Method using factor B inhibitors

Abstract

The present invention describes a method for treating gMG (generalized myasthenia gravis) with iptacopan, a factor B inhibitor, or a pharmaceutically acceptable salt or hydrate thereof.

Description

[Technical Field]

[0001] The present disclosure relates to a method for treating complement-driven diseases with iptacopan, which is a factor B inhibitor, or a pharmaceutically acceptable salt or hydrate thereof, specifically for treating myasthenia gravis (MG), and more specifically for treating generalized myasthenia gravis (gMG). [Background Art]

[0002] Myasthenia gravis (MG) is a rare autoimmune disease that develops in the postsynaptic membrane of the neuromuscular junction (NMJ). It is caused by autoantibodies against various components of the NMJ. The main symptom of this disease is fluctuating muscle weakness, which is typically milder in the morning as a result of overnight inactivity, which allows replenishment of acetylcholine levels at the presynaptic motor nerve terminals. However, the symptoms worsen during the day due to repeated muscle activity (Jayam Trouth et al. Autoimmune Dis 2012 874680; Gilhus, N Engl J Med, 2016, 2570-81). Rarely, weakness of respiratory muscles occurs, which can lead to a life-threatening condition known as myasthenic crisis.

[0003] In the Myasthenia Gravis Foundation of America (MGFA) clinical classification, MG is divided into 5 main classes and several subclasses. This classification is designed to identify different subgroups of patients with different disease severity, different prognosis or different response to treatment. Generalized myasthenia gravis (gMG) corresponds to MGFA classes II to V (Jayam Trouth et al. 2012).

[0004] Generalized MG occurs in approximately 85% of all MG patients and affects multiple muscle groups throughout the body. Furthermore, approximately 80% of MG patients have detectable antibodies against acetylcholine receptors (AChR+), which is the target population of the present study.

[0005] MG has an annual incidence of 8 to 10 cases per 1 million people and a prevalence of 150 to 250 cases per 1 million people, and is therefore the most common disease that onset at the NMJ (Gilhus 2016). MG mainly occurs in two incidence peaks. The first early-onset peak occurs in young adults aged 30 to 50 years. Women are most commonly affected under 40 years of age, with a female-to-male ratio of 3:1. The second peak occurs after middle age, and it occurs equally in women and men in their 40s. However, after 50 years of age, it occurs more frequently in men, with a male-to-female ratio of 3:2. Furthermore, in men, the incidence increases steadily with age, reaching the highest rate at 60 to 89 years (Dresser et al., J Clin Med, 2021, 10(11)).

[0006] There are available treatments for MG (e.g., gMG), but most of these treatments act via non-specific suppression of the autoimmune response, like corticosteroids (classified as immunosuppressive therapy (IST) or non-steroidal immunosuppressive therapy (NSIST)). Furthermore, this use is associated with disadvantages that may negatively affect patients' quality of life and disease burden, such as the risk of infection, malignant tumors, and a wide range of systemic side effects (Bacci et al., BMC Neurol 2019, 335). This is particularly true for patients suffering from other comorbidities such as diabetes or hypertension. In addition, most NSIST have delayed onset of action, an estimated 10% of patients remain refractory, and other patients cannot tolerate conventional IST (Mantegazza et al., Curr Opin Neurol 2018, 517-25).

[0007] These limitations have recently led to strong encouragement for the development of MG treatments, now encompassing a variety of drug classes (e.g., complement inhibitors, neonatal crystallizable fragment receptor (FcRn) receptor inhibitors, and direct and indirect B-cell inhibitors). However, therapies such as FcRn receptor inhibitors are not sustained in effectiveness, as symptoms relapse at the end of treatment cycles (Howard et al., 2021). Therefore, many of these newer therapies (i.e., eculizumab, ravulizumab, efgultigimod) require repeated administration via intravenous or subcutaneous injection, which can be burdensome for patients, leaving an unmet need in the MS population. [Overview of the project]

[0008] This disclosure relates to a method for treating myasthenia gravis (MG), specifically generalized myasthenia gravis (gMG), with iptacopan or a pharmaceutically acceptable salt or hydrate thereof. Iptacopan is also known as LNP023.

[0009] Specifically, the Disclosure provides a method for treating generalized myasthenia gravis (gMG) in a subject of interest (e.g., a patient), comprising administering iptacopan or a pharmaceutically acceptable salt or hydrate thereof to the subject (e.g., a patient). The Disclosure further provides a method for reducing the total Myasthenia Gravis Activity of Daily Living (MG-ADL) score in a subject of interest (e.g., a patient), comprising administering iptacopan or a pharmaceutically acceptable salt or hydrate thereof to the subject. The Disclosure further provides a method for reducing the total Quantitative Myasthenia Gravis (QMG) score in a subject of interest (e.g., a patient), comprising administering iptacopan or a pharmaceutically acceptable salt or hydrate thereof to the subject.

[0010] Specifically, this disclosure provides iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use in the treatment of generalized myasthenia gravis (gMG) in a subject of interest (e.g., a patient). This disclosure further provides iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use in reducing the total score of myasthenia gravis activities of daily living (MG-ADL) in a subject of interest (e.g., a patient).

[0011] This disclosure further provides iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use in reducing the quantitative myasthenia gravis (QMG) total score in a required subject (e.g., a patient).

[0012] Specifically, the Disclosure provides a pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable carrier for use in the treatment of generalized myasthenia gravis (gMG) in a subject of interest (e.g., a patient). The Disclosure further provides a pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable carrier for use in reducing the total MG-ADL score of a subject of interest (e.g., a patient). The Disclosure further provides a pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable carrier for use in reducing the total Quantitative Myasthenia Gravis (QMG) score of a subject of interest (e.g., a patient).

[0013] Specifically, this disclosure provides the use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof for the manufacture of a pharmaceutical product for the treatment of generalized myasthenia gravis (gMG) in a target subject (e.g., a patient). This disclosure further provides the use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof for the manufacture of a pharmaceutical product for reducing the total MG-ADL score in a target subject (e.g., a patient). This disclosure further provides the use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof for the manufacture of a pharmaceutical product for reducing the total Quantitative Myasthenia Gravis (QMG) score in a target subject (e.g., a patient).

[0014] In one embodiment, iptacopan or a pharmaceutically acceptable salt or hydrate thereof is administered orally. In another embodiment, iptacopan or a pharmaceutically acceptable salt or hydrate thereof is administered in doses of about 50 mg to 500 mg, for example, about 50 mg to about 250 mg, about 100 mg to about 200 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, with each dose administered twice daily (bid), for example, every 12 hours, thereby treating the subject (e.g., patient) (where the dose refers to anhydrous iptacopan free base).

[0015] In some embodiments of the methods and uses provided herein, the subject is suffering from anti-acetylcholine receptor antibody-positive (AChR+) generalized myasthenia gravis (gMG). In further embodiments, the methods or uses further include administering to the subject an immunosuppressant, a corticosteroid, nonsteroidal immunosuppressive therapy (NSIST), and / or a cholinesterase inhibitor.

[0016] In some embodiments, the methods or uses provided herein are a. Achieve a reduction of, for example, at least 2, at least 3, at least 4, at least 5, or at least 6 points in the total Myasthenia Gravis Activities of Daily Living (MG-ADL) score compared to baseline at, for example, 1 month, 3 months, and 6 months; b. Achieve a reduction in the quantitative myasthenia gravis (QMG) total score of, for example, at 1 month, 3 months, and 6 months, compared to baseline, by, for example, at least 3 points, for example, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points; c. Achieve a reduction in the composite myasthenia gravis (MGC) total score compared to baseline, for example, at 1 month, 3 months, and 6 months; d. Achieve a reduction in the MG-QOL15r survey score compared to baseline, for example, at 1 month, 3 months, and 6 months; e. Achieve an increase in EQ-5D-5L survey scores on the EQ VAS scale, for example, at 1 month, 3 months, and 6 months, compared to baseline. Includes one or more of the following.

[0017] Non-limiting embodiments of this disclosure are described in the following embodiments: Embodiment 1: A method for treating myasthenia gravis (Mg) in a subject of interest, specifically generalized myasthenia gravis (gMG), comprising administering iptacopan or a pharmaceutically acceptable salt or hydrate thereof to the subject.

[0018] Embodiment 2: The method according to Embodiment 1, for subjects suffering from anti-acetylcholine receptor antibody-positive (AChR+) gMG.

[0019] Embodiment 3: The method according to Embodiment 1 or 2, further comprising achieving a reduction of, for example, at least 2 points, at least 3 points, at least 4 points, at least 5 points, or at least 6 points in the total myasthenia gravis activities of daily living (MG-ADL) score at, for example, 1 month, 3 months, or 6 months compared to baseline.

[0020] Embodiment 4: The method according to Embodiment 3, wherein the decrease in the total MG-ADL score is at least 2 points, specifically, the decrease in the total MG-ADL score is at least 2 points over 6 months compared to baseline.

[0021] Embodiment 5: The method according to Embodiment 4, wherein the decrease in the total MG-ADL score is at least 3 points, specifically, the decrease in the total MG-ADL score is at least 3 points over 6 months compared to baseline.

[0022] Embodiment 6: The method according to any one of Embodiments 1 to 5, further comprising achieving a reduction of, for example, at least 3 points, for example, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points in the quantitative myasthenia gravis (QMG) total score at, for example, 1 month, 3 months, or 6 months, compared to baseline.

[0023] Embodiment 7: The method according to Embodiment 6, wherein the decrease in the total QMG score is at least 4 points compared to the baseline, specifically, the decrease in the total QMG score is at least 4 points over 6 months compared to the baseline.

[0024] Embodiment 8: The method according to Embodiment 7, wherein the decrease in the total QMG score is at least 5 points compared to the baseline, specifically, the decrease in the total QMG score is at least 5 points over 6 months compared to the baseline.

[0025] Embodiment 9: The method is, a) Achieve a reduction in the total Myasthenia Gravis Activities of Daily Living (MG-ADL) score of, for example, at 1 month, 3 months, and 6 months, compared to baseline, by, for example, at least 2 points, at least 3 points, at least 4 points, at least 5 points, or at least 6 points; b) Achieving a reduction in the quantitative myasthenia gravis (QMG) total score of, for example, at 1 month, 3 months, and 6 months, compared to baseline, by, for example, at least 3 points, for example, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, and at least 10 points; c) Achieve a reduction in the composite myasthenia gravis (MGC) total score compared to baseline, for example, at 1 month, 3 months, and 6 months; d) Achieve a reduction in the MG-QOL15r survey score compared to baseline, for example, at 1 month, 3 months, and 6 months; e) Achieve an increase in EQ-5D-5L survey scores on the EQ VAS scale, for example, at 1 month, 3 months, and 6 months, compared to baseline. The method according to any one of Embodiments 1 to 8, which includes one or more of the above.

[0026] Embodiment 10: A method for reducing the total score of activities of daily living (MG-ADL) for myasthenia gravis in a subject of interest, comprising administering iptacopan or a pharmaceutically acceptable salt or hydrate thereof to the subject.

[0027] Embodiment 11: The method according to Embodiment 10, wherein a reduction of at least 2 points in the total MG-ADL score compared to baseline is achieved, and for example, a reduction of at least 3 points, at least 4 points, at least 5 points, or at least 6 points compared to baseline is achieved at, for example, 1 month, 3 months, and 6 months.

[0028] Embodiment 12: The method according to Embodiment 11, wherein the method achieves a reduction of at least 2 points in the total MG-ADL score compared to baseline, specifically, the method achieves a reduction of at least 2 points in the total MG-ADL score compared to baseline at 6 months.

[0029] Embodiment 13: The method according to Embodiment 12, wherein the method achieves a reduction of at least 3 points in the total MG-ADL score compared to baseline, specifically, the method achieves a reduction of at least 3 points in the total MG-ADL score compared to baseline at 6 months.

[0030] Embodiment 14: A method for reducing the quantitative myasthenia gravis (QMG) total score of a subject of interest, comprising administering iptacopan or a pharmaceutically acceptable salt or hydrate thereof to the subject.

[0031] Embodiment 15: The method according to Embodiment 14, wherein a reduction of, for example, at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points in the total QMG score at, for example, 1 month, 3 months, or 6 months, compared to the baseline.

[0032] Embodiment 16: The method according to Embodiment 15, wherein the method achieves a reduction of at least 4 points in the total QMG score compared to the baseline, specifically, the method achieves a reduction of at least 4 points in the total QMG score compared to the baseline at 6 months.

[0033] Embodiment 17: The method according to Embodiment 16, wherein the decrease in the total QMG score is at least 5 points compared to the baseline, specifically, the decrease in the total QMG score is at least 5 points compared to the baseline over 6 months.

[0034] Embodiment 18: The method according to any one of Embodiments 1 to 17, comprising administering iptacopan hydrochloride to a subject.

[0035] Embodiment 19: The method is the same as in Embodiment 18, comprising administering iptacopan hydrochloride monohydrate to a subject.

[0036] Embodiment 20: The method is the method according to any one of Embodiments 1 to 19, comprising administering iptacopan to a subject in a dose of approximately 50 mg to 500 mg, for example, approximately 50 mg to approximately 250 mg or approximately 100 mg to approximately 200 mg, each dose administered twice daily (bid).

[0037] Embodiment 21: The method is the method according to any one of Embodiments 1 to 20, comprising administering iptacopan to a subject in doses of approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, or approximately 200 mg, each administered twice daily (bid).

[0038] Embodiment 22: The method according to any one of Embodiments 1 to 21, wherein the dosage is approximately 50 mg twice a day.

[0039] Embodiment 23: The method according to any one of Embodiments 1 to 21, wherein the dosage is approximately 100 mg twice a day.

[0040] Embodiment 24: The method according to any one of Embodiments 1 to 21, wherein the dosage is approximately 200 mg twice a day.

[0041] Embodiment 25: The method according to any one of Embodiments 1 to 24, wherein iptacopan or a pharmaceutically acceptable salt or hydrate thereof is administered orally.

[0042] Embodiment 26: The method according to any one of Embodiments 1 to 25, further comprising administering an immunosuppressant to a subject.

[0043] Embodiment 27: The method according to Embodiment 26, wherein the immunosuppressant is at least one of azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, and cyclophosphamide.

[0044] Embodiment 28: The method according to Embodiment 26 or 27, wherein the subject is administered an immunosuppressant for at least 6 months.

[0045] Embodiment 29: The method according to any one of Embodiments 1 to 28, further comprising administering a corticosteroid to a subject.

[0046] Embodiment 30: The method according to Embodiment 29, wherein the subject is administered corticosteroids for at least four weeks.

[0047] Embodiment 31: The method according to any one of Embodiments 1 to 30, wherein the subject is vaccinated against at least one of Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae before administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof.

[0048] Embodiment 32: The method according to any one of Embodiments 1 to 31, wherein the subject is vaccinated against Neisseria meningitidis and Streptococcus pneumoniae before administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof.

[0049] Embodiment 33: The method according to any one of Embodiments 1 to 32, wherein the subject is vaccinated against Haemophilus influenzae before administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof.

[0050] Embodiment 34: The subject is a patient who has not been optimally controlled with one type of nonsteroidal immunosuppressive therapy (NSIST) for more than 6 months, and the method according to any one of Embodiments 1 to 33.

[0051] Embodiment 35: The subject is a patient who has not been optimally controlled for more than 6 months with two or more nonsteroidal immunosuppressive therapies (NSISTs) according to any one of Embodiments 1 to 33.

[0052] Embodiment 36: The method according to Embodiment 34 or 35, wherein NSIST is azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, or cyclophosphamide.

[0053] Embodiment 37: The method according to any one of Embodiments 1 to 36, relating to a patient who has not been optimally controlled for more than 6 months with gMG treatment, which is rituximab or a neonatal crystallizable fragment receptor (FcRN) antagonist approved for gMG.

[0054] Embodiment 38: The subject is a patient who has not been optimally controlled for more than 6 months with frequent (e.g., at least 4 times a year) plasma separation, plasma exchange, or intravenous immunoglobulin administration to control symptoms despite treatment with steroids and nonsteroidal immunosuppressive therapy (NSIST), according to any one of Embodiments 1 to 37.

[0055] Embodiment 39: The method according to any one of Embodiments 1 to 38, further comprising administering azathioprine to a subject.

[0056] Embodiment 40: The method according to Embodiment 39, further comprising administering azathioprine to a subject for at least 6 months.

[0057] Embodiment 41: The method according to any one of Embodiments 1 to 40, further comprising administering a cholinesterase inhibitor to a subject.

[0058] Embodiment 42: The method according to Embodiment 41, further comprising administering a cholinesterase inhibitor to a subject for at least two weeks.

[0059] Embodiment 43: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use in the treatment of myasthenia gravis (MG) in the required subjects, specifically for use in the treatment of generalized myasthenia gravis (gMG).

[0060] Embodiment 44: gMG is anti-acetylcholine receptor antibody-positive (AChR+) gMG, iptacopane for use as described in Embodiment 43, or a pharmaceutically acceptable salt or hydrate thereof.

[0061] Embodiment 45: Use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to Embodiment 43 or 44, further comprising achieving a reduction of, for example, at least 2 points, at least 3 points, at least 4 points, at least 5 points, or at least 6 points in the total myasthenia gravis activities of daily living (MG-ADL) score at, for example, 1 month, 3 months, or 6 months, compared to baseline.

[0062] Embodiment 46: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to Embodiment 45, wherein the reduction in the total MG-ADL score is at least 2 points compared to baseline, specifically, the reduction in the total MG-ADL score is at least 2 points over 6 months compared to baseline.

[0063] Embodiment 47: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to Embodiment 46, wherein the reduction in the total MG-ADL score is at least 3 points compared to baseline, specifically, the reduction in the total MG-ADL score is at least 3 points over 6 months compared to baseline.

[0064] Embodiment 48: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 43 to 47, further comprising achieving a reduction of, for example, at least 3 points, for example, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points in the quantitative myasthenia gravis (QMG) total score at, for example, 1 month, 3 months, or 6 months, compared to baseline.

[0065] Embodiment 49: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to Embodiment 48, wherein the reduction in the total QMG score is at least 4 points compared to the baseline, specifically, the reduction in the total QMG score is at least 4 points over 6 months compared to the baseline.

[0066] Embodiment 50: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 49, wherein the reduction in the total QMG score is at least 5 points compared to the baseline, specifically, the reduction in the total QMG score is at least 5 points over 6 months compared to the baseline.

[0067] Embodiment 51: Use is, a) Achieve a reduction in the total Myasthenia Gravis Activities of Daily Living (MG-ADL) score of, for example, at 1 month, 3 months, and 6 months, compared to baseline, by, for example, at least 2 points, at least 3 points, at least 4 points, at least 5 points, or at least 6 points; b) Achieving a reduction in the quantitative myasthenia gravis (QMG) total score of, for example, at 1 month, 3 months, and 6 months, compared to baseline, by, for example, at least 3 points, for example, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, and at least 10 points; c) Achieve a reduction in the composite myasthenia gravis (MGC) total score compared to baseline, for example, at 1 month, 3 months, and 6 months; d) Achieve a reduction in the MG-QOL15r survey score compared to baseline, for example, at 1 month, 3 months, and 6 months; e) Achieve an increase in EQ-5D-5L survey scores on the EQ VAS scale, for example, at 1 month, 3 months, and 6 months, compared to baseline. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of embodiments 43 to 50, comprising one or more of the above.

[0068] Embodiment 52: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use in the reduction of the total activity of daily living (MG-ADL) score in patients with myasthenia gravis.

[0069] Embodiment 53: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 52, which, by use, achieves a reduction of at least 2 points, for example, at least 3 points, at least 4 points, at least 5 points, or at least 6 points in the MG-ADL total score, for example, at 1 month, 3 months, or 6 months, compared to baseline.

[0070] Embodiment 54: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 53, wherein use results in a reduction of at least 2 points in the total MG-ADL score compared to baseline, specifically, a reduction of at least 2 points in the total MG-ADL score compared to baseline at 6 months.

[0071] Embodiment 55: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 54, wherein use results in a reduction of at least 3 points in the total MG-ADL score compared to baseline, specifically, a reduction of at least 3 points in the total MG-ADL score compared to baseline at 6 months.

[0072] Embodiment 56: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use in reducing the quantitative myasthenia gravis (QMG) total score of a target subject.

[0073] Embodiment 57: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 56, which, by use, achieves a reduction of, for example, at least 3 points, for example, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points in the quantitative myasthenia gravis (QMG) total score at, for example, 1 month, 3 months, or 6 months, compared to baseline.

[0074] Embodiment 58: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to Embodiment 57, wherein use results in a reduction of at least 4 points in the total QMG score compared to baseline, specifically, a reduction of at least 4 points in the total QMG score compared to baseline at 6 months.

[0075] Embodiment 59: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 58, wherein the reduction in the total QMG score is at least 5 points compared to baseline, specifically, the reduction in the total QMG score is at least 5 points compared to baseline over 6 months.

[0076] Embodiment 60: Use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 43 to 59, comprising administering iptacopan hydrochloride to a subject.

[0077] Embodiment 61: Use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to Embodiment 60, comprising administering iptacopan hydrochloride monohydrate to a subject.

[0078] Embodiment 62: Use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 43 to 61, comprising administering to a subject in doses of approximately 50 mg to 500 mg, for example, approximately 50 mg to approximately 250 mg or approximately 100 mg to approximately 200 mg, each administered twice daily (bid).

[0079] Embodiment 63: Use comprises administering to a subject a dose of iptacopan of approximately 50 mg, or approximately 75 mg, or approximately 100 mg, or approximately 150 mg, or approximately 200 mg, each dose administered twice daily (bid), using iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 43 to 62.

[0080] Embodiment 64: The dose is approximately 50 mg twice daily of iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 43 to 63.

[0081] Embodiment 65: The dose is approximately 100 mg twice daily of iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 43 to 63.

[0082] Embodiment 66: The dose is approximately 200 mg twice daily of iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 43 to 63.

[0083] Embodiment 67: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 43 to 66, administered orally.

[0084] Embodiment 68: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 43 to 67, further comprising administering an immunosuppressant to a subject.

[0085] Embodiment 69: Iptacopan for use as described in Embodiment 68 or a pharmaceutically acceptable salt or hydrate thereof, wherein the immunosuppressant is at least one of azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, and cyclophosphamide.

[0086] Embodiment 70: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to Embodiment 68 or 69, wherein the subject has been administered an immunosuppressant for at least 6 months.

[0087] Embodiment 71: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 43 to 70, further comprising administering a corticosteroid to a subject.

[0088] Embodiment 72: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 71, wherein the subject is administered corticosteroids for at least four weeks.

[0089] Embodiment 73: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 43 to 72, wherein the subject is vaccinated against at least one of Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae prior to administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof.

[0090] Embodiment 74: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 43 to 73, wherein the subject is vaccinated against Neisseria meningitidis and Streptococcus pneumoniae prior to administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof.

[0091] Embodiment 75: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 43 to 74, wherein the subject is vaccinated against Haemophilus influenzae before administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof.

[0092] Embodiment 76: The subject is iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 43 to 75, which has not been optimally controlled for more than 6 months with a single nonsteroidal immunosuppressive therapy (NSIST).

[0093] Embodiment 77: The subject is iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 43 to 75, which has not been optimally controlled for more than 6 months with two or more nonsteroidal immunosuppressive therapies (NSISTs).

[0094] Embodiment 78: Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to Embodiment 76 or 77, wherein NSIST is azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, or cyclophosphamide.

[0095] Embodiment 79: The subject is iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 43 to 78, for patients who have not been optimally controlled for more than 6 months with gMG treatment, which is rituximab or a neonatal crystallizable fragment receptor (FcRN) antagonist approved for gMG.

[0096] Embodiment 80: The subject is iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 43 to 79, which has not been optimally controlled for more than 6 months with frequent (e.g., at least 4 times a year) plasma separation, plasma exchange, or intravenous immunoglobulin injection to control symptoms despite treatment with steroids and nonsteroidal immunosuppressive therapy (NSIST).

[0097] Embodiment 81: Use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof according to any one of Embodiments 43 to 80, further comprising administering azathioprine to a subject.

[0098] Embodiment 82: Use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to Embodiment 81, further comprising administering azathioprine to a subject for at least 6 months.

[0099] Embodiment 83: The method further comprises administering a cholinesterase inhibitor to a subject, wherein iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 43 to 82.

[0100] Embodiment 84: The method further comprises administering a cholinesterase inhibitor to a subject for at least two weeks, wherein iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use is as described in Embodiment 83.

[0101] Embodiment 85: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable carrier, for use in the treatment of myasthenia gravis (MG) in a required subject, specifically for use in the treatment of generalized myasthenia gravis (gMG).

[0102] Embodiment 86: A pharmaceutical composition comprising iptacopan for use as described in Embodiment 85, or a pharmaceutically acceptable salt or hydrate thereof, wherein the gMG is anti-acetylcholine receptor antibody-positive (AChR+) gMG, and at least one pharmaceutically acceptable carrier.

[0103] Embodiment 87: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to Embodiment 85 or 86, and at least one pharmaceutically acceptable carrier, further comprising achieving a reduction of, for example, at least 2 points, at least 3 points, at least 4 points, at least 5 points, or at least 6 points in the total myasthenia gravis activities of daily living (MG-ADL) score at, for example, 1 month, 3 months, or 6 months, compared to baseline.

[0104] Embodiment 88: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 87, and at least one pharmaceutically acceptable carrier, wherein the reduction in the total MG-ADL score is at least 2 points compared to baseline, specifically, the reduction in the total MG-ADL score is at least 2 points over 6 months compared to baseline.

[0105] Embodiment 89: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 88, and at least one pharmaceutically acceptable carrier, wherein the reduction in the total MG-ADL score is at least 3 points compared to baseline, specifically, the reduction in the total MG-ADL score is at least 3 points over 6 months compared to baseline.

[0106] Embodiment 90: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 85 to 89, and at least one pharmaceutically acceptable carrier, further comprising achieving a reduction of, for example, at least 3 points, for example, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points in the quantitative myasthenia gravis (QMG) total score at, for example, 1 month, 3 months, or 6 months, compared to baseline.

[0107] Embodiment 91: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 90, and at least one pharmaceutically acceptable carrier, wherein the reduction in the total QMG score is at least 4 points compared to the baseline, specifically, the reduction in the total QMG score is at least 4 points over 6 months compared to the baseline.

[0108] Embodiment 92: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 91, and at least one pharmaceutically acceptable carrier, wherein the reduction in the total QMG score is at least 5 points compared to the baseline, specifically, the reduction in the total QMG score is at least 5 points over 6 months compared to the baseline.

[0109] Embodiment 93: Use is, a) Achieve a reduction in the total Myasthenia Gravis Activities of Daily Living (MG-ADL) score of, for example, at 1 month, 3 months, and 6 months, compared to baseline, by, for example, at least 2 points, at least 3 points, at least 4 points, at least 5 points, or at least 6 points; b) Achieving a reduction in the quantitative myasthenia gravis (QMG) total score of, for example, at 1 month, 3 months, and 6 months, compared to baseline, by, for example, at least 3 points, for example, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, and at least 10 points; c) Achieve a reduction in the composite myasthenia gravis (MGC) total score compared to baseline, for example, at 1 month, 3 months, and 6 months; d) Achieve a reduction in the MG-QOL15r survey score compared to baseline, for example, at 1 month, 3 months, and 6 months; e) Achieve an increase in EQ-5D-5L survey scores on the EQ VAS scale, for example, at 1 month, 3 months, and 6 months, compared to baseline. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of embodiments 85 to 92, including one or more of the above, and at least one pharmaceutically acceptable carrier.

[0110] Embodiment 94: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable carrier, for use in reducing the total activity of daily living (MG-ADL) score of a target patient with myasthenia gravis.

[0111] Embodiment 95: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 94, and at least one pharmaceutically acceptable carrier, wherein use achieves a reduction of at least 2 points, for example, at least 3 points, at least 4 points, at least 5 points, or at least 6 points in the total MG-ADL score, for example, at 1 month, 3 months, or 6 months, compared to baseline.

[0112] Embodiment 96: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 95, and at least one pharmaceutically acceptable carrier, wherein use achieves a reduction of at least 2 points in the total MG-ADL score compared to baseline, specifically, a reduction of at least 2 points in the total MG-ADL score over 6 months compared to baseline, and at least one pharmaceutically acceptable carrier.

[0113] Embodiment 97: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 96, and at least one pharmaceutically acceptable carrier, wherein use results in a reduction of at least 3 points in the total MG-ADL score compared to baseline, specifically, a reduction of at least 3 points in the total MG-ADL score over 6 months compared to baseline, and at least one pharmaceutically acceptable carrier.

[0114] Embodiment 98: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable carrier for use in reducing the quantitative myasthenia gravis (QMG) total score of a target subject.

[0115] Embodiment 99: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 98, and at least one pharmaceutically acceptable carrier, which, upon use, achieves a reduction of, for example, at least 3 points, for example, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points in the quantitative myasthenia gravis (QMG) total score at, for example, 1 month, 3 months, or 6 months, compared to baseline.

[0116] Embodiment 100: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 99, and at least one pharmaceutically acceptable carrier, wherein use results in a reduction of at least 4 points in the total QMG score compared to baseline, specifically, a reduction of at least 4 points in the total QMG score compared to baseline at 6 months, and at least one pharmaceutically acceptable carrier.

[0117] Embodiment 101: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 100, and at least one pharmaceutically acceptable carrier, wherein the reduction in the total QMG score is at least 5 points compared to baseline, specifically, the reduction in the total QMG score is at least 5 points over 6 months compared to baseline.

[0118] Embodiment 102: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 85 to 101, and at least one pharmaceutically acceptable carrier, wherein use comprises administering iptacopan hydrochloride to a subject.

[0119] Embodiment 103: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 102, and at least one pharmaceutically acceptable carrier, wherein use comprises administering iptacopan hydrochloride monohydrate to a subject.

[0120] Embodiment 104: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 85 to 103, and at least one pharmaceutically acceptable carrier, wherein use is administered to a subject in doses of approximately 50 mg to 500 mg, for example, approximately 50 mg to approximately 250 mg or approximately 100 mg to approximately 200 mg, each administered twice daily (bid).

[0121] Embodiment 105: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 85 to 104, and at least one pharmaceutically acceptable carrier, wherein use comprises administering to a subject in doses of approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, or approximately 200 mg, each administered twice daily (bid).

[0122] Embodiment 106: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 85 to 105, and at least one pharmaceutically acceptable carrier, with a dosage of about 50 mg twice daily.

[0123] Embodiment 107: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 85 to 105, with a dose of about 100 mg twice daily, and at least one pharmaceutically acceptable carrier.

[0124] Embodiment 108: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 85 to 105, with a dose of about 200 mg twice daily, and at least one pharmaceutically acceptable carrier.

[0125] Embodiment 109: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 85 to 108, and at least one pharmaceutically acceptable carrier, for oral administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof.

[0126] Embodiment 110: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 85 to 109, and at least one pharmaceutically acceptable carrier, the use further comprising administering an immunosuppressant to a subject.

[0127] Embodiment 111: A pharmaceutical composition comprising iptacopan for use as described in Embodiment 110 or a pharmaceutically acceptable salt or hydrate thereof, wherein the immunosuppressant is at least one of azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, and cyclophosphamide, and at least one pharmaceutically acceptable carrier.

[0128] Embodiment 112: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to Embodiment 110 or 111, and at least one pharmaceutically acceptable carrier, wherein the subject is administered an immunosuppressant for at least six months.

[0129] Embodiment 113: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 85 to 112, and at least one pharmaceutically acceptable carrier, the use further comprising administering a corticosteroid to a subject.

[0130] Embodiment 114: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 113, and at least one pharmaceutically acceptable carrier, wherein the subject is administered corticosteroids for at least four weeks.

[0131] Embodiment 115: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 85 to 114, wherein the subject is vaccinated against at least one of Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae before administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable carrier.

[0132] Embodiment 116: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 85 to 115, and at least one pharmaceutically acceptable carrier, wherein the subject is vaccinated against Neisseria meningitidis and Streptococcus pneumoniae prior to administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof.

[0133] Embodiment 117: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 85 to 116, and at least one pharmaceutically acceptable carrier, wherein the subject is vaccinated against Haemophilus influenzae before administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof.

[0134] Embodiment 118: The subject is a pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 85 to 117, for patients who have not been optimally controlled for more than six months with a nonsteroidal immunosuppressive therapy (NSIST), and at least one pharmaceutically acceptable carrier.

[0135] Embodiment 119: The subject is a pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 85 to 117, for patients who have not been optimally controlled for more than six months with two or more nonsteroidal immunosuppressive therapies (NSISTs), and at least one pharmaceutically acceptable carrier.

[0136] Embodiment 120: NSIST is a pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 118 or 119, which is azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, or cyclophosphamide, and at least one pharmaceutically acceptable carrier.

[0137] Embodiment 121: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 85 to 120 for patients who have not been optimally controlled for more than 6 months with gMG treatment, which is rituximab or a neonatal crystallizable fragment receptor (FcRN) antagonist approved for gMG, and at least one pharmaceutically acceptable carrier.

[0138] Embodiment 122: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 85 to 121, and at least one pharmaceutically acceptable carrier, for a patient whose symptoms have not been optimally controlled for more than six months with frequent (e.g., at least four times a year) plasma separation, plasma exchange, or intravenous immunoglobulin injections to control symptoms, despite treatment with steroids and nonsteroidal immunosuppressive therapy (NSIST), etc.

[0139] Embodiment 123: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 85 to 122, and at least one pharmaceutically acceptable carrier, the use further comprising administering azathioprine to a subject.

[0140] Embodiment 124: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 123, and at least one pharmaceutically acceptable carrier, further comprising administering azathioprine to a subject for at least six months.

[0141] Embodiment 125: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of Embodiments 85 to 124, and at least one pharmaceutically acceptable carrier, the use further comprising administering a cholinesterase inhibitor to a subject.

[0142] Embodiment 126: A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use as described in Embodiment 125, and at least one pharmaceutically acceptable carrier, further comprising administering a cholinesterase inhibitor to a subject for at least two weeks.

[0143] Embodiment 127: Use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof for the manufacture of a pharmaceutical product for the treatment of myasthenia gravis (MG) in a required subject, specifically for the treatment of generalized myasthenia gravis (gMG). [Brief explanation of the drawing]

[0144] [Figure 1]LNP023 protects against passively induced experimental autoimmune myasthenia gravis (PT-EAMG). Anti-AChR antibody (mAb35) was injected at time 0, and animals were monitored twice daily for A) clinical symptoms and B) body weight. C) A trend toward shorter disease duration was observed. D) Maximum disease score was significantly reduced with LNP023. E) Compound muscle action potentials (cMAP) were measured 36 hours after disease induction, and no significant difference was observed after LNP023 treatment. F) LNP023 significantly reduced disease incidence. Means and standard errors of the means are shown. In C-E, each point represents an individual animal. Statistical analysis was performed using GraphPad Prism version 10.1.2, using the Kruskal-Wallis test followed by Dunn's multiple comparison test. For cMAP, the Brown-Forsythe test and Welch ANOVA test were used, followed by Dunnett's T3 multiple comparison test. Regarding disease incidence, the log-rank (Mantel-Cox) test was used to compare the mAb35 vehicle treatment group and the mAb 35 LNP023 treatment group (*p<0.05). [Modes for carrying out the invention]

[0145] Myelomyelitis (MG) is considered a typical example of an antibody-mediated autoimmune disease. MG can also be seen as an example of a type II hypersensitivity reaction, as IgG autoantibodies react with intracellular or extracellular antigens, causing damage to peripheral organs. Most MG patients have autoantibodies against acetylcholine receptors, and a small number are serologically positive for antibodies against muscle-specific tyrosine kinase (MuSK) or low-density lipoprotein receptor-associated protein 4 (LRP4). These antibodies also serve as a basis for defining subgroups of the disease and help to clarify phenotypic variants (Dresser et al. 2021).

[0146] AChR antibodies primarily belong to the IgG1 and IgG3 subclasses. While IgG2 and IgG4 subclasses have also been identified, they are less common. The pathogenic mechanisms and functional spectrum of AChR antibodies are diverse, but generally, these antibodies impair receptor function through binding, blockade, or modulation of activity. Three mechanisms exist by which AChR autoantibodies act to reduce synaptic transmission at NMJs: 1. Blocking the binding of acetylcholine (ACh) to AchR; 2. Promotion of internalization and degradation of AChR cross-linked by autoantibodies; 3. Complement activation.

[0147] The main mechanisms involve antibody binding and activation of the complement cascade, which lead to the formation of membrane invasion complexes (MACs). This formation causes damage to the postsynaptic membrane and disruption of the synaptic fold, which includes AChRs and related proteins such as voltage-gated sodium channels (Morgan et al., Clin Exp Immunol, 2006, 294-302, and Howard et al., Exp Opin Investig Drugs 2017, 483-93).

[0148] Iptacopan is a first-in-class oral small molecular weight (LMW) inhibitor of factor B (FB) (Schubart et al. 2019, Small-molecule factor B inhibitor for the treatment of complement-mediated diseases. Proc Natl Acad Sci USA pp.7926-7931), and FB is an important protease for AP (Complement System Part I - Molecular Mechanisms of Activation and Regulation. Front Immunol p.262). Inhibition of FB prevents amplification of all pathways and the construction of AP-inducible C3 and C5 convertases. At the same time, iptacopan has only a limited effect on the activation of terminal pathways induced by the classical pathway. Iptacopan inhibits FB in association with C3 convertase, thereby blocking the amplification of AP-dependent C3 activation and CP and LP-dependent C5 activation. However, iptacopan does not block MAC production initiated by CP and LP. This is important because it means that MAC-dependent killing of Neisseria species by CP activation will be maintained in immunized individuals.

[0149] The terms "Iptacopan" and "LNP023" are used synonymously herein. Iptacopan, IUPAC name: (4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)piperidine-2-yl))benzoic acid) belongs to the class of complement pathway factor B inhibitors and acts by inhibiting or suppressing complement system amplification caused by C3 activation, regardless of the initial activation mechanism.

[0150] Iptacopan hydrochloride is 4-((2S,4S)-(4-ethoxy-1-((5-methoxy-7-methyl-1H-indole-4-yl)methyl)piperidine-2-yl))benzoate of the following formula (I): [ka] It has been chemically named as such.

[0151] Iptacopan hydrochloride and a method for preparing the same are disclosed in International Application PCT / US2014 / 046515 (see International Publication 2015 / 009616, Brochure, Example 26d), which is incorporated herein by reference in its entirety. In some embodiments, iptacopan hydrochloride of formula (I) is provided as a crystalline solid. In preferred embodiments, iptacopan hydrochloride of formula (I) is provided in the form of a crystalline monohydrate, which is hereafter also referred to as "formula HB". Formula H of Iptacopan Hydrochloride Monohydrate B The formula is as follows: [ka] As shown.

[0152] In one embodiment, iptacopan hydrochloride monohydrate (formula H B ) is Cu-K alpha with a wavelength of 0.15419 nm. 1,2 When measured using radiation at temperatures in the range of 20-30°C, it is characterized by PXRD (powder X-ray diffraction) peaks identified at two theta angles: (4.6±0.2)°, (9.2±0.2)°, and (19.1±0.2)°.

[0153] In one embodiment, iptacopan hydrochloride monohydrate (formula H B ) is Cu-K alpha with a wavelength of 0.15419 nm. 1,2 When measured using radiation at temperatures in the range of 20-30°C, it is characterized by PXRD peaks identified at two theta angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, and (19.1±0.2)°.

[0154] In one embodiment, iptacopan hydrochloride monohydrate (formula H B), it has a powder X-ray diffractogram comprising one or more peaks at 2θ angles selected from (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (19.1±0.2)°, and (24.6±0.2)°, when measured at a temperature ranging from 20 to 30°C using Cu-Kα₁,₂ radiation with a wavelength of 0.15419 nm.

[0155] In one embodiment, iptacopan hydrochloride monohydrate (formula H B ) is characterized by PXRD peaks identified at 2θ angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (12.2±0.2)°, (19.1±0.2)°, and (24.6±0.2)°, when measured at a temperature ranging from 20 to 30°C using Cu-Kα 1,2 radiation with a wavelength of 0.15419 nm.

[0156] In one embodiment, iptacopan hydrochloride monohydrate (formula H B ) is characterized by PXRD peaks identified at 2θ angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (12.2±0.2)°, (19.1±0.2)°, (21.3±0.2)°, and (24.6±0.2)°, when measured at a temperature ranging from 20 to 30°C using Cu-Kα 1,2 radiation with a wavelength of 0.15419 nm.

[0157] In one embodiment, iptacopan hydrochloride monohydrate (formula H B ) is characterized by PXRD peaks identified at 2θ angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (16.6±0.2)°, (19.1±0.2)°, (21.3±0.2)°, and (24.6±0.2)°, when measured at a temperature ranging from 20 to 30°C using Cu-Kα 1,2 radiation with a wavelength of 0.15419 nm.

[0158] In one embodiment, iptacopan hydrochloride monohydrate (formula H B ) is Cu-K alpha with a wavelength of 0.15419 nm. 1,2 When measured using radiation at temperatures in the range of 20-30°C, it is characterized by PXRD peaks identified at 2-theta angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (16.6±0.2)°, (19.1±0.2)°, (21.3±0.2)°, and (24.6±0.2)°.

[0159] In one embodiment, iptacopan hydrochloride monohydrate (formula H B ) is Cu-K alpha with a wavelength of 0.15419 nm. 1,2 When measured using radiation at temperatures in the range of 20-30°C, it is characterized by PXRD peaks identified at 2-theta angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (16.6±0.2)°, (19.1±0.2)°, (21.3±0.2)°, and (24.6±0.2)°.

[0160] In one embodiment, iptacopan hydrochloride monohydrate (formula H B ) is Cu-K alpha with a wavelength of 0.15419 nm. 1,2 It is characterized by a crystalline form that may be LNP023 hydrochloride (formula HB), which may be characterized by PXRD peaks identified at 2-theta angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (19.1±0.2)°, (21.3±0.2)°, and (24.6±0.2)° when measured using radiation at a temperature in the range of 20-30°C.

[0161] In one embodiment, iptacopan hydrochloride monohydrate (formula H B ) is Cu-K alpha with a wavelength of 0.15419 nm. 1,2When measured using radiation at temperatures in the range of 20-30°C, it is characterized by PXRD peaks identified at 2-theta angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (21.3±0.2)°, and (24.6±0.2)°.

[0162] In one embodiment, iptacopan hydrochloride monohydrate (formula H B ) is Cu-K alpha with a wavelength of 0.15419 nm. 1,2 When measured using radiation at temperatures in the range of 20-30°C, it is characterized by PXRD peaks identified at 2-theta angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21.3±0.2)°, and (24.6±0.2)°.

[0163] In one embodiment, iptacopan hydrochloride monohydrate (formula H B ) is Cu-K alpha with a wavelength of 0.15419 nm. 1,2 When measured using radiation at temperatures in the range of 20-30°C, it is characterized by PXRD peaks identified at 2-theta angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21.3±0.2)°, (24.0±0.2)°, and (24.6±0.2)°.

[0164] In one embodiment, iptacopan hydrochloride monohydrate (formula H B ) is Cu-K alpha with a wavelength of 0.15419 nm. 1,2When measured using radiation at temperatures in the range of 20-30°C, it is characterized by PXRD peaks identified at 2-theta angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21.3±0.2)°, (22.2±0.2)°, (24.0±0.2)°, and (24.6±0.2)°.

[0165] In one embodiment, iptacopan hydrochloride monohydrate (formula H B ) is Cu-K alpha with a wavelength of 0.15419 nm. 1,2 When measured using radiation at temperatures in the range of 20-30°C, it is characterized by PXRD peaks identified at 2-theta angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21.3±0.2)°, (22.2±0.2)°, (24.0±0.2)°, (24.6±0.2)°, and (28.0±0.2)°.

[0166] In one embodiment, iptacopan hydrochloride monohydrate (formula H B ) is Cu-K alpha with a wavelength of 0.15419 nm. 1,2When measured using radiation at temperatures in the range of 20-30°C, the PXRD peaks identified at two-theta angles of (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (12.2±0.2)°, (19.1±0.2)°, and (24.6±0.2)° are characterized by at least one more peak selected from the group consisting of (10.0±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, (20.7±0.2)°, (21.3±0.2)°, (22.2±0.2)°, (24.0±0.2)°, and (28.0±0.2)°.

[0167] In one embodiment, iptacopan hydrochloride monohydrate (formula H B ) is Cu-K alpha with a wavelength of 0.15419 nm. 1,2 When measured using radiation at temperatures in the range of 20-30°C, the PXRD peak identified at a 2-theta angle was: (4.6±0.1)°, (9.2±0.1)°, and (19.1±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, and (19.1±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (19.1±0.1)°, and (24.6±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (12.2±0.1)°, (19.1±0.1)°, and (24.6±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (12.2±0.1)°, (19.1±0.1)°, (21.3±0.1)°, and (24.6±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (12.2±0.1)°, (12.6±0.1)°, (16.6±0.1)°, (19.1±0.1)°, (21.3±0.1)°, and (24.6±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (10.0±0.1)°, (12.2±0.1)°, (12.6±0.1)°, (16.6±0.1)°, (19.1±0.1)°, (21.3±0.1)°, and (24.6±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (10.0±0.1)°, (12.2±0.1)°, (12.6±0.1)°, (16.6±0.1)°, (19.1±0.1)°, (21.3±0.1)°, and (24.6±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (10.0±0.1)°, (12.2±0.1)°, (12.6±0.1)°, (15.3±0.1)°, (16.6±0.1)°, (19.1±0.1)°, (21.3±0.1)°, and (24.6±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (10.0±0.1)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (21.3±0.2)°, and (24.6±0.2)°; or (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21.3±0.2)°, and (24.6±0.2)°; or (4.6±0.2)°, (6.8±0.2)°, (9.2±0.2)°, (10.0±0.2)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.2)°, (16.6±0.2)°, (17.2±0.2)°, (19.1±0.2)°, (20.7±0.2)°, (21.3±0.2)°, (24.0±0.2)°, and (24.6±0.1)°; or (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (10.0±0.1)°, (12.2±0.1)°, (12.6±0.1)°, (15.3±0.1)°, (16.6±0.1)°, (17.2±0.1)°, (19.1±0.1)°, (20.7±0.1)°, (21.3±0.1)°, (22.2±0.1)°, (24.0±0.1)°, and (24.6±0.1)°; or It is characterized by (4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (10.0±0.1)°, (12.2±0.2)°, (12.6±0.2)°, (15.3±0.1)°, (16.6±0.1)°, (17.2±0.1)°, (19.1±0.1)°, (20.7±0.1)°, (21.3±0.1)°, (22.2±0.1)°, (24.0±0.1)°, (24.6±0.1)°, and (28.0±0.1)°.

[0168] In one embodiment, iptacopan hydrochloride monohydrate (formula H B ) is Cu-K alpha with a wavelength of 0.15419 nm. 1,2 When measured using radiation at temperatures in the range of 20-30°C, the PXRD peaks identified at two-theta angles of (4(4.6±0.1)°, (6.8±0.1)°, (9.2±0.1)°, (12.2±0.1)°, (19.1±0.1)°, and (24.6±0.1)° are characterized by at least one or more peaks selected from the group consisting of (10.0±0.1)°, (12.6±0.1)°, (15.3±0.1)°, (16.6±0.1)°, (17.2±0.1)°, (20.7±0.1)°, (21.3±0.1)°, (22.2±0.1)°, (24.0±0.1)°, and (28.0±0.1)°.

[0169] In one embodiment, iptacopan hydrochloride monohydrate (formula H B ) is (3452±2)cm² when measured using a diamond ATR cell at temperatures in the range of 20-30°C. -1 , (2875±2)cm -1 , (1692±2)cm -1 , (1439±2)cm -1, and (1243±2)cm -1 It is characterized by having a Fourier transform infrared spectrum that includes a peak at a certain wavenumber.

[0170] In one embodiment, iptacopan hydrochloride monohydrate (formula H B ) is (3452±4)cm² when measured using a diamond ATR cell at temperatures in the range of 20-30°C. -1 , (2875±4)cm -1 (1692±4)cm -1 (1439±4)cm -1 , (1243±4)cm -1 , and (767±4)cm -1 It is characterized by having an FTIR spectrum that includes a peak at a certain wavenumber.

[0171] In one embodiment, iptacopan hydrochloride monohydrate (formula H B ) is (3452±4)cm² when measured using a diamond ATR cell at temperatures in the range of 20-30°C. -1 , (2875±4)cm -1 (2732±4)cm -1 (1692±4)cm -1 (1439±4)cm -1 , (1243±4)cm -1 , and (767±4)cm -1 It is characterized by having an FTIR spectrum that includes a peak at a certain wavenumber.

[0172] In one embodiment, iptacopan hydrochloride monohydrate (formula H B The compound is characterized by having a DSC (Differential Scanning Calorimetry) curve that, when measured at a heating rate of 10 K / min, shows a broad endothermic event ending at approximately 170°C, followed by exothermic decomposition at approximately 200°C. In one embodiment, iptacopan hydrochloride monohydrate (formula H) B This device is characterized by having a differential scanning calorimetry curve that includes endothermic events in the range of 35°C to 170°C when measured at a heating rate of 10K / min.

[0173] Iptacopan hydrochloride monohydrate (formula H B The material is characterized by having a thermogravimetric analysis curve that shows a mass loss at approximately 220°C (e.g., a temperature of 200°C to 220°C) due to the loss of water and residual solvent of 4.5% by weight or less, for example 4.3% by weight or less, for example 4.0% by weight or less, for example 3.8% by weight or less, for example 3.4% by weight or less, based on the weight of the crystalline form, when heated from 30 to 300°C at a rate of 20K / min.

[0174] Iptacopan hydrochloride monohydrate (formula H B This product is characterized by exhibiting a mass change of 4.5% by weight or less, for example, 4.0% by weight or less, for example, 3.0% by weight or less, for example, 2.0% by weight or less, for example, 1.8% by weight, 1.6% by weight, 1.5% by weight or less, or 1.4% by weight or less, relative to the weight of the crystalline form at 0% relative humidity, when measured using dynamic vapor adsorption at a relative humidity in the range of 0 to 95% and a temperature of (25±1.0)℃.

[0175] Iptacopan hydrochloride monohydrate (formula H B ) advantageously possesses a crystal habit that is essentially equiaxed or columnar in shape.

[0176] Iptacopan hydrochloride monohydrate (formula H B Typically, the aspect ratio is approximately 0.4 to 0.7, for example, approximately 0.45 to 0.6.

[0177] Iptacopan hydrochloride monohydrate (formula H B ) is advantageous in terms of particle size distribution X 90 The size ranges from approximately 30 μm to approximately 150 μm, for example, from approximately 35 μm to approximately 130 μm, and for example, from approximately 40 μm to approximately 105 μm.

[0178] Iptacopan hydrochloride monohydrate (formula HB) is advantageous in terms of particle size distribution X 50 The size ranges from approximately 5 μm to approximately 100 μm, for example, from approximately 10 μm to approximately 70 μm, and for example, from approximately 15 μm to approximately 55 μm.

[0179] Iptacopan hydrochloride monohydrate (formula HB ) is advantageous in terms of particle size distribution X 10 The size ranges from approximately 0.1 μm to approximately 50 μm, for example, from approximately 1 μm to approximately 30 μm, and for example, from approximately 2 μm to approximately 20 μm.

[0180] Iptacopan hydrochloride monohydrate (formula H B Generally, the consolidated bulk density (15 kPa) is approximately 0.40 g / ml to approximately 0.70 g / ml, for example, approximately 0.50 g / ml to approximately 0.65 g / ml, for example, approximately 0.55 g / ml to approximately 0.60 g / ml.

[0181] Iptacopan hydrochloride monohydrate (formula H B The preparation methods thereof are disclosed in U.S. Patent Applications No. 63 / 026,637 and No. 63 / 052,699, and published in International Publication Brochure No. 2021 / 234544, each of which is incorporated herein by reference in whole.

[0182] Iptacopan hydrochloride monohydrate (formula H B ) may be advantageously used as an investigational drug for the study of the present disclosure (see the examples below).

[0183] Described herein are methods for treating generalized myasthenia gravis (gMG) in a subject of need, comprising administering iptacopan or a pharmaceutically acceptable salt or hydrate thereof to the subject. Accordingly, described herein are methods for treating gMG in a patient of need, comprising administering to the patient orally, for example in capsule form, iptacopan or a pharmaceutically acceptable salt or hydrate thereof in two doses per day (e.g., approximately every 12 hours) (where the dose refers to anhydrous iptacopan free base). Similarly described herein are methods for reducing the total MG-ADL score and / or the total Quantitative Myasthenia Gravis (QMG) score in a subject of need (e.g., a patient), comprising administering iptacopan or a pharmaceutically acceptable salt or hydrate thereof to the subject. Described herein are iptacopan or its pharmaceutically acceptable salts or hydrates for use in the treatment of generalized myasthenia gravis (gMG) in a subject of interest (e.g., a patient). Similarly, described herein are iptacopan or its pharmaceutically acceptable salts or hydrates for use in reducing the total MG-ADL score and / or the total Quantitative Myasthenia Gravis (QMG) score in a subject of interest (e.g., a patient). Similarly, described herein are pharmaceutical compositions comprising iptacopan or its pharmaceutically acceptable salts or hydrates and at least one pharmaceutically acceptable carrier for use in the treatment of generalized myasthenia gravis (gMG) in a subject of interest (e.g., a patient). Similarly described herein are pharmaceutical compositions comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable carrier, for use in reducing the total MG-ADL score of a target subject (e.g., a patient) and / or reducing the total quantitative myasthenia gravis (QMG) score of a target subject (e.g., a patient). The disclosure further provides the use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof for the manufacture of pharmaceuticals for reducing the total quantitative myasthenia gravis (QMG) score of a target subject (e.g., a patient).Similarly described herein are methods for selecting a target patient population, methods for monitoring treatment of the target patient population, and methods for evaluating the safety and effectiveness of treatment of the target patient population.

[0184] Details of this disclosure are described in the attached specification below. Similar or equivalent methods and materials may be used in the practice or testing of this disclosure, but hereafter, exemplary methods and materials are described. Other features, purposes, and advantages of this disclosure will become apparent from this description and the claims. In this specification and the claims, singular nouns also include plural nouns unless otherwise explicitly indicated by the context. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure pertains. All patents and publications referenced herein are incorporated herein by reference in their entirety.

[0185] definition Unless otherwise specified, the nomenclature, procedures, and techniques used in relation to analytical chemistry, synthetic organic chemistry, and pharmaceutical and medicinal chemistry described herein are well-known and commonly used in the art. Standard techniques may be used in 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 incorporated herein by reference for all purposes. Where permitted, all patents, applications, published applications, and other publications and data referenced throughout this disclosure are incorporated herein by reference in their entirety.

[0186] Unless otherwise specified, the following terms have the meanings set forth below.

[0187] As used herein, “approximately” means within ±10% of the value, in addition to including the value or parameter itself. As used herein, the term “approximately” includes and describes the value or parameter itself. For example, “approximately x” includes and describes “x” itself. As used herein, when used in relation to a measurement, or when used to modify a value, unit, constant, or range of values, the term “approximately” refers to a variation of ±1 to 10% (e.g., ±10%), in addition to including the value or parameter itself. In some embodiments, when used in relation to a measurement, or when used to modify a value, unit, constant, or range of values, the term “approximately” refers to a variation of ±1, ±2, ±3, ±4, ±5, ±6, ±7, ±8, ±9, or ±10%.

[0188] As used herein, “administering” or “dosing” means providing a medicinal agent to an individual, including, but not limited to, administration by a medical professional and self-administration. Administration of a medicinal agent to an individual may be continuous, prolonged, short-term, or intermittent.

[0189] As used herein, the terms “obtain” or “to acquire” mean, as used herein, to obtain ownership of a physical entity (e.g., a sample, e.g., a blood sample or a plasma sample) or a value (e.g., a numerical value) by “directly obtaining” or “indirectly obtaining” that physical entity or value. “Directly obtaining” means performing a process (e.g., an analytical method) to obtain the physical entity or value. “Indirectly obtaining” means receiving the physical entity or value from another party or source (e.g., a third-party laboratory that directly obtained the physical entity or value). Directly obtaining a value includes performing a process that involves a physical change of a sample or another substance, e.g., performing an analytical process that involves a physical change of a substance (e.g., a sample), or performing an analytical method (e.g., a method described herein) by, for example, mass spectrometry, e.g., LC-MS, e.g., LC-MS / MS, e.g., sample analysis of a body fluid (e.g., blood).

[0190] As used herein, “baseline” refers to the time prior to treatment with respect to the characteristics of the subject or patient.

[0191] As used herein, “dose” means a specified amount of a pharmaceutical agent provided in a single dose or within a specified period. In certain embodiments, the dose may be administered in capsule form. As used herein, this dose refers to anhydrous iptacopan free base.

[0192] As used herein, “individual,” “patient,” “participant,” or “subject” means a human being selected for treatment or therapy. As used herein, the term “adult” means an individual aged 18 years or older. As used herein, the term “adult” means an individual aged 12 to 17 years.

[0193] As used herein, “pharmaceutically acceptable salt” means a physiologically and pharmaceutically acceptable salt of iptacopan, i.e., a salt that retains the desired biological activity of iptacopan and does not impart any undesirable toxic effects to iptacopan. The terms “pharmaceutically acceptable salt” or “salt” include salts prepared from pharmaceutically acceptable non-toxic acids or bases, including inorganic or organic acids and inorganic or organic bases. “pharmaceutically acceptable salts” of iptacopan can 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). Iptacopan hydrochloride and its preparation method are disclosed in International Publication No. 2015 / 009616 (see Example 26d), which is incorporated herein by reference in its entirety.

[0194] As used herein, “hydrate” means a crystalline form containing one or more water molecules in a three-dimensional periodic arrangement. Examples of hydrates include non-stoichiometric hydrates or stoichiometric hydrates (e.g., hemihydrate, monohydrate, dihydrate, and trihydrate).

[0195] As used herein, the terms “to treat,” “to treat,” and “treatment” mean reducing, inhibiting, attenuating, decreasing, restricting, or stabilizing the onset or progression of a disorder or disease (e.g., gMG). The terms “to treat,” “to treat,” and “treatment” include therapeutic, prophylactic treatments and applications that reduce the risk to a subject of developing a disorder (e.g., MG, e.g., gMG) or other risk factors. Treatment does not need to cure the disorder and encompasses the reduction of symptoms or underlying risk factors. As used herein, the terms “to treat,” “to treat,” and “to treat” mean reduction or remission of the progression or severity of MG (e.g., gMG), or remission of one or more symptoms, preferably one or more identifiable symptoms of MG (e.g., gMG). In specific embodiments, the terms “to treat,” “treatment,” and “to treat” refer to improvement in at least one measurable physical parameter of MG (e.g., gMG), for example, achieving or at least partially achieving a desired effect (e.g., partial decrease in the total myasthenia gravis activities of daily living (MG-ADL) score, partial decrease in the total quantitative myasthenia gravis (QMG) score, partial decrease in the total myasthenia gravis composite (MGC) score, partial decrease in the MG-QOL15r survey score, partial increase in the EQ-5D-5L survey score on the EQ VAS scale). As used herein, the term “total myasthenia gravis activities of daily living (MG-ADL) score” refers to a clinical assessment tool used to measure the degree of physical and functional impairment in patients with myasthenia gravis. This score is based on eight items, including the severity of weakness in the ocular, globus, respiratory, and limb muscles, each item graded from 0 (normal) to 3 (severe impairment), with a score range of 0 to 24. The higher the score, the greater the functional impairment.

[0196] As used herein, the term “Quantitative Myasthenia Gravis (QMG) Total Score” refers to a clinical tool used to quantify the severity of muscle weakness in patients with myasthenia gravis. The total QMG score is calculated based on an assessment of 13 items, including various muscle groups and functions (e.g., ocular muscles, globus muscles, respiratory muscles, and limb muscles). Each item is rated from 0 (no symptoms) to 3 (severe weakness), so the total QMG score ranges from 0 to 39, with higher scores indicating more severe muscle weakness. This helps monitor disease progression and assess the effectiveness of treatment.

[0197] As used herein, the term “Myasthenia Gravis Composite (MGC) Total Score” refers to a clinical assessment tool used to evaluate the clinical severity of muscle weakness in individuals with myasthenia gravis. The MGC score is derived from a total of 10 items that assess the function of the eyes, eyeballs, respiration, and gross motor functions. Each item is scored based on the severity of the symptom, with higher scores indicating greater severity or impairment. The composite total score can range from 0 (indicating no clinical weakness) to 50 (indicating severe muscle weakness). It is used to track the progression of symptoms and response to treatment in patients with MG.

[0198] As used herein, the term “MG-QOL15r survey” refers to a disease-specific questionnaire used to assess the impact of myasthenia gravis on a patient’s quality of life. The survey consists of 15 questions covering various aspects of life that the disease may affect (e.g., physical, emotional, and social functioning). Each question is scored from 0 (not at all) to 4 (very much). Patients answer these questions based on their experiences over the past two weeks, and the total score ranges from 0 to 60, with higher scores indicating a worse quality of life. Thus, the MG-QOL15r survey provides a useful indicator of patient-reported outcomes for both clinical practice and research.

[0199] As used herein, the term “EQ-5D-5L Survey” refers to a standardized means of measuring general health status developed by the EuroQol Group. It provides a simple and versatile health index for clinical and economic assessment and can be used for a wide range of health conditions and treatments. The survey consists of two parts: the EQ-5D Descriptive System and the EQ Visual Analog Scale (EQ-VAS). The Descriptive System comprises five aspects: mobility, self-care, daily living activities, pain / discomfort, and anxiety / depression. Each aspect has five levels: no problem, mild problem, moderate problem, severe problem, and severe problem. The EQ-VAS records the respondent's self-assessed health on a vertical axis, with endpoints labeled “best possible health” and “worst possible health.” Scores from these two parts provide an overall health profile and measure an individual’s quality of life. These are particularly used to measure the effectiveness of various medical treatments and interventions.

[0200] As used herein, the term “equant” refers to equidimensional crystals, such as cubes or spheres. As used herein, the term “prismatic” refers to elongated prismatic crystals that are wider and thicker than needles. The definitions of crystal habits for such crystals are consistent with those commonly used in the art; see, for example, “Polymorphism in the Pharmaceutical Industry” edited by Rolf Hilfiker (Wiley-VCH, 2006); Chapter 7, Light Microscopy (Gary Nichols).

[0201] Unless otherwise specified, all formulas and groups assume and achieve the conventional definition of the term "control" and conventional stable valencies.

[0202] In this disclosure, the articles “a” and “an” are used to refer to one or more (e.g., at least one) grammatical objects of the article. For example, “an element” means one or more elements. Unless otherwise required by context, singular terms as used herein include plural terms, and plural terms include singular terms.

[0203] Usage and Method In one embodiment, the Specified provides a method for treating myasthenia gravis in a subject of interest, specifically generalized myasthenia gravis (gMG), comprising administering iptacopan or a pharmaceutically acceptable salt or hydrate thereof to the subject. In another embodiment, the Specified provides a method for reducing the total MG-ADL score of a subject of interest (e.g., a patient), comprising administering iptacopan or a pharmaceutically acceptable salt or hydrate thereof to the subject. In yet another embodiment, the Specified provides a method for reducing the total quantitative myasthenia gravis (QMG) score of a subject of interest (e.g., a patient), comprising administering iptacopan or a pharmaceutically acceptable salt or hydrate thereof to the subject. In one embodiment, provided herein are methods for treating myasthenia gravis in a subject (e.g., a patient), specifically for treating generalized myasthenia gravis (gMG), or for reducing the total myasthenia gravis activities of daily living (MG-ADL) score in a subject (e.g., a patient), or for reducing the total quantitative myasthenia gravis (QMG) score in a subject (e.g., a patient), wherein the subject (e.g., a patient) is given iptacopan or a pharmaceutically acceptable salt thereof. The method involves administering the hydrate in doses of approximately 50 mg to approximately 500 mg (for example, orally), for example, in doses of approximately 50 mg to approximately 250 mg, approximately 100 mg to approximately 200 mg, or approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, or approximately 200 mg, with each dose administered twice a day (bid), for example, at approximately 12 hours apart (where the dose refers to anhydrous iptacopan free base), thereby treating the subject (or patient).

[0204] In another aspect, the Disclosure provides iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use in the treatment of myasthenia gravis in a subject of interest (e.g., a patient), specifically for use in the treatment of generalized myasthenia gravis (gMG). In another aspect, the Disclosure provides iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use in reducing the total MG-ADL score in a subject of interest (e.g., a patient). In another aspect, the Disclosure provides iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use in reducing the total Quantitative Myasthenia Gravis (QMG) score in a subject of interest (e.g., a patient). In one embodiment, the treatment or use involves administering to the subject (e.g., a patient) iptacopan or a pharmaceutically acceptable salt or hydrate thereof in doses of about 50 mg to about 500 mg (e.g., orally), for example, in doses of about 50 mg to about 250 mg, about 100 mg to about 200 mg, or about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, with each dose administered twice daily (bid), for example, at about 12 hours apart (where the dose refers to anhydrous iptacopan free base).

[0205] In another aspect, the Disclosure provides the use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof in the manufacture of a pharmaceutical product for the treatment of generalized myasthenia gravis in a target subject (e.g., a patient), specifically for the treatment of generalized myasthenia gravis (gMG). In another aspect, the Disclosure provides the use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof in the manufacture of a pharmaceutical product for reducing the total MG-ADL score in a target subject (e.g., a patient). In another aspect, the Disclosure provides the use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof in the manufacture of a pharmaceutical product for reducing the total Quantitative Myasthenia Gravis (QMG) score in a target subject (e.g., a patient). In one embodiment, this treatment or use involves orally administering iptacopan or a pharmaceutically acceptable salt or hydrate thereof to the subject (e.g., a patient) in doses of about 50 mg to about 500 mg, for example, orally in doses of about 50 mg to about 250 mg, about 100 mg to about 200 mg, or orally in doses of about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, with each dose administered, for example, twice daily (bid) at about 12 hours apart (where the dose refers to anhydrous iptacopan free base), thereby treating the subject (e.g., a patient). In one embodiment, the subject (e.g., a patient) has or has been diagnosed with gMG.

[0206] In another aspect, the Disclosure provides a pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable carrier for use in the treatment of myasthenia gravis in a subject of interest (e.g., a patient), specifically for use in the treatment of generalized myasthenia gravis (gMG). In another aspect, the Disclosure provides a pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable carrier for use in reducing the total MG-ADL score of a subject of interest (e.g., a patient). In another aspect, the Disclosure provides a pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof and at least one pharmaceutically acceptable carrier for use in reducing the total Quantitative Myasthenia Gravis (QMG) score of a subject of interest (e.g., a patient). In one embodiment, the pharmaceutical composition is administered orally in doses of about 50 mg to about 500 mg of iptacopan or a pharmaceutically acceptable salt or hydrate thereof, for example, in doses of about 50 mg to about 250 mg, about 100 mg to about 200 mg, or about 50 mg, about 75 mg, about 100 mg, about 150 mg, or about 200 mg, with each dose administered twice daily (bid), for example, at about 12 hours apart (where the dose refers to anhydrous iptacopan free base), thereby treating the subject (e.g., a patient).

[0207] The embodiments described below are applicable to any of the aforementioned embodiments provided herein and may be combined in any order.

[0208] In one embodiment, the method or use involves administering iptacopan hydrochloride to a subject. In another embodiment, the method involves administering iptacopan hydrochloride monohydrate (formula H) to a subject. B This includes administering )

[0209] In one embodiment, the pharmaceutical composition comprises iptacopan hydrochloride and at least one pharmaceutically acceptable carrier for use in the treatment of myasthenia gravis, specifically for use in the treatment of generalized myasthenia gravis (gMG). In another embodiment, the pharmaceutical composition comprises iptacopan hydrochloride monohydrate (formula H B ) and at least one pharmaceutically acceptable carrier for use in the treatment of myasthenia gravis, specifically for use in the treatment of generalized myasthenia gravis (gMG).

[0210] In yet another embodiment, the method or use involves administering iptacopan to a subject in doses of approximately 50 mg to approximately 500 mg, for example, approximately 50 mg to approximately 250 mg and approximately 100 mg to approximately 200 mg, each administered twice daily (bid).

[0211] In yet another embodiment, the method or use involves administering iptacopan to a subject in doses of approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, or approximately 200 mg, each administered twice daily (bid).

[0212] In one embodiment, this dose is about 50 mg twice daily. In another embodiment, this dose is about 100 mg twice daily. In yet another embodiment, this dose is about 200 mg twice daily.

[0213] In yet another embodiment, iptacopan or a pharmaceutically acceptable salt or hydrate thereof is administered orally.

[0214] In one embodiment, the subjects suffer from Myasthenia Gravis Foundation of America (MGFA) Class II-IV MG.

[0215] In one embodiment, the subject has anti-acetylcholine receptor antibody-positive (AChR+) gMG. In one embodiment, the anti-acetylcholine receptor antibody (AChR) antibody is at least one of the IgG1, IgG2, IgG3, and IgG4 subclasses. In one embodiment, the anti-acetylcholine receptor antibody (AChR) antibody is at least one of the IgG1 and IgG3 subclasses.

[0216] In one embodiment, the subject suffers from refractory gMG.

[0217] In one embodiment, the subject suffers from refractory anti-acetylcholine receptor antibody-positive (AChR+) gMG.

[0218] In some embodiments, the subject (e.g., patient) is an adult. In some embodiments, the adult subject is 18 years of age or older. In one embodiment, the subject (e.g., patient) is a young person. In some embodiments, the young person subject is in the range of 12 to 18 years of age.

[0219] In another embodiment, the method further includes administering an immunosuppressant to the subject. In yet another embodiment, the immunosuppressant is at least one of azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, and cyclophosphamide. In yet another embodiment, the subject is administered the immunosuppressant for at least 6 months.

[0220] In one embodiment, the method further includes administering corticosteroids to the subject. In another embodiment, the subject is administered corticosteroids for at least four weeks.

[0221] In one embodiment, the method further includes administering a cholinesterase inhibitor to a subject. In another embodiment, the method further includes administering a cholinesterase inhibitor to a subject for at least two weeks.

[0222] In one embodiment, the method further includes subjecting the subject to plasma separation, plasma exchange, or intravenous immunoglobulin injection at least four times a year.

[0223] In one embodiment, the method further includes administering to a subject at least one FcRN antagonist (i.e., fgultigimod, rozanolixizumab).

[0224] In one embodiment, the method further includes administering a complement inhibitor (e.g., eculizumab, ravulizumab, zircoplan) to the subject.

[0225] In one embodiment, the method further includes administering a B-cell inhibitor (e.g., inebilizumab) to the subject.

[0226] In one embodiment, the subject (e.g., a patient) is vaccinated before treatment with iptacopan or a pharmaceutically acceptable salt or hydrate thereof, for example, before administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof. In another embodiment, the subject (e.g., a patient) is vaccinated against at least one of Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae before administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof. In yet another embodiment, the subject (e.g., a patient) is vaccinated against Neisseria meningitidis and Streptococcus pneumoniae before administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof. In one embodiment, the subject (e.g., a patient) is vaccinated against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae before administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof.

[0227] In one embodiment, the subject (e.g., a patient) is vaccinated against Neisseria meningitidis (types A, C, Y, W-135, and B) prior to administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof.

[0228] In one embodiment, the subject (e.g., a patient) is vaccinated against Streptococcus pneumoniae (Pneumovax-23) before administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof.

[0229] In one embodiment, the subject (e.g., a patient) is vaccinated against Haemophilus influenzae before administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof.

[0230] In another embodiment, the subject is not optimally controlled for more than six months with one nonsteroidal immunosuppressive therapy (NSIST). In yet another embodiment, the subject is not optimally controlled for more than six months with two or more nonsteroidal immunosuppressive therapies (NSIST). In yet another embodiment, the NSIST is at least one of azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, and cyclophosphamide.

[0231] In one embodiment, the subject is not optimally controlled for more than 6 months with gMG treatment, which is rituximab or a neonatal crystallizable fragment receptor (FcRN) antagonist approved for gMG. In another embodiment, the subject is not optimally controlled for more than 6 months with frequent (e.g., at least 4 times per year) plasma separation, plasma exchange, or intravenous immunoglobulin administration to control symptoms, despite treatment with steroids and nonsteroidal immunosuppressive therapy (NSIST).

[0232] In one embodiment, the method further includes administering azathioprine to a subject. In another embodiment, the method further includes administering azathioprine to a subject for at least six months.

[0233] In one embodiment, the subject has a baseline MG-ADL total score of at least 6 (50% or more of the MG-ADL score attributable to non-ocular symptoms). In one embodiment, the method or use further includes achieving a reduction in the MG-ADL total score of, for example, at 1 month, 3 months, 6 months, by at least 2 points, at least 3 points, at least 4 points, at least 5 points, or at least 6 points compared to baseline.

[0234] In one embodiment, the method or use further includes achieving a reduction in the total QMG score of, for example, at 1 month, 3 months, or 6 months, by, for example, at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points compared to a baseline.

[0235] In one embodiment, the method or use further includes achieving a reduction of at least 3 points, for example, at least 4 points, at least 5 points, or at least 6 points in the composite myasthenia gravis (MGC) total score, for example, at 1 month, 3 months, or 6 months, compared to baseline.

[0236] In some embodiments, the methods or uses provided herein are a. Achieve a reduction of, for example, at least 2, at least 3, at least 4, at least 5, or at least 6 points in the total Myasthenia Gravis Activities of Daily Living (MG-ADL) score compared to baseline at, for example, 1 month, 3 months, and 6 months; b. Achieve a reduction in the quantitative myasthenia gravis (QMG) total score of, for example, at 1 month, 3 months, and 6 months, compared to baseline, by, for example, at least 3 points, for example, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points; c. Achieve a reduction in the composite myasthenia gravis (MGC) total score compared to baseline, for example, at 1 month, 3 months, and 6 months; d. Achieve a reduction in the MG-QOL15r survey score compared to baseline, for example, at 1 month, 3 months, and 6 months; e. Achieve an increase in EQ-5D-5L survey scores on the EQ VAS scale, for example, at 1 month, 3 months, and 6 months, compared to baseline. Includes one or more of the following.

[0237] In specific embodiments, the methods or uses provided herein include achieving a reduction of at least 2 points in the MG-ADL total score, specifically, a reduction of at least 2 points in the MG-ADL total score over 6 months compared to baseline. In more specific embodiments, the methods or uses provided herein include achieving a reduction of at least 3 points in the MG-ADL total score, specifically, a reduction of at least 3 points in the MG-ADL total score over 6 months compared to baseline.

[0238] In specific embodiments, the methods or uses provided herein include achieving a reduction of at least 4 points in the total QMG score compared to a baseline, specifically, a reduction of at least 4 points in the total QMG score compared to a baseline over a 6-month period. In more specific embodiments, the methods or uses provided herein include achieving a reduction of at least 5 points in the total QMG score compared to a baseline, specifically, a reduction of at least 5 points in the total QMG score compared to a baseline over a 6-month period.

[0239] In specific embodiments, the methods or uses provided herein include (i) achieving a reduction of at least 2 points in the total MG-ADL score, specifically, a reduction of at least 2 points in the total MG-ADL score over 6 months compared to baseline, and (ii) achieving a reduction of at least 4 points in the total QMG score, specifically, a reduction of at least 4 points in the total QMG score over 6 months compared to baseline. In more specific embodiments, the methods or uses provided herein include (i) achieving a reduction of at least 3 points in the total MG-ADL score, specifically, a reduction of at least 3 points in the total MG-ADL score over 6 months compared to baseline, and (ii) achieving a reduction of at least 5 points in the total QMG score, specifically, a reduction of at least 5 points in the total QMG score over 6 months compared to baseline.

[0240] In one embodiment, the method further includes achieving a reduction in the dose of a corticosteroid. In one embodiment, the corticosteroid is an oral corticosteroid. [Examples]

[0241] The present disclosure will be further illustrated by the following embodiments, but this should not be construed as limiting the present disclosure to the scope or intent of any particular procedure described herein. These embodiments are provided to illustrate a particular embodiment and are not intended to limit the scope of the present disclosure. Furthermore, it should be understood that various other embodiments, modifications, and equivalents thereof may be used, which may be suggested to those skilled in the art without departing from the intent of the present disclosure and / or the appended claims.

[0242] List of abbreviations

[0243] [Table A]

[0244] Glossary

[0245] [Table B]

[0246] [Table C]

[0247] [Table D]

[0248] [Table E]

[0249] Example 1. A randomized, double-blind, placebo-controlled phase III trial to evaluate the efficacy, safety and tolerability of eptacopan in patients with generalized myasthenia gravis (gMG), followed by an open-label extension phase Objective The objective of this trial is to evaluate the efficacy, safety and tolerability of eptacopan in patients with anti-acetylcholine receptor antibody positive (AChR+) gMG receiving stable standard of care (SOC) treatment.

[0250] Eptacopan is administered to patients as eptacopan hydrochloride monohydrate (formula H B ) as defined herein. The preparation method of eptacopan hydrochloride monohydrate (formula H B ) is disclosed in Examples 1, 2 and 3 of the pamphlet of International Publication No. WO 2021 / 234544.

[0251] This trial aims to evaluate whether treatment with iptacopan results in a reduction in the total score on the Myasthenia Gravis Activities of Daily Living (MG-ADL) scale 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.

[0252] This Phase III trial will evaluate the efficacy and safety of iptacopan compared to placebo in patients with AChR+ gMG. This patient population was selected because of the mechanism of action of iptacopan as an inhibitor of alternative complement pathways, combined with the role of the complement system in the pathophysiology of AChR+ myasthenia gravis, further supported by evidence that anti-complement therapy is beneficial in gMG.

[0253] Objective, endpoint, and estimate

[0254] [Table 1-1]

[0255] [Table 1-2]

[0256] Major Estimates The primary clinical question at hand is as follows: What is the effect of iptacopan treatment compared to placebo on the change in total MG-ADL score from baseline to 6 months post-treatment in patients with gMG receiving stable SOC myasthenia gravis treatment, assuming no interruption of the study treatment for any reason, no permitted changes in SOC MG treatment, and no emergency medications or strongly confounding prohibited drugs?

[0257] The primary basis for the estimate is that it captures both the effect of the test treatment and the effect of the acceptable SOC MG treatment, reflecting the clinical practice.

[0258] The main estimand is described by the following attributes: · Population: Participants aged 18 to 75 years old with an MG-ADL score of at least 6 at baseline (at least 50% are non-ocular) and receiving stable SOC treatment for myasthenia gravis. For further details on this population, refer to the inclusion / exclusion criteria. · Endpoint: Change from baseline in the total MG-ADL score at 6 months. · Target treatment: Randomized treatment (iptacopan or placebo) with or without allowed SOC MG treatment, regardless of changes to the allowed SOC MG treatment

[0259] Handling of intercurrent events: 1. Discontinuation of study treatment for any reason is handled in accordance with the treatment policy strategy. That is, data after treatment discontinuation are collected and used for the primary analysis.

[0260] 2. Changes to allowed SOC MG treatment are handled in accordance with the treatment policy strategy. That is, data after changes to the allowed SOC MG treatment are collected and used for the primary analysis.

[0261] 3. Use of rescue medication is handled in accordance with a strategy that assumes the participant would continue to be treated without taking rescue medication, regardless of the potential occurrence of other intercurrent events. Rescue medication is particularly likely to confound the interpretation of the treatment effect in the placebo-controlled setting of this trial, where participants randomized to placebo tend to take rescue medication more frequently than participants randomized to the iptacopan group. Measurements after rescue medication use are excluded from the analysis, and this is supplemented by a modeling approach that considers rescue medication as a potential indicator of exacerbated disease.

[0262] 4. The use of prohibited drugs, which are strong confounding factors, will be handled according to a strategy that does not consider the possibility of other intermediate events occurring, assuming that participants are not taking prohibited drugs and are continuing treatment. Prohibited drugs are particularly likely to confuse the interpretation of treatment effects in the placebo-controlled setting of this trial, as in this trial, participants randomly assigned to placebo tend to take other prohibited drugs more frequently than participants randomly assigned to the iptacopan group. This approach complements the analysis by excluding measurements taken after the administration of prohibited drugs, which are strong confounding factors, and by considering emergency medications as potential indicators of disease progression.

[0263] Aggregation scale: Difference in the mean change in the total MG-ADL score from baseline to 6 months between treatments.

[0264] Secondary estimates Changes in QMG total score from baseline to 6 months The clinical questions concerning these secondary estimates are defined similarly to those concerning the primary estimates, but instead focus on the change in the total QMG score from baseline to 6 months. The population, treatment or objective, aggregate scale, intermediate events, and their corresponding treatment strategies are the same as outlined above.

[0265] Percentage of participants who experienced a 5-point decrease in their total QMG score from baseline to 6 months without the use of emergency medications or strongly confounding prohibited drugs. The clinical question regarding this secondary estimate is as follows: Regardless of any discontinuation of the study treatment for any reason, or any permitted change in SOC MG treatment, what is the effect of iptacopan treatment compared to placebo on the proportion of participants with systemic myasthenia gravis receiving stable SOC myasthenia gravis treatment who experience a decrease of 5 points or more in the total QMG score from baseline to 6 months without the use of emergency medications or strongly confounding prohibited drugs?

[0266] The target population and treatment are the same as the main estimate. Other attributes are listed below.

[0267] Endpoint: The proportion of participants who experienced a 5-point reduction in the total QMG score from baseline to 6 months without the use of emergency medications or strongly confounding prohibited medications.

[0268] Handling of intermediate events: 1. Interruption of a trial procedure for any reason will be handled according to the treatment policy strategy. Specifically, data after the interruption will be collected and used for primary analysis.

[0269] 2. Handling acceptable SOC MG treatment changes in accordance with the treatment policy strategy. That is, collecting data after acceptable SOC MG treatment changes for use in primary analyses.

[0270] 3. The administration of emergency medication should be handled according to a combined strategy, regardless of the potential occurrence of other intermediate events. The administration of emergency medication should be considered a treatment failure and therefore part of the endpoint definition, and the patient should be considered a non-responder.

[0271] 4. Taken use of prohibited drugs, which are strong confounding factors, should be managed according to a combined strategy, regardless of the potential occurrence of other intermediate events. Taken use of prohibited drugs, which are strong confounding factors, should be considered treatment failure and therefore part of the endpoint definition, and the patient should be considered a non-responder.

[0272] Aggregated scale: Odds ratio from a covariate-adjusted logistic regression model.

[0273] Percentage of participants experiencing a 3-point decline in MG-ADL from baseline to 6 months without the use of emergency medications or strongly confounding prohibited drugs. The clinical question concerning this secondary estimate is defined as above, but instead concerns the proportion of participants who experience a 3-point decrease in the MG-AGL total score from baseline to 6 months without the use of emergency medications or strongly confounding prohibited medications. The population, treatment or objective, aggregate scale, intermediate events, and their corresponding treatment strategies are the same as above.

[0274] Changes in MGC total score from baseline to 6 months The clinical questions concerning these secondary estimates are defined similarly to those concerning the primary estimates, but instead focus on the change in the MGC total score from baseline to 6 months. The population, treatment or objective, aggregate scale, intermediate events, and corresponding treatment strategies are the same as those described above.

[0275] Changes in MG-QOL15r survey scores from baseline to 6 months The clinical questions concerning these secondary estimates are defined similarly to those concerning the primary estimates, but instead focus on the change in the MG-QOL15r survey score from baseline to 6 months. The population, treatment or objective, aggregate scale, intermediate events, and their corresponding treatment strategies are the same as those described above.

[0276] Test design This study is a randomized, double-blind, placebo-controlled, multicenter phase III trial to evaluate the efficacy, safety, and tolerability of iptacopan in AChR+ gMG patients receiving stable status of care (SOC). Eligible subjects will be randomly assigned in a 1:1 ratio to receive either iptacopan 200 mg orally twice daily for 6 months (up to day 180), or an equivalent placebo, while continuing stable SOC treatment. This randomization will be stratified based on region.

[0277] This exam consists of a core part and an extension part.

[0278] This core part consists of the following three periods: Screening period: A period of up to eight weeks to assess participants' eligibility and administer necessary vaccinations (vaccination should be started as early as possible to avoid extending the screening period). If participants have received all necessary vaccinations prior to the screening period, the screening period may be completed in less than eight weeks. Double-blind treatment period: A 6-month randomized, double-blind, placebo-controlled treatment period for primary efficacy and safety analysis. Safety follow-up period: A period consisting of two safety follow-up consultations for all participants who did not continue treatment or discontinued it prematurely during the extension phase.

[0279] The extended portion consists of the following two periods: Open-label extension period: A 24-month open-label single-arm treatment period during which eligible participants receive iptacopan treatment. Safety follow-up period: This period consists of two safety follow-up consultations for all participants in this open-label extension.

[0280] Co-parts: Screening period During screening, participants are required to review and sign an Informed Consent Form (ICF) before any trial-related assessments are conducted. Following the signing of the ICF, the inclusion and exclusion criteria will be evaluated during the screening consultation to verify the participant's eligibility for enrollment in this trial.

[0281] Participants must be positive for AChR+ antibody serological testing and have documented a history of gMG diagnosis supported by at least one of the following three tests: • History of neuromuscular transmission disorders as demonstrated by single-fiber electromyography or repetitive nerve stimulation. • History of positive edrophonium chloride test • Demonstrated improvement of MG symptoms with oral acetylcholinesterase inhibitors

[0282] To determine eligibility for this study, all participants must have a blood sample taken at screening and be evaluated for the presence of AChR+ antibodies by a central laboratory. Other screening assessments include physical examination, vital signs, infectious disease surveillance, demographics, medical history, past medications / concomitant medications, electrocardiogram (ECG), blood tests, clinical chemistry tests, and urinalysis.

[0283] For participants requiring vaccination according to inclusion criteria, the screening period extends up to 8 weeks (-56 days) before baseline (BL) to allow time for vaccination or revaccination. However, while the screening period for these unvaccinated participants may extend up to 8 weeks, safety assessments (particularly laboratory safety testing) must be conducted within 2 weeks (-14 days) before BL to improve the accuracy of eligibility records. For participants who have completed vaccination, the screening period may be shortened to 2 weeks (-14 days), and this period includes conducting all pre-BL screening assessments.

[0284] Every effort should be made to ensure that the final vaccination is administered at least two weeks before the initiation of iptacopan treatment. If there is no other option but to initiate iptacopan within two weeks of vaccination, participants must be given prophylactic antibiotics from the initiation of iptacopan administration until at least two weeks after vaccination. Throughout the protocol, “baseline” refers to the Day 1 examination (pre-dose). Vaccination must be completed according to the inclusion criteria defined below. The vaccine should cover as many serotypes as possible (e.g., meningococcal serotypes A, C, Y, W-135, and B). To minimize patient burden, the use of multivalent vaccines is recommended, provided they are locally available and in accordance with local guidelines and regulations (e.g., a quadrivalent vaccine for meningococcus (N. meningitidis) covering serotypes A, C, Y, and W-135, and Pneumovax-23 covering 23 serotypes of Streptococcus pneumoniae). For vaccination, type and booster requirements should be based on local guidelines and the use of locally available vaccines (and refer to their package inserts and local guidelines).

[0285] Participants who are receiving a stable dose of standard treatment for gMG at the time of screening must continue these medications throughout the double-blind treatment period and the open-label extension period. During the double-blind treatment period of this study, the dosage of SOC medications may not be changed, nor may new SOC medications be added or discontinued, unless the principal investigator determines that a change is medically necessary. Participants who do not meet the study eligibility criteria should be disqualified from screening. However, in some cases, participants who are disqualified during the screening process due to a temporary condition (e.g., safety laboratory values) may be allowed to re-examine and re-determine their eligibility within the same screening period, on a case-by-case basis. Participants who do not meet the eligibility criteria during the screening period may be re-screened at a later date and, if all inclusion and exclusion criteria are met, may be randomly assigned to this study; however, this should be considered on a case-by-case basis. Screen-disqualified participants undergoing re-screening will be required to sign a different ICF and will be assigned a new participant number.

[0286] Double-blind treatment period Participants meeting the eligibility criteria will be randomly assigned in a 1:1 ratio to receive either iptacopan 200 mg orally twice daily for 6 months (up to day 180), or an equivalent placebo, while continuing stable SOC treatment. This randomization will be stratified based on region. At baseline, prior to randomization, all participants will be reassessed for eligibility based on the study's inclusion and exclusion criteria. The MG-ADL scale must be administered before all other efficacy or quality of life assessments, followed by other patient-reported scales.

[0287] During this consultation, vital signs, ECG, blood tests, clinical chemistry tests, biomarkers, myasthenia gravis-related assessments and scales, and baseline values ​​for the quality of life questionnaire will be completed.

[0288] The study treatment will begin on the first day of administration (day 1) and continue for 6 months (up to day 180). Participants will return to the study site for scheduled consultations on days 15, 30, 60, 90, 120, 150, and 180 of the study, during which the efficacy and safety of the study will be evaluated. Blood samples for pharmacokinetics and biomarkers will be collected pre-dose (i.e., before administration of the study drug) on ​​days 15, 30, 90, and 150 of the double-blind treatment period, and at the end-of-surgery (EOS) consultation. Interactive response technology (IRT) communication, preparation, and management of the study drug (accountability) will be conducted as needed at each consultation.

[0289] During the randomization treatment period, no dose adjustments of iptacopan are permitted, and further details regarding dose interruption or discontinuation of the study drug can be found below. Furthermore, the dose of the SOC drug must remain stable throughout this treatment period and must not be changed.

[0290] However, if a participant's MG condition worsens or there is a risk of MG crisis, as determined by the principal investigator and the definition of exacerbation described below, the participant may receive emergency treatment. This emergency treatment may be either IVIG or plasma exchange as described below, and the participant may continue the blinded study procedure if deemed safe by the principal investigator's medical judgment. In such cases, the emergency treatment used for a given participant is at the discretion of the principal investigator. Note: Alternative or additional emergency medications as described below are not permitted. Participants taking prohibited medications must discontinue the study procedure.

[0291] The double-blind treatment period will end upon completion of the 6-month (180-day) medical evaluation. All participants will receive a core part End-of-Service (EOS) examination upon completion of the 6-month (180-day) examination, or if a participant discontinues the treatment period early (i.e., discontinues the double-blind study treatment and does not wish to participate in any further scheduled follow-up study examinations). Upon completion of all evaluations at the 6-month (180-day) examination, all eligible participants who have completed the double-blind treatment period will be offered continuation to OLE, where iptacopan will be administered for a period of 24 months, as outlined below.

[0292] For participants who permanently discontinue treatment during the double-blind treatment period, efforts should be made to encourage them to remain in the study for further monitoring and complete the full evaluation up to day 180 (6-month / EOS examination). Participants who discontinued double-blind treatment early and wish to continue the study should receive an End-of-Treatment (EOT) examination at the time of discontinuation of the double-blind study drug, and these participants are ineligible to participate in the open-label extension part. These discontinued participants will complete safety follow-up examinations 7 and 30 days after the 6-month EOT / EOS examination.

[0293] Participants who complete the double-blind treatment period (including those who received emergency treatment and those whose continuation of the study treatment was safely guaranteed) are eligible to participate in the open-label extension part of this study and are not required to complete safety follow-up examinations.

[0294] Due to the known risks of complement inhibitor treatment for infections caused by encapsulated bacteria (most importantly, Neisseria meningitidis), all participants will be provided with a participant safety card. Participants will be instructed to remain vigilant for any clinical signs of bacterial infection, to immediately contact the principal investigator or local physician if an infection is suspected, and to begin antibiotic treatment as soon as possible.

[0295] When 33% of participants are enrolled, an interim analysis (IA) will be performed by an independent team on the changes from baseline in MG-ADL and QMG at 3 months to provide an opportunity for early termination of the trial due to futility. Recruitment will continue during the IA. Before completion of enrollment to the core part of the trial, when 70% of patients are enrolled, a blinded data analysis (i.e., treatment codes have not been decoded) will be performed to re-evaluate the sample size assumptions regarding the primary endpoint. Based on this blinded analysis, the number of enrolled participants may be increased to a maximum of 190 randomized participants.

[0296] Safety tracking period This period consists of two safety follow-up assessments for all participants who did not continue treatment in the extension phase: one 7 days after the last dose of the study treatment (i.e., EOT / EOS+7 days at 6 months) and another 30 days after the last dose of the study treatment (i.e., EOT / EOS+30 days). These follow-ups may be conducted by telephone or by visiting the study site. Information collected regarding the 6-month EOT / EOS+7 consultation should be compiled into the eCFR. Information collected regarding the 6-month EOT / EOS+30 consultation should be entered into the eCRF. SAE reporting should continue during this period as described below. Records of attempts to contact participants must be documented in the original materials.

[0297] Extended part Open-label extension period Participants who have completed all examinations related to the study treatment by 6 months (180 days) of the double-blind treatment period are eligible to participate in the open-label extended treatment period (OLE), and all participants will receive iptacopan 200 mg as a bid. This is a blind transition from the double-blind treatment period to the OLE of the study.

[0298] Participants who are eligible for and consent to participate in the OLE procedure will begin the procedure at the completion of their 6-month (180-day) check-up, after the completion of all evaluations during the double-blind treatment period. The efficacy and safety evaluations conducted at this check-up will be used for the EOS check-up and registration / baseline check-up (OLE Day 1) during the double-blind treatment period. Participants who are not eligible for or do not consent to continue with OLE after the completion of the 6-month double-blind treatment will complete the OLE evaluation.

[0299] During each consultation, IRT contact, preparation of experimental medications, and management will be carried out.

[0300] All participants will return for a safety follow-up examination 30 days after their 24-month EOT / EOS examination.

[0301] Safety tracking period This period consists of two safety follow-up assessments for all participants in the extension phase: one 7 days after the last dose of the study treatment (i.e., EOT / EOS+7 days at 24 months) and another 30 days after the last dose of the study treatment (i.e., EOT / EOS+30 days at 24 months). These follow-ups may be conducted by telephone or by visiting the study site. Information collected regarding the 24-month EOT / EOS+7 consultation should be compiled into the eCFR. Information collected regarding the 24-month EOT / EOS+30 consultation should be entered into the eCRF. SAE reporting should continue during this period as described below. Records of attempts to contact participants are required to be documented in the original documentation.

[0302] The treatments covered Randomized treatment (iptacopan 200 mg bid or equivalent placebo) and stable standard of care (SOC) treatment.

[0303] Rational basis for selecting control drugs or combination drugs and background therapy Participants in this clinical trial may continue receiving stable standard treatment assigned by the treating physician. Participants receiving SOC treatment have received this treatment for a specified period prior to baseline (see inclusion criteria) and are required to continue the same stable treatment during the randomization period of this clinical trial. Unless emergency medication is permitted, any change in SOC due to disease exacerbation or progression may cause discontinuation of the investigational treatment (iptacopan or placebo) to the participant.

[0304] This study will consider enrolling patients treated with various non-steroidal inhibitors (NSISTs) commonly prescribed for gMG and frequently taken in combination by patients (including azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, or cyclophosphamide), corticosteroids, and acetylcholinesterase inhibitors. These treatments are expected to vary from patient to patient based on the clinical judgment of the principal investigator / administering physician, taking into account the clinical situation and local SOC practices. Stable doses of existing treatments for gMG (e.g., acetylcholinesterase inhibitors, corticosteroids, or NSISTs) before baseline and during the study are permitted and required in accordance with the enrollment criteria. With regard to cholinesterase inhibitors, increases in cholinesterase therapy required as a result of other medical causes of comorbidity or exacerbation are permitted, but the dose should be returned to the baseline dose level as soon as possible, and this change should be notified to the sponsor. The dose of corticosteroids or NSISTs must remain stable throughout the study period. The prohibited drugs are listed below.

[0305] Participants who have not previously responded to other complement inhibitors were excluded because they were unlikely to respond to iptacopan due to the very similar mechanism of action (see inclusion / exclusion criteria).

[0306] Patients will be randomly assigned in a 1:1 ratio to receive either iptacopan 200 mg bid or an equivalent placebo over a 6-month double-blind treatment period to evaluate efficacy, safety, and tolerability.

[0307] In this study, due to the unstable and potentially life-threatening nature of the disease, a placebo control has been selected in addition to stable SOC background therapy (permitted in both treatment arms). This is considered appropriate for maintaining a balance between a robust assessment of efficacy and safety in this registration trial and ensuring that patients are maintained at SOC to prevent decompensation. This risk is further mitigated by not enrolling patients with MGFA class V. Therefore, patients randomly assigned to the placebo group are not expected to experience significant harm during the 6-month treatment period, even in the absence of other more recently approved treatments.

[0308] Furthermore, if the disease is worsening or progressing, emergency treatment, IVIG, or PLEX may be administered to the patient in accordance with local treatment guidelines.

[0309] At the end of the double-blind treatment period, all patients who have completed this period will be given the option to transition to an open-label extension and receive iptacopan 200 mg on a bid basis.

[0310] Treatment group Participants will be assigned in a 1:1 ratio to one of the following two treatment arms / groups at the randomized examination (Day 1): • Iptacopan arm: 6 months of oral iptacopan at 200 mg bid (double-blind), followed by a further 24 months of open-label iptacopan at 200 mg bid. • Placebo arm: Placebo oral administration for 6 months (double-blind), followed by open-label iptacopan administration at 200 mg bid for 24 months.

[0311] Definition of the end of the exam The end of the study is defined as the date of the last medical examination for the last participant in this study, or, overall, as the last scheduled procedure or follow-up for the last participant in this study.

[0312] This trial includes a core part and an extension part. Completion of the core part of the trial is defined as the date on which the last participant has completed the trial examination and all related repeat assessments have been adequately demonstrated and followed up by the principal investigator, or, in the case of an early trial termination decision, the date of that decision.

[0313] Participants who complete the double-blind treatment period may be eligible to enroll in the extension part. Completion of the extension part is defined as when the last participant has completed the study examination and all related repeat assessments have been adequately demonstrated and followed up by the principal investigator, or, in the case of an early termination decision, the date of that decision.

[0314] Participants who drop out of the double-blind treatment period early for any reason are not eligible to enroll in the extension part.

[0315] All randomized and / or treatment participants who do not proceed to the extension part for any reason should undergo safety follow-up consultations 7 and 30 days after the completion of the study treatment consultation (6 months / EOT / EOS). All participants who proceed to the open-label extension part and discontinue the treatment for any reason or complete all consultations should undergo safety follow-up consultations 7 and 30 days after the completion of the 24-month / EOT / EOS consultation. This follow-up may be by telephone or by visit to the study site. The information collected should be recorded in each eCFR. SAE reporting should continue during this period. Records of attempts to contact participants should be documented in the original documents.

[0316] Number of participants This trial enrolls approximately 146 male and female patients (18–75 years old diagnosed with gMG) with diseases classified as Class II–IV by MGFA, who are being treated with a stable regimen of SOC treatment (see inclusion / exclusion criteria for SOC treatment requirements), but who still exhibit symptoms of gMG that are not optimally controlled at baseline (i.e., an MG-ADL score of at least 6, with ≥50% of the MG-ADL score attributable to non-ocular symptoms). The defined trial population includes only patients with AChR+ antibodies. At least 20% of enrolled participants should have been treated with a single NSIST.

[0317] Inclusion Criteria Participants eligible for inclusion in this study must meet all of the following criteria: 1. Patients who understand the requirements of this study, can provide written informed consent, and are capable of following the procedures of the study protocol. 2. Adult patients (18-75 years old) with generalized myasthenia gravis. 3. Positive serological test for AChR+ antibody at the time of screening. 4. gMG of MGFA class II-IV, and the principal investigator's assessment that the patient is unlikely to require mechanical ventilation during the study period. 5. Confirmation of the gMG diagnosis should be documented and supported by one of the following three tests: • History of neuromuscular transmission disorders as demonstrated by single-fiber electromyography or repetitive nerve stimulation. • History of positive edrophonium chloride test • Patients have demonstrated improvement in MG symptoms with oral acetylcholinesterase inhibitors, as evaluated by the treating physician. A baseline MG-ADL score of 6.6 or higher, and more than 50% of the total score attributable to non-ocular symptoms. Participants who have not been optimally controlled for 7.6 months or more as described below. • A single NSIST; or • Two or more NSISTs; or • Frequent (at least four times a year) plasma separation, plasma exchange, or intravenous immunoglobulin injections to control symptoms despite treatment with steroids and NSISTs; or • One of the following gMG treatments: • FcRN antagonist approved by gMG • Rituximab • Other approved gMG therapies excluding complement inhibitors Note: Nonsteroidal immunosuppressive therapy (NSIST) includes azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, or cyclophosphamide. 8. Participants receiving azathioprine must have received azathioprine for at least 6 months prior to baseline, and at a stable dose for at least 2 months. 9. Participants receiving other immunosuppressive therapies (i.e., mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, or cyclophosphamide) must have received this immunosuppressive therapy for at least 6 months prior to baseline and at a stable dose for at least 1 month. 10. Participants receiving oral corticosteroids must have been receiving a stable dose for at least 4 weeks (i.e., 28 days or more) prior to baseline. 11. Participants receiving cholinesterase inhibitors must have been receiving a stable dose for at least two weeks prior to baseline. 12. As with all other iptacopan trials, participants must be vaccinated against Neisseria meningitidis and Streptococcus pneumoniae. In addition, participants will be vaccinated against Haemophilus influenzae, depending on local regulations and vaccine availability in the country where the trial is being conducted. Vaccination should be administered at least two weeks before the first dose of iptacopan and should cover as many serotypes as possible. If iptacopan treatment is initiated earlier than two weeks after vaccination, prophylactic antibiotic treatment must be initiated and administered for up to two weeks after vaccination.

[0318] Main exclusion criteria Participants who meet any of the following criteria are not eligible for inclusion in this study. 1. Prior to baseline, the patient had been treated with IVIg / PLEX within the past month, rituximab within the past six months, eculizumab within the past two months, ravulizumab or another complement inhibitor within the past three months, fgaltigimod or another anti-FcRn therapy within the past three months, or underwent thymectomy within the past six months, or was scheduled to undergo thymectomy during this study period. 2. Patients with clinically significant active or chronically uncontrolled bacterial, viral, or fungal infections at the time of screening, for example, patients who test positive for active viral infection at the time of screening as follows: Active hepatitis B virus (HBV): Serological panel test results indicating active (acute or chronic) infection; Active hepatitis C virus (HCV): Serologically positive for HCV-Ab; Serologically positive for human immunodeficiency virus (HIV) associated with a condition defining acquired immunodeficiency syndrome (AIDS) or a surface antigen classification 4 (CD4) count of ≤200 cells / mm3. 3. A history of hypersensitivity to either the test drug or its excipients, or to drugs of a similar chemical class to iptacopan. 4. Female participants who are pregnant or breastfeeding, or who are planning to become pregnant. 5. Women of childbearing capacity, all women, are defined as physiologically capable of becoming pregnant unless they use an effective method of contraception during the administration of the experimental treatment. Effective methods of contraception include: • Complete self-control (if this aligns with the participant's preferred normal lifestyle). Periodic self-control (e.g., calendar method, ovulation method, symptomatic body temperature method, post-ovulation method), and withdrawal are not acceptable methods of contraception. • The woman has undergone a sterilization procedure (including or hysterectomy, or bilateral oophorectomy), a total hysterectomy, or bilateral tubal ligation at least 6 weeks prior to taking the investigational drug. In the case of oophorectomy alone, the woman's reproductive status must be confirmed by follow-up hormone level assessment. • Male sterilization (at least 6 months prior to screening). For female participants in this study, a male partner who has undergone vasectomy should be the participant's sole partner. • Barrier methods of contraception: condoms or occlusive caps (e.g., diaphragms or cervical / fornix caps) • Use of oral (estrogen and progesterone), injectable or implantable hormonal contraception, or other forms of hormonal contraception with comparable effectiveness (failure rate <1%), such as hormonal vaginal rings or percutaneous hormonal contraception, or placement of an intrauterine device (IUD) or intrauterine system (IUS). • When using oral contraception, women should be stable on the same pill for at least three months prior to taking the trial treatment. A woman is considered postmenopausal if she has had 12 months of spontaneous amenorrhea with a suitable clinical profile (e.g., reasonable age, history of vasomotor symptoms). A woman is considered ineligible to give birth if she is postmenopausal or has undergone surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least 6 weeks prior to enrollment in the study. In the case of oophorectomy alone, a woman is considered ineligible to give birth only if her reproductive status has been confirmed by follow-up hormone level assessment. • If local regulations are stricter than the contraceptive methods listed above to prevent pregnancy, local regulations apply and are described in the ICF. 6. Any serious episode within 14 days prior to administration of the study drug, including an active, systemic bacterial, viral (including COVID-19), or fungal infection, or an infection requiring hospitalization or injectable antimicrobial therapy. 7. History of recurrent invasive infections caused by encapsulated organisms, such as N. meningitidis and S. pneumoniae. 8. Presence of a fever of 38°C (100.4°F) or higher within 7 days prior to administration of the test drug. 9. A history of autoimmune diseases other than MG (e.g., thyroiditis, rheumatoid arthritis, etc.) that may hinder the accurate assessment of clinical symptoms. 10. Lack of demonstrated clinical response to PLEX 11. Participants with clinical evidence of other serious illnesses that could interfere with the results of this study or pose an excessive risk to the patient, or patients who have recently undergone major surgery. 12. Participation in any other investigational drug trial or use of any other investigational drug at the time of registration, or within 5 half-lives of registration or within 30 days of registration, whichever is longer; or longer if required by local regulations. 13. Current treatment history for acute or chronic hepatitis, cirrhosis, or liver failure; or aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), or alkaline phosphatase (ALP) levels exceeding three times the upper limit of normal (ULN); or serum bilirubin levels exceeding two times the ULN (excluding participants with a known confirmed diagnosis of Gilbert's syndrome). 14. A history of malignant tumors of any organ system, treated or untreated, within the past five years, regardless of whether there is evidence of local recurrence or metastasis (excluding focal basal cell carcinoma of the skin or in situ cervical cancer). 15. Participants whose muscle weakness is worsening due to a co-infection or medication (such as aminoglycosides, fluoroquinolones, or beta-blockers). 16. A history or current diagnosis of ECG abnormalities that indicate a significant safety risk to participants in this study, such as: • Concomitant clinically significant cardiac arrhythmias, such as sustained ventricular tachycardia, and clinically significant second- or third-degree AV block without a pacemaker. • A history of familial long QT syndrome, or a known family history of Torsades de Pointes. • Resting heart rate less than 60 bpm (physical examination or 12-lead ECG) 17. History of T lymphocyte or T lymphocyte receptor vaccination, transplantation (e.g., solid organ, stem cell, and bone marrow transplantation), and / or treatment for anti-rejection. 18. Participants who do not respond to eculizumab, ravulizumab, or other complement inhibitors. 19. Known or suspected hereditary complement deficiencies 20. Major comorbidities including, but not limited to, severe renal disease (e.g., eGFR <30 mL / min, dialysis), advanced heart disease (e.g., NYHA class IV), severe lung disease (e.g., severe pulmonary hypertension) (WHO class IV), or liver disease (e.g., active hepatitis). 21. Ongoing drug or alcohol abuse that may interfere with patient participation in this study 22. Participants with a history of attempted suicide or suicidal behavior within six months prior to screening, and / or participants who present with intent to commit suicide as evidenced by a "yes" response to Q4 or Q5 on the Columbia Suicidal Severity Rating Scale (CSSRS) at the time of screening.

[0319] Test treatments and combination therapies Study participants will be randomly assigned in a 1:1 ratio to receive either iptacopan 200 mg or placebo twice daily (bid), while continuing their stable dose of existing SOC treatment for gMG both before baseline and throughout the study, as permitted and required in accordance with the inclusion criteria.

[0320] Treatment period The planned duration of the randomized treatment is 6 months (180 days) relative to the double-blind treatment period of the core part. Participants may experience temporary interruption or early termination of treatment due to unacceptable toxicity, lack of efficacy (progression of underlying disease), drug use, bacterial infection, and / or termination at the discretion of the principal investigator. If a participant's treatment is terminated for any reason, all efforts must be made to continue the study evaluation up to 6 months of the double-blind treatment period. After completing a 6-month double-blind treatment period, participants will be offered an open-label extension in which iptacopan will be administered for 24 months. If a participant discontinues iptacopan treatment during this open-label extension, the principal investigator should follow the recommended discontinuation procedures.

[0321] Handling of other or additional measures Participants in the study are permitted to continue the SOC treatment outlined above. Furthermore, gMG SOC treatment, including corticosteroids and IST drugs, must be maintained at the same dose throughout the study unless emergency treatment is required. Emergency treatment may be administered if there is a deterioration in the participant's clinical condition or if the principal investigator determines there is a risk of MG crisis. In such cases, IVIG or PLEX treatment may be administered to the participant as emergency treatment.

[0322] This SOC should be allocated at the discretion of the principal investigator, in accordance with local treatment guidelines, and, as already stated, should be kept stable throughout the entire study period. The use of SOC drugs during the study should be recorded in the patient's original medical records / charts and eCRF. No special monitoring is required, except for verifying stable SOC procedures and documenting them on the corresponding CRF page.

[0323] Dosage change Administer iptacopan or an equivalent placebo at a 200 mg bid. Dosage adjustments for the investigational treatment or other test treatments are not permitted.

[0324] Dosage gradual increase Administer iptacopan or an equivalent placebo at a bid of 200 mg. Dose escalation for the investigational treatment is not permitted.

[0325] Combination therapy Immunosuppressants Patients receiving other immunosuppressive therapies (i.e., azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, or cyclophosphamide) must have received these therapies for at least 6 months and have been receiving stable doses prior to baseline and throughout the entire study (see inclusion / exclusion criteria).

[0326] Cholinesterase inhibitors For patients participating in trials receiving cholinesterase inhibitors at screening, the dose and schedule of cholinesterase inhibitors must be maintained consistently throughout the double-blind treatment period and the open-label extension period, unless there is a compelling medical need. Increases in cholinesterase treatment required as a result of comorbidities or other medical causes of exacerbation are permitted, but the dose must be returned to the trial-start dose level as soon as possible, and this change should be notified to the sponsor. 1. Treatment with cholinesterase inhibitors must be discontinued for at least 10 hours prior to performing the QMG and MGC tests. 2. If a reduction in cholinesterase inhibitor dosage is considered based on clinical evaluation, the sponsor's approval must be obtained before the patient's dosage is changed in order to continue the trial.

[0327] Adrenocortical steroids Participants receiving oral corticosteroids must have received a stable dose for at least 4 weeks (i.e., 28 days or more) prior to baseline.

[0328] Equivalents Those skilled in the art will be able to identify or confirm numerous equivalents to the specific embodiments described herein by means of routine experimentation. Such equivalents are intended to be covered within the following claims.

[0329] Example 2: Iptacopan (LNP023) inhibits the onset of paralysis in a PTMG rat model. Example 2 presents data obtained from a study conducted to evaluate the efficacy of LNP023 (iptacopan) in a PTMG model. This study included a group of rats in which severe PTMG was induced using 1 mg / kg of mAb35. The results showed a significant effect on disease onset, as well as a trend toward maximum score and weight loss, suggesting the potential of LNP023 as a therapeutic agent for PTMG.

[0330] method Six-week-old female Lewis rats were injected intraperitoneally with either PBS (n=5, healthy control) or a monoclonal antibody against the acetylcholine receptor nicotinic α1 subunit (rat IgG1) at a dose of 1 mg / kg (mAb35, n=25). Prior to this, animals injected with mAb35 were randomly assigned to either a vehicle (disease control, n=10) or LNP023 treatment (60 mg / kg, forced oral twice daily, n=15). Treatment was initiated one hour before mAb35 injection. The vehicle used was 0.5% MC / 0.5% Tween80. Animals were monitored twice daily for clinical symptoms and weight changes. Clinical symptoms were scored as follows: 1: normal behavior, 2: mild weakness, tail completely flaccid, 3: marked weakness. At least two of the following symptoms were present: tail completely flaccid, hunched back, drooping jaw. 4: Severe weakness: One or more limbs are immobile and / or breathing is difficult. Euthanize the animal on the same day. Score 5: Dying and barely or completely immobile. Euthanize the animal immediately.

[0331] Compound muscle action potentials (cMAPs) were measured in the left hind limb of anesthetized animals 36 hours after mAb35 injection. The sciatic nerve was stimulated at ultra-maximal intensity (20mA) with a 0.1ms duration square wave pulse at 10Hz (with 10-30 second pauses between pulses), and the CMAP response of the sciatic nerve was obtained. CMAP responses were acquired for each stimulus. The CMAP from the 15th stimulus was normalized relative to the CMAP from the first stimulus.

[0332] Statistical analysis was performed using GraphPad Prism version 10.1.2, employing the Kruskal-Wallis test followed by Dunn's multiple comparison test. For cMAP, the Brown-Forsythe and Welch ANOVA tests were used, followed by Dunnett's T3 multiple comparison test. *p<0.05.

[0333] result Injection of female Lewis rats with a rat antibody against the acetylcholine receptor (AChR, mAb35, 1 mg / kg, ip) resulted in rapid progression of debilitation in 6 out of 10 vehicle-treated control rats (Figure 1A). The first clinical symptoms were observed 24 hours post-injection, and rats developed marked debilitation (score 3) by 48 hours post-injection. The remaining rats did not develop any clinical symptoms, except for one rat which showed mild debilitation at a single time point (60 hours, duration less than 12 hours). Clinical symptoms were associated with marked weight loss in affected animals (Figure 1B). By 72 hours post-injection, 5 out of 7 diseased rats had recovered from the illness.

[0334] Unexpectedly, two rats injected with PBS instead of mAb35 also developed mild transient weakness (score 2) at time points 1 and 2 (less than 12 hours and less than 24 hours), respectively, but this was unrelated to weight loss in either rat.

[0335] Treatment with LNP023 (60 mg / kg bid, initiated 1 hour before mAb35 injection) significantly reduced the incidence and severity of the disease and showed a strong tendency towards a shorter duration of clinical symptoms compared to vehicle-treated rats (Figures 1A-D). Four out of 15 rats developed mild transient weakness, of which only one out of 15 showed marked weakness (score 3), which lasted for less than 12 hours (summarized in the graph in Figure 1A). After LNP023 treatment, the disease was associated with a slight decrease in body weight loss compared to the vehicle-treated group (Figure 1B). Disease duration was assessed by quantifying the number of times the animal's clinical score exceeded 1, thereby obtaining a measure of disease duration (Figure 1C). As shown in Figure 1D, treatment with LNP023 significantly reduced disease severity, and the animals showed a decrease in maximum clinical score.

[0336] Compound muscle action potentials (cMAPs) were measured in the left hind limb 36 hours after disease induction, and were found to be significantly reduced in vehicle-treated animals compared to healthy simulants. Due to the large variability among animals, only an improvement trend in cMAPs was observed after treatment with LNP023 (Figure 1E). In addition, treatment with LNP023 significantly delayed the onset of the disease compared to the vehicle-treated group (Figure 1F).

[0337] conclusion These data demonstrate that treatment with LNP023 (iptacopan) significantly reduces the incidence and severity of PTMG in Lewis rats.

Claims

1. A method for treating generalized myasthenia gravis (gMG) in a subject requiring treatment, comprising administering iptacopan or a pharmaceutically acceptable salt or hydrate thereof to the subject.

2. The method according to claim 1, wherein the subject is suffering from anti-acetylcholine receptor antibody-positive (AChR+) gMG.

3. The method according to claim 1 or 2, further comprising achieving a reduction of, for example, at least 2 points, at least 3 points, at least 4 points, at least 5 points, or at least 6 points in the total myasthenia gravis activities of daily living (MG-ADL) score at, for example, 1 month, 3 months, or 6 months compared to baseline.

4. The method according to claim 3, wherein the decrease in the MG-ADL total score is at least 2 points, specifically, the decrease in the MG-ADL total score is at least 2 points over 6 months compared to the baseline.

5. The method according to claim 4, wherein the decrease in the MG-ADL total score is at least 3 points, specifically, the decrease in the MG-ADL total score is at least 3 points over 6 months compared to the baseline.

6. The method according to any one of claims 1 to 5, further comprising achieving a reduction of, for example, at least 3 points, for example, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points in the quantitative myasthenia gravis (QMG) total score at, for example, 1 month, 3 months, or 6 months, compared to baseline.

7. The method according to claim 6, wherein the decrease in the total QMG score is at least 4 points compared to the baseline, specifically, the decrease in the total QMG score is at least 4 points over 6 months compared to the baseline.

8. The method according to claim 7, wherein the decrease in the total QMG score is at least 5 points compared to the baseline, specifically, the decrease in the total QMG score is at least 5 points over 6 months compared to the baseline.

9. The aforementioned method, a. Achieve a reduction of, for example, at least 2, at least 3, at least 4, at least 5, or at least 6 points in the total Myasthenia Gravis Activities of Daily Living (MG-ADL) score compared to baseline at, for example, 1 month, 3 months, and 6 months; b. Achieve a reduction in the quantitative myasthenia gravis (QMG) total score of, for example, at 1 month, 3 months, and 6 months, compared to baseline, by, for example, at least 3 points, for example, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points; c. Achieve a reduction in the composite myasthenia gravis (MGC) total score compared to baseline, for example, at 1 month, 3 months, and 6 months; d. Achieve a reduction in the MG-QOL15r survey score compared to baseline, for example, at 1 month, 3 months, and 6 months; e. Achieve an increase in the EQ-5D-5L survey score on the EQ VAS scale, for example, at 1 month, 3 months, and 6 months, compared to the baseline. The method according to any one of claims 1 to 8, comprising one or more of the above.

10. A method for reducing the total activity of daily living (MG-ADL) score of a subject with myasthenia gravis, comprising administering iptacopan or a pharmaceutically acceptable salt or hydrate thereof to the subject.

11. The method according to claim 10, wherein the method achieves a reduction of at least 2 points in the total MG-ADL score compared to the baseline, and for example, a reduction of at least 3 points, at least 4 points, at least 5 points, or at least 6 points compared to the baseline at 1 month, 3 months, 6 months, etc.

12. The method according to claim 11, wherein the method achieves a reduction of at least 2 points in the MG-ADL total score compared to the baseline, and more specifically, the method achieves a reduction of at least 2 points in the MG-ADL total score compared to the baseline at 6 months.

13. The method according to claim 12, wherein the method achieves a reduction of at least 3 points in the MG-ADL total score compared to the baseline, and more specifically, the method achieves a reduction of at least 3 points in the MG-ADL total score compared to the baseline at 6 months.

14. A method for reducing the quantitative myasthenia gravis (QMG) total score of a subject of interest, comprising administering iptacopan or a pharmaceutically acceptable salt or hydrate thereof to the subject.

15. The method according to claim 14, wherein the method achieves a reduction in the total QMG score of, for example, at least 3 points, for example, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points compared to the baseline at, for example, 1 month, 3 months, or 6 months.

16. The method according to claim 15, wherein the method achieves a reduction of at least 4 points in the total QMG score compared to the baseline, and more specifically, the method achieves a reduction of at least 4 points in the total QMG score compared to the baseline at 6 months.

17. The method according to claim 16, wherein the decrease in the total QMG score is at least 5 points compared to the baseline, specifically, the decrease in the total QMG score is at least 5 points compared to the baseline over a period of 6 months.

18. The method according to any one of claims 1 to 17, comprising administering iptacopan hydrochloride to the subject.

19. The method according to claim 18, comprising administering iptacopan hydrochloride monohydrate to the subject.

20. The method according to any one of claims 1 to 19, comprising administering iptacopan to the subject in a dose of about 50 mg to 500 mg, for example, in a dose of about 50 mg to about 250 mg or about 100 mg to about 200 mg, each administered twice a day (b.i.d.).

21. The method according to any one of claims 1 to 20, comprising administering iptacopan to the subject in doses of approximately 50 mg, approximately 75 mg, approximately 100 mg, approximately 150 mg, or approximately 200 mg, each administered twice daily (b.i.d.).

22. The method according to any one of claims 1 to 21, wherein the dose is approximately 50 mg twice a day.

23. The method according to any one of claims 1 to 21, wherein the dose is approximately 100 mg twice a day.

24. The method according to any one of claims 1 to 21, wherein the dose is approximately 200 mg twice a day.

25. The method according to any one of claims 1 to 24, comprising orally administering iptacopan or a pharmaceutically acceptable salt or hydrate thereof.

26. The method according to any one of claims 1 to 25, further comprising administering an immunosuppressant to the subject.

27. The method according to claim 26, wherein the immunosuppressant is at least one of azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, and cyclophosphamide.

28. The method according to claim 26 or 27, wherein the subject is administered the immunosuppressant for at least six months.

29. The method according to any one of claims 1 to 28, further comprising administering a corticosteroid to the subject.

30. The method according to claim 29, wherein the subject is administered corticosteroids for at least four weeks.

31. The method according to any one of claims 1 to 30, wherein the subject is vaccinated against at least one of Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae before administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof.

32. The method according to any one of claims 1 to 31, wherein the subject is vaccinated against Neisseria meningitidis and Streptococcus pneumoniae before administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof.

33. The method according to any one of claims 1 to 32, wherein the subject is vaccinated against Haemophilus influenzae before administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof.

34. The subject is a patient who has not been optimally controlled for six months or more with one type of nonsteroidal immunosuppressive therapy (NSIST), according to any one of claims 1 to 33.

35. The method according to any one of claims 1 to 33, wherein the subject is not optimally controlled for six months or more with two or more nonsteroidal immunosuppressive therapies (NSISTs).

36. The method according to claim 34 or 35, wherein the NSIST is azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, or cyclophosphamide.

37. The subject is a patient who has not been optimally controlled for more than six months with gMG treatment, which is rituximab or a neonatal crystallizable fragment receptor (FcRN) antagonist approved for gMG, according to any one of claims 1 to 36.

38. The method according to any one of claims 1 to 37, wherein the subject has not been optimally controlled for more than six months with frequent (e.g., at least four times a year) plasma separation, plasma exchange, or intravenous immunoglobulin administration to control symptoms despite treatment with steroids and nonsteroidal immunosuppressive therapy (NSIST).

39. The method according to any one of claims 1 to 38, further comprising administering azathioprine to the subject.

40. The method according to claim 39, further comprising administering azathioprine to the subject for at least six months.

41. The method according to any one of claims 1 to 40, further comprising administering a cholinesterase inhibitor to the subject.

42. The method according to claim 41, further comprising administering the cholinesterase inhibitor to the subject for at least two weeks.

43. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use in the treatment of generalized myasthenia gravis (gMG) in patients requiring it.

44. gMG is anti-acetylcholine receptor antibody-positive (AChR+) gMG, in the use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof according to claim 43.

45. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 43 or 44, further comprising achieving a reduction of, for example, at least 2 points, at least 3 points, at least 4 points, at least 5 points, or at least 6 points in the total myasthenia gravis activities of daily living (MG-ADL) score at, for example, 1 month, 3 months, or 6 months, compared to baseline.

46. The decrease in the MG-ADL total score is at least 2 points compared to baseline, specifically, the decrease in the MG-ADL total score is at least 2 points over 6 months compared to baseline, for use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof according to claim 45.

47. The decrease in the MG-ADL total score is at least 3 points compared to baseline, specifically, the decrease in the MG-ADL total score is at least 3 points over 6 months compared to baseline, for use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof according to claim 46.

48. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 43 to 47, further comprising achieving a reduction of, for example, at least 3 points, for example, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points in the quantitative myasthenia gravis (QMG) total score at, for example, 1 month, 3 months, or 6 months, compared to baseline.

49. The reduction in the total QMG score is at least 4 points compared to the baseline, specifically, the reduction in the total QMG score is at least 4 points over 6 months compared to the baseline, for use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof according to claim 48.

50. The reduction in the total QMG score is at least 5 points compared to the baseline, specifically, the reduction in the total QMG score is at least 5 points over 6 months compared to the baseline, for use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof according to claim 49.

51. The aforementioned use is, a. Achieve a reduction of, for example, at least 2, at least 3, at least 4, at least 5, or at least 6 points in the total Myasthenia Gravis Activities of Daily Living (MG-ADL) score compared to baseline at, for example, 1 month, 3 months, and 6 months; b. Achieve a reduction in the quantitative myasthenia gravis (QMG) total score of, for example, at 1 month, 3 months, and 6 months, compared to baseline, by, for example, at least 3 points, for example, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points; c. Achieve a reduction in the composite myasthenia gravis (MGC) total score compared to baseline, for example, at 1 month, 3 months, and 6 months; d. Achieve a reduction in the MG-QOL15r survey score compared to baseline, for example, at 1 month, 3 months, and 6 months; e. Achieve an increase in the EQ-5D-5L survey score on the EQ VAS scale, for example, at 1 month, 3 months, and 6 months, compared to the baseline. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 43 to 50, comprising one or more of the above.

52. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use in patients with myasthenia gravis who require treatment for a decline in the total activity of daily living (MG-ADL) score.

53. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 52, wherein the use results in a reduction of at least 2 points, for example, at least 3 points, at least 4 points, at least 5 points, or at least 6 points in the MG-ADL total score compared to baseline, for example, at 1 month, 3 months, or 6 months.

54. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 53, wherein the use results in a reduction of at least two points in the MG-ADL total score compared to baseline, specifically, the use results in a reduction of at least two points in the MG-ADL total score compared to baseline at six months.

55. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 54, wherein the use results in a reduction of at least 3 points in the MG-ADL total score compared to baseline, specifically, a reduction of at least 3 points in the MG-ADL total score compared to baseline at 6 months.

56. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use in reducing the quantitative myasthenia gravis (QMG) total score in the target population.

57. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 56, wherein the use results in a reduction of, for example, at least 3 points, for example, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points in the quantitative myasthenia gravis (QMG) total score at, for example, 1 month, 3 months, or 6 months, compared to baseline.

58. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 57, wherein the use results in a reduction of at least 4 points in the total QMG score compared to baseline, specifically, a reduction of at least 4 points in the total QMG score compared to baseline at 6 months.

59. The decrease in the total QMG score is at least 5 points compared to baseline, specifically, the decrease in the total QMG score is at least 5 points over 6 months compared to baseline, for use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof according to claim 58.

60. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 43 to 59, wherein the use comprises administering iptacopan hydrochloride to the subject.

61. The use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 60, comprising administering iptacopan hydrochloride monohydrate to the subject.

62. The use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 43 to 61, comprising administering iptacopan to the subject in a dose of about 50 mg to 500 mg, for example, in a dose of about 50 mg to about 250 mg or about 100 mg to about 200 mg, each administered twice daily (b.i.d.).

63. The use comprises administering to the subject iptacopan in doses 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.), using iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 43 to 62.

64. The aforementioned dose is approximately 50 mg twice daily, for use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof according to any one of claims 43 to 63.

65. The aforementioned dose is approximately 100 mg twice daily, of iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 43 to 63.

66. The aforementioned dose is approximately 200 mg twice daily, of iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 43 to 63.

67. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 43 to 66, administered orally.

68. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 43 to 67, wherein the use further comprises administering an immunosuppressant to the subject.

69. The immunosuppressant is at least one of azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, and cyclophosphamide, in the iptacopan for use according to claim 68 or a pharmaceutically acceptable salt or hydrate thereof.

70. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 68 or 69, wherein the subject is administered the immunosuppressant for at least six months.

71. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 43 to 70, wherein the use further comprises administering a corticosteroid to the subject.

72. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 71, wherein the subject is administered corticosteroids for at least four weeks.

73. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 43 to 72, wherein the subject is vaccinated against at least one of Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae before administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof.

74. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 43 to 73, wherein the subject is vaccinated against Neisseria meningitidis and Streptococcus pneumoniae before administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof.

75. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 43 to 74, wherein the subject is vaccinated against Haemophilus influenzae before administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof.

76. The subject is iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 43 to 75, which has not been optimally controlled for more than six months with one type of nonsteroidal immunosuppressive therapy (NSIST).

77. The subject is iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 43 to 75, which has not been optimally controlled for six months or more with two or more nonsteroidal immunosuppressive therapies (NSISTs).

78. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 76 or 77, wherein the NSIST is azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, or cyclophosphamide.

79. The subject is iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 43 to 78, for patients who have not been optimally controlled for more than six months with gMG treatment, which is rituximab or a neonatal crystallizable fragment receptor (FcRN) antagonist approved for gMG.

80. The subject is iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 43 to 79, which has not been optimally controlled for more than six months with frequent (e.g., at least four times a year) plasma separation, plasma exchange, or intravenous immunoglobulin injection to control symptoms despite treatment with steroids and nonsteroidal immunosuppressive therapy (NSIST).

81. Iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 43 to 80, further comprising administering azathioprine to the subject.

82. The use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 81 further comprises administering azathioprine to the subject for at least six months.

83. The method further comprises administering a cholinesterase inhibitor to the subject, wherein iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 43 to 82.

84. The method further comprises administering the cholinesterase inhibitor to the subject for at least two weeks, relating to the use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof according to claim 83.

85. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable carrier, for use in the treatment of generalized myasthenia gravis (gMG) in subjects requiring treatment.

86. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 85, wherein gMG is anti-acetylcholine receptor antibody-positive (AChR+) gMG, and at least one pharmaceutically acceptable carrier.

87. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 85 or 86, and at least one pharmaceutically acceptable carrier, further comprising achieving a reduction of, for example, at least 2 points, at least 3 points, at least 4 points, at least 5 points, or at least 6 points in the total myasthenia gravis activities of daily living (MG-ADL) score at, for example, 1 month, 3 months, or 6 months, compared to baseline.

88. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 87, and at least one pharmaceutically acceptable carrier, wherein the reduction in the MG-ADL total score is at least 2 points compared to baseline, specifically, the reduction in the MG-ADL total score is at least 2 points over 6 months compared to baseline.

89. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 88, and at least one pharmaceutically acceptable carrier, wherein the reduction in the MG-ADL total score is at least 3 points compared to baseline, specifically, the reduction in the MG-ADL total score is at least 3 points over 6 months compared to baseline.

90. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 85 to 89, further comprising achieving a reduction of, for example, at least 3 points, for example, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points in the quantitative myasthenia gravis (QMG) total score at, for example, 1 month, 3 months, or 6 months, compared to baseline, and at least one pharmaceutically acceptable carrier.

91. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 90, and at least one pharmaceutically acceptable carrier, wherein the reduction in the total QMG score is at least 4 points compared to the baseline, specifically, the reduction in the total QMG score is at least 4 points over 6 months compared to the baseline.

92. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 91, and at least one pharmaceutically acceptable carrier, wherein the reduction in the total QMG score is at least 5 points compared to the baseline, specifically, the reduction in the total QMG score is at least 5 points over 6 months compared to the baseline.

93. The aforementioned use is, a. Achieve a reduction of, for example, at least 2, at least 3, at least 4, at least 5, or at least 6 points in the total Myasthenia Gravis Activities of Daily Living (MG-ADL) score compared to baseline at, for example, 1 month, 3 months, and 6 months; b. Achieve a reduction in the quantitative myasthenia gravis (QMG) total score of, for example, at 1 month, 3 months, and 6 months, compared to baseline, by, for example, at least 3 points, for example, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points; c. Achieve a reduction in the composite myasthenia gravis (MGC) total score compared to baseline, for example, at 1 month, 3 months, and 6 months; d. Achieve a reduction in the MG-QOL15r survey score compared to baseline, for example, at 1 month, 3 months, and 6 months; e. Achieve an increase in the EQ-5D-5L survey score on the EQ VAS scale, for example, at 1 month, 3 months, and 6 months, compared to the baseline. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 85 to 92, including one or more of the above, and at least one pharmaceutically acceptable carrier.

94. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable carrier, for use in the reduction of the total activity of daily living (MG-ADL) score in patients with myasthenia gravis who require it.

95. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 94, and at least one pharmaceutically acceptable carrier, wherein the use results in a reduction of at least 2 points, for example, at least 3 points, at least 4 points, at least 5 points, or at least 6 points in the MG-ADL total score compared to baseline, for example, at 1 month, 3 months, or 6 months.

96. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 95, and at least one pharmaceutically acceptable carrier, wherein the use results in a reduction of at least two points in the MG-ADL total score compared to baseline, specifically, a reduction of at least two points in the MG-ADL total score compared to baseline at six months, by the use described above.

97. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 96, and at least one pharmaceutically acceptable carrier, wherein the use results in a reduction of at least 3 points in the MG-ADL total score compared to baseline, specifically, a reduction of at least 3 points in the MG-ADL total score compared to baseline at 6 months, and at least one pharmaceutically acceptable carrier.

98. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable carrier, for use in reducing the quantitative myasthenia gravis (QMG) total score of a target subject.

99. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 98, and at least one pharmaceutically acceptable carrier, wherein the use results in a reduction of, for example, at least 3 points, for example, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, or at least 10 points in the quantitative myasthenia gravis (QMG) total score at, for example, 1 month, 3 months, or 6 months, compared to baseline.

100. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 99, and at least one pharmaceutically acceptable carrier, wherein the use results in a reduction of at least 4 points in the total QMG score compared to baseline, specifically, a reduction of at least 4 points in the total QMG score compared to baseline at 6 months, by the use described above.

101. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 100, and at least one pharmaceutically acceptable carrier, wherein the reduction in the total QMG score is at least 5 points compared to the baseline, specifically, the reduction in the total QMG score is at least 5 points over 6 months compared to the baseline.

102. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 85 to 101, wherein the use comprises administering iptacopan hydrochloride to the subject, and at least one pharmaceutically acceptable carrier.

103. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 102, and at least one pharmaceutically acceptable carrier, wherein the use comprises administering iptacopan hydrochloride monohydrate to the subject.

104. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 85 to 103, wherein the use comprises administering iptacopan to the subject in a dose of about 50 mg to 500 mg, for example, about 50 mg to about 250 mg or about 100 mg to about 200 mg, each administered twice daily (b.i.d.), and at least one pharmaceutically acceptable carrier.

105. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 85 to 104, wherein the use comprises administering iptacopan to the subject in doses 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.), and at least one pharmaceutically acceptable carrier.

106. The aforementioned dosage is approximately 50 mg twice daily, and the pharmaceutical composition comprises iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 85 to 105, and at least one pharmaceutically acceptable carrier.

107. The aforementioned dosage is approximately 100 mg twice daily, and the pharmaceutical composition comprises iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 85 to 105, and at least one pharmaceutically acceptable carrier.

108. The aforementioned dosage is approximately 200 mg twice daily, and the pharmaceutical composition comprises iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 85 to 105, and at least one pharmaceutically acceptable carrier.

109. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 85 to 108, and at least one pharmaceutically acceptable carrier, for oral administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof.

110. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 85 to 109, and at least one pharmaceutically acceptable carrier, wherein the use further comprises administering an immunosuppressant to the subject.

111. A pharmaceutical composition comprising iptacopan for use according to claim 110 or a pharmaceutically acceptable salt or hydrate thereof, wherein the immunosuppressant is at least one of azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, and cyclophosphamide, and at least one pharmaceutically acceptable carrier.

112. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 110 or 111, and at least one pharmaceutically acceptable carrier, wherein the subject is administered the immunosuppressant for at least six months.

113. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 85 to 112, and at least one pharmaceutically acceptable carrier, wherein the use further comprises administering a corticosteroid to the subject.

114. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 113, and at least one pharmaceutically acceptable carrier, wherein the subject is administered a corticosteroid for at least four weeks.

115. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 85 to 114, wherein the subject is vaccinated against at least one of Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae before administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable carrier.

116. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 85 to 115, wherein the subject is vaccinated against Neisseria meningitidis and Streptococcus pneumoniae before administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable carrier.

117. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 85 to 116, wherein the subject is vaccinated against Haemophilus influenzae before administration of iptacopan or a pharmaceutically acceptable salt or hydrate thereof, and at least one pharmaceutically acceptable carrier.

118. The subject is a pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 85 to 117, which has not been optimally controlled for six months or more with one type of nonsteroidal immunosuppressive therapy (NSIST), and at least one pharmaceutically acceptable carrier.

119. The subject is a pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 85 to 117, which has not been optimally controlled for six months or more with two or more nonsteroidal immunosuppressive therapies (NSISTs), and at least one pharmaceutically acceptable carrier.

120. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 118 or 119, wherein the NSIST is azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, tacrolimus, or cyclophosphamide, and at least one pharmaceutically acceptable carrier.

121. The subject is a pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 85 to 120, for patients who have not been optimally controlled for more than six months with gMG treatment, which is rituximab or a neonatal crystallizable fragment receptor (FcRN) antagonist approved for gMG, and at least one pharmaceutically acceptable carrier.

122. The subject is a pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 85 to 121, and at least one pharmaceutically acceptable carrier, which has not been optimally controlled for more than six months with frequent (e.g., at least four times a year) plasma separation, plasma exchange, or intravenous immunoglobulin injection to control symptoms despite treatment with steroids and nonsteroidal immunosuppressive therapy (NSIST).

123. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 85 to 122, and at least one pharmaceutically acceptable carrier, wherein the use further comprises administering azathioprine to the subject.

124. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 123, and at least one pharmaceutically acceptable carrier, wherein the use further comprises administering azathioprine to the subject for at least six months.

125. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to any one of claims 85 to 124, and at least one pharmaceutically acceptable carrier, wherein the use further comprises administering a cholinesterase inhibitor to the subject.

126. A pharmaceutical composition comprising iptacopan or a pharmaceutically acceptable salt or hydrate thereof for use according to claim 125, and at least one pharmaceutically acceptable carrier, further comprising administering the cholinesterase inhibitor to the subject for at least two weeks.

127. Use of iptacopan or a pharmaceutically acceptable salt or hydrate thereof for the manufacture of pharmaceuticals for the treatment of generalized myasthenia gravis (gMG) in subjects requiring treatment.

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