Phase III Randomized, Double-Blind, Placebo-Controlled Study of Remibrutinib in Generalized Myasthenia Gravis Patients with Stable Standard of Care

The primary objective of this study is to demonstrate the **efficacy** of remibrutinib compared to placebo in patients with generalized myasthenia gravis (gMG) on stable standard of care (SOC) in reducing the total score of the Myasthenia Gravis Activity of Daily Living (MG-ADL) scale at 6 months (Day 180) of treatment. This is clinically relevant as it aims to provide evidence for remibrutinib's potential to improve daily functioning in patients with gMG, a chronic autoimmune neuromuscular disorder characterized by muscle weakness.

Secondary objectives include: - Assessing whether remibrutinib is superior to placebo in reducing the Quantitative MG (QMG) total score at 6 months of treatment. - Evaluating the proportion of study participants achieving a reduction from baseline to Month 6 of QMG total score ≥ 5 points without rescue medication and/or strongly confounding prohibited medication. - Assessing the reduction from baseline to Month 6 of MG-ADL total score ≥ 3 points without rescue medication and/or strongly confounding prohibited medication. - Evaluating the achievement of Minimal Symptom Expression (MSE) at Month 6, defined as an MG-ADL of 0 or 1 at Month 6 without rescue therapy and/or strongly confounding prohibited medication. - Assessing the reduction of Myasthenia Gravis Composite (MGC) total score at Month 6 of treatment. - Evaluating the reduction of MG-QOL15r survey score at Month 6 of treatment. - Evaluating the safety and tolerability of remibrutinib compared to placebo. - Evaluating the efficacy of remibrutinib on other efficacy endpoints. - Assessing the long-term effect of remibrutinib in reducing the total score of the MG-ADL during the Extension Part. - Assessing the long-term effect on the proportion of study participants achieving a reduction in oral corticosteroids (OCS) dose till the end of the Extension Part. - Assessing long-term safety and tolerability of remibrutinib.

The clinical trial involves a total of **143 participants** diagnosed with **Generalized Myasthenia Gravis** (gMG). The study population includes both male and female adults aged between 18 and 75 years. Participants were selected based on a confirmed diagnosis of MGFA Class II-IV gMG, with documented evidence of positive serologic testing for AChR+ or MuSK+ antibodies, or seronegative status for both. The trial excludes vulnerable populations. Participants are required to have a baseline MG-ADL score of at least 6, with a significant portion attributed to non-ocular symptoms. They must be on a stable dose of at least one treatment for gMG, such as non-steroidal immunosuppressants, acetylcholinesterase inhibitors, or steroids, for specified durations prior to baseline. The ability to safely swallow the study medication is also a prerequisite. Lifestyle factors such as diet and physical activity are not specified in the trial data provided.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** phase III study to evaluate the efficacy, safety, and tolerability of **remibrutinib** in patients with **generalized myasthenia gravis**. The trial will be followed by an open-label extension phase. The primary objective is to demonstrate the efficacy of remibrutinib compared to placebo in reducing the total score of the Myasthenia Gravis Activity of Daily Living (MG-ADL) scale at 6 months (Day 180) of treatment. The trial is expected to commence recruitment on May 23, 2025, and conclude by July 31, 2032.

Participants will be involved in the study for a maximum treatment period of 66 weeks. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor progress and safety, and an end-of-study visit to assess final outcomes. The inclusion criteria require adult patients aged 18-75 years with a confirmed diagnosis of MGFA Class II-IV generalized myasthenia gravis, who are not likely to need a respirator during the study. Participants must have a baseline MG-ADL score of at least 6, with at least 50% of the total score due to non-ocular symptoms, and must be on stable doses of specified treatments for generalized myasthenia gravis prior to baseline.

Participants will be randomly assigned to receive either remibrutinib or a placebo, administered as a film-coated tablet for oral use. The study will assess primary and secondary endpoints, including changes in MG-ADL and Quantitative MG (QMG) scores, the proportion of participants achieving significant score reductions, and the incidence of adverse events. Conditions that may lead to early termination from the study include the inability to safely swallow the study medication or the need for rescue therapy that could confound the study results. The trial will ensure rigorous monitoring of participants' health and adherence to the study protocol throughout the duration of their involvement.

The clinical trial involves the administration of **remibrutinib**, an experimental medication, in the form of a film-coated tablet. The pharmaceutical form is specifically designed for **oral use**. Remibrutinib is a low molecular weight compound that covalently binds and inhibits Bruton’s tyrosine kinase. The medication is provided by Novartis Pharma AG and is identified by the sponsor product code LOU064. The trial does not specify a maximum daily dose or total dose amount, but the maximum treatment period is set at 66 days. The trial aims to evaluate the efficacy, safety, and tolerability of remibrutinib in patients with generalized myasthenia gravis.

In addition to the experimental treatment, a placebo is used as a comparator in this double-blind, placebo-controlled study. The placebo is designed to match the remibrutinib film-coated tablet in appearance but does not contain any active substance. The placebo serves to ensure that the effects observed in the trial can be attributed to the active medication rather than other factors. The placebo is administered in the same manner as the experimental drug, maintaining the integrity of the study's blinding process.

The efficacy of remibrutinib in the treatment of generalized **myasthenia gravis** (gMG) will be assessed in a randomized, double-blind, placebo-controlled phase III clinical trial. The primary endpoint for evaluating efficacy is the change from baseline to Month 6 in the Myasthenia Gravis Activity of Daily Living (MG-ADL) total score. Secondary endpoints include changes from baseline to Month 6 in the Quantitative MG (QMG) total score, the proportion of participants with significant reductions in QMG and MG-ADL scores without the use of rescue medication, and the achievement of minimal symptom expression (MSE) at Month 6. Additional secondary endpoints involve changes in the Myasthenia Gravis Composite (MGC) total score, the revised MG Quality of Life Questionnaire (MG-QOL15r) survey score, and the EuroQol-5 Dimensions-5 Level (EQ-5D-5L) score.

Data collection will occur at specified timepoints, with the primary endpoint being assessed at 6 months (Day 180) of treatment. The trial will utilize validated scales such as the MG-ADL, QMG, and MGC to measure symptom improvement. The proportion of early MG-ADL responders, defined as those with a ≥2-point improvement by week 4, will also be evaluated. The incidence of adverse events and changes in clinical laboratory values, vital signs, and electrocardiograms will be monitored to ensure safety and tolerability. The trial aims to demonstrate the efficacy of remibrutinib compared to placebo in patients with gMG on stable standard of care (SOC) therapy.