with a vaccine and / or an attenuated vaccine. In such cases, patients may experience a complication after discontinuing LOU064 treatment (e.g., after discontinuing LOU064 treatment). 5-10 days or 7 or 8 days after vaccination), quadrivalent influenza vaccine, PPV-23 vaccine In one aspect of this embodiment, the patient is vaccinated with a tetravalent influenza or KLH neoantigen vaccine. Patients receiving the Luenza vaccine had a significantly higher risk of developing the disease 28 days after vaccination compared to baseline. Achieve a response as defined by a >4-fold increase in antihemagglutinin antibody titer at time point In another aspect of this embodiment, the patient receiving the PPV-23 vaccine has IgG Achieve a >2-fold increase in titer 28 days after vaccination compared to baseline. In another embodiment, patients receiving the KLH neoantigen vaccine are administered within 28 days of vaccination. A T-cell dependent antibody response was achieved as measured by anti-KLH IgG and IgM titers days later. LOU064 treatment will then begin and continue 29 days after vaccination.

[0198] LOU064 or a pharmaceutically acceptable salt thereof is conveniently administered orally. The duration of oral treatment with the pharmaceutical composition will depend on the severity of the disease and condition being treated and on the individual patient. The effectiveness of the pharmaceutical compositions of the present disclosure will vary depending on the individual's response. It will also determine the appropriate duration of oral therapy and the timing of administration of the therapy. In this case, the patient is treated for at least 16 weeks, at least 24 weeks, at least 36 weeks, HS according to the claimed method for at least 48 weeks, at least 52 weeks In one embodiment, 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 comprises about For subjects weighing 50 to 70 kg, the unit dose is approximately 25 mg to approximately 100 mg of the active ingredient. The therapeutically effective dose of the compound or pharmaceutical composition may vary depending on the species, weight, age, and It depends on the individual condition and the severity of the contrast-induced nephropathy. each of the active ingredients necessary to prevent, treat, or inhibit the progression of a disorder or disease The effective amount can be readily determined.

[0200] A preferred formulation contains about 25 mg to about 100 mg of LOU064, as well as a filler, a disintegrant, a binder, and optionally one or more excipients independently selected from a lubricant and a glidant; In a preferred embodiment, the capsule or tablet The composition comprises approximately 25 mg of LOU064 or a pharmaceutically acceptable salt thereof, as well as a filler, disintegrant, or the like. one or more independently selected from a disintegrant, a binder, and optionally a lubricant and a glidant; In yet another embodiment, the capsule or tablet composition comprises about 50 mg of excipients. LOU064 or about 100 mg of LOU064 and a filler, a disintegrant, a binder, and Optionally, it includes one or more excipients independently selected from lubricants and glidants.

[0201] A method of treating hidradenitis suppurativa (HS), comprising administering to a patient in need thereof approximately 50 mg to approximately 200 mg of LOU064, or a pharmaceutically acceptable salt thereof, once daily Disclosed herein are methods comprising orally administering the dose in a once-daily dose regimen. The patient may be administered either a once-daily or twice-daily dosing regimen. The method comprises administering to a patient in need thereof a dose of about 25 mg to about 100 mg of LOU064 In a preferred aspect of this embodiment, The method comprises administering to said patient orally twice daily (BID) a dose of about 25 mg of LOU064. In another preferred aspect of this embodiment, the method comprises administering about 100 mg of The method comprises orally administering to said patient an amount of LOU064 twice daily (BID).

[0202] In a preferred embodiment of the disclosed methods, uses and kits, the patient is Hidradenitis suppurativa clinical response (HiSCR), HiSCR50, HiSCR75, HiSCR90 , Numerical Rating Scale (NRS), Hidradenitis Suppurativa-Physician Global Assessment (HS-PGA), or Skin Dermatology Life Quality Index (DLQI), Severity Assessment of HS (SASH), or International HS Severity Index Achieve a sustained response one year after treatment as measured by the Inter-Human Score System (IHS4) .

[0203] In preferred embodiments of the disclosed methods, uses and kits, the Prior to treatment with LOU064, the patient had been previously treated with systemic agents for HS. In preferred embodiments of the disclosed methods, uses and kits, the systemic agent is a topical treatment , antibiotics, immune system suppressants, TNF-α inhibitors, IL-1 antagonists, and their combinations thereof.

[0204] In certain embodiments of the disclosed methods, uses and kits, the LO described herein Prior to treatment with U064, patients were previously treated with systemic or topical medications for HS. not (i.e., patients are treatment-naïve or biologic-naïve).

[0205] In one embodiment of the disclosed methods, uses and kits, the LOUs described herein 064 (or a pharmaceutically acceptable salt thereof) is an antibiotic, a JAK inhibitor, a TYK2 inhibitor , a PDE4 inhibitor, or an immunosuppressant.

[0206] In preferred embodiments of the disclosed methods, uses and kits, The dose of LOU064 is about 25 mg to about 100 mg BID. In another preferred embodiment of the use and kit, the dose of LOU064 is about 25 mg B ID or 100mg BID.

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

[0208] As used herein, the phrase "moderate to severe" means that a patient has > 3 Active inflammatory lesions [i.e., deep-seated inflammatory lesions such as abscesses and / or inflammatory nodules] ], 15 or fewer fistulas and at least two anatomical sites must be involved in the HS lesion. This refers to HS disease.

[0209] In preferred embodiments 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 a patient with moderate to severe HS. Adults with severe HS disease.

[0210] In certain embodiments of the disclosed methods, uses and kits, the patient is an adolescent patient (1 In one embodiment, the patient is aged 2 years or older. In one embodiment, the patient is afflicted with moderate to severe HS. The patient is an adolescent.

[0211] In certain embodiments of the disclosed methods, uses and kits, the patient is He has been diagnosed with HS for many years.

[0212] In certain embodiments of the disclosed methods, uses and kits, the patient is diagnosed with HS as a result of No extensive scarring (i.e., <20 fistulas, draining or non-draining, preferably (15 or fewer fistulas).

[0213] In certain embodiments of the disclosed methods, uses and kits, the patient is treated with conventional systemic HS. had a previous inadequate response to treatment;

[0214] In a preferred embodiment of the disclosed methods, uses and kits, treatment with LOU064 Prior to treatment, patients had an HS-PGA score of ≥3.

[0215] In preferred embodiments of the disclosed methods, uses and kits, patients are treated at week 16 of treatment. Achieve (simplified) HiSCR within a short time.

[0216] In preferred embodiments of the disclosed methods, uses and kits, patients are treated at week 16 of treatment. Achieve an NRS30 (eg, pain NRS30 or skin pruritus NRS30) by the eye.

[0217] In preferred embodiments of the disclosed methods, uses and kits, patients are treated at week 16 of treatment. There is a reduction in HS erythema up to the eyes.

[0218] In preferred embodiments of the disclosed methods, uses and kits, patients are treated at week 16 of treatment. By the end of the study, a reduction of ≦6 as measured by DLQI was achieved.

[0219] In a preferred embodiment, the disclosed methods, uses or kits are used to treat moderate to severe rheumatoid arthritis. When treating a population of patients with severe HS, at least 40% of the patients receive the In response to the treatment, HiSCR (sHiSCR, HiSCR50, Achieve HiSCR75 or HiSCR90).

[0220] In another preferred embodiment, the disclosed method, use or kit is used to treat moderate When treating a population of patients with mild or severe HS, the proportion of responders (e.g., HS To the treatment, HiSCR response (sHiSCR, HiSCR50, HiSCR75 or H Patients achieving an iSCR90 response) vs. responders in placebo-treated patients The difference between the rates was at least 15%, at least 25%, or at least 15% by week 16 of treatment. At least 30%.

[0221] In preferred embodiments of the disclosed methods, uses and kits, patients are treated at week 16 of treatment. By the end of the study, there was a decrease in the modified Sartorius score.

[0222] In preferred embodiments of the disclosed methods, uses and kits, patients are treated at week 16 of treatment. There was an improvement in DLQI by the end of the study.

[0223] In a preferred embodiment, the disclosed methods, uses or kits are used to treat moderate to severe rheumatoid arthritis. When treating a population of patients with severe HS, at least 25% (preferably at least 30%) respond to said administration step by 16 weeks of treatment with an NRS3 Achieve 0.

[0224] In a preferred embodiment, the disclosed methods, uses or kits are used to treat moderate to severe rheumatoid arthritis. When treating a population of patients with severe HS, less than 15% of the patients experience the same symptoms as those seen in the administering step. In response to HS erythema occurs during 16 weeks of treatment.

[0225] In preferred embodiments of the disclosed methods, uses and kits, the patient is a patient having a steroid drug as described herein. In combination with LOU064, at least one topical agent and at least one The patient is further treated with an antiseptic.

[0226] In preferred embodiments of the disclosed methods, uses and kits, the patient receives at least one 6 weeks, at least 24 weeks, at least 36 weeks, at least 48 weeks or at least and treated with LOU064 as described herein for 52 weeks. Patients will be treated for at least 16 weeks.

[0227] In a preferred embodiment of the disclosed methods, uses and kits, the patient is Approximately one or two weeks after the first administration, the patient's condition is evaluated by VAS or NRS, preferably NRS. The present invention has a pain relief as measured by the following:

[0228] In a preferred embodiment of the disclosed methods, uses and kits, the patient is reduction in skin pruritus as measured by NRS about one or two weeks after the first dose of For example, a patient may experience itchy skin one or two weeks after the first dose of LOU064. Achieve NRS30.

[0229] In a preferred embodiment of the disclosed methods, uses and kits, the patient is Approximately one or two weeks after the first dose of There is a reduction in RP (a reduction of about 25 to about 30%).

[0230] In a preferred embodiment of the present disclosure, LOU064 is disclosed in WO 2020 / 2347 The anhydrous crystalline form A of the free base is disclosed in Pamphlet No. 79 (Example 1). In one aspect of this embodiment, LOU064 Form A is in a substantially pure phase.

[0231] General Provisions The details of one or more embodiments of the disclosure are set forth in the accompanying description above. Any methods and materials similar or equivalent to those described may be used in the practice or testing of this disclosure. Although any method or material that can be used, the preferred methods and materials are described herein. The advantages and benefits of the present invention will be apparent from the specification and claims. Within the scope of the claim, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Unless otherwise defined in the specification, all technical and scientific terms used herein are within the meaning of the present disclosure. The terms "terms" and "terms" have the same meaning as commonly understood by one of ordinary skill in the art to which they pertain. All patents and publications cited herein are incorporated by reference. 1 is shown to more particularly illustrate a preferred embodiment of the present invention. [Example]

[0232] Abbreviation AE Adverse Effect Bid or BID twice a day qd once a day ECG electrocardiogram PK Pharmacokinetics PD Pharmacodynamics po oral (by mouth)

[0233] Example 1: LOU064 signature in the hidradenitis suppurativa transcriptome dataset Necha (genes downregulated by LOU064) Figure 1: Gene expression in skin from healthy donors and in lesioned and non-lesional skin from HS patients. Affymetrix GeneChip HG-U133 Plus 2 in skin We measured BTK expression (probe 2055 04_at) was significantly higher in lesional (but not non-lesional) skin compared with healthy controls. It was found to be significantly upregulated in the skin.

[0234] Figure 2 shows the LOUs in the hidradenitis suppurativa (bulk) transcriptome dataset. The LOU064 signature was generated by analyzing whole blood with Ig These were generated by stimulation with M followed by treatment with LOU064. The transcriptome profile of the samples was measured using Ampliseq. were significantly down-regulated by LOU064 (FDR<0.05) compared with stimulation alone. The 52 genes that we found to have the same LOU signature were defined as the "LOU signature."

[0235] Bulk transcriptomics data were measured by Affy chips (C arlos A.Penno et al.,J.Invest.Dermatol.2 020,Vol 140,Issue 21,2421-2432.e10)-52 49 signature genes were also present in this data, with a total of 106 probes. Each gene can be targeted by multiple probes. The 106 probes were analyzed using an algorithm called GSVA (Sonja Hanzelma nn et al.BMC Bioinformatics 2013,14(7)-h ttps: / / doi.org / 10.1186 / 1471-2105-14-7) This algorithm is used for signature enrichment by comparing all other measured values ​​for each sample. Calculate the enrichment of these 106 probes compared to the probes in the gene set General method on gene set enrichment):Aravind Subramanian et al.PN AS 2005,102(43)15545-15550). The results are shown in Figure 1. Using the Wilcoxon test, no significant differences were found between healthy and diseased HS samples. The signature enrichment was as follows (p~2.7e-7).

[0236] Data show LOU064-repressed genes (LOU064 signature) in hidradenitis lesions. demonstrate upregulation of

[0237] Example 2: Dosage Rationale Using the translational PK / PD model simulation described below, turnover and efficacy were Assuming there are no relevant interspecies differences in the human peripheral tissue occupancy of remibrutinib ( The PK / PD model was focused on B cells, This is believed to be a relevant primary target of BTK inhibition in HS, as discussed above. B cells are typically found in the circulating fraction. n), as well as in lymph nodes and the spleen. In HS, B cells also play a major role in lymphocyte proliferation. In the so-called "tertiary lymphoid organs" in HS-affected tissues, the characteristics are similar to those of lymph nodes and germinal centers. B cells present in the spleen, lymph nodes, or tertiary lymphoid organs in HS lesions These cells are thought to exhibit a faster BTK turnover compared to circulating B cells in peripheral blood. Translational PK / PD model simulations are needed to evaluate the efficacy and safety of LOU064 for the treatment of HS. This guided dose selection.

[0238] Prediction of BTK occupancy using a translational PK / PD model for LOU064 BTK occupancy in blood is dependent on the dose and pharmacological properties of LOU064 (irreversible binding). It is not a useful biomarker for selection. ... D203c, skin prick test) before showing pharmacological activity. The tissue occupancy rate is more representative of the expected efficacy of LOU064. obtain.

[0239] the purpose The purpose of this analysis was to characterize the pharmacokinetics (PK) of LOU064 in healthy volunteers. The efficacy of the drug was assessed over a range of doses and administrations using a previously developed translational target occupancy model. B in human spleen / tissues across regimens (twice daily (BID) vs. once daily (QD)) The aim was to simulate the TK occupancy rate.

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

[0241] method Translational target occupancy model to simulate BTK occupancy in spleen / tissues, It was developed using a two-step method.

[0242] In the first step, a population PK model was developed as described by Kaul et al. (2021). The data was established to explain the LOU064 PK data from the Phase I clinical trial reported in In the second step, the parameter estimates from the population PK model were compared with those from the BTK occupancy model. The results were used in the analysis to predict BTK occupancy in blood and spleen / tissues. Using the TK occupancy model, different doses and different dosing regimens (once daily (QD), twice daily) were used. The BTK occupancy in spleen / tissues was predicted for each BID.

[0243] result A population PK model was developed based on the Phase I clinical trial reported by Kaul et al. (2021). Developed to describe interim PK from the floor study after repeated administration of doses less than 50 mg To address changes in clearance (compared to Day 1 with no difference at the high dose) (lower clearance at steady state on day 12 at 50 mg Exponential time decay for doses below 50 mg and constant clearance for doses above 50 mg The population models obtained generally explained the PK data to some extent. It was revealed.

[0244] PK parameter estimates were used in a translational BTK occupancy model to determine the steady-state The BTK occupancy simulation was performed twice a day (B. ID) administration compared with once daily (QD) administration of the same dose to achieve higher BTK occupancy. The results showed that the dose was more effective than the placebo (at trough or averaged over a 24-hour period).

[0245] Regarding selected dosing frequencies for once-daily (QD) and twice-daily (BID) regimens , trough and average steady-state BTK occupancy over a 24-hour period, once daily at 10 m g, 35 mg, 100 mg and twice-daily 10 mg, 25 mg and 100 mg regimens 4A (steady-state BTK occupancy trough over 24 hours) and Figure 4B (24-hour average of BTK occupancy at steady state). The figure shows that a maximum daily dose of 200 mg (100 mg twice daily (BID)) demonstrated that this may be required to achieve trough BTK occupancy ≥ 80% in target tissues. vinegar.

[0246] Simulations were performed to compare different dosing regimens. Simulated steady-state twice-daily (BID) vs. 100 mg once-daily (QD) A comparison of splenic BTK occupancy between the BTK-positive and BTK-negative spleens is shown in Figure 3. The graph shows the predicted occupancy from first principles. As shown, the occupancy rate from twice-daily (BID) dosing was significantly higher than that from once-daily (QD) dosing. indicates a higher and less change.

[0247] Conclusion: The model demonstrated that overall significantly higher BTK occupancy was achieved using the b.i.d. dosing regimen. Approximately 70-95% trough BTK occupancy was observed at 25 mg bilirubin. d. Dosage regimen predicted in human tissues, while 100 mg bid The program is expected to achieve a trough BTK occupancy of ≥ 90%.

[0248] Example 3: Clinical Trial Design Blinding of subjects and investigators was performed based on the number of lesions or total HS-PGA score in the HS, and This allows for unbiased assessment of subjective readouts such as adverse events.

[0249] A randomized, subject- and investigator-blinded, placebo-controlled, multicenter, parallel-group study LOU064 (Remib) in subjects with moderate to severe hidradenitis suppurativa (HS) to evaluate the efficacy, safety, and tolerability of several active therapeutic compounds, including rutinib After the screening period, the treatment period lasts for 16 weeks, followed by approximately 4 weeks. A safety follow-up of 12 weeks will follow. Subjects will receive 25 mg BID po LOU0 64, 100 mg BID po, or placebo BID po. The subjects were randomly assigned, with 60 receiving the active drug (30 receiving 100 mg b id, 30 received 25 mg bid), and 10 received placebo. can be.

[0250] The primary objective is to compare LOU06 in HS subjects after 16 weeks of treatment compared to placebo. The objective of this study is to demonstrate the preliminary efficacy of treatment with 4. After a 16-week treatment period, The follow-up period will demonstrate that the durability of effect can be sustained or increased after 16 weeks of treatment. Included to observe.

[0251] Protocol Summary Primary Objective: The primary objective of this study is to evaluate the clinical response (SAR) of patients with hidradenitis suppurativa after 16 weeks of treatment. By comparing the proportion of patients achieving a clinical response as defined by the HiSCR Remibrutinib compared with placebo in patients with moderate to severe inflammatory HS The purpose of this study is to evaluate the effectiveness of the method.

[0252] Secondary Objectives: At baseline and repeatedly through the study completion visit, (i) the number and severity of AEs and (ii) the severity of the condition as determined by physical examination, vital signs, safety laboratory measurements, and ECG. Safety and efficacy of remibrutinib in patients with moderate to severe hidradenitis suppurativa (HS) To assess efficacy and tolerability.

[0253] Study Design: This is a randomized controlled trial of hidradenitis suppurativa (HISU) in subjects with moderate to severe HISU. A non-confirmatory, randomized, placebo-controlled study to evaluate the efficacy, safety, and tolerability of mibrutinib This is a subject- and investigator-blinded, placebo-controlled, multicenter, parallel-group comparative study. The maximum duration of participation for any subject in this study was greater than 25 weeks for remibrutinib. The study consisted of a 35-day screening period, a 16-week treatment period, and a 4-week safety It will be terminated by follow-up. LOU0 from Day 1 (Week 1) to Day 113 (Week 17) 64 (remibrutinib), 100 mg bidpo or 25 mg bid Subjects will be randomized to receive either remibrutinib or placebo in a 3:3:1 ratio. Participants will be randomized to either the steroid group or its matching placebo.

[0254] Population: Patients diagnosed with recurrent inflammatory lesions for at least 12 months prior to screening Adult male and female participants aged 18-65 years with moderate to severe hidradenitis suppurativa were included. person.

[0255] Key eligibility criteria: Clinically diagnosed for at least 12 months prior to screening Male and female subjects aged 18 to 65 years (inclusive) with established HS; screening Minimum weight of 50 kg (endpoints included); assessed at screening (pre-dose on Day 1) Therefore, patients with moderate to severe HS: - a total of at least 3 inflammatory lesions, i.e., abscesses and / or inflammatory nodules, and - 15 or fewer fistulas, and - At least two anatomical sites must be involved in the HS lesion.

[0256] Key exclusion criteria: - At screening or within 30 days or 5 half-lives of randomization whichever is longer; or if required by local regulations, within a longer time period of other investigational drugs. use; - Highly effective during treatment with remibrutinib and for at least 2 weeks after the last dose Women who are physiologically capable of becoming pregnant unless they use contraception - Significant bleeding risk or coagulation disorder, e.g.: Clinically relevant, e.g., associated with nonsteroidal anti-inflammatory drug (NSAID) use History of gastrointestinal bleeding: Anticoagulant medications (e.g., warfarin or new oral anticoagulants) within 2 weeks prior to randomization Use of non-steroidal anti-inflammatory drugs (NOACs) International normalized ratio (INR) greater than 1.5 at screening - Antiplatelet therapy [dual antiplatelet therapy (e.g., acetonitrile)] within 2 weeks prior to randomization Use of cyclosalicylic acid (including clopidogrel) Note: Monotherapy with acetylsalicylic acid (up to 100 mg / day) or clopidogrel is not excluded. Major surgery within 8 weeks prior to screening or surgery scheduled during the study treatment period.

[0257] Main efficacy measures: - Simplified and original Hidradenitis Suppurativa Clinical Response (HiSCR) rates - International Hidradenitis Suppurativa Severity Scoring System (IHS4) - Hidradenitis Suppurativa - Physician Global Assessment (HS-PGA) score and responder rate - HS inflammatory lesion count - Hidradenitis Suppurativa Severity Scale (SAHS)

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

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

[0260] [Table 2]

[0261] [Table 3]

[0262] [Table 4]

[0263] Further clinical assessment: Simplified HiSCR was selected as the primary endpoint. The original HiSCR (Kimball et al. 2014) used in the phase 3 clinical trial 16 N Engl J Med 375:422-34) has been demonstrated. Simplified H iSCR is defined as a 50% reduction in the total number of abscesses and inflammatory nodules, not including an increase in draining fistulas. However, in contrast to the original HiSCR, if the previous conditions are met, Tumor growth is accepted to constitute a clinical response. Inflammatory lesions of HS are characterized by discrete lesions (inflammatory nodules, abscesses) in typical anatomical locations. In addition to the counts, a global rating scale (purulent sweating, Hidradenitis Suppurativa Severity Assessment Score (HS-PGA or HS-PGA) and Composite Score (Hidradenitis Suppurativa Severity Assessment Score) Abscesses and nodules will also be presented as AN counts. Deaf. HS-PGA (Hidradenitis Suppurativa - Physician Global Assessment): The score is a Kimball AB, Kerdel F, Adams D, et al(2012)Adalimumab for the treatment of moderate to severe Hidradenitis suppu rativa:a parallel randomized trial.Ann I Intern Med;157:846-55. The SAHS score is a composite score (Hessam S, Scholl L, Sa nd M,et al(2018)A Novel Severity Assessm ent Scoring System for Hidradenitis Supp urativa.JAMA Dermatol;154(3):330-335.), flame It is derived from the collected information of the number of lesions, number of fistulas, and NRS pain. Location and new or spread of existing tumors will be collected in both cohorts. cormorant. Several patient-reported outcomes were used, including the Dermatology Life Quality Index (DLQI). Finally, from the subject's perspective, skin-related pain is the most important symptom, A numeric rating scale (NRS) for pain is included. Other patient-reported outcomes (PROs) are available in many countries and languages ​​using validated strategies. Dermatology Quality of Life Index (DL) as a core-based dermatology-related quality of life (QoL) instrument It will include a Patient Global Assessment (PGA) as well. Skin Pain-NRS (Numeric Rating Scale for Pain): For skin-related pain The NRS was used in the adalimumab trial (Kimball et al. (201 6)N Engl J Med 375:422-34), one of the greatest burdens on patients It will be used for skin or HS-related pain (Matusiak et al. (2018) 17) J Am Acad Dermatol;76:670-5). HS-related pain , on average over the previous 24 hours and at the worst point (over the previous 24 hours) cormorant. Pruritus NRS is included when pruritus is recognized here as a symptom in HS patients. (Nguyen et al. 2021, Fernandez et al. 20 twenty one).

[0264] Example 5: 100 mg film-coated tablets A preferred pharmaceutical composition (film-coated tablet) is shown below.

[0265] [Table 5]

[0266] Example 6: 50 mg film-coated tablets A preferred pharmaceutical composition (film-coated tablet) is shown below.

[0267] [Table 6]

[0268] Example 7: 25 mg film-coated tablets A preferred pharmaceutical composition (film-coated tablet) is shown below.

[0269] [Table 7]

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

[0271] Short-term safety of LOU064 in a Phase I clinical trial It is administered as a single dose or in a dose range of 0.5 mg to 600 mg for up to 18 days. as multiple doses over a period of up to 18 days, and as a further dose over a period of up to 12 days The short-term safety of LOU064 at 100 and 200 mg twice daily (bid) was , demonstrated in a Phase I clinical trial (Kaul, M. et al. (2021). Rem ibrutinib(LOU064):A selective potent ora l BTK inhibitor with promising clinical safety and pharmacodynamics in a randomi zed phase I trial.Clinical and Translati onal Science.10.1111 / cts.13005).

[0272] Summary of safety in the Phase 2b extension phase of CSU subjects (interim results) Long-term safety and efficacy of LOU064 in eligible subjects with CSU enrolled in a Phase 2b study The drug will be used in a 52-week open-label extension study to evaluate safety and tolerability. The dose was 100 mg twice daily (bid).

[0273] Safety signals were observed with a median exposure of 17.86 weeks (range: 2.9 weeks to 44.7 weeks). Based on an interim analysis of 100 subjects who received at least one dose of OU064 At the cutoff, 93 subjects (93%) were ongoing and Seven subjects discontinued the study; none of the discontinuations were due to adverse events Table 4 shows the safety data observed in the Phase 2b study up to the cutoff date for the interim analysis. A summary of the following is shown.

[0274] [Table 8]

[0275] Fifty-eight subjects (58%) experienced at least one treatment-emergent AE. The majority of E were not serious, did not lead to treatment discontinuation, and were mild in severity. The most commonly affected SOC was infections and infestations (14%), followed by cutaneous and subcutaneous tissue The most common adverse events were tissue disorders (13%) and no trends for specific adverse events. The preferred adverse event terms (≥2%) were headache (6%), diarrhea (4%), dizziness (3%), and gastroenteritis ( 3%); bleeding events (broad bleeding SMQ and platelet aggregation abnormalities, decreased platelet aggregation, small blood vessels) Issues under PT include platelet aggregation inhibition, platelet dysfunction, abnormal platelet function tests, and platelet toxicity No events were reported under SOC Blood and lymphatic system disorders (defined as 'hypertensive') or SOC Blood and lymphatic system disorders Three SAEs were reported: ovarian cyst, chest pain, and appendicitis; all were related to the study drug. was not considered to be present.

[0276] Conclusions from the Phase 2b study and corresponding open-label extension study Combined, safety data from the Phase 2b study were consistent across all doses evaluated. Additionally, open-label LOU064 100 mg twice daily (bid) was administered. In the corresponding CSU extension study used in the study, the safety signal was None were observed in 100 subjects enrolled as of 2020. The highest dose of 100 mg LOU064 twice daily (bid) was well tolerated. It was considered to be effective and had a favorable safety profile.

[0277] Phase 2b in CSU subjects (interim results / patients with median exposure of 35.14 weeks) Summary of safety in the extension phase of the study The dose was 100 mg twice daily (bid) in patients with CSU who participated in a Phase 2b study. to evaluate the long-term safety and tolerability of LOU064 in eligible subjects. A new interim analysis was conducted at 35.14 weeks of exposure in a 52-week open-label extension study of The results were analyzed in patients with a median age (N=183) and were analyzed in a (1:1:1:1:1:1:1) Remi Brutinib 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 Adults with CSU were given a maximum of 12 weeks (wks) (NCT03926611). Safety Results from a Randomized, Double-Blind, Placebo-Controlled Phase 2b Core Study in Human Patients compared with (Table 5).

[0278] In the long-term exposure to ES (median 35.14 weeks, N=183), Patients with at least one adverse effect (AE) to the treatment (57.4% [n=105]) The proportion of patients with CS (as indicated by any remibrutinib dose) was similar to that of CS (58 0.1% [n=155]; median 12.14 weeks, N=267). There were six serious adverse events (SAEs) leading to treatment discontinuation and death. The incidence of AEs by system organ class (SOC) reported in S was similar: infections and parasitic diseases (23.0% and 24.0%), followed by skin / subcutaneous tissue disorders (17.5% and 16.9%) (Table 5). The incidence of AEs reported by preferred term was 10.4% in ES and CS. The most common side effects were headache (6.6% and 9.7%) and infection (23%). The incidence of AESIs in ES, such as bleeding (4.4%) and cytopenia (0.5%), was The significant increase in newly occurring aminotransferases was consistent with ES (personal theory). In one patient who discontinued early due to a reason, an isolated ALT >3× normalized within 4 weeks. ULN) and CS (ALT > 5 × ULN in one patient, normalized to treatment ) was 1 in both groups. Analysis of laboratory parameters did not reveal any significant safety concerns. No clinically significant changes in vital signs were observed in any of the patients. There were no significant ECG findings or a QT of >500 ms.

[0279] [Table 9]

[0280] [Table 10]

[0281] conclusion Remibrutinib demonstrated a favorable safety profile across the entire dose range, with CSU Longer exposure to a dose of 100 mg bid for up to 52 weeks in patients with No new safety signals were observed throughout the study.

[0282] Example 9: Three Different Clinical Trials of Simultaneous and Intermittent Administration of Remibrutinib in Healthy Subjects Evaluating modulation of immune responses to different types of vaccines

[0283] [Table 11]

[0284] Study design Overall Design This randomized, double-blind, placebo-controlled study has a parallel-group design. Approximately 9 months was required to achieve a minimum of 72 evaluable completers, taking into account an estimated dropout rate of 20%. 0 healthy female and male participants of non-childbearing potential were randomized to one of three treatment groups. The study consisted of a 28-day screening period, a 43-day treatment period, and then a final The safety profile will consist of a study completion assessment (Day 57) within 2 weeks after the final study drug administration. A follow-up call will be conducted approximately 30 days (day 73) after the last dose of study medication. Settling in from Day -1 to Day 1 and Days 14-17. Overall, the maximum study duration for each participant was , about 85 days.

[0285] Concurrent and Intermittent Remibrutinib Treatment Scenarios for Influenza / Pneumo The effects of vax®23 and Immucothel® compared to placebo and evaluate.

[0286] Testing Screening and Baseline Participants who meet the eligibility criteria at screening will undergo a baseline assessment on Day -1 All baseline safety assessments must be available before the first dose. At baseline, participants were randomized to one of three treatment groups, as described below. It can be divided into four types.

[0287] treatment All participants received study medication (remibrutinib 100 mg or prasugrel) from Day 1 to Day 42. Patients were administered sebo twice daily (bid) and visited the clinic for an end of treatment visit on day 43. All participants received the quadrivalent influenza vaccine, PPV-23 vaccine, on day 15. The vaccines will be administered 3 hours after the administration of the test drug. It should be done.

[0288] During clinical visits and enrolment (days -1 to 1 and 14-17), participants were treated at the clinic. Upon discharge from the clinical visit during the treatment period, a medication diary and In both cases, participants will be given the study medication to self-administer at home.

[0289] Safety assessments included physical examination, ECG, vital signs, and standard clinical laboratory assessments (hematology, Blood chemistry, urinalysis) including adverse event and serious adverse event monitoring.

[0290] Multiple blood samples were collected on days 8, 15, and 3 to assess remibrutinib pharmacokinetics. Obtained from all participants on day 6.

[0291] Group A (concurrent remibrutinib treatment): Participants will be monitored to achieve PK / PD steady state prior to administration of the three vaccines on Day 15. Placebo (twice daily (bid)) on days 1-7, followed by levothyroxine (LVO) on days 8-15 of the study. Treatment with mibrutinib (100 mg twice daily (bid)) will be administered. Patients received remibrutinib (100 mg twice daily (bid)) until day 42. It continues to be used.

[0292] Group B (intermittent remibrutinib treatment): Participants received 1 dose of remibrutinib on days 1-7 to achieve PK / PD steady-state conditions. 00 mg twice daily (bid), followed by placebo (10 mg bid) on days 8-28. Two doses (bid) will be administered, and three vaccines will be administered on the 15th day. Treatment with remibrutinib 100 mg twice daily (bid) was performed on days 29-42. This is a treatment that will be resumed in the future.

[0293] Group C (placebo): Participants in Group C received placebo (bid) on days 1-42 and under placebo conditions On the 15th day, you will receive three vaccines.

[0294] Key eligibility criteria Signed informed consent must be obtained prior to study participation . Healthy or mildly obese or otherwise healthy, aged 18-55 years (inclusive) Male and female participants of non-childbearing potential. Participants completed a medical history, screening, and baseline physical as indicated. Be in good health as determined by examination, vital signs, ECG, and clinical examination should be. At screening and baseline, vital signs (systolic and diastolic blood pressure and pulse rate) (number of subjects) were assessed in a sitting position and again in an upright position (if required by the assessment schedule). Sitting vital signs (after 3 minutes of sitting) should be within the following ranges: · Tympanic temperature of 35.0~37.5℃. · Systolic blood pressure (SBP) between 90 and 139 mmHg (end points included). · Diastolic blood pressure (DBP) between 50 and 89 mmHg (end points included). · Pulse rate between 45 and 90 bpm (end points included). Participants must weigh at least 50 kg and be 18 years of age to participate in the study. Must have a body mass index (BMI) in the range of ~34.9 kg / m2. Participants will remain in clinical settings as required by the protocol and will be Must be willing to comply with the requirements / instructions outlined. Ability to read, speak and understand the local language in order to understand and comply with the exam requirements do.

[0295] Key exclusion criteria Use of other investigational drugs within 1.5 half-lives or 30 days prior to the first dose, whichever is longer. For. 2. Current evidence or history of clinically significant ECG abnormalities or long QT syndrome or Family history of other abnormalities in cardiac conduction (grandparents, parents, and siblings), torsades de History of additional risk factors for TdP (e.g., heart failure, hypokalemia) and and / or known history or current clinically significant arrhythmias. PR > 220 msec, QRS complex QTcF > 120 msec for both men and women, or QTcF > 450 msec for both men and women, or early repolarization , abnormal E defined as any other morphological change other than nonspecific ST or T wave changes CGI. 3. Previously treated cancer within the past 5 years, with or without evidence of local recurrence or metastasis Treated or untreated malignant tumors of any organ system (localized basal cell carcinoma of the skin or in situ uterine carcinoma) History or presence of cancer other than cervical cancer. 4. Cardiovascular (including but not limited to) conditions that have not resolved within 2 weeks prior to the first dose Any system organ class, including pulmonary, metabolic, hepatic, renal, hematological, endocrine, nervous system, or psychiatric disorders History or presence of any clinically significant disease. 5. Hypersensitivity to remibrutinib or drugs from the same compound class or its excipients sex. 6. Any acute infection, fever, or any related component of the vaccine administered in this study Hypersensitivity reactions or known hypersensitivity to ingredients (e.g., chicken eggs or shellfish / KLH) , Pneumovax 23, influenza, or KLH vaccine use A taboo. 7. Vaccination history or registration for 2022-2023 seasonal influenza vaccine Known clinical cases of influenza infection prior to the 2022-2023 influenza season diagnosis. 8. History of previous exposure or immunization with KLH.

Claims

1. A BTK inhibitor, such as a selective BTK inhibitor, such as LOU064, for use in the treatment and / or prevention of HS.

2. 2. The method of claim 1, wherein LOU064 is administered at a dose of about 50 mg to about 200 mg daily.

3. 3. The use of claim 2, wherein LOU064 is administered at a dose of about 25 mg twice a day to about 100 mg twice a day.

4. 3. The use of claim 2, wherein LOU064 is administered at a dose of about 100 mg twice daily.

5. 3. The use of claim 2, wherein LOU064 is administered at a dose of about 25 mg twice daily.

6. 2. The use of claim 1, wherein LOU064 is administered over a short period of time, such as less than 6 months, preferably less than 3 months.

7. 7. The use of claim 6, wherein LOU064 is administered for up to 16 weeks, such as for 4, 12 or 16 weeks.

8. 2. The method of claim 1, wherein LOU064 is administered for chronic use over a long period of time; for example, for more than 6 months, for more than 1 year.

9. 2. The use of claim 1, wherein LOU064 is administered as monotherapy.

10. 2. The method of claim 1, wherein LOU064 is not administered simultaneously with a strong inhibitor of CYP3A.

11. 2. The method of claim 1, wherein LOU064 is not administered simultaneously with a strong inhibitor of CYP3A4.

12. 2. The use of claim 1, wherein LOU064 or a pharmaceutical composition comprising 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 the treatment and / or prevention of HS in a patient in need of such treatment and / or prevention.

14. 14. LOU064 for use according to claim 13, wherein the patient is further treated with at least one topical agent and at least one antiseptic in combination with LOU064.

15. 10. The method of claim 1, wherein the patient has not been previously treated with a systemic or topical therapeutic agent for HS prior to treatment with LOU064.

16. 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 prior to treatment with LOU064; or c) prior to treatment with LOU064, the patient does not have extensive scarring of 15 or fewer fistulas as a result of HS; d) the patient has a clinical diagnosis of HS for at least 12 months; e) LOU064 for the use according to claim 1, wherein the patient has at least two anatomical sites involved in HS lesions.

17. If the patient has, by 16 weeks of treatment, one of the following: a) Simplified HiSCR; b) Reduction of HS erythema; c) a reduction in pain as measured by the Pain NRS, e.g., the Pain NRS 30; d) reduction in skin pruritus as measured by a Pruritus NRS, e.g., a Skin Pruritus NRS 30 f) a reduction in the total or various types of HS inflammatory lesion counts, e.g., AN50, AN75, AN90, or AN100; g) a decrease in IHS4 score; h) a decrease of ≦6 as measured by DLQI; and / or i) Improvement of DLQI 2. The method of claim 1, wherein the method achieves at least one of the following:

18. When the method is used to treat a population of patients with moderate to severe HS, at least 40% of the patients experience, by week 16, the following: a) HiSCR50; b) HiSCR75; c) HiSCR90; or d) Simplified HiSCR 2. The method of claim 1, wherein the method achieves at least one of the following:

19. 2. The method of claim 1, wherein by 16 weeks of treatment, at least 25% of the patients achieve an NRS30 response (e.g., a pain NRS30 or a skin itch NRS30 response); or less than 15% of the patients develop HS erythema.

20. If the patient, about one or two weeks after the first dose of LOU064, experiences one of the following: a) a reduction in pain as measured by the Pain NRS, for example, the patient achieves a Pain NRS of 30; b) reduction in skin pruritus as measured by the Pruritus NRS; e.g., the patient achieves a Skin Pruritus NRS of 30; c) a reduction in CRP as measured using a standard CRP assay, a reduction of at least 25% 2. The method of claim 1, wherein the LOU064 has at least one of the following:

21. 2. The method of claim 1, wherein the patient achieves a sustained response three months after the end of the treatment as measured by inflammatory lesion counts, e.g., AN50, Hidradenitis Suppurativa Clinical Response (HiSCR) (e.g., sHiSCR, HiSCR50, HiSCR75 or HiSCR90), Pruritus or Pain Numeric Rating Scale (NRS), Hidradenitis Suppurativa - Physician Global Assessment (HS-PGA), HS Severity Assessment (SASH), International HS Severity Scoring System (IHS4) or Dermatology Life Quality Index (DLQI).

22. 22. LOU064 for the use of claim 21, wherein the patient achieves a sustained response 3 months after the end of treatment as measured by simplified HiSCR (sHiSCR), HiSCR50, HiSCR75 or HiSCR90.

23. 2. The use of claim 1, wherein LOU064 is disposed in a pharmaceutical composition, said pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, each independently selected from a filler, a lubricant, a binder, a disintegrant, and a glidant.

24. 24. LOU064 for use according to claim 23, wherein the pharmaceutical composition is in tablet or capsule form.

25. 24. LOU064 for use according to claim 23, wherein the pharmaceutical composition comprises nano-sized particles of LOU064.

26. 26. The use of claim 25, wherein said pharmaceutical composition comprises nano-sized particles of LOU064 having an average particle size of about 50 nm to about 750 nm as measured by PCS.

27. 24. The use of claim 23, wherein the pharmaceutical composition comprises LOU064 and a binder in a weight ratio of about 2:

1.

28. 28. LOU064 for use according to claim 27, wherein the pharmaceutical composition comprises LOU064, a binder and a surfactant in a weight ratio of about 2:1:0.

08.

29. 24. The use of claim 23, wherein the pharmaceutical composition comprises LOU064 and a binder in a weight ratio of about 1:

1.

30. 30. LOU064 for use according to claim 29, wherein the pharmaceutical composition comprises LOU064, a binder and a surfactant in a weight ratio of about 1:1:0.

05.

31. 24. The use of LOU064 according to claim 23, wherein the pharmaceutical composition comprises LOU064, polyvinylpyrrolidone-vinyl acetate copolymer as a binder and sodium lauryl sulfate as a surfactant.

32. When LOU064 is measured at a temperature of about 25° C. and an X-ray wavelength, λ, of 1.5405 Å, the following peaks are observed: 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, 2 32. LOU064 for use according to any one of claims 1 to 31 in a crystalline form of the anhydrous free base characterized by an X-ray powder diffraction pattern comprising one or more representative peaks at 2θ selected from the group consisting of 3.4±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.

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