Methods of treatment using LOU064

Abstract

To provide novel and safe treatments for food allergies.SOLUTION: Provided is a BTK inhibitor, e.g., an irreversible BTK inhibitor, e.g., LOU064, or a pharmaceutically acceptable salt thereof, for use in treating or preventing an IgE-induced allergic reaction to one or more allergens, e.g., a food, drug, or toxin allergic reaction, e.g., treating or preventing an anaphylactic reaction.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention provides a method for the effective inhibition of IgE-induced allergic reactions to one or more allergens. and a BTK inhibitor, such as LOU064 or a pharma- ceutically acceptable salt thereof, for use in relates to polymorphism. [Background technology]

[0002] Food allergies affect millions of people of all ages in every country and are on the rise The incidence rate suggests that it is an emerging public health priority (Warr The underlying cause of food allergy is allergen-specific I gE is synthesized in response to allergen exposure and is expressed in the surface membrane of mast cells and basophils. IgE binds to the high affinity receptor (FcεRI receptor) via the Fc region. Food allergies are a global problem. It affects approximately 10% of the population, with consistent epidemiological trends in North America, Europe, Asia and Australia. The most common allergens are peanuts, nuts, and seafood. , eggs, milk, wheat, soybeans and seeds (Warren et al. 2020,Si cherer and sampson 2017). For peanuts, nuts and seafood Allergies caused by bacteria are usually lifelong (Jones and Burks 2017, Sicherer and Sampson 2017). In addition, food allergies, including in adults, Between one-third and one-half of people with allergies are likely to be allergic to two or more foods ( Gupta et al. 2011, Gupta et al. 2019). Anaphylaxis Kissing can sometimes result in life-threatening total immunity to substances such as food, drugs, or stinging insect venom. The aim of immunotherapy is to reduce allergies to these substances. Despite efforts to combat anaphylaxis, the incidence of anaphylaxis is increasing (Lieberm an P.et al.,Ann Allergy Asthma Immunol.2 006;97(5):596-602). Unfortunately, it lacks immediate comprehensive medical treatment. Even when treatment is administered, it is often fatal (J. Allergy Clin. Immunol. ol.2020;145(4):1082). Preventing IgE-mediated anaphylaxis There is no known treatment that can do this.

[0003] The IgE pathway is involved in food allergies, drug allergies, allergic rhinitis, asthma, and chronic It plays a central role in the pathogenesis of most allergic diseases, including urticaria. Allergen-specific IgE binds to high affinity antigens on the surface of mast cells and basophils. When FcεRI crosslinks the FcεRI receptor, an activated signaling cascade is initiated. and histamine, prostaglandins, leukotrienes, which are involved in inducing symptoms. and causes the release of many allergic mediators, including cytokines.

[0004] To date, treatment of allergic diseases has focused on blocking specific mediators (e.g., anti-histamines). agonists or leukotriene receptor antagonists) and / or corticosteroids The study relied heavily on broad immunosuppression with

[0005] Currently, there is no effective treatment that can prevent anaphylaxis, and the main treatment is traction. However, particularly in the case of food allergies, strict prevention is required. Because avoidance is not always possible, standard treatment is early detection of signs and symptoms, as well as This consists of administering epinephrine intramuscularly after the reaction has occurred. However, skin testing, allergen immunotherapy (IT), and drug desensitization (all procedures are performed in a timely manner to prevent severe allergic reactions) were also performed. There are situations in which people are intentionally exposed to an allergen, such as during a medical event (where there is a risk of a physical reaction). Desensitization to allergens, such as food allergens or drugs, typically occurs when High costs due to the need to hospitalize patients due to the risk of potentially life-threatening reactions It requires effort.

[0006] Oral immunotherapy (OIT), sublingual immunotherapy (SLIT), percutaneous immunotherapy (EPIT), and and OIT combined with an anti-IgE monoclonal antibody (omalizumab). There are several immunotherapies being tested for allergies. The efficacy and safety of peanut allergy have been demonstrated in one Phase III study. In addition, there have been three randomized controlled trials of the omalizumab-OIT combination. These were low-powered, single-center studies; The evidence level was low. Studies with long-term follow-up were rare, and therefore clinical Tolerability is unclear and remains unknown (Shoichiro T et al. EMJ.2019;4[4]:63-70).

[0007] Currently, there are no approved oral immunotherapy (OIT) treatments for peanut allergy patients. There is only one: forzia(TM).

[0008] BTK mediates FcεRI-mediated signaling in human mast cells and basophils. BTK is an essential kinase for B cell maturation. It is also important for B cell maturation. , which are being pharmacologically targeted for the treatment of B-cell malignancies. There are currently three There are BTK inhibitors (BTKis) approved by the FDA. 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.

[0009] In addition, some BTK inhibitors (BTKis) have been shown to be effective in treating rheumatoid arthritis (RA), multiple sclerosis (MS), and osteoarthritis (OA). For the treatment of autoimmune diseases such as myelopathy (MS) and systemic lupus erythematosus (SLE) are currently in clinical trials. ONO-4059 (tirabrutinib), HM71224 (posertinib) and ABBV- 105 (upadacitinib) is an anti-inflammatory drug for the treatment of B-cell malignancies and / or RA, Sjögren's syndrome ( Their efficacy in autoimmune diseases such as SjS and SLE is currently being tested. In addition, evobrutinib, trebrutinib and fenebrutinib have been shown to be effective in treating MS patients. is in Phase III trials, and olebrutinib is being studied in Phase II trials. , BIIB091 was tested in a Phase I trial for its efficacy in treating MS. .

[0010] Studies have also been conducted on skin prick tests to aeroallergens and foods in allergy sufferers. The ability of ibrutinib to reduce or eliminate seroresponsiveness (Dispenza et al. .J.Allergy Clin Immunol.2018;141(5):1914 -1916.e7) and skin tests returned to baseline 1 week after discontinuation of ibrutinib. demonstrated that the efficacy of 100 mg / kg / day was significantly improved, suggesting a short duration of efficacy (2021). However, the inhibitory effect seen in the skin prick test may not be due to inhibition in organs other than the skin. It is unclear whether this will lead to the administration of BTK to various tissues in which mast cells reside. Penetrance is unknown. Ibrutinib prevents IgE-mediated activation of circulating basophils. Although BTKis has been shown to have rapid efficacy in the treatment of pulmonary, skin, and gastrointestinal Can we sufficiently inhibit IgE-mediated activation of tissue-resident mast cells in multiple organs such as the immune system? It is unclear whether this is the case.

[0011] BTK inhibitors may be used to prevent and / or treat allergic reactions to plants. Despite the suggestion that BTK inhibitors may be a potential treatment for allergic reactions, and / or has not yet been shown to prevent anaphylaxis in humans. Brutinib is currently used to treat peanut allergens in adults with peanut allergy. It is currently in Phase II trials for the prevention of allergic reactions associated with food allergies. No clinical efficacy data for BTK inhibitors have been reported to date.

[0012] In addition, several earlier developed BTK inhibitors (e.g., acalabrutinib, ibuprofen) Due to the lack of selectivity of the BTK inhibitors (Brutinibe), these inhibitors are difficult to treat, especially in patients with long-term / chronic and stable disease. For the treatment of indications requiring comprehensive use and / or for the pediatric or adolescent population The best of the currently approved BTK inhibitors are The most common side effects include nausea, diarrhea, rash, infection, cytopenia, bleeding, and irregular heartbeat. In particular, the long-term toxicity of ibrutinib, a first-in-class inhibitor The profile is well characterized and includes no evidence of arrhythmia, bleeding, infection, diarrhea, arthralgia, or hypertension. The US Food and Drug Administration (US Food and Drug Administration) The first second-generation BTKi to receive approval from the US Food and Drug Administration (FDA) Calabrutinib demonstrates improved kinase selectivity against BTK, but is not associated with infections, Commonly observed adverse reactions include abdominal pain, diarrhea, and vomiting (Hematology Am Soc Hematol Educ Program.2020 Dec 4;2020 (1):336-345).

[0013] Long-term safety data are not available for the BTK inhibitors currently in development, but Available safety data for brutinib is the biggest obstacle BTK inhibitors may face may suggest whether side effects during chronic use are tolerable. The major events noted in the Phase IIa study of fenebrutinib were 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 BTKis are particularly restrict their use to treating or preventing non-malignant indications, where administration may be required In addition, 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, BTK inhibitors are approved for use in the treatment or prevention of IgE-induced allergic reactions in children. It is unclear whether this is a viable option for

[0014] Due to increasing prevalence (including multiple food allergies), currently limited treatment options are available. Treatment options, potentially life-threatening consequences, and the inability to avoid food alone to provide protection The lack of evidence supporting the current approach to food allergy and the often lifelong burden of disease have led to new There is a great medical need to develop new and safer treatments. [Brief description of the drawings]

[0015] [Figure 1] Passive cutaneous anaphylaxis (PCA) in mice: LOU064 inhibits skin edema. [Diagram 2] BTK occupancy in the spleen of BALB / c mice 2.5 hours after administration. [Diagram 3] Reverse passive Arthus (RPA) response in mouse skin: LOU064 inhibits skin swelling. [Figure 4] BTK occupancy in the spleen of C57B16 mice 5 hours after administration. [Diagram 5] Time-dependent pharmacological effects of LOU064 on skin swelling. [Figure 6] Comparison of time-dependent BTK occupancy in spleen and lung upon pharmacological inhibition of skin swelling following a single dose of 30 mg / kg LOU064. [Figure 7]Effects on total number of cells in bronchoalveolar lavage fluid (BALF) after treatment with LOU064 (10 mg / Kg and 30 mg / kg, orally (po), twice daily (bid)) or vehicle (10 mL / Kg, orally (po), twice daily (bid)) in sensitized mice challenged with 1% w / v OVA or saline (aerosol, days 21-24) and with PBS at 16 hours and PBS at 16 hours (intrathecal (it) groups 1 and 2) or polyinosinic-polycytidylic acid (Poly I:C 100 μg / animal, intrathecal (it)). BALF was collected 24 hours after OVA challenge. [Figure 8] Effects on the number of eosinophils in bronchoalveolar lavage fluid (BALF) after treatment with LOU064 (10 mg / Kg and 30 mg / kg, orally (po), twice daily (bid)) or vehicle (10 mL / Kg, orally (po), twice daily (bid)) in sensitized mice challenged with 1% w / v OVA or saline (aerosol, days 21-24) and with PBS at 16 hours and PBS at 16 hours (intrathecal (it) groups 1 and 2) or polyinosinic-polycytidylic acid (Poly I:C 100 μg / animal, intrathecal (it)). BALF was collected 24 hours after OVA challenge. [Figure 9] Effects on the number of neutrophils in bronchoalveolar lavage fluid (BALF) after treatment with LOU064 (10 mg / kg and 30 mg / kg, orally (po), twice daily (bid)) or vehicle (10 mL / Kg, orally (po), twice daily (bid)) in sensitized mice challenged with 1% w / v OVA or saline (aerosol, days 21-24) and PBS at 16 hours and PBS at 16 hours (intrathecal (it) groups 1 and 2) or polyinosinic-polycytidylic acid (Poly I:C 100 μg / animal, intrathecal (it)). BALF was collected 24 hours after OVA challenge. [Figure 10]Effects on the number of macrophages in bronchoalveolar lavage fluid (BALF) after treatment with LOU064 (10 mg / kg and 30 mg / kg, orally (po), twice daily (bid)) or vehicle (10 mL / Kg, orally (po), twice daily (bid)) in sensitized mice challenged with 1% w / v OVA or saline (aerosol, days 21-24) and PBS at 16 hours and PBS at 16 hours (intrathecal (it) groups 1 and 2) or polyinosinic-polycytidylic acid (Poly I:C 100 μg / animal, intrathecal (it)). BALF was collected 24 hours after OVA challenge. [Figure 11] Effects on the number of lymphocytes in bronchoalveolar lavage fluid (BALF) after treatment with LOU064 (10 mg / Kg and 30 mg / kg, orally (po), twice daily (bid) or vehicle (10 mL / Kg, orally (po), twice daily (bid)) in sensitized mice challenged with 1% w / v OVA or saline (aerosol, days 21-24) and with PBS at 16 hours and PBS at 16 hours (intrathecal (it) groups 1 and 2) or polyinosinic-polycytidylic acid (Poly I:C 100 μg / animal, intrathecal (it)). BALF was collected 24 hours after OVA challenge. [Figure 12] Favorable particle size distribution of nano-sized LOU064. [Figure 13] Simulation of splenic BTK occupancy at steady state. [Figure 14] (A) 24-hour trough of BTK occupancy at steady state, with median predictions as points and vertical lines showing 95% prediction intervals. (B) 24-hour average of BTK occupancy at steady state, with median predictions as points and vertical lines showing 95% prediction intervals. Summary of the Invention

[0016] The problem underlying the present invention is the determination of IgE-induced allergic reactions, e.g. food, drug allergies. or toxic allergic reactions, especially to one or more allergens, e.g. food allergens The safety and efficacy of IgE-induced allergic reactions, more particularly IgE-induced anaphylactic reactions, e.g. The objective of the present invention is to provide an effective treatment or a safe and effective prevention. Safe and effective long-term treatment or prevention of induced food allergic reactions, e.g., anaphylactic reactions. The aim of the study is to provide a defense.

[0017] Thus, the present invention relates to the treatment of IgE-induced allergic reactions, such as food, drug, or toxin allergies. and / or for use in the treatment and / or prevention of food allergic reactions, more particularly food allergic reactions. In particular, the present invention relates to IgE-induced BTK inhibitors, such as reversible or irreversible BTK inhibitors. Induced allergic reactions, such as food, drug or poison allergic reactions, more particularly food allergies Safe and suitable for long-term use (i.e., chronic use) in the treatment and / or prevention of reactions Particularly useful in the present invention are BMX, ITK and TXK inhibitors. BTK inhibitors that are selective over other structurally similar Tec family kinases More particularly, those useful in the present invention are those that are selective for BTK over tec (e.g., For example, at least 10-fold, at least 20-fold, at least 30-fold BTK / Tec selectivity It is a BTK inhibitor.

[0018] Another object of the present invention is to provide a method for treating IgE-induced allergic reactions, such as food, drug, or toxin allergies. - To provide improved treatment and / or prevention of allergic reactions, more particularly food allergic reactions. One aspect of the present invention is to detect the presence of inflammatory bowel disease induced by, for example, one or a mixture of food allergens. The object of the present invention is to provide improved prevention of IgE-induced anaphylaxis. One goal is to develop a more effective treatment with BTK inhibitors than with other BTK inhibitors (e.g., less selective BTK inhibitors). Effective and / or safer than treatment with, in particular, acalabrutinib or ibrutinib To provide an effective and / or safer treatment for the treatment or prevention of IgE-induced allergies Another object of the present invention is to provide a method for treating IgE-related disorders that is more effective than treatment with anti-IgE monoclonal therapy. and / or more convenient treatment for IgE-induced allergic reactions, particularly food allergies. The present invention provides a method for treating and / or preventing rheumatoid arthritis. Faster onset of action (e.g., 8-12 weeks) compared to anti-IgE monoclonal therapy Treatment of IgE-induced allergic reactions with and providing treatment and / or prevention that is more conveniently administered at home and without the use of a medical facility. The aim of the present invention is to provide a treatment method that does not require

[0019] Thus, IgE-induced allergic reactions, such as food, drug, or toxin allergic reactions, For example, methods for preventing or treating anaphylactic reactions, more particularly, methods for treating one or more food allergies. Gen (e.g. peanuts, nuts, milk, wheat, soybeans, eggs, sesame, seafood, or mixtures thereof) A method for preventing or treating an IgE-induced allergic reaction to a substance, comprising the steps of: The method includes administering a suitable dose of LOU064 to a subject in need thereof. Disclosed in the specification.

[0020] Another aspect of the invention is a method for treating a food allergen-containing dietary supplement comprising administering to a patient a dietary supplement that is free of one or more allergens (e.g., peanuts, nuts, milk, wheat, etc.). IgE inducers for food allergens such as soybeans, eggs, sesame, seafood, or mixtures thereof To treat or prevent food-induced allergic reactions, preferably against one or more allergens. Irreversible BTK inhibitors, such as L, are being used to prevent IgE-induced food allergic reactions. OU064 or a pharma- ceutically acceptable salt thereof.

[0021] A further subject of the invention is a method for the manufacture of a medicament for use in the treatment described above. be.

[0022] Further aspects, advantageous features and preferred embodiments of the present invention are summarized in the following embodiments E1 to E39. The preferred embodiments, taken individually or in combination, contribute to achieving the object of the present invention. stand:

[0023] E1. Identification of one or more allergens (e.g., drugs, toxins, or foods) in a subject in need thereof A method for treating or preventing an IgE-induced allergic reaction to an allergen (substance allergen), comprising the steps of: and administering to the patient a therapeutically effective dose of a selective BTK inhibitor, e.g., LOU064. Methods including:

[0024] E2. One or more allergens include or are a food allergen; The method described in E1.

[0025] E3. Food allergens include peanuts, nuts, milk, wheat, eggs, soybeans, sesame, seafood, The method according to E2, in particular selected from peanuts.

[0026] E4. The therapeutically effective dose of LOU064 is about 20 mg to about 200 mg daily. The method according to claim E1, E2 or E3.

[0027] E5. The therapeutically effective dose of LOU064 is about 10 mg twice daily to about 100 mg twice daily. The method according to E4, wherein the

[0028] E6. The therapeutically effective dose of LOU064 is approximately 10 mg twice daily, as described in E5 How to.

[0029] E7. The therapeutically effective dose of LOU064 is approximately 25 mg twice daily, as described in E5. How to.

[0030] E8. The therapeutically effective dose of LOU064 is approximately 100 mg twice daily, as described in E5. Method of posting.

[0031] E9.LOU064 is administered for a short period of time, e.g., less than 6 months, preferably less than 3 months or The method according to any one of E1 to E8, wherein the method is administered for less than a month.

[0032] E10.LOU064 may be administered for up to 18 weeks, e.g., at 4, 10, 12, 16 or 18 The method according to claim 9, wherein the administration is for a period of 1 week.

[0033] E11.LOU064 is administered for a long period of time, e.g., more than 6 months, e.g., more than 1 year, preferably more than 1 year The method according to any one of E1 to E8, wherein the method is administered over a period of time.

[0034] E12.LOU064 is administered as monotherapy on any one of E1-E11 The method described.

[0035] E13.LOU064 is a potent inhibitor of CYP3A, e.g., potent inhibitor of CYP3A4. The method according to any one of E1 to E12, wherein the method is not administered simultaneously with a toxin-causing agent.

[0036] E14. Any of E1-E11 and E13, in which LOU064 is co-administered with a therapeutic agent. The method described in one.

[0037] E15.LOU064 is administered in combination with corticosteroids and / or immunosuppressants (e.g., inhaled corticosteroids). tycosteroids), leukotriene receptor antagonists (LTRAs), short-acting beta co-administered with a long-acting beta agonist (SABA) or a long-acting beta agonist (LABA), 14. The method according to claim 14.

[0038] E16.LOU064 is a combination of oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and transdermal immunotherapy. Immunotherapy (EPIT), preferably co-administered with OIT, claims E1 to E11 and E 13. The method according to any one of claims 1 to 13.

[0039] E17.LOU064 is being evaluated for oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and transdermal immunotherapy. The method according to E16, which is an adjunct to immunotherapy (EPIT), preferably OIT.

[0040] E18. Oral immunotherapy is peanut protein (e.g. Palforzia) , E16 or E17.

[0041] E19.LOU064 should be administered for at least 2 days (e.g., at least 2 The method according to any one of E16 to E18, wherein the administration begins before E16 (-14 days).

[0042] E20. The method of E19, wherein LOU064 is administered during the titration phase of immunotherapy treatment. .

[0043] E21. Any one of E1 to E20, wherein the method is prevention of IgE-induced allergic reactions. The method according to claim 1.

[0044] E22. Accidental exposure to any allergen or mixture of allergens (e.g. food allergens) The method according to any one of E1 to E21 for preventing post-exposure anaphylaxis.

[0045] E23.LOU064 is administered at least 2 days after treatment (e.g., 2-14 days, preferably 2 The method according to claim 1, wherein the method achieves maximum protection on day E21 or E22 (after 3 days).

[0046] E24. The patient meets the following criteria: (a) Male and female patients, aged 2 years or older (e.g., 2–5 years, or 6–11 years, or 12–17 years) or 18-55 years old); (b) Contains, but is not limited to, peanuts, tree nuts, wheat, eggs, milk, soybeans, fish and shellfish. A confirmed history of allergies to foods; (c) positive allergen-specific IgE (e.g., peanut sIgE at screening) ≥ 6 kUA / L); and (d) A positive skin prick test result for an allergen to which the patient is allergic (e.g. For example, as a wheal with a mean diameter (longest diameter and midpoint perpendicular diameter) of ≥ 4 mm compared to the negative control. (defined) The method according to any one of E1 to E23, selected according to one or more of:

[0047] E25. The patient is an adult patient (18 years or older) or an adolescent (12-17 years old), The method according to any one of E1 to E24.

[0048] E26. The patient is a child aged 2 to 11 years, for example 2 to 5 years or 6 to 11 years, E1 to E 24. A method according to any one of claims 24 to 24.

[0049] E27. At least one of the following applies: After up to 4 weeks (e.g., 1 week, or 2 weeks, or 3 weeks) of treatment with LOU064 or 4 weeks later), At least 90% of treated patients consumed a diet containing 600 mg of peanut protein Does not cause allergic reactions when loaded b. At least 90% of treated patients receive a diet of 1000 mg of peanut protein. Does not cause allergic reactions when loaded with food. c. At least 80% of treated patients receive a diet of 3000 mg of peanut protein. The method according to any one of E1 to E26, which does not show an allergic reaction upon food challenge.

[0050] E28. Patient has baseline FAQLQ total domain score of 0.45-0.5. The method of any one of E1-E27, wherein the method achieves a reduction from

[0051] E29. The patient achieves a reduction from baseline in the FAIM total domain score, The method according to any one of E1 to E28.

[0052] E30. Double-blind placebo control with 600 mg of allergen (e.g., peanut allergen) The observed difference in response rates between treated and untreated patients in a controlled food challenge was greater than 35%. excellent, where the response rate was less than or equal to a mild response to a 600 mg oral food challenge. The method of any one of E1 to E29, wherein said method is defined as

[0053] E31. Alanine aminotransferase by week 12 or week 24 of treatment (ALT), aspartate aminotransferase (AST), and lipase levels E1 The method according to any one of claims 1 to 30.

[0054] E32. LOU064 is a suitable oral pharmaceutical formulation comprising nano-sized particles of LOU064 The method of any one of E1 to E31, wherein the administration is in the form of a pharmaceutical formulation.

[0055] E33.LOU064 has an average wavelength of about 50 nm to about 750 nm when measured by PCS. The drug is administered in the form of a suitable oral pharmaceutical formulation containing nano-sized particles of LOU064 having a uniform particle size. The method according to any one of E1 to E32,

[0056] E34. A preferred composition comprising LOU064 and a binder in a weight ratio of about 2:1. The method according to any one of E1 to E33, wherein the compound is administered in the form of an oral pharmaceutical formulation.

[0057] E35.LOU064 is mixed with LOU064, binder and Any one of E1 to E34, which is administered in the form of a suitable oral pharmaceutical formulation containing a surfactant. The method according to claim 1.

[0058] E36. A preferred composition comprising LOU064 and a binder in a weight ratio of about 1:1. The method according to any one of E1 to E33, wherein the compound is administered in the form of an oral pharmaceutical formulation.

[0059] E37.LOU064 is mixed with LOU064, binder and and a surfactant. Any method as described above.

[0060] E38.LOU064, Polyvinylpyrrolidone as a binder A suitable oral formulation comprising vinyl acetate copolymer and sodium lauryl sulfate as a surfactant. The method according to any one of E1 to E37, administered in the form of a pharmaceutical formulation.

[0061] E39.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± Selected from the group consisting of 0.2° 2θ, 27.2±0.2° 2θ, and 29.6±0.2° 2θ. The X-ray powder diffraction pattern includes one or more representative peaks at selected 2θ. The method of any of E1-E38, wherein the compound is a crystalline form of the anhydrous free base. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0062] definition As used herein, Bruton's tyrosine kinase (BTK) refers to a cytoplasmic tyrosine kinase that is involved in the regulation of tyrosine kinase activity. BTK is a member of the mitochondrial kinase and TEC kinase families. Selected members of the adaptive and innate immune system, including phages, mast cells / basophils, and platelets BTK is expressed in cells that bind to the Fcε receptor (FcεR1 for IgE) and activates Fcγ receptors (FcγR in the case of IgG), as well as B cell antigen receptors (BCR) and B It is essential for signaling through BTK inhibitors such as ibrutinib. The agent is approved for the treatment of B-cell malignancies (Hendriks et al. 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 lesion size (Smiljkovic et al. 2013). 17;Regan et al. 2017;Dispenza et al. 2018) Therefore, inhibition of BTK may be an effective treatment for rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus. , 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 of these include non-covalent, reversible BTK inhibitors such as fenebrutinib, and evo Brutinib, trebrutinib, rilzabrutinib, tirabrutinib, branebrutinib, Non-covalent binding of BTK, such as olebrutinib and remibrutinib (LOU064) Irreversible inhibitors are included.

[0063] As used herein, IgE refers to immunoglobulin E.

[0064] The term "comprising" means "including" as well as and "consisting of," for example, X is "comprised The "ising" composition may consist of X alone or may contain something additional. It may be, for example, X+Y.

[0065] 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.

[0066] As used herein, the term "pharmaceutical acceptable" means a compound that is The risk of undue toxicity, irritation, or allergy may be reduced or eliminated, within the bounds of sound medical judgment, commensurate 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

[0067] The term "salt" or "salts" refers to an acid salt of a compound of the present invention. The term "salt" specifically refers to a "pharmaceutically acceptable salt." The term "salts that are reasonably acceptable" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and are typically In most cases, the compounds of the present invention are salts that are not biologically or otherwise harmful. The presence of an amino group on this makes it possible to form acid salts. Examples of salts can be found in ref. International Publication No. WO 2020 / 234779 and International Publication No. This is disclosed in brochure publication No. 2015 / 079417.

[0068] As used herein, the term "polymorphism" refers to a group of molecules, atoms, and / or ions in a crystal form that has the same chemical composition but a different spatial arrangement. The crystalline form of 64 is disclosed in WO 2020 / 234779, which is incorporated herein by reference. This will be disclosed in the brochure.

[0069] The term "administering" in reference to a compound, e.g., LOU064, refers to administering by any route, preferably Preferably, it is used to refer to delivery of the compound to a subject by oral administration.

[0070] As used herein, a compound of the present disclosure (i.e., a compound of formula (I) or The term "therapeutically effective amount or dose" of a pharma- ceutically acceptable salt or polymorph of A biological or medical response in a subject (e.g., a decrease in enzyme or protein activity or or induce inhibition, or ameliorate symptoms, alleviate pathology, slow disease progression, or The term "compound" refers to an amount of a compound of the present disclosure that delays or prevents disease. The therapeutically effective dose of the compound or combinations thereof will depend on the species, weight, age, sex, and individual characteristics of the patient. The frequency of administration depends on the condition of the body, the disorder or disease being treated, or their severity. It will vary depending on the compound used and the particular condition being treated or prevented.

[0071] As used herein, the term "pharmaceutically acceptable carrier" means a As is known (e.g., Remington's Pharmaceutical Sciences,18th Ed.Mack Printing Company,1 990, pp. 1289-1329), any solvent, dispersion medium, coating, boundary Surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonicity agents, absorption delaying agents, salts , preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, etc. Except insofar as any conventional carrier is incompatible with the active ingredient, it is not intended to be used in the treatment of Its use in therapeutic applications or pharmaceutical compositions is envisaged.

[0072] The term "treatment" or "treating" refers to the treatment of a subject (preferably a human) or BTK inhibitors, such as LOU064 or its derivatives, into isolated tissues or cell lines. or a pharmaceutical composition comprising LOU064 or a pharma- ceutical acceptable salt thereof. The term "therapeutic agent" refers to the administration or administration of a therapeutic agent to a subject, said therapeutic agent being administered to said subject in a therapeutically effective manner. IgE-induced food allergies), symptoms associated with the disease (e.g., IgE-induced food allergies), allergic reaction) or predisposition to develop a disease (if applicable) and the purpose is to To cure (if applicable), reduce the severity of, or otherwise alleviate one or more symptoms of the disease alleviating or ameliorating such symptoms, improving the disease, or alleviating any associated symptoms of the disease or the disease itself. The term "treatment" or "treating" refers to the reduction or amelioration of a person's tendency to develop a disease. The term refers to subjects suspected of having a disease as well as subjects who are ill or suffering from a disease or condition. The present invention includes treating a subject diagnosed with a pulmonary edema.

[0073] As used herein, "prevention" of a disease or disorder (e.g., IgE-induced food allergy) The terms "," "prevent" and "preventing" refer to the prophylactic treatment of a disease or disorder; or delaying and / or inhibiting the onset or progression of a disease or disorder (e.g., The term "prevention" refers to the inhibition of IgE-induced food allergic reactions. Sensitization of a patient subject to an allergen for an allergic reaction to the allergen Reduce sensitivity to allergens (i.e., reduced sensitivity to allergens as assessed by oral food challenge) This term refers to, for example, increasing the threshold for sensitivity to 80% (e.g., 85%, 90% from baseline) of known allergens (e.g., food This term includes reducing food allergic reactions upon oral exposure to food allergens. , potentially life-threatening IgE-induced allergic reactions and more particularly IgE-induced anaphylaxis. This also includes protection against tyraxis.

[0074] As used herein, the term "anaphylaxis" refers to a potentially life-threatening A severe, life-threatening condition characterized by rapid onset and potentially airway, respiratory, or circulatory system involvement. As a life-threatening systemic hypersensitivity reaction, the World Allergy Organizat Defined in accordance with the ION Guidance 2020 and usually, but not necessarily, It is accompanied by skin and mucous membrane changes. A wide variety of molecules can induce anaphylaxis. These include: The most common proteins or mast cells that induce anaphylaxis in an IgE-dependent manner IgE-mediated anaphylaxis is mediated by effector cells, primarily , allergen-specific IgE / high affinity receptors expressed in mast cells and basophils ( By the interaction of allergens (usually proteins) with the FcεRI complex. be caused.

[0075] As used herein, the phrase "population of subjects" refers to a group of subjects. It is used to

[0076] As used herein, the term "subject" refers to an animal. Typically, an animal The subject may also be, for example, a primate (e.g., a human, male or female). , cattle, 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 it refers to a human is equivalent to "patient." It is used literally.

[0077] As used herein, a subject is one who has undergone a biological, medical, or qualitative transformation from a treatment. If such a subject would benefit from the treatment of life, he or she is in need of treatment or prophylaxis. "This is what they say."

[0078] In some embodiments of the disclosed methods, a BTK inhibitor, such as LOU064 or its The pharma- ceutically acceptable salts are intended to inhibit IgE-induced food allergic reactions to one or more allergens. The present invention is used to treat a population of subjects having

[0079] As defined herein, "IgE-induced allergy to one or more allergens" means - (or allergic reaction)" or "IgE-mediated allergy (or allergic reaction)" The terms "allergic reaction" and "allergic reaction to drugs" are used interchangeably and include, for example, drug allergy, poison allergy, or Food allergies (or allergic reactions), preferably peanuts, nuts, milk, wheat, Allergic reactions to food allergens such as soybeans, eggs, sesame, seafood, or mixtures thereof In certain embodiments, food allergy also refers to a reaction to, for example, one or more allergens. Adults and children aged 2 years and older with a definite or suspected diagnosis of IgE-induced food allergy to cereals Including anaphylaxis following accidental exposure to food allergens in pediatric patients Refers to indications for preventing allergic reactions. "IgE-induced food allergic reactions" The term is an adverse reaction to food and is caused by an unregulated type 2 immune response.

[0080] In certain embodiments, drug allergy can be, for example, an IgA allergy to one or more allergens. Patients with a confirmed or suspected diagnosis of E-induced allergy, such as adults and children aged 2 years or older Prevention of allergic reactions, including anaphylaxis, following exposure to drug allergens in individuals Refers to indications for

[0081] IgE-mediated reactions are usually classified as immediate-onset reactions (occurring within 2 hours of food ingestion) and immediate-onset reactions. It is divided into early and late (immediate onset symptoms followed by prolonged or persistent symptoms). E-mediated drug- or food-related reactions include cutaneous symptoms (e.g., angioedema, acute urticaria, gastrointestinal reactions (symptoms include itching and swelling of the lips, tongue, and palate, laryngeal edema, nausea, abdominal cramps, convulsions, vomiting and diarrhea); respiratory reactions (e.g. allergic rhinitis, conjunctivitis and bronchoconstriction) systemic reactions (rapidly progressive anaphylaxis, typically gastrointestinal (GI) or Combined with respiratory symptoms, it is a multi-organ system response including cardiovascular collapse.

[0082] For treatment with a BTK inhibitor, such as LOU064 or a pharma- ceutically acceptable salt thereof Non-responders were those who failed to achieve at least 80% improvement over baseline. Subjects who have had a history of or have had a worsening of symptoms. Responders to treatment with a commercially acceptable salt were those who achieved a minimum of 80% improvement from baseline. A subject who achieves a good outcome is defined as a subject who achieves a good outcome.

[0083] The term "oral immunotherapy" or "OIT" refers to a method in which a patient with an allergy administers the allergen To induce a safer immune response to rugen and induce some degree of desensitization, Exposure to increasing amounts of allergens to which you are allergic (e.g. food allergens) over a period of months OIT therapy consists of two phases: 1. Allergy A titration phase consisting of slowly increasing the amount of and 2. a maintenance phase where patients stay on the same dose. Patients who are able to achieve a maintenance dose generally have a high risk of developing severe allergic reactions, including rhagia. As long as you take OIT, you will be protected from reactions resulting from accidental exposure.

[0084] The term "sublingual immunotherapy" or SLIT generally refers to the daily administration of allergens under the tongue. Another form of allergy immunotherapy involves the use of serotoninib in combination with other drugs. The only forms of LIT are directed against northern grasses such as ragweed, timothy grass, and house dust mites. The tablet is placed under the tongue for 1-2 minutes and then as it dissolves, The process is repeated three or four days a week. The pills increase resistance to pollen. For continued effectiveness, treatment should be continued for 3 years or more. Allergy tablets for ragweed and grass pollen only are currently available. do.

[0085] The term "transdermal immunotherapy" or EPIT refers to a drug that is administered by repeated application to the skin. EPIT is another form of allergen immunotherapy that delivers allergens through a patch. The use of sensitization agents to allergens has been shown to be associated with persistent sensitization or tolerance to allergens due to continuous (and constant) exposure to the skin. The purpose is to produce sexuality.

[0086] As used herein, "select" and "selected" in reference to a patient are A particular patient may have a greater chance of being diagnosed based on the particular patient having a given criterion. Similarly, the term "selective treatment" is used to mean specifically selected from a group of "Selectively prevent" or "selectively prevent" refers to patients with a particular disease (e.g., a particular food allergy). Patients with known or suspected allergic reactions to gen or prevention, where the patient is a particular patient having a predefined criterion. Based on the specificity of the subject, the subject is specifically selected from a larger group of patients. Based on (by) a particular patient with a given criterion, a particular group of patients is selected from a larger group of patients. "Select" refers to administering a drug to specifically selected patients. " and "selectively administer" means to a patient based solely on membership in a larger group. Rather than a standard treatment plan being delivered, the patient's medical history (e.g., previous therapeutic interventions, (e.g., previous treatment with a biologic), biology (e.g., specific genetic markers), and and / or individualized treatments are delivered to patients based on symptoms (e.g., failure to meet certain diagnostic criteria). As used herein, with respect to the method of treatment, selecting means does not refer to the coincidental treatment of patients with certain criteria, but to It refers to the careful selection of administering treatment to a patient based on the patient's medical history. The treatment is based on the assumption that the patient has a particular disease, regardless of the patient's medical history, disease symptoms, and / or biology. Unlike standard treatments / administrations that deliver a particular drug to every patient. , patients were selected based on having a known allergic reaction to exposure to food allergens. were selected for treatment.

[0087] The term "pharmaceutical combination" as used herein means a combination of two or more active ingredients. This specification means the product obtained from the use or mixing or combining thereof. A pharmaceutical combination as used herein means a fixed combination of active ingredients and a fixed The term "fixed combination" should be understood to include both fixed combinations and combinations that are not fixed. The term "combination" refers to the administration of an active ingredient, e.g. a compound of formula (I) or its or a pharma- ceutically acceptable salt or polymorph thereof, and one or more of the combination partners are a single entity. or dosage form administered to a patient simultaneously. In such cases, the term Refers to a fixed-dose combination in one unit dosage form (e.g., capsule, tablet, or sachet). "non-fixed combination" or " Any term "kit of parts" refers to a combination of active ingredients, e.g., a compound of the present disclosure and one or more The combination partners and / or one or more of the co-agents may be administered simultaneously, in parallel, without any specific time limit. Administered to a patient independently as separate entities or co-administered, either simultaneously or sequentially. Such administration means that these time intervals are particularly important when the combination partners are coadministered The combination of two compounds in a patient's body allows them to have the same effect, e.g., an additive or synergistic effect. The term "non-fixed combination" refers to a combination of The term "fixed" also applies to therapeutic approaches, for example the administration of three or more active ingredients. The term "non-combined" refers to compounds described herein that are used independently of one another, i.e. That is, they may be administered at the same time or at different times, and in particular, administration, use, composition or defines a formulation. The term "non-fixed combination" refers to a single drug, e.g., LOU06 4 or its pharma- ceutically acceptable salts or polymorphs thereof, each of which contains different amounts of the active ingredient therein. The combination of one or more fixed combination products with each of the individual formulations may be used together. It should be understood that the combination products described herein are also encompassed by the term "combination products" and "combination products" as used herein. The term "non-fixed combination" refers to a combination of active ingredients (including the compounds described herein) ), where the combination partners are completely separate pharmaceutical agents that are also sold independently of each other. It should further be understood that the pharmaceutical composition may be administered in any form or pharmaceutical formulation. Instructions for use of the combination may be provided on the packaging, e.g. a leaflet or the like, or by a physician and / or medical It is or may be provided in other information provided to staff, including independent The agents or parts of the formulation, product or composition may be administered simultaneously or at staggered times. , i.e., each individual part in the kit of parts can be may be administered at different times and / or with equal or different time intervals. The time interval between administrations is determined by the effect of the combined use of the parts on the disease to be treated. obtained by using only the compound of formula (I) or a pharma- ceutically acceptable salt or polymorph thereof. and thus, the pharmaceutical effects described herein are selected to be greater / higher than those achieved by the The compounds used in the combination are synergistically active. The ratio of the total amount of the compound of formula (I) or a pharma- ceutically acceptable salt or polymorph thereof to the agent. The needs of the particular patient subpopulation being treated, or for example, the patient's age, sex, weight, etc. It may be altered or adjusted to better suit the needs of a given individual patient.

[0088] As used herein, terms such as "co-administration" or "administration in combination" refer to one or more of the compounds described herein, together with selected combination partners, and administering the therapeutic agent 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.

[0089] The terms "adjuvant" or "adjuvant therapy" or "adjuvant therapy" refer to any agent that is effective in maximizing efficacy. It is a treatment given in addition to first-line or initial treatment to improve efficacy and safety. In the context of the present invention, adjunctive therapy is a BTK inhibitor in addition to a primary therapy of oral immunotherapy (OIT). For example, adjunctive therapy (i.e., BTK inhibitors or LOU064) was used to evaluate the efficacy and safety of allergic reactions and inflammatory bowel disease before major treatment (e.g., OIT) and during the titration phase. It is given during the titration phase of OIT to prevent anaphylactic and / or anaphylactic reactions.

[0090] 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 an anti-Bruton's type tyrosine kinase inhibitor. WO 2015 / 079417 A as a drug candidate for selective inhibition of tyrosine kinase The compound is disclosed in the brochure of issue 1. It is a potent, highly selective, irreversible covalent BT LOU064 is a potent cytotoxic T cell-associated kinase (BTK) inhibitor. Due to its binding to the inactive conformation of BTK, LOU064 has excellent catalytic activity. Demonstrates kinase selectivity, thus reducing kinase off-target binding and covalent inhibition 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).

[0091] LOU064 for use in the methods of the present invention has the formula (I): [ka] It is a free base represented by:

[0092] In another embodiment, N-(3-(6-amino-5-(2-(N-methylacrylamide 5-fluoro-2-methylphenyl)-4-(2-methylphenyl)-5-fluoro-2-methylphenyl Cyclopropyl-2-fluorobenzamide is disclosed in the International Publication No. 2003 / 013363, 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

[0093] Chronic spontaneous urticaria (CSU) (International Publication No. 2020 / 234782 A1 Brochure 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 Sj Currently being tested in clinical trials for S (Phase 2); CSU and MS (Phase 3). do.

[0094] In the International Publication No. 2020 / 234782 A1 pamphlet, Doses of 100 mg and 100 g given twice daily (bid) were associated with the greatest efficacy in CSU. It was generally suggested that achieving sexual maturity was the goal.

[0095] Control with H1-antihistamines, with at least moderately active CSU To evaluate the efficacy and safety of remibrutinib over 12 weeks in underserved patients In a phase 2b, randomized, double-blind, placebo-controlled study, patients were given 10 mg of remibrutinib g qd (once a day), 35 mg qd, 100 mg qd, 10 mg b .id (twice daily), 25 mg bid, 100 mg bid, or prednisolone Patients were administered placebo (1:1:1:1:1:1:1:1 ratio) at 25 mg bid. Jimen proved to be particularly effective.

[0096] BTK occupancy in blood and / or tissues has been investigated in clinical trials such as the CSU and SjS studies. It has been reported that the marker is a suitable biomarker for selecting the dose for Brochure No. 2020 / 234782 and Brochure No. WO 2020 / 234781 Let).

[0097] 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). .

[0098] BTK occupancy in different tissues may be important for efficacy in different indications and optimal dose selection. However, multiple allergies caused by food allergies are All tissues involved in the reaction and therefore treat or prevent IgE-induced food allergic reactions There is currently no consensus on which tissues need to be infiltrated to achieve this. As reported, BTK occupancy and BTK half-life were measured in blood and various tissues. are different.

[0099] Furthermore, the BTK occupancy half-life is related to the turnover rate (the rate at which BTK protein is repopulated within cells). Such turnover rates vary from tissue to tissue and are species-specific. BTK occupancy further depends on the PK / PD properties of the compound, which are also species specific. do.

[0100] Therefore, clinical responses to oral food challenge should be evaluated for CSU dose or other indications. No predictions can be made with any of the doses shown.

[0101] Pharmaceutical compositions for use in the methods of the present invention BTK inhibitors, i.e., compounds of formula (I) or pharma- ceutically acceptable salts thereof The polymorphs, when combined with a pharma- ceutically acceptable carrier, can be used as pharmaceutical compositions. Such compositions comprise a compound of formula (I) or a pharma- ceutically acceptable salt or polymorph thereof. In addition, carriers, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and other suitable agents may be used. The characteristics of the carrier will depend on the route of administration. The pharmaceutical compositions for use in the methods include additional therapeutic options for the treatment of specific targeted disorders. A therapeutic agent may also be included. For example, the pharmaceutical composition may also include an anti-inflammatory or antipruritic agent. The additional factor and / or agent may be a compound of formula (I) or a pharma- ceutically acceptable salt thereof. or to produce a synergistic effect with polymorphs or polymorphs, or to inhibit the synthesis of a compound of formula (I) or a pharma- ceutically acceptable derivative thereof. In order to minimize side effects caused by salts or polymorphs, In a preferred embodiment, a pharmaceutical composition for use in the disclosed methods The product may be about 10 mg, about 20 mg, about 25 mg, about 50 mg or about 100 mg, preferably , about 25 mg, about 50 mg or about 100 mg of the compound of formula (I) or a pharmaceutical This includes acceptable salts or polymorphs.

[0102] 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 The composition intended for oral administration contains an effective amount of a compound of the present invention in the form of a pharmaceutical preparation. The composition may be prepared according to any method known in the art for the manufacture of such compositions. Such compositions may be formulated with sweeteners, flavoring agents, and / or other additives to provide a pharma- ceutical elegant and palatable formulation. The tablet may contain one or more agents selected from the group consisting of a stearate agent, a coloring agent, and a preservative. The active ingredient may be contained in admixture with non-toxic pharma- ceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients include, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, etc. inert diluents such as calcium or sodium phosphate; granulating and disintegrating agents, e.g., tomo 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 , which may be 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. For oral administration, the active ingredient may be dissolved in an inert solid diluent, such as calcium carbonate. as hard gelatin capsules mixed with calcium carbonate, 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.

[0103] 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 salts. salts and / or polyethylene glycol; and for tablets c) Binders, such as magnesium aluminum silicate, starch paste, gelatin Tin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or or polyvinylpyrrolidone; as required d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or saccharides. and / or e) Absorbents, colouring agents, flavourings and sweeteners It is a tablet or gelatin capsule containing the active ingredient together with

[0104] Thus, the pharmaceutical composition for use in the methods of the present invention comprises LOU064 and 1 or more pharma- ceutically acceptable carriers, each of which may independently comprise a filler, a lubricant, It is selected from a binder, a disintegrant and a glidant.

[0105] In another embodiment, the preferred pharmaceutical composition, LOU064, is any pharma- ceutically acceptable The pharmaceutical composition may be in the form of a tablet or capsule. The tablets may be film-coated or enteric-coated according to methods known in the art. The L-glutamate may be incorporated into the pharmaceutical composition / formulation as nano- or micro-sized particles. It may also be preferable to include OU064.

[0106] 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.

[0107] 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 from 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 LO may be from about 120 nm to about 180 nm or from about 120 nm to about 160 nm, preferably from about 1 The average particle size of U064 may be from about 150 nm to about 200 nm.

[0108] When LOU064 is present in the pharmaceutical formulation in the form of nano-sized particles, oral administration is preferred. Preferably, the dose is about 50 mg to about 150 mg twice a day, more preferably about 1 mg twice a day. The dosage is 00mg.

[0109] 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. The average particle size of 4 may be 1.1 to 1.3 μm.

[0110] When LOU064 is present in the pharmaceutical formulation in the form of micro-sized particles, oral administration Preferably, the dose is about 100 mg to about 300 mg twice a day, for example, about 100 mg twice a day. The dosage is g.

[0111] In a preferred embodiment, the polydispersity index (PI) is from 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. As shown.

[0112] The average particle size above is intensity weighted. The average particle size was 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.

[0113] Preferably, the measurements are performed by wet chromatography 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~ 9, in particular 5. The measurement is preferably carried out at 25° C. Further features of the measurement system The preferred configuration is as follows: Cell: Disposable sizing cuvette Count rate (kcPs): 315 Duration: 60 seconds Measurement position (mm): 4.65.

[0114] In one embodiment of the 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.

[0115] In one embodiment, the formulation for LOU064 is No. 63 / 141,558 or family members thereof (e.g., International Formulated according to the formulations disclosed in Publication No. 2022 / 162513. do.

[0116] According to the present invention, a suitable pharmaceutical composition for oral administration comprises LOU064 and a binder. nothing.

[0117] Suitable binders include polyvinylpyrrolidone-vinyl acetate copolymers, polyvinyl L-pyrrolidone, Hydroxypropyl cellulose, Hydroxypropyl methylcellulose, 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 mixtures thereof. Preferably, the binder is polyvinylpyrrolidone- It is a vinyl acetate copolymer.

[0118] The weight ratio of LOU064 and the 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.

[0119] Preferably, a suitable pharmaceutical composition for oral administration comprises LOU064, a binder and a surfactant. Contains sexual agents.

[0120] 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.

[0121] 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. 4. The weight ratio of the binder and the surfactant is about 2:1:0.08 or about 1:1:0.05. It is.

[0122] In a particularly preferred embodiment, the pharmaceutical composition suitable for oral administration is LOU064, 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 diameter 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.

[0123] Treatment or prevention using LOU064 or a pharma- ceutically acceptable salt or crystalline form thereof How to. In a subject in need thereof, one or more allergens, such as toxins, drugs or foods, e.g. Preventing, treating or modifying the course of IgE-induced allergic reactions, e.g. to peanuts and methods for use in treating the inflammatory bowel disease, and BTK inhibitors, e.g., irreversible BTK inhibitors, e.g. For example, a compound of formula (I) (i.e., LOU064) or a pharma- ceutically acceptable salt thereof, Polymorphs are disclosed herein and are described herein as therapeutically effective doses of LOU064 or its pharmaceutical formulations. In one aspect of this embodiment, the method comprises administering to the subject a physiologically acceptable salt of the present invention. The disclosure provides a method for the detection of allergens, such as peanut allergens, in a subject in need thereof. or a drug thereof for use in preventing IgE-induced food allergic reactions in mice For the purposes of the present invention, a therapeutically effective dose of LOU064 or a pharma- ceutically acceptable salt thereof is administered. The method includes administering to a subject a salt of LOU064 that is As described above, it can be incorporated into pharmaceutical compositions and used by patients with poison, drug or food allergies (including those with food allergies). The compounds may be administered in vivo to treat a patient, i.e., a human patient.

[0124] For example, an IgE-induced food allergic reaction to one or more allergens is called a food allergen. ghee reactions, e.g. peanut allergy reactions.

[0125] In yet another example, an IgE-induced food allergic reaction to one or more allergens. The disease or disorder is peanut, nut, milk, wheat, soy, egg, sesame, seafood allergy reaction. Refers to response.

[0126] In another embodiment, the subject suffers from a food allergy, e.g., a peanut allergy. cormorant.

[0127] The ability of LOU064 to inhibit a defined allergen response was assessed in first-in-human In the multiple ascending dose (MAD) portion of the Hayman study, The skin prick test (SPT) was used to evaluate the allergens. Pollen mixture, birch pollen, alder pollen, hazel pollen, house dust mites, cat dander and faeces (skin dander) before any administration (baseline) and after the first administration and for 11 days The study was conducted at different time points after once-daily administration of 100 mg of A dose-dependent decrease was demonstrated. Above 100 mg, no dose-dependent trend was evident. However, the greatest reduction was observed at the highest dose tested (600 mg qd). Across the trials, participants experienced an average increase in wheal size of 3 m at doses of 100 mg qd or higher. showed a decrease in m (Kaul et al. Clin. Transl. Sci. 2021 ;14(5),pp 1756-1768).

[0128] Dose-dependent inhibition of FcεR1-mediated basophil activation was also observed in first-in-human This was demonstrated with LOU064 during the single ascending dose study (SAD) of LOU064. Ex vivo blood basophil activation, as measured by CD63, was significantly greater at the 60 mg dose At the high dose, inhibition was nearly complete (>89%) at 24 hours after administration, reaching nearly 100% inhibition. Doses of 100 mg and above demonstrated nearly complete inhibition. In contrast, other basophil The activation marker, CD203c+, was highest at 8 hours in the 200 mg cohort. In a multiple ascending dose study (MAD), Complete inhibition of blood basophil activation, as measured by ≥50 mg of LOU064, was observed Daily doses were achieved throughout the entire treatment period (Days 1-12) and beyond. The trough inhibition of CD63 on the last day of treatment was 80% at the lowest dose tested; this was more potent at any of the higher doses. Dependent inhibition was observed in the CD63 marker at the last day of dosing at 100 mg q. d. and above, trough inhibition of >97% was achieved. Inhibition of CD203c+ basophils was The rates were 63% and 67%, respectively, and were highest at 400 mg qd and 200 mg bid. (Kaul et al.Clin.Transl.Sci.2021;14(5), pp. 1756-1768).

[0129] Furthermore, the present inventors have developed an ovalbumin-induced anaphylaxis mouse model (see Example 1). 3) Treatment with LOU064 (10mg / kg, 30mg / Kg) improved pulmonary anaemia. The number of cells involved in phylaxis (eosinophils, basophils, macrophages and lymphocytes) The results and the translation model between animals and humans (J ournal of basic and clinical pharmacy,7( 2), 27-31), the calculated human equivalent dose (H ) for 30 mg / kg was The ED is approximately 170 mg for a 70 kg person, the lowest effective dose of 10 mg / kg. The calculated human equivalent dose (HED) for the dose is approximately 56 mg for a 70 kg person. (Nair, A.B., & Jacob, S. (2016).

[0130] Finally, an in-house predictive model for splenic BTK occupancy in humans (Example 7) showed that 1 day Twice-dose (bid) administration increases the Q of the same dose to achieve higher BTK occupancy. D administration was shown to be more effective than 25 mg bid (Figure 13). The dose of LOU064 is the minimum effective dose in humans, and the dose of 100 mg bid is It has been shown to be effective in humans.

[0131] Suitable dosages can be determined, for example, by administering to a patient a particular pharma- ceutically acceptable salt of LOU064, LOU064 The particular polymorphic form of, the host, the method of administration, the pharmaceutical composition, and the nature and severity of the condition being treated. The dosage will vary depending on the severity of the treatment, as well as the nature of prior treatments the subject has received.

[0132] In a preferred embodiment, LOU064 is administered regardless of weight, sex, age, or race. For example, a 35-year-old woman weighing 60 kg may be given It is preferable that the patient is administered the same dose as a 50-year-old man. has no clinically significant effect on the pharmacokinetics of LOU064.

[0133] Ultimately, the attending healthcare professional will decide the amount of LOU064 with which to treat each individual subject. In one embodiment, the attending medical professional will administer a low dose of LOU064. and the subject's response can be observed.

[0134] In one embodiment of the disclosure, LOU064 or a pharma- ceutically acceptable salt thereof is administered at a dose of about It is administered orally in doses of 20 mg to about 200 mg.

[0135] In another embodiment, LOU064 or a pharma- ceutically acceptable salt thereof is administered at a dose of about 25 mg daily. g daily, or about 50 mg daily, or about 75 mg daily, or about 100 mg daily. In one aspect of this embodiment, LOU064 is administered at about 25 mg QD (once a day), or at a dose of about 50 mg QD, or about 75 mg QD, or about 100 mg QD. can be.

[0136] In one embodiment of the present disclosure, LOU064 or a pharma- ceutically acceptable salt thereof is administered twice a day. About 10 mg to about 100 mg twice a day, e.g., about 10 mg twice a day (BID), Doses of about 25 mg BID, about 50 mg BID, or about 100 mg BID It is administered orally.

[0137] In another embodiment, LOU064 is administered orally at a dose of about 10 mg twice daily. .

[0138] In another embodiment, LOU064 is administered orally at a dose of about 25 mg twice daily. .

[0139] In another embodiment, LOU064 is administered orally at a dose of about 50 mg twice daily. .

[0140] In another embodiment, LOU064 is administered orally at a dose of about 75 mg twice daily. .

[0141] In another embodiment, LOU064 is administered orally at a dose of about 100 mg twice daily. do.

[0142] The duration of treatment using the pharmaceutical compositions of the present disclosure will depend on the severity of the disease or disorder being treated, as well as the severity of each It will vary depending on the condition and personal response of each individual subject. , the subject is administered the drug for a short period of time, e.g., up to 4 weeks, e.g., up to 6 weeks, e.g., up to 8 weeks, For example, LOU064 is administered for up to 10 weeks, for example for up to 12 weeks. OU064 is intended to treat severe food allergic reactions and triggers, for example, during business trips and / or vacations. to prevent exposure to allergens, or any other situation in which exposure to allergens is not adequately controlled; It may, for example, be administered for a short period of time, as defined herein above.

[0143] In one embodiment, LOU064 is a potent inhibitor of the inflammatory response to exposure to an allergen (e.g., a food allergen). In another embodiment, LOU06 is administered at least 2 days prior to the potential risk of exposure. 4 is at least 1 day before the potential risk of exposure to an allergen (e.g., food allergen). It is administered within a week, for example 1 week, 2 weeks, 3 weeks, or 4 weeks before anti-IgE therapy. The advantage of LOU064 over other treatments is the ability to achieve maximum protection / prevention of allergic reactions. It has a fast onset of action.

[0144] In certain other embodiments, the subject is administered LOU064 for a long period of time ( For example, LOU064 may be used for as long as a disease exists that justifies its use, e.g., at least At least 6 months, e.g. at least 10 months, e.g. 1 year, e.g. 1 year, 2 years, 3 years LOU064 or its equivalent may be used for an unlimited period of time, for example, 4 years, 10 years or more. Pharmaceutically acceptable salts are protected for up to 2 years, 5 years, 10 years, 15 years, 20 years or In one embodiment, treatment with LOU064 can be used for chronic treatment. It is treatment.

[0145] In carrying out some of the methods of treatment or use of the present disclosure, a therapeutically effective dose of LOU0 64 or a pharma- ceutically acceptable salt thereof is administered to a subject, e.g., a mammal (e.g., a human). The disclosed method comprises the step of detecting IgE-induced food allergens using LOU064 or a salt thereof. While it is understood that the present invention provides treatment or prevention of glycemic reactions, this does not mean that treatment is necessarily the only option. It is not meant to be a therapy.

[0146] In one embodiment of the invention, a BTK inhibitor, e.g., an irreversible BTK inhibitor, e.g., LOU 064 will be administered to subjects as monotherapy.

[0147] In another embodiment of the present invention, a BTK inhibitor, such as an irreversible BTK inhibitor, such as LO U064 is administered to the subject as a combination therapy.

[0148] Indeed, if a subject is selected for treatment with LOU064, LOU064 and combination with other drugs and therapies for treating subjects suffering from diseases or disorders involving IgE. In combination, for example, at least one additional therapeutic agent, such as an anti-IgE antibody (e.g. omalizumab or ligelizumab), corticosteroids or immunosuppressants, e.g. systemic May be administered according to the methods of the present disclosure in combination with corticosteroids or immunosuppressants .

[0149] In certain embodiments of the disclosed uses, methods, and kits, the subject is have an IgE-induced allergic reaction to an allergen, where the allergen is a drug or food In one embodiment, the subject also has an asthma and / or hives, e.g., asthma, allergic asthma, rhinitis, allergies The patient has a disease or disorder selected from the group consisting of allergic rhinitis, urticaria, and CSU. In certain embodiments of the uses, methods, and kits, the subject is exposed to one or more allergens (e.g. For example, peanuts, nuts, milk, wheat, soybeans, eggs, sesame, seafood, or mixtures thereof. have an IgE-induced food allergic reaction to food allergens.

[0150] In other embodiments of the disclosed uses, methods, and kits, the subject is have an IgE-induced food allergic reaction to an allergen, where the allergen is food, For example, peanuts.

[0151] For example, if the subject being treated is allergic, or if the subject also suffers from asthma, rash, or other conditions, and rhinitis, e.g., allergic asthma, CSU, and allergic This may be the case if the patient suffers from another disease or disorder selected from rhinitis.

[0152] When co-administered with one or more additional agents, LOU064 or a pharma- ceutically acceptable derivative thereof The drug may be administered simultaneously with the other drug or sequentially. If administered sequentially, the doctor The present invention relates to an appropriate method for administering LOU064 or a pharma- ceutical acceptable salt thereof in combination with other drugs. The appropriate sequence and dosages for co-delivery will be determined by the individual.

[0153] A variety of therapeutic approaches are disclosed herein for treating diseases or disorders involving IgE. Such therapeutic approaches include, for example, Anti-IgE antibodies (e.g., omalizumab, ligelizumab), corticosteroids (e.g., inhaled or systemic corticosteroids, immunosuppressants, leukotriene receptor antagonists Long-acting beta agonists (LTRAs), short-acting beta agonists (SABAs) or long-acting beta agonists Examples include LABA.

[0154] In certain embodiments of the disclosed uses, methods, and kits, LOU064 or a drug thereof Clinically acceptable salts may be prescribed as first-line therapy or added to either standard of care. It is possible.

[0155] In another embodiment, LOU064 or a pharma- ceutical acceptable salt is administered to an IgE-inducing food allergen. In combination with other drugs and therapies for treating allergic reactions, It can be administered.

[0156] In one embodiment, LOU064 or a pharma- ceutically acceptable salt thereof is used in oral immunotherapy ( OIT), sublingual immunotherapy (SLIT), transdermal immunotherapy (EPIT), preferably OIT In one aspect of this embodiment, LOU064 is administered in combination with adjunctive therapy for OIT. It is administered as a treatment.

[0157] Oral immunotherapy (OIT) involves administering increasing amounts of food allergens under medical supervision. These procedures include desensitization to allergens. OIT therapy is used to treat these typically potentially life-threatening reactions. The risk of infection requires hospitalization of the patient, making it costly and labor intensive.

[0158] In one embodiment, a BTK inhibitor, such as an irreversible BTK inhibitor, such as LOU06 4, when administered according to the methods of the present disclosure, is effective in treating OIT, SLIT, EPIT, preferably , OIT-related side effects (e.g., severe systemic reactions, such as anaphylaxis) Reduces the frequency and severity of allergic reactions.

[0159] In another embodiment, a BTK inhibitor, such as an irreversible BTK inhibitor, such as LOU0 64, when administered according to the methods of the present disclosure, can be used to increase OIT titration (i.e., increase the titration phase of OIT). ) to allow more patients to successfully complete OIT, for example. do.

[0160] In one embodiment, a BTK inhibitor, such as an irreversible BTK inhibitor, such as LOU06 4 will be administered as an adjunct to peanut protein-based OIT treatment.

[0161] To date, no single drug has been shown to reduce allergic reactions in peanut allergy sufferers. The currently approved OIT product is Palforzia. TK inhibitors, such as irreversible BTK inhibitors, e.g., LOU064t, are As an adjunct to a protein (e.g., Palforzia™), administered according to the methods of the present disclosure can be given.

[0162] In one embodiment, a BTK inhibitor for use in accordance with the methods described herein For example, irreversible BTK inhibitors, such as LOU064, may be used to at least partially inhibit the administration of oral immunotherapy. At least 2 days before, or at least 1 week (7 days) before, or at least 2 weeks (14 days) before In one aspect of this embodiment, the compound is administered in accordance with the methods described herein. BTK inhibitors for use in the present invention, such as irreversible BTK inhibitors, preferably LOU064 , further administered during the titration phase of immunotherapy treatment, and then at the start of the maintenance phase of OIT. to abort LOU064.

[0163] Patient Selection In one embodiment, the patient is an adult (18 years of age or older).

[0164] In another embodiment, the patient is an adolescent (ages 12-17).

[0165] In yet another embodiment, the patient is a pediatric patient (ages 2-11 or 6-11). .

[0166] In another embodiment of the present invention, for the treatment or prevention of IgE-induced food allergic reactions Patients receiving BTK inhibitors, such as irreversible BTK inhibitors, e.g., LOU064, , selected according to the following criteria: a) Male and female patients, aged 2 years or older (e.g., 2-5 years or 6-11 years, 12-17 years or 18-55 years old); b) Including but not limited to peanuts, tree nuts, wheat, eggs, milk, soybeans, fish and shellfish A confirmed history of allergies to food; c) Positive allergen-specific IgE (e.g., peanut sIgE ≥ 1 at screening) 6 kUA / L); d) A positive skin prick test to an allergen to which the patient is allergic (e.g. , defined as a wheal with a mean diameter (longest diameter and midpoint perpendicular diameter) of ≥ 4 mm compared with the negative control. (defined as

[0167] In one aspect of the above embodiment, administration of LOU064 or a pharma- ceutically acceptable salt thereof Patients included were those with uncontrolled asthma, defined as having one of the following criteria: do not have: - Patient has a predicted normal FEV1 < 80% at the time of the first screening visit - One hospitalization for asthma within the 12 months prior to the screening visit.

[0168] Effectiveness In one embodiment, the present invention provides a method for the preparation of a medicament for use in any of the methods described herein. The present invention relates to a BTK inhibitor for the treatment of cancer, e.g., an irreversible BTK inhibitor, e.g., LOU064, wherein A BTK inhibitor, e.g., an irreversible BTK inhibitor, e.g., LOU064, is administered at x weeks of treatment. In one aspect of this embodiment, prevention is achieved with a minimum of 100% reduction from baseline. 80% reduction (e.g., a minimum of 85% reduction or a minimum of 90% reduction from baseline) It is defined as "small."

[0169] In one embodiment, the present invention provides a method for the preparation of a medicament for use in the methods described herein. With respect to TK inhibitors, e.g., irreversible BTK inhibitors, e.g., LOU064, wherein At least one of the following applies: After up to 4 weeks (e.g., 1 week, or 2 weeks, or 3 weeks) of treatment with LOU064 or 4 weeks later), At least 90% of treated patients are able to tolerate 600 mg of food allergen (e.g., 600 mg of peanut protein) did not show any allergic reaction. At least 90% of treated patients are able to tolerate 1000 mg of food allergen (e.g., 10 00mg of peanut protein) did not show any allergic reaction, At least 80% of treated patients are able to tolerate 3000 mg of food allergen (e.g. 30 00mg peanut protein) did not produce an allergic reaction upon food challenge.

[0170] In another embodiment, the present invention provides a method for treating a patient having a total domain score F of 0.45 to 0.5. In the methods described herein, which achieve a reduction from baseline in AQLQ This document relates to LOU064 for use in

[0171] The Food Allergy Quality of Life Questionnaire (FALQLQ) is a questionnaire to assess the quality of life of food allergies. Disease-specific health-related quality of life (HRQoL) measures for patients with They are the Adult Questionnaire (AF), the Child Questionnaire (CF), and the Teenage Questionnaire (TQQ). The Food Allergy Questionnaire (TF) and two questions completed by parents of food-allergic children The questionnaires (Parent Questionnaire PF and Parent Questionnaire Teenager PFT) were developed. These questionnaires are recognized as a method to assess HRQoL (health-related quality of life). It is a reliable and valid means of measuring the impact of food allergy on the Qualitatively, the Food Allergy Quality of Life Questionnaire (FAQLQ) was used to assess participants' H Assess the impact of food allergy on RQoL (i.e., the domains are accidental exposure, risk, emotional effects, allergen avoidance and dietary restrictions). (8-12 years old)(Flokstra-de Blok BM et al(2009)C linical.Exp.Allergy;39:(1)127-37), FAQLQ- Teenager Questionnaire (13-17 years old) (Flokstra-de Block B M et al. (2008) J. Allergy Clinical Immunol ogy;122:139-44,144.e1-2) and FAQLQ-Adult Questionnaire (≧1 8 years old)(Flokstra-de Blok BM et al(2009)Aller gy;64(8):1209-17) is a self-administered, validated food allergy-specific HR The FAQLQ-Parent Questionnaire (FAQLQ-PF) is a QoL questionnaire for food allergies. The questionnaire was completed by parents of children aged 0–12 years with pulmonary embolism (Dunn Galvin t al(2008),Clin Exp Allergy,40(2010),476 -485).

[0172] The number of items and domains varies depending on the FAQLQ document being administered. HRQoL is scored on a 7-point scale ranging from “none” to “maximum” The total score is the arithmetic mean of all nonmissing items. is calculated similarly.

[0173] In yet another embodiment, the present invention provides a method for determining whether a patient has a FAIM score based on the total domain score FAIM. Regarding LOU064 for use in the methods of the invention to achieve a reduction in do.

[0174] The Food Allergy Independent Measure (FAIM) is a valid and reliable measure for predicting patient outcomes. It is a highly reliable instrument and is used in children (FAIM-CF), adolescents (FAIM TF) and adults. Developed for people (FAIM AF) (Flokstra-de Block et al.Allergy 65(5):630-5). Food Allergy Independent Measure (FAI) M) reflects participants' perceived food allergy severity and food allergy-related risk. The FAIM contains four questions that are also scored from 0 to 6, with higher scores indicating Poorer prediction of adverse outcome if the allergen is accidentally ingested (e.g. severe reaction or Death.

[0175] In yet another embodiment, the present invention provides a method for preparing a food product containing 600 mg of an allergen (e.g., peanut Between treated and untreated patients in a double-blind, placebo-controlled food challenge with tsarallergen The observed difference in response rate is greater than 35%, where the response rate is greater than 600 mg of oral food. The method described herein is defined as having no more than a mild response to stress. This document relates to LOU064 for use in

[0176] In a further embodiment, the present invention relates to a method for treating a patient having a mild response to an oral food challenge. have no or mild reaction (e.g., to 600 mg of allergen (e.g., peanut after receiving a dose of the Tuberculosis protein) for use in the methods described herein. Mild reactions were defined as any food allergy reaction that included one or more of the following: Consortium of Fellows for Clinical Oncology (CoFAR: Sampson HA et al. J. Aller gy Clin. Immunol;130(6):1260-74) : On the skin - limited (slight) or localized hives, swelling (e.g. mild lip edema), skin flushing (e.g., some areas of mild erythema) or mild itching (e.g., , occasional scratching) Respiratory - rhinorrhea (e.g. occasional sniffling or sneezing), stuffy nose, occasional cough, sore throat Illness GI - Mild abdominal discomfort (including mild nausea with or without decreased activity) , isolated vomiting thought to be secondary to choking (gag).

[0177] In another embodiment, the present invention provides a method for treating a patient suffering from a moderate to severe reaction to an oral food challenge. No reaction occurs (for example, when 600 mg of an allergen (e.g., peanut protein) is administered) and administering to the subject a therapeutically effective amount of LOU064 for use in the methods described herein. Moderate reactions are defined as any reaction to food allergies reported by the Food Allergy Surveillance Consortium that includes one or more of the following: (CoFAR: Sampson HA et al. J. Allergy Clin. Immunol;130(6):1260-74): Skin - generalized urticaria (e.g., many or widespread hives), swelling (e.g. For example, significant lip or facial swelling, itching causing persistent scratching, erythema in several areas Areas of or marked erythema Respiratory - Throat tightness without hoarseness, persistent cough, wheezing without difficulty in breathing GI - Persistent moderate abdominal pain / cramps / nausea, vomiting with reduced activity

[0178] Severe reactions were classified as consortium-based food allergy surveillance criteria that included one or more of the following: oFAR:Sampson HA et al.J.Allergy Clin.Imm UNOL;130(6):1260-74) Skin - Severe generalized urticaria / angioedema / erythema Respiratory - Laryngeal edema, throat tightness with hoarseness, wheezing with dyspnea ), stridor GI - Severe abdominal pain / cramps / recurrent vomiting Nervous system - mental state changes · Circulatory system - clinically significant reduction in blood pressure

[0179] safety Up to 600 mg as a single dose plus 100 mg bi for up to 18 days d. The short-term safety of LOU064 was demonstrated in a Phase I clinical trial. However, no data related to long-term safety are currently available.

[0180] Dose Limitations Observed with the Covalent Irreversible BTK Inhibitors Evobrutinib and Trebrutinib Considering the limited side effects, evobrutinib was administered at a dose of 75 mg biweekly in Phase II clinical trials. 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 It is encouraging that no significant increase in the incidence of adverse events was observed with LOU064, even at higher doses. The inventors have demonstrated that long-term (up to 52 weeks) administration of 100 mg bid We demonstrated that LOU064 is safe even at high doses of . U064 has been shown to be 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.

[0181] Thus, one object of the present invention is to provide LOU064 for use in the methods described. where 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 rifapril did not change by more than 10% compared to baseline levels at the start of treatment. do not have.

[0182] Therefore, LOU064 is a potent inhibitor of IgE-induced allergic reactions (e.g., food allergic reactions). ), but also effectively prevents other Better safety profile compared to BTK inhibitors, especially compared to acalabrutinib It was particularly surprising that the company also has a file that is currently being developed primarily for the treatment of hematological malignancies. Currently approved BTK inhibitors (ibrutinib, acalabrutinib, and zanubrutinib) ) has known safety issues. The major safety issues include infections, platelet function These include effects on blood flow (risk of bleeding), and cytopenias. Other safety concerns regarding Kis include cardiac arrhythmias (atrial fibrillation and flutter) and For brutinib only, heart failure and hypertension are included.

[0183] Thus, in a preferred embodiment of the present invention, an IgE-induced allergic reaction (e.g. LOU064 or a pharmaceutical composition thereof for use in treating or preventing a food allergic reaction The term chronic treatment is used in conjunction with LOU064. or a pharma- ceutically acceptable salt thereof is used for a long period of time. OU064 or a pharma- ceutical acceptable salt thereof is administered for 6 months, 10 months, 1 year, 2 years, or 3 years. LOU064 or its pharmacologic equivalents may be used safely for 1 year, 4 years, or more than 10 years. The salts that are allowed are those that are allowed for up to 2 years, 5 years, 10 years, 15 years, 20 years, or a lifetime. It can be used as follows.

[0184] In one embodiment, LOU064 is used to treat IgE-induced allergic reactions (e.g., food allergies). Not only does it effectively prevent erythema (a type of hypercalcaemia), but it also has the following characteristics: - 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: .

[0185] LOU064 oral drug exposure is associated with increased risk of developing CYP3A inhibitors, particularly potent CYP3A inhibitors, e.g. For example, it is expected that the effect may be increased several-fold when administered with a strong CYP3A4 inhibitor. Similarly, strong inducers of CYP4A, e.g., CYP3A4, significantly reduce exposure. These properties of LOU064 may result in reduced efficacy of LOU064. The present invention relates to the treatment and / or prevention of E-induced allergic reactions, as well as any BTK-mediated pathology. Strong CYP3A inhibitors or inducers are also relevant for the treatment and / or prevention of , as defined according to the FDA 2020 guidelines. Therefore, strong CYP3A inhibitors Drugs that cause side effects (e.g., CYP3A4 inhibitors) may be associated with increased toxicity after coadministration with LOU064 compared with LOU064 alone. A >5-fold increase in area under the curve (AUC) or >80% decrease in clearance compared to placebo Strong CYP3A inducers (e.g. strong CYP3A4 inducers) ) increased the AUC by 80% after coadministration with LOU064 compared to administration of LOU064 alone. An inducer that reduces by more than 85%, 90%, or 95%.

[0186] Strong CYP3A inhibitors and / or inducers, e.g. strong CYP3A4 inhibitors and / or Coadministration with inducers may potentially cause large changes in LOU064 drug exposure, Strong CYP3A4 inhibitors include boceprevir and clarithromycin. Mycin, cobicistat, conivaptan, danoprevir / ritonavir, darunavir / ritonavir Tonavir, 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. may be included.

[0187] Thus, in another preferred embodiment, LOU064 is, e.g., Concomitant administration of strong CYP3A4 inhibitors and / or inducers, as defined above It won't be done.

[0188] LOU064 was shown to be effective in treating ethinyl estrastatin-related It has further been found that the drug may be co-administered with oral contraceptives such as diol or levonorgestrel. Thus, in a preferred embodiment, LOU064 is co-administered with an oral contraceptive. will be done.

[0189] In a preferred embodiment, no premedication is administered prior to the first administration of LOU064. .

[0190] As a covalent irreversible BTK inhibitor, LOU064 inhibits BTK synthesis by de novo protein synthesis. It acts by irreversible inhibition of BTK, which is counterbalanced by the Although we do not wish to be limited by this, reconstitution of the B cell pool after B cell depletion may take several months. Although recovery of B cell function following BTK inhibition is achieved soon after cessation, typically within a few days. Therefore, if necessary, this therapy can be stopped quickly. , thereby providing easier and faster support to clinicians and patients when unexpected situations arise. This gives the player quick reaction time.

[0191] In another embodiment, if the patient is scheduled to receive chemotherapy within the next 12 months: LOU064 is advantageously selected.

[0192] 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 clinical risk. This is likely to lead to over-reliance.

[0193] However, LOU064 does not result in depletion of the B cell pool, and therefore does not prevent cessation of treatment. Inhibition of B-cell function 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.

[0194] According to the present invention, LOU064 is administered during an infection, e.g., during COVID-19 infection. Therefore, LOU064 administration should be continued during infection, e.g., COVID-19 infection. It can be done.

[0195] Preferably, LOU064 administration is continued for an active infection, such as COV, until the infection is resolved. Delayed in patients with ID-19.

[0196] Thus, one embodiment of the present invention relates to a method for treating acutely infected or previously infected with COVID-19. Infected patients are treated, and treatment of IgE-induced allergic reactions (e.g. food allergic reactions) The present invention relates to LOU064 for use in the treatment or prevention of

[0197] In a further embodiment, LOU064 treatment is continued during COVID-19 infection. do.

[0198] In a preferred embodiment, LOU064 treatment is interrupted during COVID-19 infection. , and will continue after the infection is overcome.

[0199] Yet another embodiment of the present invention is where the patient is vaccinated during LOU064 treatment. For use in the treatment or prevention of IgE-induced allergic reactions (e.g. food allergic reactions) Alternatively, the patient may be protected from LOU064 treatment with a non-live vaccine. In one embodiment, patients may be vaccinated during LOU064 treatment (e.g., 15 days after starting OU064 treatment) Quadrivalent influenza vaccine, PPV-2 In one aspect of this embodiment, the patient is vaccinated with the 4 vaccine or the KLH neoantigen vaccine. Patients receiving a 2-valent influenza vaccine had a higher incidence of vaccination compared to baseline Response as defined by a >4-fold increase in antihemagglutinin antibody titer at day 28 In another aspect of this embodiment, a patient receiving a PPV-23 vaccine achieved a >2-fold increase in IgG titers 28 days after vaccination compared to baseline In yet another embodiment, the patient receiving the KLH neoantigen vaccine is T cell-dependent responses were observed as measured by anti-KLH IgG and IgM titers 28 days after vaccination. Achieve an antibody response.

[0200] Another embodiment of the invention is when LOU064 treatment is discontinued for vaccination, in particular Preferably, LOU064 treatment is administered 5 to 10 days, e.g., 7 or 8 days, prior to vaccination. , 6 weeks prior to vaccination, preferably 5 to 20 days after vaccination. Preferably, the IgE-inducing antigen is administered 5 to 10 days later, or most preferably, 10 to 15 days later. LOU06 for use in the treatment or prevention of an allergic reaction (e.g. a food allergic reaction) In an alternative embodiment, vaccination is with a live and / or attenuated vaccine. In a particular aspect of this embodiment, the patient is vaccinated with a LO. After discontinuing U064 treatment (e.g., 5 to 10 days or 7 or 8 days later), quadrivalent influenza vaccine, PPV-23 vaccine or KLH neoantigen vaccine In one aspect of this embodiment, a quadrivalent influenza vaccine is administered. Patients receiving the vaccine had a higher incidence of antihemagglutinin antibodies at 28 days after vaccination compared to baseline A response is achieved as defined by a >4-fold increase in titer. In the study, patients receiving the PPV-23 vaccine had a significantly higher IgG titer compared to baseline. In yet another embodiment, a >2-fold increase is achieved 28 days after vaccination. Patients receiving the LH neoantigen vaccine had anti-KLH IgG and achieves a T cell dependent antibody response as measured by LOU0 and IgM titers. 64 Treatment begins 29 days after vaccination and continues.

[0201] 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 herein may be used in the practice or testing of this disclosure. Although any method or material that may be used, the preferred methods and materials are described herein. The advantages and benefits of the present invention will be apparent from the following description and the accompanying claims. In the scope of the claim, the singular forms "a," "the," and "the" include plural referents unless the context clearly dictates otherwise (e.g. (For example, a reaction may include several reactions.) Unless otherwise specified, All technical and scientific terms used are understood to be within the skill of those of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference in their entirety. The following examples more particularly illustrate preferred embodiments of the present disclosure. It is shown to

[0202] These examples are within the scope of the disclosed subject matter, as defined by the appended claims. should in no way be construed as limiting the EXAMPLES

[0203] Example 1: Passive Cutaneous Anaphylaxis (PCA) in Mice LOU064 was tested in a mouse PCA model. The model included mice aged 8-10 weeks. BALB / c mice were used. For passive sensitization with hapten-specific IgE, isoflavone was administered. Mice were anesthetized with Lulan and injected with 20 μl of anti-DNP IgE in saline into the right ear and 20 μl of anti-DNP IgE in saline into the left ear. Mice were given an intradermal injection of 20 μl of saline. In the case of FcεR-specific PCA, mice were given For maximum PCA, mice were given a high dose of 25 ng of anti-DNP IgE.

[0204] LOU064 was administered orally (po) in a volume of 5 ml / kg body weight. The first dose was The following morning, 2 hours before hapten challenge, the mice were given 100 mg of ... The mice were given a second oral dose of LOU064. The mice were placed in a heated chamber. Mice were challenged with the hapten 2 hours after the second administration by administering , 100 μg of hapten DNA in 200 μl of 2% Evans Blue diluted in PBS P-HSA (dinitrophenyl-human serum albumin) was injected intravenously (iv). The mice were then returned to their cages for exactly 30 minutes. After 30 minutes, the animals were then After anesthetizing with isoflurane, use EDTA-coated blood collection tubes for analysis of compound exposure. Orbital bleeding was performed. Mice were then sacrificed by cervical dislocation. 6 mm punch biopsy Skin biopsies were taken from both the left and right ears and placed in 100 μl of formalin. The dye was extracted by incubating at 80°C overnight. After 24 hours, 80 μl of formalin was added. The solutions were transferred to clear flat-bottom 96-well plates and the optical absorbance was read at 620 nm. , by subtracting the left ear (saline) from the right ear (IgE), It was determined whether dye was released into the biopsied skin tissue. Statistical significance was determined by ANOVA. Spleens were removed for BTK occupancy analysis.

[0205] Blood Level Analysis: Blood samples were taken as indicated and compound measurements were performed. Blood Samples A structurally similar internal standard mixed with acetonitrile (4 volumes) was added to the solution, and approximately 40 The mixture was centrifuged at 100 rpm (4°C). The supernatant was then transferred to a microtiter plate. An aliquot of each sample was injected into the LC-MS / MS system for determination of the concentration of the parent molecule. I entered.

[0206] The concentration of LOU064 present in the blood of mice 2.5 hours after administration of the second compound was Low dose IgE sensitization is shown in Table 1.

[0207] [Table 1]

[0208] Analysis of BTK occupancy in the spleen (Figure 2) The levels of BTK occupancy following administration of LOU064 were measured using total BTK protein and bound BTK. (=free BTK) was determined in a separate ELISA. Binding was determined as the ratio of free BTK (i.e., not covalently occupied by compound) and total BTK. K protein was determined using an immunoassay. For free BTK measurements, samples were Biotinylated covalent BTK probe (Pulz R et al, ACS Med.Ch em.Lett.2019,10,1467-1472), then incubated with The samples are then added to a streptavidin ELISA plate to measure binding of the probe-bound BTK. Binding of the probe to BTK is mutually exclusive with compound binding to BTK. Plate-bound BTK was visualized by immunoblotting with an anti-BTK antibody (D3H5, Cell Signaling T For total BTK measurement, the ELISA plate was Then, the antibody was coated with D3H5 anti-BTK to capture total BTK. The captured BTK was analyzed using a 100% BTK antibody (no. 53, BD Biosciences). BTK was detected. The respective free BTK levels for each sample were compared with those in the same sample. Normalized to total BTK levels, these ratios are expressed as a percentage of vehicle control samples. It is expressed as:

[0209] For splenic BTK occupancy, grind each spleen and incubate for 10 min on ice with protease inhibitors. Mixture (Complete, Roche #11 836 170 001) and 5 mM 0.4 ml of cold Pierce IP Lysis Buffer (Thermo S Scientific #87787), GentleMACS (Miltenyi, The spleen lysate was removed by centrifugation and lysed in a 5% CO2 tube. , aliquot 10 µM covalently bound biotinylated BTK probe at room temperature for 2 h. Two separate ELISA assays were performed to measure the total BTK protein. The relative levels of protein and BTK-bound covalent probe (corresponding to free, unoccupied BTK) were It has been decided.

[0210] Relative BTK occupancy was calculated as the ratio of free BTK to total BTK (similarity of bound BTK) for each sample. The ratio of free BTK to total BTK was calculated as: Ri = free BTK / total BTK. Individual Ri values ​​were then Normalized to the vehicle group, percent occupancy: (Ri vehicle group mean -Ri) / ( Ri vehicle group) * Expressed as 100%.

[0211] Figure 2 shows the relative BTK occupancy in the spleen 2.5 hours after a second oral dose of LOU064. High and near-maximal levels of BTK occupancy were observed for all dose levels. The occupancy level relative to the vehicle control was 89.1% ± 1.7 for 3 mg / kg. The efficacy was 98.4-99.7% for doses of 10-100 mg / kg.

[0212] Conclusion: Based on the above results, the BTK inhibitor, LOU064, inhibits Fc expression in cutaneous mast cells. This test is effective in inhibiting the εR response (Figure 1). Complete inhibition was observed at doses of around 3 mg / kg. The blood concentration of LOU064 at 0.5 hours showed a dose-proportional increase. Blood exposure at the same time points was comparable in spleen BTK occupancy compared with the lower dose. The results showed nearly perfect target coverage with proportionality in terms of quantity. Significantly inhibits cutaneous anaphylaxis in a mouse PCA model after two oral doses It has been proven that this is the case.

[0213] Example 2: Reverse passive Arthus (RPA) reaction in mouse skin The effects of a single dose of LOU064 were evaluated in an acute mouse reverse passive arthropathy (RPA) model. The results showed that the IgG immune complex induces the activation of FcGRIII on mast cells. The present study evaluated its effect on cutaneous anaphylactic reactions mediated by cutaneous anaphylactic shock protein (ASC) in 8- to 10-week-old mice. Female C57Bl6 mice (Charles River, France) were used. The backs of the mice were shaved 24 hours before the cutaneous injections to prevent any potential irritation of the skin. The Arthus reaction was observed 2 hours or 4 hours after the compound was administered in a dose-response test. was induced at the indicated time points in a time course study. The control site was injected with 50 μl of PBS (C6534, Sigma) at a concentration of 30 μg in PBS. ) or polyclonal rabbit anti-ovalbumin IgG was administered intradermally (id) in the dorsal skin. Immediately after the intradermal injection, 200 μl of saline (05450 Fluka) was administered. Ovalbumin (20 mg / kg) was administered intravenously (iv). Three hours after injection, mice were sacrificed and bled for compound concentration monitoring, and the spleens were The injected control and anti-ovalbumin IgG skin sections were then removed for TK occupancy measurement. The thickness of the omentum at the site of anti-ovalbumin IgG injection was then measured using a digital caliper. Thickness minus saline control sites was calculated for mice in all treatment groups.

[0214] Single oral (po) nanosuspension gavage doses of 3, 10, 30 and 100 mg / kg; The effect of LOU064 treatment on skin swelling in mice, administered intravenously, is shown in Figure 3. Compared to vehicle-treated mice, the 2-h administration prior to the time of Arthus reaction induction LOU064 demonstrated a dose-related reduction in skin swelling response at 3 hours. The inhibition of the SAS response was 73.0% ± 0.05 at the two highest doses of 30 and 100 mg / kg, respectively. 14.6 and 61.2% ± 14.5, which were statistically significant.

[0215] Analysis of LOU064 levels in blood Blood samples were taken as indicated and compound measurements were performed. A structurally similar internal standard mixed with 100 ml of ethanol (4 volumes) was added and incubated at approximately 4000 rpm (4 °C). The supernatant was then transferred to a microtiter plate. The aliquots were injected into the LC-MS / MS system for determination of the concentration of the parent molecule. The concentrations of LOU064 in mouse blood 5 hours after administration of LOU064 are shown in Table 2. .

[0216] [Table 2]

[0217] BTK occupancy analysis: For BTK occupancy in the spleen, experiments were performed as described in the PCA example. For lung BTK occupancy, organs were perfused with saline (50% lysis buffer volume) After removing the blood in the same manner as for the spleen, except that the volume was 0 μl, the entire Lysates were prepared from whole lungs. Lung lysates were then assayed for free BTK in a separate ELISA. This was analyzed using anti-BTK (Cell Signaling Technology The process consisted of a capture step using IgG1, #8547, no carrier. The BTK protein was incubated with 1 μM of covalently bound biotinylated BTK protein for 1 h at room temperature. The BTK-bound biotinylated probe was incubated with streptavidin. -HRP conjugate (Cell Signaling Technologies, #3999, used at a dilution of 1:1'000) and chemiluminescent substrate (Supersig nal ELISA Pico, Thermo Scientific, #37070) Luminescence values ​​were measured in the absence of BTK capture antibody for the total BTK ELISA. Control samples measured in the absence of probe for BTK binding ELISA and in the absence of probe for BTK binding ELISA, respectively. The relative BTK occupancy was corrected for ELISA background readings from each The ratio of free BTK to total BTK for the sample (covalently biotinylated probe-bound BTK) was calculated. The individual Ri values ​​were then calculated as: R = free BTK / total BTK. Normalized to the vehicle group, percent occupancy: (Ri vehicle group mean -Ri) / (R i) Mean of vehicle group * Expressed as 100%.

[0218] FIG. 4 shows the relative BTK occupancy in the spleen 5 hours after oral administration of LOU064. A dose-dependent increase in BTK occupancy was observed, with 68.1% ± 10.0% at 3 mg / kg. , 82.1% ± 2.92 for 10 mg / kg, and 91.3% ± 30 mg / kg A mean BTK occupancy of 99.3% ± 0.7 was achieved for 3.62 and 100 mg / kg. Ta.

[0219] In subsequent studies, the inventors investigated the duration of the pharmacological action of LOU064 in the skin. The Arthus reaction was evaluated 2 hours after oral administration of 30 mg / kg LOU064. When induced at the same time points as in the previous study, the inhibition of skin swelling was 65.7% ( At this point, the effects were in a similar range to previous studies. If the Arthus reaction was induced at a later time point, the drug It was clear that the therapeutic effect had returned to vehicle levels by the 45-hour time point (Figure 1). 5).

[0220] From the same animals, BTK occupancy in the spleen and lung was measured at the end time point (minus the Arthus reaction). The BTK occupancy in the spleen and lungs was analyzed in relation to skin swelling. Compared with the pharmacological action, the kinetics followed very similarly (Figure 6).

[0221] Compound exposure was assessed at the first time point following a single dose of 30 mg / kg LOU064 ( Table 3).

[0222] [Table 3]

[0223] Conclusion: This experiment demonstrated that delayed cutaneous anaemia was mediated by IgG immune complexes and inflammatory FcγRs. The effect of LOU064 on mouse RPA, a model of phylaxis, was shown. LOU06 at a single dose of 3, 10, 30 and 100 mg / kg 2 hours prior to induction of the response Oral treatment with 4 dose-dependently reduced skin swelling 3 h after immune complex challenge. The inhibition of skin swelling was statistically significant at both the 30 and 100 mg / kg doses. Five hours after oral administration, blood concentrations of LOU064 increased with dose, with some proportional excess. This limited proportionality was observed in the Tm It is unclear whether this reflects a change in ax or AUC. The splenic BTK occupancy rate increased dose-dependently and reached a maximum level at 3 and 10 mg. At the two lower doses of 0.01 mg / kg, spleen occupancy appeared to exceed the effect on skin swelling. This is due to the fact that a single dose of erythropoietin was administered to the poorly perfused skin compared to the highly perfused spleen. This may reflect slightly slower target occupancy kinetics after dosing. The pharmacological effect of 064 was maximal when the Arthus reaction was induced 2 hours after oral administration. When the Arthus reaction was induced at a later time point, the effect was reduced and At 45 hours, the skin swelling reached a similar level to the vehicle group. Baseline drift in harm was associated with increased Althusian load across herds over time. The vehicle group was measured on day 1 at the same time as the 2 and 5 hour compound groups. Over the same time course, BTK occupancy was monitored in the spleen and lungs. In tissues, BTK occupancy was very similar compared to the pharmacological effect on skin swelling. In the absence of a sufficiently sensitive method to measure BTK occupancy in the skin, In this study, the skin BTK occupancy rate after a single oral dose of LOU064 was significantly higher than that of the spleen occupancy rate and skin pharmacology. It can be assumed that similar kinetics are followed. In conclusion, LOU064 significantly increased the Significantly and dose-dependently inhibited skin swelling in the mouse reverse passive Arthritis model. It has been proven.

[0224] Example 3: Ovalbumin-induced anaphylaxis mouse model This experiment was performed using OVA-sensitized mice injected with polyinosinic-polycytidylic acid (Poly I:C). To investigate the anti-inflammatory effects of LOU064 (10mg and 30mg / Kg) in mice Went there.

[0225] [Table 4]

[0226] animal: Male Balb / c mice (20–30 g, Charles Rivers UK Ltd) ) were housed in five cages for 7 days prior to the start of the study and were kept under a 12:12 h light:dark cycle. Mice were fed standard mouse chow and had water available ad libitum.

[0227] Allergen Exposure: Mice were treated with ovalbumin (15 μg, subcutaneously (sc)) and The mice were actively sensitized with 25 μL of Imject Alum and 25 μL of Imject Alum. To perform the aspiration, mice were treated with an ultrasonic nebulizer (A 1% w / v oocyte in phosphate buffered saline (PBS) produced by erythrocyte erythrocyte stimulating factor (ER) The mice were repeatedly exposed to aerosols of OVA. After 2 h, polyinosinic-polycytidylic acid (Poly I:C, 100 μg / animal) or vehicle (PBS), ketamine (100 mg / Kg, intraperitoneally (ip)) and xylazine (1 Under anesthesia with 100 mg / Kg, intraperitoneal (ip)), FMJ-250 high pressure syringe, P Using a Microsprayer (Model IA-1C) with Enn-Century Delivered intratracheally.

[0228] LOU064 and vehicle treatment: Mice were treated with LOU064 or vehicle (0.5% Tween 80 / 0.5% methyl Cellulose (400 cP) / 99% water) orally (po) twice daily (BID) Then, one hour before Poly I:C, a single dose of vehicle (67% PEG200 / 33 % PBS).

[0229] [Table 5]

[0230] Bronchoalveolar lavage (BAL) and cell counts: Twenty-four hours after the final OVA challenge, blood samples were collected by venipuncture using pre-chilled LiCl. Each sample was gently mixed and kept on wet ice for a maximum of 15 minutes. Then, the mixture was centrifuged (1500 g, 4° C. for 10 minutes) to prepare plasma. The blood was aliquoted and stored at -80°C until shipment. Immediately after blood collection, the animals were The trachea was then dissected by midline incision in the neck and separation of the muscle layers. A small incision was made in the trachea and a plastic cannula was inserted and held in place with sutures. The lungs were then flushed with 0.5 mL of phosphate buffered saline. The airways were then washed and the procedure was repeated until the recovered volume was 1.6 mL. The isolated BALF was then centrifuged at 1500 rpm for 10 min at 4°C. The supernatant was aliquoted (400 μL) at −80° C. for any future cytokine analysis. The cell pellet was then resuspended in 1.6 mL of phosphate-buffered saline and the BAL cells were cultured. Cells were analyzed for total and differential numbers. Total and differential cell counts of BAL fluid samples were performed using an XT-2000iV analyser (Sys The cell types that were classified differently were eosinophils (Figure 8), neutrophils (Figure 9), or monocytes (macrophages (Figure 10) and lymphocytes (Figure 11).

[0231] Conclusion: Treatment with LOU064 (10mg / kg, 30mg / Kg) was effective in preventing pulmonary anaphylaxis. The number of cells involved in oxidative stress (eosinophils, basophils, macrophages, and lymphocytes) was significantly increased. It was reduced.

[0232] Example 4: Inhibition of FcεR-induced mast cell degranulation in LAD2 cells Rationale and Methods: The human mastocytosis cell line LAD2 expresses FcεRI and mediates receptor cross-linking. At that time, the cells degranulate and express inflammatory mediators such as β-tryptase and hexosaminidase. (Wernersson et al. 2014, Immunol ogy;14(7):478-94). The assay was performed using 4-hydroxy-3-iodo-5- Nitrophenylacetic acid (NIP) haptenized bovine serum albumin (BSA) and NIP specific The chimeric IgE antibody JW8 (Neuberger, MS et al. (198 5),Nature 314(6008),pp 268-70.doi:10.103 8 / 314268a0). LAD2 cells were sensitized with JW8 IgE antibody and then incubated for 37 h. The cells were incubated with serial compound dilutions at 4° C. for 30 minutes. Degranulation was then Haptenized NIP-BSA was added to trigger cross-linking of FcεR. After 1 hour, supernatants were collected and analyzed for β-tryptase levels.

[0233] Results: Consistent with its potent activity in the basophil activation assay, LOU064 It showed an IC50 of 7.0 nM ± 2.6 (n = 3) and an IgE / FcεR induction in LAD2 cells. The study showed potent inhibition of acute mast cell degranulation.

[0234] Example 5: Inhibition of FcεR-induced degranulation of peripheral blood mononuclear cell (PBMC)-derived mast cells Rationale and Methods: Primary human mast cells were generated from CD34-positive progenitor cells isolated from PBMCs. (Neuberger, MS et al. (1985), Nature 3 14(6008),pp 268-70.doi:10.1038 / 314268a0) Blood from healthy volunteers was donated with informed consent and ss Human Research Act and approval by a responsible ethical committee (Et hikkommission Nordwest-und Zentralschwei z) by the Novartis Tissue Donor Program Briefly, CD34+ cells were isolated from peripheral blood by positive selection. After 6 weeks of differentiation culture, Mast cells were harvested and phenotypically characterized for expression of c-Kit (CD117) and FcεRI. Degranulation was evaluated using NIP-haptenized BSA and NIP-specific chimeric IgE antibody JW. 8 (described in RD-2013-00412). Sensitized with IgE antibodies and then incubated with serial compound dilutions for 30 min at 37°C. Next, degranulation was confirmed by adding haptenized NIP-BSA to crosslink FcεR. After 1 hour, the supernatant was collected and analyzed for β-tryptase levels. We analyzed the following.

[0235] Results: Similar to other FcεR inhibitory activities, LOU064 had a potent inhibitory effect of 5.7 nM ± 2.4 (n = 7 Potently and effectively induced in vitro degranulation of primary human PBMC-derived mast cells at IC50 of 100 mg / kg / day (donor) Completely blocked it.

[0236] Example 6: Inhibition of skin-derived human mast cells. Rationale and Methods: Skin tissue was used as a source of primary human tissue mast cells. Waste samples were provided with informed consent and submitted to the Swiss Human Research Center. The study was approved by the Ethics Committee under the Research Act and the responsible ion Nordwest und Zentralschweiz) The skin tissue was collected by the Basel General Hospital. Intact mast cells were cultured according to the protocol of Kulka and Metcalfe (Kulk a et al.2010, Immunology;SUPPL.90:1-11 The isolated mast cells were prepared according to the current protocol ( The degranulation assay was performed as described above (Neuberger, M. et al., l.(1985), Nature 314(6008), pp 268-70.doi: Mast cells were sensitized with JW8 IgE antibody and then Then, the plates were preincubated with serial compound dilutions for 30 minutes at 37°C. Degranulation was then induced by adding haptenized NIP-BSA to crosslink FcεRI. After 30 min, the supernatant was collected and analyzed by HTRF-based immunoassay (Cisbio Histamine was analyzed using a ELISA kit (Microbial Bioassays).

[0237] Results: As well as the activity in the previous type of FcεRI-induced cell signaling, LO U064 inhibited primary human skin-derived adipose tissue with an IC50 of 16.5 nM ± 5.0 (n = 2 donors). It potently inhibited histamine release from human cells.

[0238] In vitro activity of LOU064 evaluated across several cell types in Examples 4-6 The intracellular potency of this compound supports its use in allergic diseases induced by the FcεR pathway. support.

[0239] Example 7: Dosage of LOU064 (Rationale) In the mouse PCA model, LOU064 reduced cutaneous obesity at doses of around 3 mg / kg. It was demonstrated that it is effective in inhibiting FcεR responses in IgE cells (Figure 1). Effectiveness in preventing and / or treating induced allergic reactions (especially food allergic reactions) Splenic BTK occupancy, which may be a more relevant biomarker for predicting At 100 mg / kg and 100 mg / kg, almost complete occupancy was observed.

[0240] In mice, BTK occupancy in the spleen and lung followed very similar kinetics. This was further demonstrated (Figure 6).

[0241] LOU064, primarily at higher doses (73% inhibition of the Arthus reaction at 30 mg / kg); It was also demonstrated to be effective in reducing skin swelling in a mouse RCA model.

[0242] Importantly, the LOU in mice in the ovalbumin-induced anaphylaxis model 064 Treatment was associated with pulmonary anaphylaxis at doses of 10 mg / kg and 30 mg / kg. It was also demonstrated that this resulted in a significant reduction in the number of cells that

[0243] All preclinical results indicate that the effective dose for LOU064 in mice is approximately 10 mg / kg. Dose support: 30 mg / kg was also shown to be effective in mice.

[0244] Further BTK occupancy in human spleens may be useful in translational studies to further aid dose selection. Predicted using PK / PD model.

[0245] Prediction of BTK occupancy using a translational PK / PD model for LOU064 BTK occupancy in blood is dose dependent on LOU064 pharmacological properties (irreversible binding) It is not a useful biomarker for selection. ... D203c, skin prick test) before showing pharmacological activity, even at low doses Uptake in tissues is more representative of the expected efficacy of LOU064. obtain.

[0246] the purpose The purpose of this analysis was to characterize the pharmacokinetics (PK) of LOU064 in healthy volunteers. The efficacy of the antibody was evaluated 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 objective was to simulate the TK occupancy rate.

[0247] data Pharmacokinetics from a Phase I clinical trial reported by Kaul et al. (2021) Morphological data were used in this analysis, including 102 patients.

[0248] method A translational target occupancy model to simulate BTK occupancy in spleen / tissues was developed: It was developed using a two-step procedure.

[0249] In the first step, a population PK model was developed as described by Kaul et al. (2021). The LOU064 PK data from the Phase I clinical trial reported in In the second step, parameter estimates from the population PK model were compared with those from the BTK occupancy model. The results were used to predict BTK occupancy in blood and spleen / tissues. Using the TK occupancy model, we investigated the effect of different doses and different dosing schedules (once daily (QD), twice daily). The BTK occupancy in spleen / tissues was predicted for each BID.

[0250] result A population PK model was developed based on the Phase I clinical trial reported by Kaul et al. (2021). Developed to describe the intermediate PK from the study. 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 / kg) Exponential time decay for doses below 50 mg and constant clearance for doses above 50 mg Overall, the resulting population models were able to explain the PK data to some extent. It was revealed.

[0251] PK parameter estimates were used in a translated BTK occupancy model to determine the steady-state The BTK occupancy simulation was performed twice a day (B. ID) versus once daily (QD) at the same dose to achieve higher BTK occupancy. The results showed that the 10-mg / kg / day dose was more effective than the 10-mg / kg / day dose (at trough or average over a 24-hour period).

[0252] Selected dosing frequency for once-daily (QD) and twice-daily (BID) regimens ,Trough and average steady-state BTK occupancy over a 24-hour period, once a day at 10 g, 35 mg, 100 mg, and twice-daily 10 mg, 25 mg, and 100 mg regimens 14A (Trough of BTK occupancy at steady state over 24 hours) ) and FIG. 14B (24-hour average of BTK occupancy at steady state). Both figures show that the maximum daily dose is 200 mg (100 mg twice a day (BID)). What may be required to achieve trough BTK occupancy ≥ 80% in peripheral target tissues Shows.

[0253] 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 rates between the 100 and 2000 control mice is shown in Figure 13. The graph shows the predicted occupancy rates from first principles. As shown, the occupancy rate from twice-daily (BID) dosing was significantly higher than that from once-daily (QD) dosing. It shows higher and less change compared to the previous one.

[0254] Conclusion: BTK occupancy simulations showed that twice-daily (BID) dosing resulted in higher BTK occupancy. showed that once-daily (QD) administration of the same dose was more effective at achieving a high prevalence rate ( (at troughs or averages over a 24-hour period).

[0255] A model for the transfer between animals and humans (Journal of basic and clinical Based on the results of the study, the dose was set at 30 mg / kg. The calculated human equivalent dose (HED) for a 70 kg person is approximately 170 mg. Correspondingly, the calculated human equivalent dose (HED) for the minimally effective dose of 10 mg / kg is , which is equivalent to approximately 56 mg for a 70 kg person (Nair, AB, & Jacob , S. (2016).

[0256] Finally, a predictive model for splenic BTK occupancy in humans suggests that twice-daily (bid) .) administration compared to once-daily (QD) administration of the same dose to achieve higher BTK occupancy. It was shown that the LOU of 25 mg bid was more effective than that of 25 mg bid (Figure 13). The dose of 064 is the minimum effective dose in humans, and the dose of 100 mg bid is also It has been shown to be effective in

[0257] Example 8: Clinical Trial Peanut Allergy Phase 2 Three dosing regimens in adult patients with demonstrated peanut allergy (LOU06 4 10 mg twice daily (BID), 25 mg twice daily (BID) and 100 mg twice daily (BID) A randomized, double-blind, placebo-controlled, randomized, placebo-controlled study evaluating Weekly exam.

[0258] The "peanut trial" consisted of two groups of mice receiving 600 mg of peanut protein four weeks after treatment. Objective allergic responses to a double-blind, placebo-controlled, oral food challenge (DBPCFC) Proportion of patients without schizophrenia with LOU064 (10 mg twice daily) compared with placebo (B. ID), 25 mg twice daily (BID), and 100 mg twice daily (BID In addition, the efficacy of LOU064 25 mg twice daily for one week was evaluated. Patients treated with 600 mg of peanut protein (BID) were also given The proportion of patients who did not show objective allergic reactions to PCFC was evaluated compared to placebo. Secondary endpoints for all treatment arms will be compared. 00mg peanut protein.

[0259] Example 9: Clinical Trial Peanut Allergy Phase 3 Approximately 300 adults and adolescents (ages 12-5 years) with peanut allergy were included in the study. A randomized, double-blind, placebo-controlled, 10- to 5-year-old male randomized controlled trial evaluating LOU064 in children 18-week study. The peanut study included 600 mg, 1000 mg, and 300 mg at 1 or 2 weeks. A double-blind, placebo-controlled, oral food challenge ( The proportion of participants without objective allergic reactions to DBPCFC compared with placebo The efficacy of LOU064 in comparison will be evaluated.

[0260] Example 10: Clinical Trial Milk and Egg Allergy Approximately 450 adults aged 12 to 55 years with nut, milk, or shrimp allergies as indicated A randomized, double-blind, placebo-controlled, study evaluating LOU064 in adolescent participants Basket exam for 10-18 weeks.

[0261] Basket studies evaluating nuts, milk, and shrimp allergens were performed at 1 or 2 weeks. 000mg (non-cumulative) and 3'000mg (non-cumulative) of nut / milk / shrimp protein complex The proportion of patients who did not show an objective allergic reaction to DBPCFC at the level of The efficacy of LOU064 compared with placebo is being evaluated.

[0262] Example 11: 100 mg film-coated tablet A preferred pharmaceutical composition (film-coated tablet) is shown below.

[0263] [Table 6]

[0264] Example 12: 25 mg film-coated tablet A preferred pharmaceutical composition (film-coated tablet) is shown below.

[0265] [Table 7]

[0266] Example 13: 10 mg film-coated tablet A preferred pharmaceutical composition (film-coated tablet) is shown below.

[0267] [Table 8]

[0268] Example 14: 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 and Sjögren's syndrome (SjS) It has been tested in healthy subject studies and Phase II / III clinical trials. .

[0269] Short-term safety of LOU064 in Phase I clinical trials It can be 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 additional doses over a period of up to 12 days The short-term safety of LOU064 at doses of 100 and 200 mg twice daily (bid) was , as shown 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).

[0270] 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).

[0271] The safety signal was L 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 time of 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 profile observed in the Phase 2b study up to the cutoff date for the interim analysis. A summary of the results is shown below.

[0272] [Table 9]

[0273] 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 diseases. 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 (wide range of bleeding SMQ and platelet aggregation abnormalities, decreased platelet aggregation, small blood vessels, Issues under PT including platelet aggregation inhibition, platelet dysfunction, abnormal platelet function tests, and thrombotoxicity No events were reported under SOC Blood and lymphatic system disorders (defined as Three SAEs were reported: ovarian cysts, chest pain, and appendicitis; all were related to the study drug. was not considered to be present.

[0274] Conclusions from the Phase 2b study and corresponding open-label extension study Combined, safety data from Phase 2b trials across all doses evaluated were 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 have a favorable safety profile.

[0275] Phase 2b in CSU subjects (interim results / patients with median exposure of 35.14 weeks) Summary of safety in the extension phase 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 the 52-week open-label extension study of The study was conducted on patients with a median age (N=183), and the results were randomized to a 1:1:1:1:1:1:1 ratio. 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 Ph2b Core Study in Human Patients compared with (Table 5).

[0276] In the long-term exposure to ES (median 35.14 weeks, N=183), Patients with at least one adverse event (AE) to the treatment (57.4% [n=105]) The proportion of patients with CR was similar to that of CS (as indicated by any remibrutinib dose) (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 The most frequent causes 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 newly developed significant increase in 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 ) and 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 >500 ms.

[0277] conclusion Remibrutinib demonstrated a favorable safety profile across the entire dose range and was associated with improved 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.

[0278] [Table 10]

[0279] Example 15: Three Different Effects of Simultaneous and Intermittent Administration of Remibrutinib in Healthy Subjects Evaluating modulation of immune responses to different types of vaccines

[0280] [Table 11]

[0281] Study design Overall Design This randomized, double-blind, placebo-controlled study has a parallel-group design. Approximately 90% of participants will be randomly assigned to the study to achieve a minimum of 72 evaluable completers, taking into account an estimated dropout rate of 20%. 0 healthy non-childbearing potential female and male participants were randomized to one of three treatment groups. The study consisted of a 28-day screening period, a 43-day treatment period, and then The safety profile will consist of a study completion evaluation (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. -1 to 1 and 14 to 17 days. Overall, the maximum study duration for each participant was , about 85 days.

[0282] Concurrent and Intermittent Remibrutinib Treatment Scenarios for Influenza / Pneumo The effects of vax®23 and Immucothel® compared to placebo and evaluate.

[0283] 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 arms, as described below. It can be divided into four types.

[0284] treatment All participants received study medication (remibrutinib 100 mg or placebo) from Day 1 to Day 42. Patients were randomly assigned to receive sebo twice daily (bid) and returned to the clinic for an end of treatment visit on day 43. All participants were vaccinated with the quadrivalent influenza vaccine, the PPV-23 vaccine, and the The mice will also be administered the immunization vaccines, the KLH neoantigen vaccine and the immunization vaccine, which will be administered 3 hours after the administration of the test drug. It should be done.

[0285] During clinical visits and enrollment (days -1 to 1 and 14-17), participants were 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.

[0286] Safety assessments included physical examination, ECG, vital signs, and standard clinical laboratory evaluations (hematology, Blood chemistry, urinalysis) including adverse event and serious adverse event monitoring.

[0287] Multiple blood samples were collected on days 8, 15, and 3 to assess remibrutinib pharmacokinetics. Results were obtained from all participants on day 6.

[0288] Group A (concurrent remibrutinib treatment): Participants were randomized 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 placebo (twice daily (bid)) on days 8-15 of the study. Patients will receive mibrutinib treatment (100 mg twice daily (bid)). Patients received remibrutinib (100 mg twice daily (bid)) until day 42. Continues to be.

[0289] Group B (intermittent remibrutinib treatment): Participants were randomized to receive 100 mg 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 to 28. The vaccine will be administered twice (bid) and on the 15th day, three doses of the vaccine will be administered. Treatment with remibrutinib 100 mg twice daily (bid) was performed on days 29 to 42. This is a treatment that will be resumed in the future.

[0290] Group C (placebo): Participants in group C received placebo (bid) on days 1-42 and under placebo conditions So, on the 15th day, you will receive three vaccines.

[0291] 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 will undergo medical history, screening and baseline physical examinations as indicated. In good health as determined by examination, vital signs, ECG, and laboratory tests It should be. At screening and baseline, vital signs (systolic and diastolic blood pressure and pulse The number of subjects (number of subjects) was assessed in a sitting position and again in an upright position (if required by the assessment schedule). Sitting vital signs (after sitting for 3 minutes) should be within the following ranges: Tympanic temperature of 35.0~37.5℃. · Systolic blood pressure (SBP) between 90 and 139 mmHg (endpoints 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 50kg to participate in the study and be 18 Must have a body mass index (BMI) in the range of ~34.9 kg / m2. Participants will remain at the clinical site as required by the protocol and will be Must be willing to follow requirements / instructions outlined. Able to read, speak and understand the local language in order to understand and comply with the testing requirements do.

[0292] 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.

[0293] 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 arrhythmia. 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.

[0294] 3. Previously treated ovarian cancer within the past 5 years, with or without evidence of local recurrence or metastasis Treated or untreated malignancies of any organ system (localized basal cell carcinoma of the skin or in situ uterine History or presence of cancer other than cervical cancer.

[0295] 4. Cardiovascular (including but not limited to) conditions that have not resolved within 2 weeks prior to the first dose Any organ system class, including pulmonary, metabolic, hepatic, renal, hematological, endocrine, nervous system, or psychiatric disorders History or presence of any clinically significant disease.

[0296] 5. Hypersensitivity to remibrutinib or drugs from the same compound class or its excipients sex.

[0297] 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) Regarding the use of the Pneumovax 23, influenza or KLH vaccines Some taboo.

[0298] 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.

[0299] 8. History of previous exposure or immunization with KLH.

Claims

1. 1. A BTK inhibitor, e.g., an irreversible BTK inhibitor, e.g., LOU064, or a pharmaceutically acceptable salt thereof, for use in treating or preventing an IgE-induced allergic reaction to one or more allergens, e.g., a food, drug, or toxin allergic reaction, e.g., treating or preventing an anaphylactic reaction.

2. 2. LOU064 or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein the one or more allergens include or are food allergens.

3. 3. LOU064 or a pharmaceutically acceptable salt thereof for use according to claim 2, wherein the food allergen is selected from peanuts, tree nuts, milk, wheat, eggs, soybeans, sesame, seafood, in particular peanuts.

4. 2. The use of claim 1, wherein LOU064 or a pharmaceutically acceptable salt thereof is administered at a dose of about 20 mg to about 200 mg daily.

5. 5. The use of claim 4, wherein LOU064 or a pharmaceutically acceptable salt thereof is administered at a dose of about 10 mg twice a day to about 100 mg twice a day.

6. 6. LOU064 or a pharmaceutically acceptable salt thereof for use according to claim 5, wherein LOU064 is administered at a dose of about 10 mg twice daily.

7. 6. LOU064 or a pharmaceutically acceptable salt thereof for use according to claim 5, wherein LOU064 is administered at a dose of about 25 mg twice daily.

8. 6. LOU064 or a pharmaceutically acceptable salt thereof for use according to claim 5, wherein LOU064 is administered at a dose of about 100 mg twice daily.

9. 2. LOU064 or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein LOU064 is administered for a short period of time, such as less than 6 months, preferably less than 3 months or less than 1 month.

10. 10. The use of claim 9, wherein LOU064 or a pharmaceutically acceptable salt thereof is administered for up to 18 weeks, such as for 4, 10, 12, 16 or 18 weeks.

11. 2. LOU064 or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein LOU064 is administered for a prolonged period, such as for more than 6 months, preferably for one year or more.

12. 11. LOU064 or a pharmaceutically acceptable salt thereof for use according to claim 10, wherein LOU064 is administered as monotherapy.

13. 2. LOU064 or a pharmaceutically acceptable salt thereof for use according to claim 1, wherein LOU064 is not administered simultaneously with a strong inhibitor of CYP3A, such as a strong inhibitor of CYP3A4.

14. 2. The method of claim 1, wherein LOU064 or a pharmaceutically acceptable salt thereof is co-administered with a therapeutic agent.

15. 15. The use of claim 14, wherein LOU064 or a pharmaceutically acceptable salt thereof is co-administered with a corticosteroid and / or an immunosuppressant (e.g., an inhaled corticosteroid), a leukotriene receptor antagonist (LTRA), a short-acting beta agonist (SABA), or a long-acting beta agonist (LABA).

16. 2. The BTK inhibitor, such as LOU064 or a pharmaceutically acceptable salt thereof, for use according to claim 1, wherein LOU064 is co-administered with oral immunotherapy (OIT), sublingual immunotherapy (SLIT), transdermal immunotherapy (EPIT), preferably OIT.

17. 17. The BTK inhibitor, such as LOU064 or a pharmaceutically acceptable salt thereof, for use according to claim 16, wherein LOU064 is an adjunct to oral immunotherapy (OIT), sublingual immunotherapy (SLIT), transdermal immunotherapy (EPIT), preferably OIT.

18. 17. The BTK inhibitor, e.g., LOU064 or a pharmaceutically acceptable salt thereof, for use according to claim 16, wherein the oral immunotherapy is a peanut protein (e.g., Palforzia™).

19. 17. The BTK inhibitor, e.g., LOU064 or a pharmaceutically acceptable salt thereof, for use according to claim 16, wherein LOU064 is administered starting at least 2 days (e.g., at least 2-14 days) before administration of the oral immunotherapy.

20. 20. The BTK inhibitor, e.g., LOU064, or a pharmaceutically acceptable salt thereof, for use according to claim 19, wherein the BTK inhibitor, e.g., LOU064, is administered during the titration phase of the immunotherapy treatment.

21. 21. The BTK inhibitor, such as LOU064 or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1 to 20, wherein the method is the prevention of IgE-induced allergic reactions.

22. 21. A BTK inhibitor, such as LOU064 or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1 to 20 for preventing anaphylaxis after accidental exposure to any allergen, such as a food allergen.

23. 22. The use of LOU064 or a pharmaceutically acceptable salt thereof according to claim 21, wherein LOU064 achieves maximum prevention after a minimum of 2 days (e.g., 2 to 14 days, preferably 2 to 7 days) of treatment.

24. The patient meets the following criteria: (e) Male and female patients, 6 years of age or older (e.g., 6-11 years, 12-17 years, or 18-55 years); (f) a confirmed history of food allergies, including but not limited to peanuts, tree nuts, wheat, eggs, milk, soy, and seafood; (g) positive allergen-specific IgE (e.g., peanut sIgE ≥ 6 kUA / L at screening); and (h) a positive skin prick test to an allergen to which the patient is allergic (e.g., defined as a mean diameter (longest diameter and midpoint perpendicular diameter) of ≥ 4 mm compared to a negative control); 21. The method of claim 1, wherein LOU064 or a pharmaceutically acceptable salt thereof is selected according to one or more of the following:

25. 21. LOU064 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 20, wherein the patient is an adult patient (18 years or older) or an adolescent (12-17 years old).

26. 21. LOU064 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 20, wherein the patient is a child aged 2 to 11 years, such as 2 to 5 years or 6 to 11 years.

27. At least one of the following is true: up to 4 weeks after treatment with LOU064 (e.g., 1 week, or 2 weeks, or 3 weeks, or 4 weeks), d. At least 90% of treated patients do not exhibit an allergic reaction upon a food challenge of 600 mg of peanut protein; e. At least 90% of treated patients do not exhibit an allergic reaction upon a food challenge of 1000 mg of peanut protein; f. LOU064 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 20, wherein at least 80% of treated patients do not exhibit an allergic reaction upon a food challenge of 3000 mg of peanut protein.

28. 21. LOU064, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1 to 20, wherein the patient achieves a reduction from baseline in the FAQLQ total domain score of between 0.45 and 0.

5.

29. 21. LOU064, or a pharmaceutically acceptable salt thereof, for use according to any one of claims 1 to 20, wherein the patient achieves a reduction from baseline in the total domain score FAIM.

30. 21. LOU064 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 20, wherein the observed difference in response rate between treated and untreated patients in a double-blind, placebo-controlled food challenge of 600 mg of allergen (e.g., peanut allergen) is better than 35%, wherein the response rate is defined as less than or equal to a mild response to a 600 mg oral food challenge.

31. 21. LOU064 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 20, wherein by 12 weeks or by 24 weeks of treatment, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lipase do not change by more than 10% compared to baseline levels at the start of treatment.

32. 21. LOU064 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 20, wherein LOU064 is administered in the form of a suitable oral pharmaceutical formulation comprising nano-sized particles of LOU064.

33. 21. LOU064 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 20, wherein LOU064 is administered in the form of a suitable oral pharmaceutical formulation comprising nano-sized particles of LOU064 having an average particle size of about 50 nm to about 750 nm as measured by PCS.

34. 21. LOU064 or a pharmaceutically acceptable salt thereof for use according to any one of claims 1 to 20, wherein LOU064 is administered in the form of a suitable oral pharmaceutical formulation comprising LOU064 and a binder in a weight ratio of about 2:

1.

35. 21. The LOU064 for use according to any one of claims 1 to 20, wherein the LOU064 is administered in the form of a suitable oral pharmaceutical formulation comprising LOU064, a binder and a surfactant in a weight ratio of about 2:1:0.

08.

36. 21. The LOU064 for use according to any one of claims 1 to 20, wherein the LOU064 is administered in the form of a suitable oral pharmaceutical formulation comprising LOU064 and a binder in a weight ratio of about 1:

1.

37. 21. LOU064 for use according to any one of claims 1 to 20, wherein LOU064 is administered in the form of a suitable oral pharmaceutical formulation comprising LOU064, a binder and a surfactant in a weight ratio of about 1:1:0.

05.

38. 21. LOU064 for use according to any one of claims 1 to 20, wherein LOU064 is administered in the form of a suitable oral pharmaceutical formulation comprising LOU064, polyvinylpyrrolidone-vinyl acetate copolymer as a binder and sodium lauryl sulfate as a surfactant.

39. 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, 23.4±0.2°2θ, 24.2±0.2°2θ, 25.0±0.2°2θ, 26.0±0.2°2θ, 27.0±0.2°2θ, 28.0±0.2°2θ, 29.0±0.2°2θ, 30.0±0.2°2θ, 31.0±0.2°2θ, 32.0±0.2°2θ, 33.0±0.2°2θ, 34.0±0.2°2θ, 35.0±0.2°2θ, 36.0±0.2°2θ, 37.0±0.2°2θ, 38.0±0.2°2θ, 39.0±0.2°2θ, 40.0±0.2°2θ, 41.0±0.2°2θ, 42.0±0.2°2θ, 43.0±0.2°2θ, 44.0±0.2°2θ, 45.0±0.2°2θ, 46.0±0.2°2 21. The use of any one of claims 1 to 20, wherein LOU064 or a pharmaceutically acceptable salt thereof is in the 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 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.

40. 1. LOU064 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in the treatment or prevention of IgE-induced allergic reactions, preferably wherein LOU064 is administered at a dose of about 10 mg twice daily to about 100 mg twice daily.

41. 1. Use of LOU064 or a pharmaceutically acceptable salt thereof for the treatment or prevention of IgE-induced allergic reactions, preferably wherein said LOU064 is administered at a dose of about 10 mg twice daily to about 100 mg twice daily.

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