Remibrutinib for use in the treatment of myasthenia gravis

Abstract

Described herein are methods of treating gMG with the BTK inhibitor remibrutinib or a pharmaceutically acceptable salt thereof.

Description

[0001] PAT059652A

[0002] LOU064 for the treatment

[0003]

[0004] ia Gravis

[0005] FIELD

[0006] The invention relates to LOU064 or a pharmaceutically acceptable salt thereof, for use in the effective and safe treatment of generalized Myasthenia Gravis (gMG).

[0007] BACKGROUND

[0008] Myasthenia gravis (MG) is a rare autoimmune disorder that affects the postsynaptic membrane of the neuromuscular junction (NMJ). It is caused by autoantibodies against different components of NMJ. The main manifestation of the disease is fluctuating muscle weakness that is typically milder in the morning as a result of overnight inactivity, which enables the replenishment of acetylcholine levels in pre-synaptic motor nerve terminals. However, the symptoms worsen during the course of the day due to repeated muscle activity (Jayam Trouth et al. Autoimmune Dis 2012874680; Gilhus, N Engl J Med, 2016, 2570-81). Infrequently, respiratory muscle weakness can occur, leading to a life-threatening condition known as myasthenic crisis.

[0009] MG has an annual incidence of 8 to 10 cases per 1 million with a prevalence rate of 150 to 250 cases per 1 million and is thus the most common disease that affects the NMJ (Gilhus 2016). MG primarily occurs at two peaks of incidence. The first early-onset peak affects younger adults, aged between 30 to 50 years. Women are most commonly affected before the age of 40, with a female: male ratio of 3 : 1. The second peak occurs later in life, with women and men equally affected during their fifth decade. However, after the age of 50, men are more often affected, with a male: female ratio of 3:2. Furthermore, in men, the incidence increases steadily with age and reaches the highest rates between 60 and 89 years (Dresser et al., J Clin Med, 2021, 10(H)).

[0010] MG is considered a classic example of antibody-mediated autoimmune disease. It can also be viewed as an example of a class II hypersensitivity reaction, as immunoglobulin G (IgG) autoantibodies react with intra or extracellular antigens, leading to end-organ damage.

[0011] The Myasthenia Gravis Foundation of America (MGFA) clinical classification divides MG into five main classes and several subclasses. This classification is designed to identify different subgroups of patients who have distinct severity of disease, that may indicate different PAT059652A

[0012] prognoses or responses to therapy. Generalized Myasthenia Gravis (gMG) corresponds to MGFA classes II-V (Jayam Trouth et al. 2012, Myasthenia gravis: a review. Autoimmune Dis;

[0013] 2012:874680). Generalized MG manifests in approximately 85% of all MG patients and affects multiple muscle groups throughout the body (Jackson et al. 2023, Neuro Ther; 12(1): 107-28.

[0014] Approximately 80% percent of MG patients have detectable antibodies against the acetylcholine receptor (AChR+), while a minority have antibodies against muscle-specific kinase (MuSK+) or lipoprotein receptor-related protein 4 (LRP4), or are double-seronegative (i.e., those with neither AChR+ nor MuSK+) (Gilhus et al. 2019; Myasthenia gravis Nat Rev Dis Primers; 5(l):30, Romi et al 2005: Seronegative myasthenia gravis: disease severity and prognosis. Eur J Neurol; 12(6):413-8). Anti-MuSK antibodies are detected in 1-10% of patients with MG while double-seronegative MG is found in around 10-15% of patients with MG (Gilhus et al. 2019; Mergenthaler et al. 2022: Seronegative myasthenic crisis: a multicenter analysis. J Neurol; 269(7):3904-911).

[0015] Even though there are available therapies for gMG, most of those therapies work via nonspecific suppression of the autoimmune response like corticosteroids (classified as immune suppressive therapies (1ST) or non-steroidal immunosuppressive therapies (NSIST)).

[0016] Moreover, their use comes with disadvantages including risks of infections, malignancies and a broad spectrum of systemic side effects which can negatively impact patient quality of life and disease burden (Baci et al 2019: Understanding side effects of therapy for myasthenia gravis and their impact on daily life. BMC Neurol; 19:335). This is especially true for patients that have other medical comorbidities such as diabetes or hypertension. Also, mostNSISTs have a delayed onset of action. Approximately 10% of patients with MG fail to respond adequately to current therapies and are considered treatment refractory, or treatment intolerant, and up to 80% have disease that fails to achieve complete stable remission (Mantegazza, Antoni 2018: When myasthenia gravis is deemed refractory: clinical signposts and treatment strategies. Ther Adv Neurol Disord; 11 : 1756285617749134).

[0017] These limitations have more recently strongly encouraged the development of MG treatments that now include various drug classes such as complement inhibitors, neonatal crystallizable fragment receptor (FcRn) receptor blockers, and direct and indirect B cell inhibitors. However, therapies like FcRn receptor blockers do not have durable efficacy as PAT059652A

[0018] symptoms return toward the end of the treatment cycle (Howard et al. 2021 : Expert Opin Investig Drugs; 30(5):483-93).

[0019] Thus, an unmet need still exists for the MG population, as many of these newer therapies (i.e., eculizumab, ravulizumab, efgartigimod) in AChR+ patients require repeated administration via intravenous or subcutaneous injection and can be burdensome for patients. Furthermore, limited treatment options exist for MuSK+ and seronegative gMG with one therapy approved for MuSK+ patients (i.e., rozanolixizumab) and currently no approved treatments for patients with seronegative gMG.

[0020] SUMMARY

[0021] The problem underlying the invention is to provide improved treatment strategies for gMG patients, especially treatment with fast onset of action, and safe long-term treatment.

[0022] Another object is to provide an improved gMG therapy, particularly exhibiting an improved safety and tolerability profile as compared to other approved therapy.

[0023] Another object is to provide an improved gMG therapy, with the convenience of an oral administration.

[0024] Another object of the invention is to provide an improved treatment to gMG patients who are not adequately controlled, e.g. patients with a MG-ADL score of at least 6, e.g. patients with a MG-ADL score of at least 6 despite being on stable standard of care (SoC) gMG treatment (e.g. cholinesterase, non-steroidal immunosuppressant treatment, steroids).

[0025] The problem has unexpectedly been solved by the administration of LOU064, or a pharmaceutically acceptable salt thereof.

[0026] Therefore, the invention relates to methods of treating generalized Myasthenia Gravis (gMG), with LOU064 or a pharmaceutically acceptable salt thereof.

[0027] In particular, the disclosure provides a method of treating generalized Myasthenia Gravis (gMG) in a subject, e.g., a patient, in need thereof, the method comprising administering to the subject, e.g., patient, LOU064 or a pharmaceutically acceptable salt. In an embodiment, LOU064 or a pharmaceutically acceptable salt thereof is administered orally. In another embodiment, LOU064 or a pharmaceutically acceptable salt thereof is administered at a dose of from about 50 PAT059652A

[0028] mg to from about 250 mg, from about 100 mg to about 200 mg, e.g. at a dose of about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose administered twice daily (b.i.d.), e.g., about every 12 hours, to thereby treat the subject, e.g., patient (wherein the dosing amount refers to the anhydrous LOU064 free base).

[0029] In an embodiment of the methods provided herein, the subject has anti-acetylcholine receptor antibody-positive (AChR+) generalized Myasthenia Gravis (gMG).

[0030] In other embodiment of the methods provided herein, the subject has MuSK positive generalized Mysathenia Gravis (gMG).

[0031] In other embodiment of the methods provided herein, the subject is seronegative for both acetylcholine receptor (AChR) and MuSk antibodies.

[0032] In further embodiments, the method further comprises administering to the subject an immunosuppressant, a corticosteroid, a non-steroidal immunosuppressive therapy (NSIST), and / or a cholinesterase inhibitor.

[0033] BRIEF DESCRIPTION OF FIGURES

[0034] Figure 1. Flowchart illustrating the clinical scoring system

[0035] Figure 2. Comparison of clinical score, survival rate, weight, and grip strength. A) Clinical score at terminal point was significantly lower in the EAMG-LOU064 and non-MG animals compared to the EAMG-vehicle group. B) There was a significant difference in survival rate after immunization between the EAMG-LOU064 and the EAMG-vehicle group. C) No differences between the three groups in weight progression (missing data from HEP animals were excluded). D) The EAMG-LOU064 group had significantly higher weight at the terminal time point compared to the EAMG-vehicle group (data from HEP animals are marked in purple).

[0036] E+F) There were no differences in grip strength between the EAMG-LOU064 and EAMG-vehicle groups at all timepoints

[0037] Figure 3. Comparison of plasma anti-torpedo AChR and anti-rat AChR levels. A) At terminal time point, there was a significant decrease in anti-torpedo AChR level in the EAMG-LOU064 group compared to the EAMG-vehicle group. B+C+D) There was a trend for lower anti-rat AChR level in the EAMG-LOU064 group, but this was not statistically significant. PAT059652A

[0038] Figure 4. BTK occupancy in spleen from EAMG animals

[0039] DETAILED DESCRIPTION

[0040] B cells, play a central role in the pathophysiology of gMG. Therefore, a B cell centered treatment approach is highly promising to address the core pathophysiology of the disease. Depletion of cells by a monoclonal antibody, rituximab, has shown efficacy in early gMG (Piehl et al 2022: Efficacy and Safety of Rituximab for New-Onset Generalized Myasthenia Gravis: The RINOMAX Randomized Clinical Trial. JAMA Neurol; 79(11): 1105-112). In contrast, remibrutinib does not lead to cell depletion, but interferes with activation of the cells.

[0041] Remibrutinib is a highly selective inhibitor of Bruton Tyrosine Kinase (BTK) (Angst et al 2020: A Potent and Highly Selective Covalent Inhibitor of Bruton's Tyrosine Kinase. J Med Chem; 63(10):5102-l 18). BTK is a cytoplasmic tyrosine kinase and member of the TEC kinase family. BTK is selectively expressed in cells of the adaptive and innate immune system including B cells, macrophages, mast cells, basophils, and thrombocytes.

[0042] BTK is indispensable for signaling through the FcsR l for immunoglobulin E (IgE) and the activating FcyR for IgG as well as the B cell antigen receptor (BCR). It is well established that BTK is involved in B cell activation and antigen presentation (Corneth et al 2016; BTK Signaling in B Cell Differentiation and Autoimmunity. Curr Top Microbiol Immunol; 393:67-105; Torke et al 2020: Inhibition of Bruton's tyrosine kinase interferes with pathogenic B-cell development in inflammatory CNS demyelinating disease. Acta Neuropathol; 140(4):535-48) and can therefore address the pathophysiology of gMG in AChR+, MuSK+, and double seronegative patients. Given the essential role of BTK in BCR and FcyR signaling, remibrutinib can act on different levels of gMG pathophysiology: to reduce secretion of autoantibodies from autoreactive cells, their differentiation into plasma cells and restimulation of autoreactive memory cells by autoantigen. In addition, remibrutinib inhibits the antigen-presenting function of autoreactive cells to T cells, as well as the autoantibody effector function via FcyR on macrophages and other myeloid cells (torke et al 2020, Neys et al 2021 : Front Cell Dev Biol; 9:668131).

[0043] / V-(3-(6-Amino-5-(2-( / V-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, (IUPAC name: N-[3-(6-Amino-5-{2- PAT059652A

[0044] [methyl(prop-2-enoyl)amino]ethoxy}pyrimidin-4-yl)-5-fluoro-2-methylphenyl]-4-cyclopropyl-2-fluorobenzamide), also known as remibrutinib, is a highly potent and selective oral Bruton’s tyrosine kinase (BTK) inhibitor:

[0045]

[0046] Remibrutinib (also known as “LOU064”) was first disclosed in WO2015 / 079417, filed November 28, 2014, in Example 6. WO2015 / 079417 is incorporated herein by reference in its entirety.

[0047] As used herein, “LOU064” and “remibrutinib” is used herein interchangeably. In one embodiment, LOU064 refers to a crystalline form of LOU064 as disclosed in Example 1 of WO2020 / 234779, which is herein incorporated by reference.

[0048] Even though there are available therapies for gMG, most of those therapies work via nonspecific suppression of the autoimmune response like corticosteroids (classified as immune suppressive therapies (1ST) or non-steroidal immunosuppressive therapies (NSIST)). Moreover, their use comes with disadvantages including risks of infections, malignancies and a broad spectrum of systemic side effects which can negatively impact patient quality of life and disease burden (Bacci et al., BMC Neurol 2019, 335). This is especially true for patients that have other medical comorbidities such as diabetes or hypertension. Also, most NSISTs have a delayed onset of action, with an estimated 10% of patients remaining refractory and others intolerant of conventional 1ST (Mantegazza et al., Curr Opin Neurol 2018, 517-25).

[0049] Described herein is a method of treating generalized Myasthenia Gravis (gMG) in a subject in need thereof comprising administering to the subject LOU064 or a pharmaceutically acceptable salt thereof. Accordingly, described herein are methods of treating gMG in a patient in need thereof, the method comprising orally administering, e.g., in capsule form, to the patient PAT059652A

[0050] a twice daily dose, e.g., about every 12 hours of LOU064 or a pharmaceutically acceptable salt thereof (wherein the dosing amount refers to the anhydrous LOU064 free base). Also described herein are methods of selecting the target patient population, methods of monitoring treatment of the target patient population, and methods of assessing safety and efficacy of treatment of the target patient population.

[0051] The details of the disclosure are set forth in the accompanying description below.

[0052] Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure are apparent from the description and from the claims. In the specification and the claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties.

[0053] Definitions

[0054] Unless specific definitions are provided, the nomenclature used in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Standard techniques may be used for chemical synthesis, and chemical analysis. Certain such techniques and procedures may be found for example in “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., 21st edition, 2005, which is hereby incorporated by reference for any purpose. Where permitted, all patents, applications, published applications and other publications and other data referred to throughout in the disclosure are incorporated by reference herein in their entirety.

[0055] Unless otherwise indicated, the following terms have the following meanings:

[0056] As used herein, “about” means within ±10% of a value.

[0057] As used herein, a patient can be “in need of’ a treatment, e.g. gMG, if such a patient would benefit medically or in terms of the quality of life from such treatment. PAT059652A

[0058] As used herein, “administering” or “administration” means providing a pharmaceutical agent, e.g. LOU064 to an individual, and includes, but is not limited to, administering by a medical professional and self-administering. Administration of a pharmaceutical agent to an individual can be continuous, chronic, short or intermittent. Administration can for example by oral routes. Administration of “in combination with” one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order and in any route of administration.

[0059] As used herein, a “therapeutically effective amount / dose” can refer to an amount / dose of LOU064 that is effective, i.e. achieves a clinically meaningful effect, e.g. meets any of the primary and / or secondary endpoints as defined herein.

[0060] The term “adverse event” (AE) can relate to any untoward medical occurrence in a patient or clinical investigation wherein the subject is administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.

[0061] As used herein, “baseline” refers to a time prior to treatment in relation to a characteristic of a subject or a patient.

[0062] As used herein, “dose” means a specified quantity of a pharmaceutical agent provided in a single administration, or in a specified time period. In certain embodiments, a dose can be administered in capsules. As used herein, the dosing amount refers to the anhydrous LOU064 free base.

[0063] As used herein, the expression "comprise", besides its literal meaning also includes and specifically refers to the expressions "consist essentially of and "consist of. Thus, the expression "comprise" refers to embodiments wherein the subject-matter which "comprises" specifically listed elements may and / or indeed does encompass further elements as well as embodiments wherein the subject-matter which "comprises" specifically listed elements does not comprise further elements. PAT059652A

[0064] As used herein, “substantially phase pure,” when used in reference to crystalline form of LOU064, means remibrutinib having a phase purity of greater than about 90% by weight, including greater than about 90, 91, 92, 93, 94, 95, 96, 97, 98, and about 99% by weight, and also including equal to about 100% by weight of the remibrutinib, based on the weight of the LOU064 on anhydrous basis. The term “phase pure” or “phase purity” herein refers to phase homogeneity with respect to a particular solid-state form of remibrutinib and does not necessarily imply a high degree of chemical purity absent an express statement to that effect. Phase purity may be determined according to methods known in the art, for example, using XRPD to do quantitative phase analysis using one or more approaches known in the art, for example, via an external standard method, direct comparisons of line (peak) characteristics which are attributed to different phases in a particular spectra, or via an internal standard method. However XRPD quantification of phase purity can be complicated by the presence of amorphous material. Accordingly, other methods that may be useful for determining phase purity include, for example, solid state NMR spectroscopy, Raman and / or infrared spectroscopy. One of skilled in the art would readily understand these methods and how to employ these additional (or alternative) methods for determining phase purity.

[0065] As used herein, “individual”, “patient”, “participant”, or “subject” means a human selected for treatment or therapy. In some embodiment, the “individual”, “patient”, “participant” or “subject” is an adult, e.g. between age of 18 to 60 years.

[0066] As used herein, “pharmaceutically acceptable salts” means physiologically and pharmaceutically acceptable salts of LOU064, i.e., salts that retain the desired biological activity of LOU064 and do not impart undesired toxicological effects thereto. The term “pharmaceutically acceptable salt” or “salt” includes a salt prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic or organic acids and bases.

[0067] “Pharmaceutically acceptable salts” of remibrutinib may be prepared by methods well-known in the art. For a review of pharmaceutically acceptable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection and Use (Wiley-VCH, Weinheim, Germany, 2002).

[0068] As used herein, the term “treat” means decrease, suppress, attenuate, diminish, arrest symptoms of a disease such as gMG, or stabilize the development or progression of a disorder or disease, e.g., gMG. Efficacy of the treatment of gMG can be assessed using Myasthenia Gravis PAT059652A

[0069] Activity of Daily Living (MG-ADL), Quantitative Myasthenia Gravis Score (QMG), Myasthenia Gravis Composite Score (MGC), Revised 15-item Myasthenia Gravis Quality of Life Questionnaire (MG-QoLl 5), EuroQoL-5 (EQ-5D-5L), quality of life in neurological disorders-fatigue-short form (Neuro-QoL-Fatigue-SF)and / or Masthenia Gravis Foundation of America Clinical classification (MGFA). In some embodiment, the term “treat” means reducing symptoms severity.

[0070] As used herein, the term “prevent” means preventing the disease to develop into severe conditions, e.g. exacerbation, e.g. severe muscle weakness particularly of the muscles that control breathing requiring immediate medical attention. Therefore, the term “prevent” means preventing life threatening manifestations of MG defined as respiratory insufficiency, e.g. requiring intubation and mechanical ventilation.

[0071] As used herein, the MG-ADL is used to measure severity of MG symptoms and their effects on daily activities with higher score indicating greater symptom severity. MG-ADL is a categorical scale that assesses MG symptoms and their effects on daily activities. The 8 items of the MG-ADL questionnaire were derived from symptom-based items included in the 13-item QMG scoring system. MG-ADL is composed of items related to patient's assessment of functional disability secondary to ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb (2 items) impairment related to effects from MG. Each item is assessed on a 4-points scale where a score 0 represents normal function and a score 3 represents loss of ability to perform that function (total score 0 to 24). The MG-ADL scale is administered as an interviewer-led questionnaire by a qualified clinical rater. The same clinical rater administers the questionnaire throughout the study to ensure consistency in measuring participant response. MG-ADL is a clinically meaningful scale for gMG patients (Muppidi et al 2022: Muscle Nerve; 65(6):630-9) and is the primary endpoint in this gMG study.

[0072] As used herein, the Quantitative Myasthenia Gravis (QMG) Score is a 13-item direct physician assessment scoring system that quantifies disease severity, based on impairments of body functions and structures. The total QMG score ranges from 0 to 39, where higher scores indicated greater disease severity. The QMG score is composed of the following items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item) and respiratory (1 item). The QMG scale is administered by a trained and qualified clinical rater. For consistency, the same evaluator administers this questionnaire throughout the study. PAT059652A

[0073] As used herein, the MGC is a 10-item instrument that measures the symptoms and signs of MG based on physician examination and patient history. Items relate to ptosis, double vision, eye closure, talking, chewing, swallowing, breathing, neck flexion, shoulder abduction, and hip flexion. Each item is scored on an ordinal scale with 4 possible categories and weighted. The total score ranges from 0 to 50, where higher scores indicating more severe impairments. This scale similar to QMG is administered by a qualified and trained clinician, and for consistency the same evaluator administers this instrument throughout the study.

[0074] As used herein, the revised MG-QoL15 is a 15-item health related quality of life questionnaire completed by participants, designed to measure quality of life in gMG Items on the MG-QoL15 relate to physical, social, and psychological components and are scored from 0 (not at all) to 2 (very much). The cumulative scores range from 0 to 30, with higher scores representing worse quality of life and dissatisfaction with MG-related dysfunction.

[0075] As used herein, The EuroQol-5 Dimensions-5 Level (EQ-5D-5L) is a widely used questionnaire designed to assess health status in adults. The measure is divided into two distinct sections, the descriptive system and the EQ visual analogue scale (EQ VAS). The first section includes one item addressing each of five dimensions (mobility, self-care, usual activity, pain / discomfort, and anxiety / depression). Participants rate each of these items from 1 of the 5 levels: no problems, slight problems, moderate problems, severe problems, or unable to / extreme. A composite health state is then defined by combining the levels for each dimension into a 5-digit number. The second section includes the EQ visual analogue scale (EQ VAS) that measures self-rated (global) health status utilizing a vertically oriented visual analogue scale where 100 represents the “best imaginable health state” and 0 represents the “worst imaginable health state.” Respondents are asked to rate their current health by placing a mark along this continuum (Rabin, de Charro 2001: Ann. Med.; 33(5):337-43).

[0076] As used herein, Neuro-QoL is a comprehensive system of PRO measures that target neurological disorders. They include item banks and short forms (SFs) for measuring physical, social, and mental domains of health-related quality of life, experienced by patients with neurological conditions. The Neuro-QoL item bank Fatigue SF assesses sensations ranging from tiredness to an overwhelming, debilitating and sustained sense of exhaustion that decreases a person's capacity for physical, functional, social and mental activities. The Neuro-QOL Scales PAT059652A

[0077] were developed with National Institutes of Health (NIH) funding to standardize assessments of these evaluations across patients with neurological diseases.

[0078] Fatigue is a frequent complaint in subjects with MG. Participants will be asked to complete the Neuro-QOL Fatigue Short Form.

[0079] The articles “a” and “an” are used in this disclosure to refer to one or more than one (e.g., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element.

[0080] Methods of Use

[0081] In one aspect, provided herein is a method of treating generalized Myasthenia Gravis (gMG) in a subject in need thereof comprising administering to the subject LOU064 or a pharmaceutically acceptable salt thereof. In an embodiment, provided herein is a method of treating generalized Myasthenia Gravis (gMG) in a subject, e.g., a patient, in need thereof, the method comprising administering, e.g., orally, to the subject, e.g., patient, LOU064 or a pharmaceutically acceptable salt thereof at a dose of from about 50 mg to from about 250 mg, from about 100 mg to about 200 mg, e.g. at a dose of about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose administered twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous LOU064 free base), to thereby treat the subject, e.g., patient.

[0082] In another aspect, the disclosure provides LOU064 or a pharmaceutically acceptable salt thereof for use in the treatment of generalized Myasthenia Gravis (gMG) in a subject, e.g., a patient, in need thereof. In an embodiment, the treatment comprises administering, e.g., orally, to the subject, e.g., patient, LOU064 or a pharmaceutically acceptable salt thereof at a dose of from about 50 mg to from about 250 mg, from about 100 mg to about 200 mg, e.g. at a dose of about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose to be administered twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous LOU064 free base).

[0083] In another aspect, the disclosure provides use of LOU064 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of generalized Myasthenia Gravis (gMG) in a subject, e.g., a patient, in need thereof. In an embodiment, the treatment comprises orally administering to the subject, e.g., patient, LOU064 or a PAT059652A

[0084] pharmaceutically acceptable salt thereof at a dose of from about 50 mg to from about 250 mg, from about 100 mg to about 200 mg, e.g. at a dose of about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each dose to be administered twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous LOU064 free base), to thereby treat the subject, e.g., patient. In an embodiment, the subject, e.g., patient, has or is diagnosed as having gMG.

[0085] In another aspect, the disclosure provides a pharmaceutical composition comprising LOU064 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier for use in treating generalized Myasthenia Gravis (gMG), in a subject, e.g., patient, in need thereof. In an embodiment, the pharmaceutical composition is to be administered orally, at a dose of from about 50 mg to from about 250 mg, from about 100 mg to about 200 mg, e.g. at a dose of about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg of LOU064 or a pharmaceutically acceptable salt thereof, each dose to be administered twice daily (b.i.d.), e.g., about every 12 hours (wherein the dosing amount refers to the anhydrous LOU064 free base), to thereby treat the subject, e.g., patient.

[0086] In another embodiment, the pharmaceutical composition comprising LOU064 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, is as described in WO / 2022 / 162513 which is herein incorporated by reference, e.g. the pharmaceutical composition is as described in example 8 of WO / 2022 / 162513.

[0087] The following embodiments apply to any of the foregoing aspects provided herein and may be combined in any order.

[0088] In an embodiment, the method comprises administering to the subject a crystalline form of LOU064. In another embodiment, the method comprises administering to the subject crystalline form A of LOU064 as disclosed in Example 1 of WO2020 / 234779. In one aspect of this embodiment, crystalline form A is characterized by an x-ray powder diffraction pattern comprising one or more representative peaks in terms of 20 selected from the group consisting of 7.8 ± 0.2 °20, 9.2 ± 0.2 °20, 12.0± 0.2 °20, 13.6 ± 0.2 °20, 15.6 ± 0.2 °20, 16.0 ± 0.2 °20, 17.8 ± 0.2 °20, 18.3 ± 0.2 °20, 18.7 ± 0.2 °20, 19.2 ± 0.2 °20, 19.9 ± 0.2 °20, 22.1 ± 0.2 °20, 23.4 ± 0.2 °20, 23.9 ± 0.2 °20, 24.8 ± 0.2 °20, 25.2 ± 0.2 °20, 25.5 ± 0.2 °20, 27.2± 0.2 °20, and 29.6 ± 0.2 °20, when measured at a temperature of about 25°C and an x-ray wavelength, A, of 1.5405 A. In another aspect of this embodiment, crystalline Form A is characterized by an x-ray powder PAT059652A

[0089] diffraction pattern comprising representative peaks in terms of 20 of 7.8 ± 0.2 °20, 9.2 ± 0.2 °20 and 12.0± 0.2 °20 when measured at a temperature of about 25°C and an x-ray wavelength, A, of 1.5405 A.

[0090] In another aspect of this embodiment, crystalline Form A is characterized by an x-ray powder diffraction pattern comprising representative peaks in terms of 20 of 7.8 ± 0.2 °20, and 12.0± 0.2 °20 when measured at a temperature of about 25 °C and an x-ray wavelength, 1, of 1.5405 A.

[0091] In another aspect of this embodiment, the method comprises administering to the subject a crystalline form of LOU064. In another embodiment, the method comprises administering to the subject crystalline form A of LOU064 as disclosed in Example 1 of WO2020 / 234779, and as characterized above, wherein crystalline form A is in substantially phase pure.

[0092] In an embodiment, the pharmaceutical composition comprises LOU064, and at least one pharmaceutically acceptable carrier for use in treating generalized Myasthenia Gravis (gMG). In another embodiment, the pharmaceutical composition comprises crystalline Form A of LOU064 as defined herein, and at least one pharmaceutically acceptable carrier for use in treating generalized Myasthenia Gravis (gMG).

[0093] In yet another embodiment, the method comprises administering to the subject LOU064 at a dose of from about 50 mg to from about 250 mg, from about 100 mg to about 200 mg, each administered twice daily (b.i.d.).

[0094] In still another embodiment, the method comprises administering to the subject LOU064 at a dose of about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, each administered twice daily (b.i.d.).

[0095] In an embodiment, the dose is about 50 mg twice daily. In another embodiment, the dose is about 100 mg twice daily. In yet another embodiment, the dose is about 150 mg twice daily.

[0096] In still another embodiment, LOU064 or a pharmaceutically acceptable salt thereof is administered orally.

[0097] In an embodiment, the subject has Myasthenia Gravis Foundation of America (MGFA) Class II-IV MG.

[0098] In an embodiment, the subject has anti-acetylcholine receptor antibody-positive (AChR+) gMG. In an embodiment, the anti-acetylcholine receptor (AChR) antibody is at least one of PAT059652A

[0099] IgGl, IgG2, IgG3 and IgG4 subclasses. In an embodiment, the anti-acetylcholine receptor (AChR) antibody is at least one of IgGl and IgG3 subclasses.

[0100] In an embodiment, the subject has refractory gMG

[0101] In an embodiment, the subject has refractory anti-acetylcholine receptor antibodypositive (AChR+) gMG.

[0102] In another embodiment, the subject has antibodies against muscle-specific kinase (MuSK+).

[0103] In another embodiment, the subject is seronegative for both AChR and MuSK antibodies. In another embodiment, the method further comprises administering to the subject an immunosuppressant. In yet another embodiment, the immunosuppressant is e.g. a non-steroidal immunosuppressant treatment, e.g. the immunosuppressant is selected from azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, and tacrolimus or combination thereof. In still another embodiment, the subject has been administered the immunosuppressant for at least six months prior to administration of LOU064.

[0104] In an embodiment, the method further comprises administering to the subject a corticosteroid. In another embodiment, the subject has been administered a corticosteroid for at least four weeks prior to administration of LOU064.

[0105] In an embodiment, the method further comprises administering to the subject a cholinesterase inhibitor. In another embodiment, the method further comprises administering to the subject the cholinesterase inhibitor for at least two weeks prior to administration of LOU064.

[0106] In an embodiment, the method further comprises administering to the subject at least quarterly plasmapheresis, plasma exchange, or intravenous immunoglobulin.

[0107] In an embodiment, the method further comprises administering to the subject at least one of anFcRN antagonist, i.e., efgartigimod, rozanolixizumab.

[0108] In an embodiment, the method further comprises administering to the subject a complement inhibitor, e.g., eculizumab, ravulizumab, zilucoplan.

[0109] In an embodiment, the method further comprises administering to the subject a B cell inhibitor, e.g., inebilizumab.

[0110] In another embodiment, the subject is not optimally controlled (e.g. the subject has a MG-ADL total score of at least 6 (>50% of the MG-ADL score due to non-ocular symptoms) ) for greater than or equal to 6 months on one non-steroidal immunosuppressive therapy (NSIST) PAT059652A

[0111] prior to administration of LOU064. In yet another embodiment, the subject is not optimally controlled (e.g. the subject has a MG-ADL total score of at least 6 (>50% of the MG-ADL score due to non-ocular symptoms)) for greater than or equal to 6 months on two or more non-steroidal immunosuppressive therapies (NSIST). In still another embodiment, the NSIST is at least one of azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, and tacrolimus.

[0112] In an embodiment, the subject is not optimally controlled (e.g. the subject has a MG-ADL total score of at least 6 (>50% of the MG-ADL score due to non-ocular symptoms)) for greater than or equal to 6 months on a gMG treatment that is rituximab or a neonatal crystallizable fragment receptor (FcRN) antagonist approved from gMG. In another embodiment, the subject is not optimally controlled (e.g. the subject has a MG-ADL total score of at least 6 (>50% of the MG-ADL score due to non-ocular symptoms)) for greater than or equal to 6 months on frequent (e.g., at least quarterly) plasmapheresis, plasma exchange, or intravenous immunoglobulin to control symptoms despite treatment with steroids and non-steroidal immunosuppressive therapies (NSISTs).

[0113] In an embodiment, the method further comprises administering to the subject azathioprine. In another embodiment, the method further comprises administering to the subject azathioprine for at least 6 months prior to administration of LOU064.

[0114] In an embodiment, the subject has a MG-ADL total score of at least 6 (>50% of the MG- ADL score due to non-ocular symptoms) at baseline.

[0115] In an embodiment, the subject is not optimally controlled on one of more of the following gMG treatments:

[0116] a. One non-steroidal immunosuppressive therapy for at least 6 months;

[0117] b. Acetylcholinesterase inhibitor for at least 1 month; and / or

[0118] c. Steroids for at least 4 months.

[0119] In one aspect of the above embodiment, the subject has a MG-ADL total score of at least 6 (>50% of the MG-ADL score due to non-ocular symptoms) despite one or more of the following gMG treatment:

[0120] a. One non-steroidal immunosuppressive therapy for at least 6 months;

[0121] b. Acetylcholinesterase inhibitor for at least 1 month; and / or

[0122] c. Steroids for at least 4 months. PAT059652A

[0123] In another embodiment, the subject continues to receive his gMG treatment, e.g. one or more of the following gMG treatment:

[0124] a. One non-steroidal immunosuppressive therapy;

[0125] b. Acetylcholinesterase inhibitor; and / or

[0126] c. Steroids; while the subject is further administered LOU064, (e.g. in a dose of about lOOmg b.i.d.)

[0127] In an embodiment, the method further comprises achieving a reduction in a MG-ADL total score, e.g., by at least 2, at least 3, at least 4, at least 5, or at least 6, e.g., at 1 month, at 3 months, at 6 months, compared to at baseline. In one aspect of this embodiment, the method further comprises achieving a reduction in a MG-ADL total score of at least 3, compared to baseline at month 6 of treatment. In one aspect of this embodiment, the percentage of patients achieving at least 3 points reduction from baseline to Month 6 of treatment of MG-ADL total score, is greater in the remibrutinib treated group than in the placebo group, e.g. at least 20% greater, e.g. the responder rate (percentage of patients achieving a reduction of at least 3 points from baseline to Month 6) in the remibrutinib group is at least 60% wherein the responder rate in the placebo group is no more than 40%.

[0128] In another embodiment, the method further comprises achieving a minimal symptom expression (MSE), defined as MG-ADL of 0 or 1, e.g. at 1 month, at 3 months or at 6 months, without rescue therapy as defined herein and / or strongly confounding prohibited medication as defined herein. In one aspect of this embodiment, the percentage of patients achieving MSE as described above at Month 6 of treatment is greater in the remibrutinib treated group than in the placebo group, e.g. at least 15% greater, e.g. the responder rate (percentage of patients achieving MSE) in the remibrutinib group is at least 20% wherein the responder rate in the placebo group is no more than 5%.

[0129] In an embodiment, the method further comprises achieving a reduction in a QMG total score, e.g., by at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, e.g., at 1 month, at 3 months, at 6 months, compared to at baseline. In one aspect of this embodiment, the method further comprises achieving a reduction in a QMG total score of at least PAT059652A

[0130] 5, compared to baseline at month 6 of treatment. In one aspect of this embodiment, the percentage of patients achieving at least 5 points reduction from baseline to Month 6 of treatment of QMG total score, is greater in the remibrutinib treated group than in the placebo group, e.g. at least 20% greater, e.g. the responder rate (reduction of at least 5 points from baseline to Month 6) in the remibrutinib group is at least 40% wherein the responder rate in the placebo group is no more than 20%.

[0131] In an embodiment, the method further comprises achieving a reduction in Myasthenia Gravis Composite (MGC) total score by at least 3, e.g., at least 4, at least 5, or least 6, e.g., at 1 month, at 3 months, at 6 months, compared to at baseline.

[0132] In an embodiment, the method further comprises achieving a reduction in corticosteroid dose. In an embodiment, the corticosteroid is an oral corticosteroid.

[0133] Further aspects of the present invention are summarized in the following embodiments El to E26, respectively alone or in combination, contribute to solving the object of the invention.

[0134] El . LOU064 or a pharmaceutically acceptable salt thereof for use in the treatment of generalized Myasthenia Gravis (gMG) in a subject in need thereof.

[0135] E2. LOU064 for use according to embodiment 1.

[0136] E3. LOU064 for use according to embodiment 2, wherein LOU064 is in a crystalline form characterized by an X-ray diffraction pattern comprising representative peaks in terms of 20 of 7.8 ± 0.2 °20, 9.2 ± 0.2 °20 and 12.0± 0.2 °20 when measured at a temperature of about 25°C and an x-ray wavelength, X, of 1.5405 A.

[0137] E4. LOU064, or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 3, wherein LOU064 is administered at a dose of from about 50 mg to about 250 mg, or from about 100 mg to about 200 mg, each administered twice daily (b.i.d.).

[0138] E5. LOU064, or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 4, wherein LOU064 is administered at a dose of about 50 mg, or about 75 PAT059652A

[0139] mg, or about 100 mg, or about 150 mg, or about 200 mg each administered twice daily (b i d).

[0140] E6. LOU064, or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 5, wherein LOU064 is administered at a dose of about 50 mg twice daily.

[0141] E7. LOU064, or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 6, wherein LOU064 is administered at a dose of about 100 mg twice daily.

[0142] E8. LOU064, or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 7, wherein LOU064 is administered wherein LOU064 or a pharmaceutically acceptable salt thereof is administered orally.

[0143] E9. LOU064, or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 8, wherein the subject has anti-acetylcholine receptor antibody-positive (AChR+) gMG.

[0144] E10. LOU064, or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 8, wherein the subject has antibodies against muscle-specific kinase (MuSK+).

[0145] Ell. LOU064, or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 8, wherein the subject is seronegative for both AChR and Musk antibodies.

[0146] El 2. LOU064, or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 11, wherein LOU064, or a pharmaceutically acceptable salt thereof is administered to the subject in combination with an immunosuppressant.

[0147] El 3. LOU064, or a pharmaceutically acceptable salt thereof for use according to embodiment 12, wherein the immunosuppressant is selected from azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, and tacrolimus or combination thereof. PAT059652A

[0148] El 4. LOU064, or a pharmaceutically acceptable salt thereof for use according to embodiment 12 or 13, wherein the immunosuppressant has been administered to the subject for at least six months prior to administration of LOU064.

[0149] El 5. LOU064, or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 14, wherein LOU064, or a pharmaceutically acceptable salt thereof is administered to the subject in combination with a corticosteroid.

[0150] El 6. LOU064, or a pharmaceutically acceptable salt thereof for use according to embodiment 15, wherein the corticosteroid is administered to the subject for at least four weeks prior to administration of LOU064.

[0151] El 7. LOU064, or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 16, wherein LOU064, or a pharmaceutically acceptable salt thereof is administered to the subject in combination with a cholinesterase inhibitor.

[0152] El 8. LOU064, or a pharmaceutically acceptable salt thereof for use according to embodiment 17, wherein the cholinesterase inhibitor is administered to the subject for at least two weeks prior to administration of LOU064.

[0153] El 9. LOU064, or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 18, wherein the subject is not optimally controlled on one of more of the following gMG treatments:

[0154] d. One non-steroidal immunosuppressive therapy for at least 6 months;

[0155] e. Acetylcholinesterase inhibitor for at least 1 month; and / or

[0156] f. Steroids for at least 4 months.

[0157] E20. LOU064, or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 18, wherein the subject is not optimally controlled for greater than or equal PAT059652A

[0158] to 6 months on a gMG treatment that is rituximab or a neonatal crystallizable fragment receptor (FcRN) antagonist approved from gMG.

[0159] E21. LOU064, or a pharmaceutically acceptable salt thereof for use according to embodiment 19 or 20, wherein the term not optimally controlled is defined as a MG-ADL total score with >50% of the MG-ADL score being due to non-ocular symptoms of at least 6.

[0160] E22. LOU064, or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 21, wherein the subject achieves a reduction in a MG-ADL total score, e.g., by at least 2, at least 3, at least 4, at least 5, or at least 6, e.g., at 1 month, at 3 months, at 6 months, compared to at baseline.

[0161] E23. LOU064, or a pharmaceutically acceptable salt thereof for use according to any one of embodiments 1 to 22, wherein the subject achieves a reduction in a QMG total score, e.g., by at least 3, e.g., at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, e.g., at 1 month, at 3 months, at 6 months, compared to at baseline.

[0162] E24. A pharmaceutical composition comprising LOU064 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier for use in the treatment of generalized Myasthenia Gravis (gMG) in a subject in need thereof, wherein LOU064 is administered to a subject at a dose of about lOOmg b.i.d.

[0163] E25. Use of LOU064, or a pharmaceutically acceptable salt thereof, in the manufacturing of a medicament for the treatment of generalized Myasthenia Gravis (gMG) in a subject in need thereof.

[0164] E26. Use of LOU064 or a pharmaceutically acceptable salt thereof, in the treatment of generalized Myasthenia Gravis (gMG) in a subject in need thereof, wherein LOU064 is administered to a subject at a dose of about lOOmg b.i.d. PAT059652A

[0165] EXAMPLES

[0166] The disclosure is further illustrated by the following examples, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and / or scope of the appended claims.

[0167] List of abbreviations

[0168]

[0169] Glossary of terms PAT059652A

[0170]

[0171] PAT059652A

[0172]

[0173] PAT059652A

[0174]

[0175] PAT059652A

[0176]

[0177] Example 1. A randomized, double-blind, placebo-controlled phase III study to evaluate the efficacy, safety, and tolerability of remibrutinib in patients with generalized Myasthenia Gravis (gMG), followed by an open label extension phase

[0178] Purpose

[0179] The purpose of this study is to evaluate the efficacy, safety and tolerability of remibrutinib in patients with generalized Musathenoa Gravis (gMG) who are acetylcholine receptor positive (AChR+), muscle-specific tyrosine kinase positive (MuSK+), or double-seronegative (AChR- and MuSK-) who are on stable, standard-of-care (SOC) treatment.

[0180] The study was designed to evaluate whether treatment with remibrutinib results in the reduction of the total score in Myasthenia Gravis Activity of Daily Living (MG-ADL) scale as compared to placebo. The MG-ADL is a patient-reported scale that measures MG symptoms and functional status and is a commonly used scale in gMG studies.

[0181] Objectives, Endpoints, and Estimands

[0182] Table 1

[0183] Objectives(s) Endpoint(s)

[0184] Primary Objectives Endpoint(s) for primary objective(s)

[0185] • To demonstrate efficacy of LOU064 • Change from baseline to Month 6 in compared to placebo in patients with Myasthenia Gravis Activity of Daily

[0186] gMG on stable SOC in reducing the Living (MG-ADL) total score

[0187] total score of the Myasthenia Gravis

[0188]

[0189] PAT059652A

[0190] Activity of Daily Living (MG-ADL)

[0191] scale at 6 months (Day 180) of

[0192] treatment

[0193] Secondary Objective(s) Endpoint(s) for secondary objective(s)

[0194] Key Secondary Objectives Key Secondary Endpoints

[0195] • To assess whether LOU064 is • Change from baseline to Month 6 in superior to placebo in patients with Quantitative MG (QMG) total score

[0196] gMG • Proportion of participants with > 5

[0197] o in reducing Quantitative MG points reduction from baseline to

[0198] (QMG) total score at 6 months of Month 6 of QMG total score without treatment rescue medication and strongly

[0199] o on the proportion of study confounding prohibited medication participants achieving a reduction • Proportion of participants with > 3

[0200] from baseline to Month 6 of points reduction from baseline to

[0201] QMG total score > 5 points Month 6 of MG-ADL total score

[0202] without rescue medication and without rescue medication and

[0203] strongly confounding prohibited strongly confounding prohibited medication medication

[0204] o on the proportion of study • Proportion of participants achieving participants achieving a reduction MSE at Month 6, defined as MG- from baseline to Month 6 of MG- ADL score of 0 or 1 at Month 6

[0205] ADL total score > 3 points without rescue therapy and / or

[0206] without rescue medication and strongly confounding prohibited

[0207] strongly confounding prohibited medication

[0208] medication • Change from baseline to Month 6 in

[0209] o in achieving Minimal Symptom Myasthenia Gravis Composite

[0210] Expression (MSE) at Month 6, (MGC) total score

[0211] defined as an MG-ADL of 0 or 1 • Change from baseline to Month 6 in

[0212] at Month 6 without rescue therapy revised MG Quality of Life

[0213] and / or strongly confounding

[0214] prohibited medication

[0215]

[0216] PAT059652A

[0217] o in reducing MGC total score at Questionnaire (MG-Q0L15r) survey Month 6 of treatment score

[0218] o in reducing MG-Q0L15r survey

[0219] score at Month 6 of treatment

[0220] Other Secondary Objectives (Core Other Secondary Endpoints (Core

[0221] Part) Part)

[0222] • To evaluate the safety and • Incidence of adverse events and

[0223] tolerability of LOU064 compared to changes in clinical laboratory values, placebo in patients with gMG vital signs, and electrocardiograms,

[0224] • To evaluate the efficacy of LOU064 Columbia Suicide Severity Rating compared to placebo in patients with • Proportion of time patients showed

[0225] gMG on other efficacy endpoints a reduction from baseline of > 2

[0226] points in MG-ADL total score that

[0227] was maintained up to Month 6

[0228] • Proportion of early MG-ADL

[0229] responders during treatment (early responders with first MG-ADL improvement from baseline of > 2

[0230] points occurring by week 4)

[0231] • Change from baseline to Month 6 in EuroQol-5 Dimensions-5 Level

[0232] (EQ-5D-5L)

[0233] • Proportion of participants achieving

[0234] a reduction of > 3 points from

[0235] baseline to Month 6 in MGC total

[0236] score

[0237] Other Secondary Objectives Other Secondary Endpoints

[0238] (Extension Part) (Extension Part)

[0239] • To assess long-term effect of • Change from baseline in MG-ADL LOU064 in patients with gMG in total score PAT059652A

[0240] reducing the total score of the MG- Proportion of participants achieving

[0241] ADL during the Extension Part a reduction from core part in oral

[0242] • To assess long-term effect of corticosteroids (OCS) dose till the LOU064 in patients with gMG on end of extension part

[0243] the proportion of study participants Incidence of adverse events

[0244] achieving a reduction from Core Part Changes in clinical laboratory

[0245] in oral corticosteroids (OCS) dose values, vital signs, and

[0246] till the end of Extension Part electrocardiograms, Columbia

[0247] • To assess long-term safety and Suicide Severity Rating at each visit tolerability of LOU064 compared to

[0248] placebo in patients with gMG

[0249] Exploratory Objectives(s) Endpoint(s) for exploratory objective(s)

[0250] • To evaluate the • Determine blood LOU064 concentrations at pharmacokinetics of LOU064 trough during the 6-month Double-blind Treatment Period.

[0251] • To explore LOU064 treatment • Evaluate the protein pathway signature in effect on blood biomarkers by relation to treatment, indication, clinical proteomics. response or genetic polymorphisms

[0252] • To perform exploratory • Evaluate the relationship of genetic pharmacogenetic analysis based polymorphisms data with drug metabolism, on blood samples for DNA the indication, the drug target pathway and (optional assessments) treatment response.

[0253] • To evaluate the efficacy of • Proportion of participants with > 5 points LOU064 compared to placebo reduction in QMG total score from baseline in patients with gMG on other by each post-baseline visit without rescue efficacy endpoints medication and / or strongly confounding prohibited medication

[0254] • Proportion of participants with > 3 points reduction in MG-ADL total score from baseline by each post-baseline visit without PAT059652A

[0255] rescue medication and / or strongly confounding prohibited medication

[0256] • Proportion of participants achieving MSE by each post-baseline visit without rescue medication and / or strongly confounding prohibited medication

[0257] • Proportion of participants with > 3 points reduction in MGC total score from baseline by each post-baseline visit without rescue medication and / or strongly confounding prohibited medication

[0258] • Change from baseline in Neuro-QoL Fatigue short form

[0259] Primary Estimands

[0260] The primary goal was to investigate the effect of LOU064 treatment versus placebo on the change in MG-ADL total score from baseline to 6 months of treatment in patients with gMG who are receiving stable SOC myasthenia gravis treatment.

[0261] The primary estimand is described by the following attributes:

[0262] • Population: Participants between 18-75 years of age, who have a MG-ADL score of at least 6 (>50% non-ocular) at baseline and are receiving stable SOC myasthenia gravis treatment. For further details about the population, see Inclusion / Exclusion criteria.

[0263] • Endpoint: change from baseline to Month 6 in MG-ADL total score.

[0264] • Treatment of interest: the randomized treatment (LOU064 or placebo) with the allowed SOC MG treatment.

[0265] Handling of inter current events: PAT059652A

[0266] 1. Discontinuation from study treatment for any reason is handled according to treatment policy strategy, i.e., data after treatment discontinuation is collected and used for the primary analysis.

[0267] 2. Change in the allowed SOC MG treatment is handled according to treatment policy strategy, i.e., data after change of allowed SOC MG treatment is collected and used for the primary analysis.

[0268] 3. Intake of rescue medication is handled irrespective of potential occurrence of other intercurrent events according to hypothetical strategy as if the participant had not taken the rescue medication and would have continued to be treated. Rescue medication has great potential to confound the interpretation of the treatment effect especially given the placebo- controlled setting of the study where participants randomized to the placebo tend to take rescue medication more often than participants randomized in the LOU064 group.

[0269] Measurements after the rescue medication is excluded from the analysis and is imputed via a modelling approach accounting for the rescue medication as potentially indicative of a worsening of condition.

[0270] 4. Intake of strongly confounding prohibited medication is handled according to hypothetical strategy irrespective of potential occurrence of other intercurrent events as if the participant had not taken strongly confounding prohibited medication and would have continued to be treated. Prohibited medication has great potential to confound the interpretation of the treatment effect, especially given the placebo-controlled setting of the study where participants randomized to the placebo tend to take other prohibited medication more often than participants randomized in the LOU064 group.

[0271] Measurements after the intake of strongly confounding prohibited medication is excluded from the analysis and is imputed via a modelling approach accounting for the rescue medication as potentially indicative of a worsening of condition.

[0272] The summary measure: the difference of mean change in MG-ADL total score from baseline to Month 6 between the treatments.

[0273] Estimands

[0274] Change from baseline to Month 6 in QMG total score PAT059652A

[0275] A secondary goal of this clinical trial was to investigate the effect of LOU064 treatment versus placebo on the change from baseline to Month 6 in QMG total score. The population, treatment or interest, summary measure, intercurrent events and their corresponding handling strategies are the same as that outlined above.

[0276] Proportion of participants with 5 points reduction from baseline to Month 6 of QMG total score without rescue medication and strongly confounding prohibited medication

[0277] The clinical goal is to determine what is the effect of LOU064 treatment versus placebo on the proportion of participants with >5 points reduction from baseline to Month 6 of QMG total score without rescue medication and strongly confounding prohibited medication in patients with generalized myasthenia gravis who are receiving stable SOC myasthenia gravis treatment, regardless of discontinuation from study treatment for any reason and change in the allowed SOC MG treatment.

[0278] The population and treatment of interest are the same as for the primary estimand. Other attributes are listed below.

[0279] Endpoint: Proportion of participants with 5 points reduction from baseline to Month 6 of QMG total score without rescue medication and strongly confounding prohibited medication.

[0280] Handling of inter current events:

[0281] 1. Discontinuation from study treatment for any reason is handled according to treatment policy strategy, i.e., data after treatment discontinuation is collected and used for the primary analysis.

[0282] 2. Change in the allowed SOC MG treatment is handled according to treatment policy strategy, i.e., data after change of allowed SOC MG treatment is collected and used for the primary analysis.

[0283] 3. Intake of rescue medication is handled according to composite strategy irrespective of potential occurrence of other intercurrent events. Intake of rescue medication is considered as treatment failure hence a part of endpoint definition, deemed as non-responder.

[0284] 4. Intake of strongly confounding prohibited medication is handled according to composite strategy irrespective of potential occurrence of other intercurrent events. Intake of strongly confounding prohibited medication is considered as treatment failure hence a part of endpoint definition, deemed as non-responder.

[0285] The summary measure: odds ratio from a logistic regression model adjusted for covariates. PAT059652A

[0286] Proportion of participants with 3 points reduction from baseline to Month 6 ofMG-ADL total score without rescue medication and strongly confounding prohibited medication

[0287] The clinical goal is to determine what is the effect of LOU064 treatment versus placebo on the proportion of participants with 3 points reduction from baseline to Month 6 ofMG-ADL total score without rescue medication and strongly confounding prohibited medication. The population, treatment or interest, summary measure, intercurrent events and their corresponding handling strategies are the same as that above.

[0288] Change from baseline to Month 6 in MGC total score

[0289] The clinical goal is to determine what is the effect of LOU064 treatment versus placebo on change from baseline to Month 6 in MGC total score. The population, treatment or interest, summary measure, intercurrent events and their corresponding handling strategies are the same as that above.

[0290] Change from baseline to Month 6 in MG-QOL15r survey score

[0291] The clinical goal is to determine what is the effect of LOU064 treatment versus placebo on change from baseline to Month 6 in MG-QOL15r survey score. The population, treatment or interest, summary measure, intercurrent events and their corresponding handling strategies are the same as that above.

[0292] Study Design

[0293] This study is a randomized, double-blind, placebo-controlled, multicenter, Phase III study, to evaluate efficacy, safety and tolerability of remibrutinib in gMG patients who are on stable standard of care treatment. Approximately 180 eligible participants are randomized and stratified according to the stratification factors: Autoantibody type: (1) participants with MuSK+ antibodies, or (2) participants with AChR+ or who are seronegative for both AChR and MuSK antibodies (double seronegative).

[0294] Furthermore, study participants must have their disease clinical severity categorized, as class II to IV (per MGFA), and have a MG-ADL score of at least 6 at baseline. The defined trial PAT059652A

[0295] population will include patients with AChR+ or MuSK+ antibodies or who are seronegative for both AChR and MuSK antibodies. The patient population also must contain at least 20 enrolled patients with MuSK+ antibodies. In addition, < 50% of the patients can be on one NSIST treatment.

[0296] The study consists of a Core Part and an Extension Part.

[0297] The Core Part consists of 3 periods:

[0298] • Screening Period: A period of up to 4 weeks to assess participants eligibility.

[0299] • Double- Blind Treatment Period: A 6-month randomized; double-blind placebo controlled treatment period for the primary efficacy and safety analyses

[0300] • Safety Follow-up Period: A period consisting of one safety follow-up visits for all participants not continuing treatment in the Extension part or discontinuing early.

[0301] The Extension Part consists of 2 periods:

[0302] • Open label Extension Period (OLE): A 60-month open-label, single arm treatment period in which eligible participants will receive remibrutinib treatment

[0303] • Safety Follow-up Period: A period consisting of one safety follow-up visits for all participants completing the open-label extension

[0304] CORE PART:

[0305] Screening Period

[0306] At screening, participants are asked to review and sign the informed consent form(s) (ICF(s)) before performing any study-related assessments. After signing the ICF, inclusion and exclusion criteria are assessed during the screening visit to verify participants' eligibility for enrollment into the study.

[0307] Participants must either have positive serology testing for AChR+ or MuSK + antibodies or seronegative for both anti-AChR and anti-MuSK autoantibodies and with a documented history of gMG diagnosis, as supported by at least 1 of the following 3 tests:

[0308] • History of abnormal neuromuscular transmission demonstrated by single- fiber electromyography or repetitive nerve stimulation PAT059652A

[0309] • History of of positive test with short-acting acetylcholinesterase inhibitors (e.g., neostigmine or edrophonium chloride)

[0310] • Demonstrated improvement in MG signs on oral acetylcholinesterase inhibitors

[0311] For the purpose of determining eligibility to the study, all participants have blood taken at screening to assess for the presence of AChR+ or MuSK+ antibodies by central laboratory testing.

[0312] Other screening assessments include a physical examination, vital signs, demography, medical history, prior / concomitant medications, ECG, hematology, clinical chemistry and urinalysis.

[0313] Participants who are being treated with stable doses of standard of care treatment for gMG at the time of screening visit are required to continue these medications throughout the Doubleblind Treatment Period and Open-label Extension Period. Dosage of the SOC medications must not be changed, and no new SOC medication may be added or discontinued during the Doubleblind Treatment Period of the study, unless changes are deemed medically necessary by the Investigator.

[0314] If study eligibility criteria are not met, the participant should be screen failed. However, in some instances, for participants who fail eligibility during the screening process due to a temporary condition (such as safety laboratory values), re-testing may be permitted within the same screening period on a case-by-case basis in consultation with Novartis Medical Monitor to redetermine eligibility. Participants that do not meet the eligibility criteria during the screening period can be re-screened once at a later date and randomized into the study if all inclusion and exclusion criteria are met, however this must be discussed and agreed with Applicant on a case-by-case basis. All required screening assessments must be performed for participants being rescreened. Screen-failed participants undergoing rescreening, are required to sign another ICF and a new participant number is assigned.

[0315] Double-blind Treatment Period

[0316] Participants who meet the eligibility criteria are randomized in a ratio of 1 : 1, to receive either remibrutinib at a dose of 100 mg orally b.i.d or matching placebo, for 6 months (Day 180) while continuing on a stable SOC treatment. The randomization is stratified based on PAT059652A

[0317] region and autoantibody type.

[0318] At the Baseline visit, before randomization, all participants are reassessed for eligibility based on the study inclusion and exclusion criteria. The MG-ADL scale needs to be performed prior to all other efficacy or quality of life assessments followed by other patient-reported scales.

[0319] Baseline values for vital signs, ECG, hematology, clinical chemistry, biomarkers, myasthenia gravis related assessments and scales as well as the quality-of-life questionnaires are completed at this visit.

[0320] Study treatment starts on the first day of dosing (Day 1) and continue for 6 months (Day 180). Participants return to the study center for scheduled visits on Days 15, 30, 45, 60, 75, 90, 120, 150 and 180 of the study, and the study efficacy and safety assessments is performed at these visits. Blood sampling for pharmacokinetics and biomarkers is collected pre-dose (i.e., prior to administration of study drug) on Day 15, 30, 90, 150 and, EOS visit of the Double-blind Treatment Period.

[0321] Interactive Response Technology (IRT) contacts, study drug dispensing and accountability will be performed as required at each of the study visits.

[0322] Dose adjustment of remibrutinib is not allowed during the randomized treatment period and further details on dose interruptions or discontinuation of study drug can be found below.

[0323] Furthermore, the dose of the SOC medication must remain stable and unchanged throughout the treatment period.

[0324] However, per the Investigator's judgment and definition for deterioration as described below, if there is a deterioration of the participant's MG status or a risk of MG crisis, the participant is permitted to receive rescue therapy. This rescue therapy can either be IVIG or plasmapharesis / plasma exchange and the participant is allowed to continue on the blinded study treatment if it is considered safe per Investigator medical judgement. In such cases, the rescue therapy used for a given participant is at the discretion of the Investigator. Note: alternative or additional rescue medications (other than those described above) are not permitted. The date and time of rescue medication administration as well as dosing regiment is recorded. Participants receiving prohibited medication must be discontinued from study treatment.

[0325] The Double-blind Treatment Period will end with completion of the Month 6 (Day 180) visit assessments. All participants will have an EOS visit for the core part either upon completion of PAT059652A

[0326] the Month 6 (Day 180) visit or if the participant prematurely discontinues the treatment period (i.e., discontinues from double-blind study treatment and is not willing to attend any further subsequent study visits as per schedule). Upon completion of all assessments at the Month 6 visit (Day 180), all eligible participants who have completed the Double-blind treatment period are offered to continue in the OLE and will receive remibrutinib for a period of 60 months as outlined below.

[0327] For participants who permanently discontinue treatment during the Double-blind Treatment Period, efforts should be made to encourage these participants to remain in the study for further monitoring and complete all assessments up to Day 180 (Month 6 / EOS visit). Participants who prematurely discontinue double-blind study treatment and who are willing to continue in the trial will have an End of Treatment (EOT) visit at the time of double-blind study medication discontinuation and these participants will not be eligible to enter the open label extension part. These discontinued participants will complete Safety Follow-up visits 28 days after the Month 6 EOT / EOS visit.

[0328] Participants who complete the double-blind treatment period, including those who received rescue therapy and for whom continuation of the study treatment was safely warranted, are eligible to enter the open label extension part of the study and are not required to complete the Safety Follow-up visit.

[0329] An interim analysis (IA) is conducted by an independent team on change from baseline in MG-ADL and QMG at Month 3 data when 33% of patients are enrolled, to provide the opportunity for an early stop of the trials for futility. Recruitment will continue while the IA is ongoing. Prior to the completion of enrollment into the Core Part of the study, a blinded data analysis (i.e., the treatment code will not be broken), is performed to re-assess sample size assumptions for primary endpoint once 33% of patients have completed their Month 6 assessments. Based on this blinded analysis, the number of participants to be enrolled may be increased to a maximum number of 242 randomized participants.

[0330] Safety Follow-up Period

[0331] A period consisting of one safety follow-up assessment 28 days after the last administration of study treatment (i.e., EOT / EOS +28 days) for all participants not continuing treatment in the PAT059652A

[0332] Extension part. This follow-up may be a phone call or a study site visit. The information collected for the Month 6 EOT / EOS +28 visit is collected on the eCRF. SAE reporting continues during this time period as described below. Documentation of attempts to contact the participant are required to be recorded in the source documentation.

[0333] Extension Part

[0334] Open-label Extension Period (OLE)

[0335] Participants completing all visits on study treatment through Month 6 (Day 180) of the Doubleblind Treatment Period are eligible to participate in the open label extension treatment period (OLE) with all participants receiving remibrutinib 100 mg b.i.d. This is a blinded transition from the Double-blind Treatment Period of study to OLE.

[0336] Participants eligible and agreeing participate in the OLE treatment start treatment upon completion of the Month 6 (Day 180) visit after completing all assessments of the Double-blind Treatment Period. Efficacy and safety assessments performed at this visit are used for the EOS visit of the Double-blind Treatment Period as well as for the enrollment / Baseline Visit (OLE Day 1). Participants not eligible or not agreeing to continue in the OLE after completing 6 months of double-blind treatment complete EOS assessments.

[0337] IRT contacts, study treatments dispensing, and accountability are performed at each visit.

[0338] All participants return for the Safety Follow-up visit 28 days after the Month 60 EOT / EOS visit.

[0339] Safety Follow-up Period

[0340] A period consisting of one safety follow-up assessments, 28 days after the last administration of study treatment (i.e., Month 60 EOT / EOS +28 days) for all participants in the Extension part. This follow-up may be a phone call or a study site visit. The information collected for the Month 60 EOT / EOS +28 visit is collected on the eCRF. Serious adverse event (SAE) reporting continues during this time period as described below. Documentation of attempts to contact the participant are required to be recorded in the source documentation.

[0341] Rationale for selection of the dose

[0342] The dose of 100 mg b.i.d. was selected for the gMG indication for the following reasons: PAT059652A

[0343] Efficacy

[0344] The primary pharmacology of remibrutinib is determined by the extent and duration of BTK target occupancy. While the initial inactivation of BTK by remibrutinib is primarily dependent on the systemic exposure of the drug, the duration of BTK inhibition is independent of drug exposure and rather determined by the turnover of the inactive drug / protein complex and by resynthesis of new BTK protein. This turnover rate is faster in tissues like spleen and lymph nodes compared to blood.

[0345] This may reflect that BTK expressing B-cells and monocytes in peripheral blood are resting with low or no metabolic activity.

[0346] Translational pharmacolkinetic (PK) / pharmacodynamic (PD) model simulations were used to predict human peripheral tissue occupancy (e.g., spleen and lymph node) of remibrutinib assuming absence of relevant inter-species differences in turnover and drug potency. These simulations project that a daily dose up to 100 mg b.i.d. would be required to achieve a trough BTK occupancy > 90% in a peripheral target tissue. (WO 2023 / 031840)

[0347] 100 mg b.i.d. dose regimen was selected in view of diverse pharmacodynamic measures in healthy volunteers and from completed phase II studies in CSU and SjS (primary endpoint (PE) analysis):

[0348] • In the Phase I studies, a maximum trough inhibition of blood basophil CD203c activation (ex vivo) at Day 12 was only achieved with b.i.d. administration of 100 mg and 200 mg remibrutinib.

[0349] • Similarly, ex vivo blood B-cell activation measured as CD69 was inhibited by > 50% at single doses of > 30 mg at 24h post-treatment and maximal (65.98%) at a dose of 200 mg. • The maximal effect of remibrutinib on skin prick test in healthy volunteers was achieved at a dose of 100 mg b.i.d.

[0350] • Remibrutinib has demonstrated significant clinical efficacy and a fast onset of action in the treatment of patients with CSU across a range of doses compared to placebo as measured by the reduction in Urticaria Activity Score (UAS)

[0351] • In a study in patients with SjS (CLOU064E 12201) remibrutinib showed significant efficacy (decrease in ESSDAI (European League Against Rheumatism (EULAR) Sjogren's syndrome disease activity index) score from baseline to week 24).

[0352] • The mouse experimental autoimmune encephalomyelitis (EAE) model based on PAT059652A

[0353] immunization with human myelin oligodendrocyte glycoprotein is specifically dependent on B-cells as the pathologic antigen-presenting cells. Remibrutinib was highly effective at inhibiting EAE induction and severity in this B-cell dependent- model.

[0354] At a dose of 30 mg / kg b.i.d., remibrutinib strongly reduced EAE-induced weight loss, as well as neurologic symptoms. The human equivalent dose (HED) based on this model is ~ 170 mg for a 70 kg person. Nuesslein-Hildesheim B et al.; J Neuroinflammation. 2023 Aug 26;20(l):194. doi: 10.1186 / s 12974-023 -02877-9. PMID: 37633912; PMCID: PMC10463946.

[0355] Safety

[0356] Remibrutinib has been found to be well tolerated with a favorable safety profile in Phase I and Phase II clinical studies at all doses tested.

[0357] There is sufficient participant exposure and an acceptable safety profile for remibrutinib, lOOmg b.i.d. in Phase I (healthy volunteers) and Phase II studies (indications of CSU and SjS) which supports the selection of this dose for this study.

[0358] • > 20 studies, involving > 2900 patients who received doses up to 600mg, including long-term exposure with lOOmg b.i.d up to 52 weeks (Phase lib trial in chronic spontaneous urticaria patients)

[0359] • Ata dose of 100 mg b.i.d., there have been no identified dose-dependent or dose limiting adverse events (AEs) or clinically relevant laboratory, vital sign or ECG results to date.

[0360] In summary, over several autoimmune indications studied, no indication specific safety differences nor dose related increase in frequency of adverse events have been observed with remibrutinib. Safety areas of interest followed for this mode of action (BTK inhibition) such as bleeding, cytopenias, infections, liver enzyme elevations or diarrhea have not been significant concern with any dose. No clustering of adverse events has been seen.

[0361] Based on the above efficacy considerations, the use of a dose of remibrutinib with the greatest possible continued inhibition of BTK in all relevant tissues is chosen to achieve maximum efficacy. The 100 mg b.i.d. dose aims to maximize the effect of remibrutinib in patients with gMG. This is supported by a favorable safety profile of this target dose regimen for the Phase II / III studies resulting in acceptable benefit-risk profile. PAT059652A

[0362] Rationale for choice of control drugs or combination drugs and background therapy Participants in this clinical trial must continue to receive stable standard of care therapy as assigned by their treating physician. Participants receiving SOC therapy are required to have been on this therapy for a defined period of time prior to baseline (see inclusion criteria) and remain on the same stable therapy throughout the duration of the randomized period of this clinical trial. Except when rescue medication is permitted, any change in SOC, because of disease worsening or progression, might result in discontinuing the participant from receiving the investigational treatment (remibrutinib or placebo).

[0363] This study allows for inclusion of patients treated with a spectrum of NSISTs (which include azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus in < 50% of participants), corticosteroids, and acetylcholinesterase inhibitors, which are commonly prescribed for gMG, and are often taken by patients in combination. These treatments are expected to vary from patient to patient based on investigator / treating physician clinical judgment given the clinical context and local SOC practices. A stable dose of preexisting treatment for gMG (e.g., acetylcholinesterase inhibitors, corticosteroids, or NSIST) before baseline and throughout the trial is permitted and required per inclusion criteria. For cholinesterase inhibitors, increases in cholinesterase therapy that are required as a result of intercurrent illness or other medical cause of deterioration are permitted, but dosing should be returned to dosing levels at study entry as soon as feasible and the Sponsor should be notified of the change. The dose of corticosteroids, or NSISTs needs to remain stable throughout the study duration. Prohibited medications are listed in below.

[0364] Participants who have not previously responded to other BTK inhibitors are excluded, as it is unlikely that they would respond to remibrutinib given the very similar mechanism of action (see inclusion / exclusion criteria).

[0365] Patients are randomized 1:1 to receive either remibrutinib lOOmg b.i.d. or matching placebo for the 6-month double-blind treatment period to assess efficacy, safety, and tolerability.

[0366] For this study, a placebo control on top of stable SOC background therapy (which is allowed in both treatment arms) has been selected due to the unstable and potentially life-threatening nature of the disease and is considered appropriate to maintain a balance between a robust evaluation of efficacy and safety in this registration study and ensuring that patients are maintained on the SOC so as to prevent decompensation. This risk is further mitigated by not including MGFA PAT059652A

[0367] class V patients. Therefore, patients randomized to the placebo group are not expected to experience significant harm during the course of the 6-month treatment period, even in the absence of other, more recently approved therapies.

[0368] Furthermore, in case of disease worsening or disease progression, patients may receive rescue treatment, IVIG or PLEX, as per local treatment guidance.

[0369] At the conclusion of the double-blind treatment period, all patients who have completed the double-blind treatment period have the option to roll over into the open-label extension where they would receive remibrutinib mg b.i.d.

[0370] Treatment Groups

[0371] Participants are assigned at Randomization visit (Day 1) to one of the following 2 treatment arms / groups in a ratio of 1 : 1 ,

[0372] • Remibrutinib arm: remibrutinib orally at 100 mg b.i.d. for 6 months (double-blind) followed by open- label remibrutinib at 100 mg b.i.d. for an additional 24 months

[0373] • Placebo arm: placebo b.i.d. orally for 6 months (double-blind) followed by open- label remibrutinib at 100 mg b.i.d. for 24 months

[0374] End of study definition

[0375] The end of the study is defined as the date of the last visit of the last participant in the study or last scheduled procedure or follow-up for the last participant in the study globally.

[0376] This study includes a Core part and an Extension part. Study completion for the Core part is defined as when the last participant finishes their End of Study visit and any repeat assessments associated with this visit have been documented and followed-up appropriately by the Investigator or, in the event of an early study termination decision, the date of that decision. Participants who complete the Double-blind Treatment Period may be eligible to enroll in the Extension part. Study completion for the Extension part is defined as when the last participant finishes their End of Study visit and any repeat assessments associated with this visit have been documented and followed-up appropriately by the Investigator or, in the event of an early study termination decision, the date of that decision.

[0377] Participants who prematurely withdraw from the Double-blind Treatment Period for any reason are not eligible to enroll in the Extension part. PAT059652A

[0378] All randomized and / or treated participants who, for whatever reason, do not continue into the Extension part should have a safety follow-up visits 28 days after completing the end of study treatment visit (Month 6 / EOT7EOS). All participants who continue into the open-label Extension part and discontinue treatment for any reason or complete all visits should have a safety followup visit conducted 28 days after completing the Month 60 / EOT / EOS visit. This follow up may be a phone call or a study site visit. The information collected is recorded in the respective eCRF. SAE reporting continues during this time period. Documentation of attempts to contact the participant are required to be recorded in the source documentation.

[0379] Study population

[0380] The study will enroll approximately 180 male and female patients, 18-75 years of age diagnosed with gMG, with disease categorized by MGFA as class II to IV, who are treated with a stable regimen of SOC treatment (see inclusion / exclusion criteria for requirements for the SOC treatments), but still presenting with sub-optimally controlled symptoms of gMG (i.e. MG-ADL of score of at least 6 at baseline. The defined trial population will include patients with AChR+ or Musk+ antibodies or who are seronegative for both AChR and MuSK antibodies. The patient population also must contain at least 20 enrolled patients with MuSK+ antibodies. In addition, < 50% of the patients can be on NSIST treatment.

[0381] Inclusion Criteria

[0382] Participants eligible for inclusion in this study must meet all of the following criteria:

[0383] 1. Adult patients with gMG (age 18-75 years) able to understand the requirements of the trial, provide written informed consent, and comply with the trial protocol procedures

[0384] 2. Confirmed diagnosis of MGFA Class II-IV gMG at screening and likely not in need of a respirator for the duration of the study, as judged by the Investigator.

[0385] 3. The confirmation of the diagnosis of gMG should be documented and supported by >1 (AChR+ and MuSK+ patients) or by > 2 (double sero-negative patients) of the following 3 tests:

[0386] History of abnormal neuromuscular transmission demonstrated by single-fiber electromyography or repetitive nerve stimulation. PAT059652A

[0387] • History of positive test with short-acting acetylcholinesterase inhibitors (e.g., neostigmine or edrophonium chloride)

[0388] • Patient has demonstrated improvement in MG signs on oral acetylcholinesterase inhibitors as assessed by the treating physician.

[0389] 4. Documented evidence of positive serologic testing for AChR+ antibody or MuSK+ antibody at screening, OR seronegative for both AChR and MuSK antibodies at screening 5. Baseline MG-ADL score > 6, with > 50% of the total score due to non-ocular symptoms 6. Participants receiving at least one of the following treatment for gMG and who have been on a stable dose for the specified time periods prior to baseline (but not optimally controlled)

[0390] • just one NSIST for > 6 months; and / or

[0391] • acetylcholinesterase inhibitors for > 1 month on a maximum stable dose; and / or

[0392] • steroids for > 4 months including the inability to taper to an acceptable level

[0393] Note: Non-steroidal immunosuppressive therapies (NSIST) include azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, or tacrolimus

[0394] 7. Participants who are receiving azathioprine, are required to have been on azathioprine for at least 6 months and on a stable dose for at least 2 months prior to baseline

[0395] 8. Participants who are receiving other immunosuppressive therapies (i.e., mycophenolate mofetil, methotrexate, cyclosporine, or tacrolimus) are required to be on these immunosuppressive therapies for at least 6 months and to have been on a stable dose for at least 1 month prior to baseline

[0396] 9. Participants receiving oral corticosteroids are required to be on a stable dose for at least 4 weeks (i.e., 28 days or longer) prior to baseline

[0397] 10. Participants receiving a cholinesterase inhibitor, are required be on a stable dose for at least 2 weeks prior to baseline

[0398] 11. Able to safely swallow the study medication according to investigator clinical judgement based on a bedside swallowing test or another formal swallowing test in line with local practice, both at Screening and Baseline

[0399] Key Exclusion Criteria

[0400] Participants meeting any of the following criteria are not eligible for inclusion in this study. PAT059652A

[0401] 1. Prior to baseline have been treated with IVIg / PLEX in the past month, with rituximab in the past 6 months, eculizumab in the past 2 months, ravulizumab or other complement inhibitors in the past 3 months, efgartigimod or other anti-FcRn therapies in the past 3 months, or had a thymectomy in the past 6 months or a planned thymectomy during the trial period

[0402] 2. Participants at risk of developing or having reactivation of hepatitis: Positive results at screening for serological markers for hepatitis (H) A, B, C, and E indicating acute or chronic infection:

[0403] • anti-HA Immunoglobulin (Ig) M (IgM)

[0404] • HB surface Antigen (HBs Ag) and / or anti-HBc IgM and / or HB virus deoxyribonucleic acid (DNA)

[0405] • anti-HBc positive

[0406] • anti-HC IgG (if positive IgG, HC Virus (HCV)-RNA Polymerase Chain Reaction will be performed and if negative, participant can be randomized)

[0407] • anti-HE IgM positive (regardless of IgG status)

[0408] 3. Participants with a known immunodeficiency syndrome (AIDS, hereditary immune deficiency, drug induced immune deficiency), or tested positive for HIV antibody, at screening

[0409] 4. Pregnant or nursing (breast feeding) women

[0410] 5. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for 1 week after stopping study treatment. Highly effective contraception methods include:

[0411] • Total abstinence (when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

[0412] • Bilateral tubal ligation, bilateral oophorectomy with or without hysterectomy, total hysterectomy, or bilateral salpingectomy at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered to be not of child-bearing potential. PAT059652A

[0413] • Male sterilization (vasectomy) of male partner(s) of the female participant at least 6 months prior to screening.

[0414] • Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception or transdermal hormone contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1 %), for example, hormone vaginal ring or transdermal hormone contraception.

[0415] In case of use of hormonal contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.

[0416] Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age-appropriate history of vasomotor symptoms). Women participants are considered not of child-bearing potential if they are post-menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral salpingectomy at least six weeks prior to enrollment on study. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered to be not of child-bearing potential.

[0417] If local regulations are more stringent than the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF.

[0418] 6. Active systemic bacterial, viral (incl. COVID- 19), parasitic, or fungal infection or any major episode of infection that required hospitalization or injectable antimicrobial therapy within 14 days prior to study drug administration

[0419] 7. Have received any live or live-attenuated vaccines (including but not limited to varicellazoster virus or measles, oral polio, nasal influenza) within 6 weeks prior to randomization or requirement to receive these vaccinations at any time during the study.

[0420] Note: It is generally encouraged to perform necessary last dose of vaccinations (including COVID-19) at least 4 weeks before randomizing participants into the trial, if available, and according to local practice. Timing of SARS-CoV-2 vaccination should be planned according to the local guidelines, e.g., at least 7 (Medicines and Healthcare products Regulatory Agency (MHRA)) to 14 (Centres for Disease Control and Prevention) days apart from any PAT059652A

[0421] prior vaccination (e.g., flu vaccine). Immune modulation of B-cells is expected to affect the response to vaccination, and thus during treatment with remibrutinib, vaccination (non-live vaccines) may be less effective.

[0422] 8. Participants with worsening muscle weakness secondary to concurrent infections or medications (aminoglycosides, fluoroquinolones, beta-blockers, etc.)

[0423] 9. History of hepatic disease that currently requires treatment or ongoing hepatic disease including, but not limited to, acute or chronic hepatitis, cirrhosis (including all Child-Pugh classes) or hepatic failure or any chronic liver or biliary disease or aspartate aminotransferase (AST) / alanine aminotransferase (ALT) levels of more than 2.0 x upper limit of normal (ULN) or total or conjugated bilirubin (TBL) greater than 1.5 x upper limit of normal (ULN), unless in the context of Gilbert’s syndrome, or International Normalized Ratio (INR) of more than 1.5, at screening

[0424] 10. History of severe renal disease or creatinine level above 1.5 x ULN at screening

[0425] 11. History of significant bleeding risk or coagulation disorders, at screening

[0426] 12. Hematology parameters at screening:

[0427] • Hemoglobin: < 10 g / dl (<100g / L)

[0428] • Platelets: < 100000 / mm3 (<100 x 109 / L)

[0429] • Absolute lymphocyte count < 800 / mm3 (<0.8 x 109 / L)

[0430] • White blood cells: <3 000 / mm3 (<3.0 x 109 / L)

[0431] • Neutrophils: < 1 500 / mm3 (<1.5 x 109 / L)

[0432] 13. Documented lack of clinical response to PLEX

[0433] 14. Major surgery within 8 weeks prior to screening

[0434] 15. Evidence of clinically significant cardiovascular (such as but not limited to myocardial infarction, unstable ischemic heart disease, New York Heart Association (NYHA) Class III / IV left ventricular failure, arrhythmia and uncontrolled hypertension within 6 months prior to screening), neurological, psychiatric, pulmonary (including, history of or active severe respiratory disease, including Chronic Obstructive Pulmonary Disease, interstitial lung disease or pulmonary fibrosis), renal, hepatic, endocrine, metabolic (e.g., severe hypoproteinemia due to nephrotic syndrome), hematological disorders or gastrointestinal disease that, in the Investigator's opinion, would compromise the safety of the participant, PAT059652A

[0435] interfere with the interpretation of the study results or otherwise preclude participation or protocol adherence of the participant, prior to randomization

[0436] 16. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases, at screening

[0437] 17. History of autoimmune disease other than MG (e.g., thyroiditis, rheumatoid arthritis, etc.) that would interfere with an accurate assessment of clinical symptoms

[0438] 18. Score “yes” on item 4 or item 5 of the suicidal ideation section of the C-SSRS, if this ideation occurred in the past 6 months, or “yes” on any item of the suicidal behavior section, except for the “Non-Suicidal Self-Injurious Behavior” (item also included in the suicidal behavior section), if this behavior occurred in the past 2 years, prior to randomization 19. Requirement for anticoagulant medication (e.g. warfarin or NOAC) or use of dual antiplatelet therapy (e.g., acetylsalicylic acid + clopidogrel). The use of acetylsalicylic acid up to 100 mg / day or clopidogrel up to 75 mg / day is permitted

[0439] 20. History or current diagnosis of ECG abnormalities indicating significant risk of safety for subjects participating in the study such as:

[0440] • Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular tachycardia, and clinically significant second or third degree atrioventricular (AV) block without a pacemaker or requiring anti-arrhythmic treatment with Class la or Class III anti-arrhythmic drugs

[0441] • History of familial long QT syndrome or known family history of Torsades de Pointes • Resting QTcF > 450 msec (male) or > 460 msec (female) as per central ECG reading at screening visit

[0442] • Use of agents known to prolong the QT interval unless they can be permanently discontinued for the duration of the study

[0443] 21. Use of strong CYP3A4 inhibitors, or use of moderate or strong CYP3A4 inducers within two weeks prior to randomization.

[0444] 22. Patient not controlled on rituximab (2 cycles) or other high efficacy therapies like complement inhibitors and FcRn antagonists PAT059652A

[0445] 23. Patient requiring frequent (quarterly or more frequent) plasmapheresis, plasma exchange, or intravenous immunoglobulin to control symptoms

[0446] 24. History of hypersensitivity to any of the study drugs or excipients (including rare hereditary problems of galactose intolerance, total lactase deficiency and glucose-galactose malabsorption) or to drugs of similar chemical classes, at screening

[0447] 25. Ongoing drug or alcohol abuse that could interfere with patient's participation in the trial 26. Participation in any other investigational drug trial or use of other investigational drugs at the time of enrollment, or within 5 elimination half-lives of enrollment, or within 30 days of enrollment whichever is longer; or longer if required by local regulations

[0448] 27. Use of prohibited medication prior to screening / randomization (as defined herein)

[0449] 28. Participants who have not previously responded to other BTK inhibitors

[0450] 29. Participants who have had a splenectomy

[0451] 30. Participants with electrolyte abnormalities (hypokalemia or hypomagnesemia) that cannot be corrected

[0452] Study Treatment(s) and concomitant therapy

[0453] Study participants are randomized to remibrutinib 100 mg or placebo twice daily (b.i.d) in 1 : 1 ratio, while remaining on stable dose of pre-existing SOC treatment for gMG before baseline and throughout the trial as permitted and required per inclusion criteria. The randomization is stratified based on the following stratification factors:

[0454] Autoantibody type: (1) participants with MuSK+ antibodies, or (2) participants with AChR+ or who are seronegative for both AChR and MuSK antibodies (double seronegative).

[0455] Dose modifications

[0456] Remibrutinib 100 mg or matching placebo is administered b.i.d. Investigational or other study treatment dose adjustments are not permitted.

[0457] Concomitant therapies

[0458] I mm unosuppressan ts

[0459] Participants who are receiving azathioprine, are required to have been on azathioprine for at PAT059652A

[0460] least 6 months and on a stable dose for at least 2 months prior to baseline.

[0461] Participants who are receiving other immunosuppressive therapies (i.e., mycophenolate mofetil, methotrexate, cyclosporine, or tacrolimus), are required to be on these immunosuppressive therapies for at least 6 months and to have been on a stable dose for at least

[0462] 1 month prior to baseline.

[0463] Cholinesterase Inhibitors

[0464] Participants receiving a cholinesterase inhibitor, are required be on a stable dose for at least 2 weeks prior to baseline. The dose and schedule of their cholinesterase inhibitor must be maintained stable throughout the entire Double-blind Treatment Period and should remain stable during the Open-label Extension Period unless there is compelling medical need.

[0465] Increases in cholinesterase therapy that are required as a result of intercurrent illness or other medical cause of deterioration are permitted, but dosing must be returned to dosing levels at study entry as soon as feasible and the Sponsor should be notified of the change. If, due to intolerable side effects, a decrease in cholinesterase therapy is considered during the Doubleblind Treatment Period based on clinical evaluation, Sponsor approval must be obtained prior to the change in dose in order for the participant to remain on study.

[0466] Cholinesterase inhibitor treatment must be withheld for at least 10 hours prior to administration of the QMG and MGC tests.

[0467] Corticosteroids

[0468] Participants receiving oral corticosteroids are required to be on a stable dose for at least 4 weeks (i.e., 28 days or longer) prior to baseline and throughout the study.

[0469] Doses of allowed concomitant therapies can be reduced or discontinued during the Open label Extension Period at Investigator’s discretion.

[0470] Prohibited medications

[0471] Should participants require the use of any of the listed medications which require permanent discontinuation of study drug, the participant must continue to attend study visits as per the visit schedule and all assessments must be completed except study drug dispensation. PAT059652A

[0472]

[0473] PAT059652A

[0474]

[0475] PAT059652A

[0476]

[0477] PAT059652A

[0478]

[0479] PAT059652A

[0480]

[0481] * Prohibited antiarrhythmic drugs that prolong QT interval (Class 1 A and Class III):

[0482] Class 1A antiarrhythmic drugs: quinidine, procainamide, disopyramide, hydroquinidine.

[0483] Class III antiarrhythmic drugs: bretylium, amiodarone, ibutilide, sotalol, dofetilide, vernakalant and dronedarone

[0484] Equivalents

[0485] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims. PAT059652A

[0486] Example 2: LOU064 in experimental autoimmune myasthenia gravis (EAMG) rat model The efficacy and mechanisms of LOU064, in treating and / or preventing myasthenia gravis (MG) in the experimental autoimmune myasthenia gravis (EAMG) rat model has been investigated.

[0487] 1.1 Materials and Methods

[0488] This study included female Lewis rats from Charles River Laboratories. At seven weeks of age, animals were distributed into four experimental groups (Table 1) with an equal group’s average weight, including two EAMG groups (EAMG-LOU064 and EAMG-vehicle) and two non-MG control groups. The 24 non-MG control animals were divided into two different treatments and pooled as one control group for analysis.

[0489] After two weeks of acclimatization in animal facility and one week of baseline measurement, EAMG was induced on the first day of week 0 in seven-week-old rats through active immunization with purified AChR extracted from the electric organ of Torpedo califomica (tAChR). Specifically, 40 pg of tAChR was dissolved in 100 pl of saline and emulsified with 100 pl of Complete Freund's Adjuvant (CFA). A total of 200 pl of the tAChR: CFA (1 : 1) emulsion was injected at five different sites at the base of the tail for all EAMG animals. Non-MG controls received the same immunization procedure, but only with 200 pl of saline: CFA (1:1) emulsion.

[0490] The treatment started on the first day of week 0. In EAMG-LOU064 group, animals received a single dose of 10 mg / kg body weight of LOU064 in the morning (7.30 to 9 am) and vehicle solution (5% Tween 80 in methylcellulose) in the evening (with a 12-hour interval) by oral gavage. The EAMG-vehicle group received vehicle solutions twice per day. The gavage dose was adjusted weekly based on the average weight recorded from each group. The non-MG animals received the same dose and frequency of LOU064 or vehicle as the EAMG animals did. The treatment duration was 8 weeks (from week 0 to week 7). All animals were sacrificed in week 8, or earlier if they met humane endpoint (HEP) criteria. PAT059652A

[0491] Table 1 : Experimental groups

[0492]

[0493] 1.2 Readouts

[0494] The primary readouts for this experiment were EAMG clinical score and decrement inducing curare infusion time in compound muscle action potential (CMAP). The secondary readouts included weight and grip strength, level of antibodies against tAChR and rat muscle AChR, tibialis anterior (TA) muscle AChR content, and BTK occupancy levels in spleens. Weight and grip strength were measured weekly. Plasma was collected every 2 weeks from vena saphena (week -1, 1, 3, 5, 7). At terminal point, plasma was collected from vena cava and organs were collected and snap frozen for further analysis.

[0495] 1.2.1 Primary readouts

[0496] The primary readouts for this study was the EAMG clinical score and the decrement inducing curare infusion dose. In general, the clinical score helped to identify the clinical MG animals, and the curare infusion time helped to identify the subclinical MG animals.

[0497] Clinical scoring was performed as described by Losen et al. [Experimental Neurology 2015, Vol 270, Pages 18-28], based on locomotion, general behavior and welfare of animals: 0 = no clinical signs observed; 1 = disease symptoms only present after exercise; 2 = disease symptoms present before exercise; 3 = no ability to grip, hindlimb paralysis, respiratory distress / apnea, or weight loss of 15% or more from the maximum body weight recorded, leading to a HEP (Figure 1). PAT059652A

[0498] After immunization, the autoantibodies attack the AChRs at the neuromuscular junctions (NMJs). Because of the safety factor of neuromuscular transmission, animals with an average AChR loss of up to 60% can present no myasthenic symptoms and these are subclinical animals. The clinical scoring distinguishes the clinical / sick animals from the subclinical ones.

[0499] CMAP was measured from tibialis anterior (TA) muscle with 8 consecutive low-frequency (3 Hz) stimulations of the tibial nerve. Decrement was defined as a >10% decrease in both amplitude and area of the fourth CMAP compared to the first one in the same recording, for three consecutive recordings. If no decrement was initially observed, the neuromuscular transmission was challenged with curare infusion. A small incision was made in the animals’ belly, and a curare solution of 20 pg / ml was injected intraperitoneally using a perfusion syringe pump at the speed of 1 ml / h (0.33 pg curare / min). During curare infusion, CMAP measurements were repeated at 30s intervals until decrement was detected in three consecutive measurements, and the infusion time was recorded.

[0500] 1.2.2 Secondary readouts

[0501] Weight and Grip strength

[0502] Body weight, muscle strength, and tail suspension test were measured weekly from week -1 (baseline) to week 7. Animals were weighed more frequently if clinical symptoms occurred. Briefly, each animal was assessed (while manually held near the base of the tail) for its ability to grasp and hold the bar of the grip strength test meter GS3, while being retracted along the axis of the sensor. Each animal was retracted five consecutive times and peak-force generation was recorded as muscle strength. Subsequently, animals were tested for their ability to climb onto the dorsal side of the experimenter’s hand after being held with the tail base and hung in air. Five attempts were allowed, with a maximum of 1 minute per attempt and 30 seconds resting intervals between attempts. If the animal could climb onto the experimenter's hand within 1 minute for 5 times and showed no myasthenic symptoms before and after the testing, it was scored 0 in clinical score. If the animal could not finish 5 climbings or started to show symptoms after the testing, it was scored 2. PAT059652A

[0503] Plasma anti-torpedo AChR and anti-rat AChR autoantibody levels

[0504] After immunization with tAChR, the animals started producing antibody against tAChR as well as antibody against rat muscle AChR. Anti-rat AChRs is pathogenic and responsible for the onset of MG in this model. The levels of anti -tAChR and anti-rat AChR in different time points were highly associated with the disease progression and treatment effect of LOU064.

[0505] The level of anti-tAChR was quantified in plasma of the terminal time point by radioimmunoassay (RIA) using 125I-Tyr54 labelled a-bungarotoxin. Briefly, 2.5 pl of 1:200 PBS-diluted test plasma was diluted 1 : 1 with 2.5 pl normal rat serum (NRS) and incubated overnight at 4 °C with 0.05 pg purified tAChR and 0.5 pl 1125 a-bungarotoxin for labelling. The immune complexes were precipitated with 250 pl goat anti-rat IgG polyclonal serum and incubated for 4 hours at 4 °C. The samples were washed three times with 1 ml of washing buffer (0.5% TritonX-100 in PBS) and subsequently centrifuged at 30000 g for 5 min at 4 °C. Gamma radiation of the precipitate was measured for 2 min per sample using the WIZARD22480 Automatic Gamma Counter.

[0506] The level of anti-rat AChR in plasma of week 3, week 5, and terminal point was also quantified by RIA using 125I-Tyr54 labelled a-bungarotoxin. In brief, 2.5 pl plasma diluted 1:1 with 2.5 pl NRS were incubated overnight at 4 °C with 100 pl denervated rat AChR and 0.5 pl 1125 a-bungarotoxin. The immune complexes were precipitated with 250 pl goat anti-rat IgG polyclonal serum and incubated for 4 hours at 4 °C. The samples were washed 3 times with 1 ml washing buffer (0.5% TritonX-100 in PBS) and subsequently centrifuged at 30000 g for 5 min at 4 °C. Gamma radiation of the precipitate was measured for 2 min per sample using the WIZARD2 2480 Automatic Gamma Counter.

[0507] The results of all RIAs were presented with the radioactivity of the precipitate for comparison (count per minute, CPM). The radioactivity measured was proportional to the amount of antibody found in the precipitate. A standard curve for the assays will be validated with a commercial RIA kit and conversion from CPM to concentration can be made afterwards.

[0508] BTK occupancy in spleens PAT059652A

[0509] Binding of LOU064 to BTK was determined with immunoassay for free BTK and total BTK proteins. For free BTK measurements, samples were incubated with a biotinylated covalent BTK probe and added to streptavidin ELISA plates to allow binding of probe-bound BTK. The binding of the probe to BTK is mutually exclusive with compound binding to BTK. Plate-bound BTK was detected with an anti -BTK antibody. For total BTK measurements, an ELISA plate was coated with D3H5 anti-BTK to capture total BTK. An anti-BTK antibody directed to a different epitope was them used to detect captured BTK. The respective free BTK levels for each sample were normalized to the total BTK level in the same sample, and these ratios were expressed as percentage of the vehicle control samples.

[0510] 1.3 Statistical analysis

[0511] GraphPad Prism 10 was used for statistical description and analysis. Clinical scores were analyzed using the Fisher’s exact test of contingency analysis. A Z-test was used for the comparison of curare infusion time, antibody level, terminal weight and grip strength, and muscle AChR content. A Two-Way Analysis of Variance (ANOVA) was applied for the comparison of grip strength and weight among all timepoints and groups. A / ?- value of 0.05 or less was considered statistically significant.

[0512] 1.4 Results

[0513] 1.4.1 LOUQ64 treatments decreased EAMG severity

[0514] All animals from the EAMG-LOU064 and non-MG groups had a clinical score of 0 at the terminal time point. Nine animals (26.47%) from the EAMG-vehicle group reached HEP before the end of week 7 and were scored 3, and three showed myasthenia related symptoms in week 7 and were scored 2. There was a significant difference between the EAMG-LOU064 and EAMG-vehicle groups in clinical score (P = 0.0016) (Figure 2A).

[0515] The survival rate was calculated based on HEP due to myasthenic symptoms occurring per group before the scheduled sacrifice in week 8. There were no animals from the EAMG-LOU064 PAT059652A

[0516] group that reached HEP, and the survival rate was 100.00%. Starting from four weeks after immunization, nine animals from EAMG-vehicle group reached HEP and were taken out before week 8, resulting in a final survival rate of 73.53%. Survival rate was significantly higher in EAMG animals receiving LOU064 treatments compared to EAMG-vehicle animals (P = 0.0002) (Figure 2B).

[0517] There were no significant differences in weight progression or grip strength between the EAMG-LOU064 and the EAMG-vehicle groups during different weeks. At the terminal time point, the weight of the EAMG-LOU064 group was 215.50 ± 10.09 g and it was 203.90 ± 22.47 g in the EAMG-vehicle group. A significant difference between the two groups was observed in terminal weight (P = 0.0090) (Figure 2D). As weight loss was a typical myasthenic symptom in this model, the significant difference in weight demonstrated a higher disease severity in EAMG-vehicle group compared to EAMG-LOU064 group at terminal time point.

[0518] 1.4.2 Anti-torpedo AChR antibodies were reduced while anti-rat AChR antibodies remained unchanged in the plasma of LOU064 treated rats

[0519] At terminal point, the level of anti-tAChR in EAMG-LOU064 group (1783 CPM) was significantly lower than that in EAMG-vehicle group (2496 CPM), showing that LOU064 was effective in reducing the production of antibody against tAChR (P = 0.0001) (Figure 3A). There was also a trend for lower anti rat AChR levels at terminal time point, (3407 CPM vs. 4747 CPM, P = 0.0568) (Figure 3D). This trend was also observed at week 3 and 5, however the differences were not significant at any time point (Figure 3B, 3C).

[0520] 1.4.3 LOUQ64 treatments showed high BTK occupancy in spleens

[0521] Compared to EAMG-vehicle group, the spleens from LOU064 treated EAMG rats showed high BTK occupancy consistent with the dosing interval and sampling time and without apparent outliers. (Figure 4) PAT059652A

[0522] 1.6 Conclusion

[0523] LOU064 showed clinical efficacy in the EAMG rat model, including reducing EAMG severity and improving survival. Furthermore, LOU064 was effective in reducing severity in the EAMG model and preventing subclinical MG from developing into clinical.

Claims

PAT059652ACLAIMS1. A method of treating generalized Myasthenia Gravis (gMG) in a subject in need thereof, the method comprising administering to the subject LOU064 or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein the method comprises administering to the subject LOU064.

3. The method according to claim 1, wherein the method comprises administering to the subject a crystalline form of LOU064 characterized by an X-ray diffraction pattern comprising representative peaks in terms of 20 of 7.8 ± 0.2 °20, 9.2 ± 0.2 °20 and 12.0± 0.2 °20 when measured at a temperature of about 25°C and an x-ray wavelength, X, of 1.5405 A.

4. The method according to any one of claims 1 to 3, wherein the method comprises administering to the subject LOU064 at a dose of from about 50 mg to about 250 mg, or from about 100 mg to about 200 mg, each administered twice daily (b.i.d.).

5. The method according to any one of claims 1 to 4, wherein the method comprises administering to the subject LOU064 at a dose of about 50 mg, or about 75 mg, or about 100 mg, or about 150 mg, or about 200 mg each administered twice daily (b.i.d.).

6. The method according to any one of claims 1 to 5, wherein the dose is about 50 mg twice daily.

7. The method according to any one of claims 1 to 5, wherein the dose is about 100 mg twice daily.

8. The method according to any one of claims 1 to 7, wherein LOU064 or a pharmaceutically acceptable salt thereof is administered orally.PAT059652A9. The method according to any one of claims 1 to 8, wherein the subject has anti-acetylcholine receptor antibody-positive (AChR+) gMG.

10. The method according to any one of claims 1 to 8, wherein the subject has antibodies against muscle-specific kinase (MuSK+).

11. The method according to any one of claims 1 to 8, wherein the subject is seronegative for both AChR and Musk antibodies.

12. The method according to any one of claims 1 to 11, wherein the method further comprises administering to the subject an immunosuppressant.

13. The method according to claim 12, wherein the immunosuppressant is selected from azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, and tacrolimus or combination thereof.

14. The method according to claim 12 or claim 13, wherein the subject has been administered the immunosuppressant for at least six months prior to administration of LOU064.

15. The method according to any one of claims 1 to 14, wherein the method further comprises administering to the subject a corticosteroid.

16. The method according to claim 15, wherein the subject has been administered a corticosteroid for at least four weeks prior to administration of LOU064.

17. The method according to any one of claims 1 to 16, wherein the method further comprises administering to the subject a cholinesterase inhibitor.

18. The method according to claim 17, wherein the subject has been administered a cholinesterase inhibitor for at least two weeks prior to administration of LOU064.PAT059652A19. The method according to any one of claims 1 to 18, wherein the subject is not optimally controlled on one of more of the following treatment gMG treatment:a. One non-steroidal immunosuppressive therapy for at least 6 months;b. Acetylcholinesterase inhibitor for at least 1 month; and / orc. Steroids for at least 4 months.

20. The method according to any one of claims 1 to 18, wherein the subject is not optimally controlled for greater than or equal to 6 months on a gMG treatment that is rituximab or a neonatal crystallizable fragment receptor (FcRN) antagonist approved from gMG.

21. The method of claim 19 or 20, wherein the term not optimally controlled is defined as a MG- ADL total score with >50% of the MG-ADL score being due to non-ocular symptoms of at least 6.

22. The method according to any one of claims 1 to 21, wherein the method further comprises achieving a reduction in a MG-ADL total score, e.g., by at least 2, at least 3, at least 4, at least 5, or at least 6, e.g., at 1 month, at 3 months, at 6 months, compared to at baseline.

23. The method according to any one of claims 1 to 22, wherein the method further comprises achieving a reduction in a QMG total score, e.g., by at least 3, e.g., at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, e.g., at 1 month, at 3 months, at 6 months, compared to at baseline.

24. LOU064 or a pharmaceutically acceptable salt thereof for use in a treatment of generalized Myasthenia Gravis (gMG) in a subject in need thereof, wherein the treatment is according to any one of the methods of treatment of claims 1 to 23.PAT059652A25. A pharmaceutical composition comprising LOU064 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier for use in the treatment of generalized Myasthenia Gravis (gMG) in a subject in need thereof, and wherein the treatment is according to any one of the methods of treatment of claims 1 to 2326. Use of LOU064 or a pharmaceutically acceptable salt thereof, in the treatment of generalized Myasthenia Gravis (gMG) in a subject in need thereof, wherein the treatment is according to any one of the methods of treatment of claims 1 to 23.

27. Use of LOU064 in the manufacturing of a medicament for the treatment of generalized Myasthenia Gravis (gMG) in a subject in need thereof, wherein the treatment is according to any one of the methods of treatment of claims 1 to 23.

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