Phase III Randomized, Double-Blind, Placebo-Controlled Study of Iptacopan in Patients with Generalized Myasthenia Gravis

The primary objective of this study is to demonstrate the **efficacy** of iptacopan 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 a potential new treatment option that could improve daily functioning and quality of life for patients with gMG.

Secondary objectives include:

• Assessing whether iptacopan 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 reduction in MGC total score at Month 6 of treatment.
• Assessing the reduction in MG-QOL15r survey score at Month 6 of treatment.
• Evaluating the safety and tolerability of iptacopan compared to placebo in patients with gMG.
• Evaluating the efficacy of iptacopan compared to placebo in patients with gMG on other efficacy endpoints.
• Assessing the long-term effect of iptacopan in reducing the total score of the MG-ADL during the Extension Part.
• Evaluating the long-term effect of iptacopan on the proportion of participants achieving a reduction in oral corticosteroids (OCS) dose compared to the Core Part that was maintained up to the end of the Extension Part.
• Assessing the long-term safety and tolerability of iptacopan in patients with gMG.
• Evaluating whether iptacopan is superior to placebo in achieving 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.

The clinical trial involves a total of **94 participants** diagnosed with **generalized Myasthenia Gravis** (gMG). The study population comprises both male and female adults aged between 18 and 75 years. Participants were selected based on specific inclusion criteria, including a positive serology test for AChR+ antibody and classification within the Myasthenia Gravis Foundation of America (MGFA) Class II-IV at screening. The trial population is required to have a baseline MG-ADL score of at least 6, with a significant portion attributed to non-ocular symptoms. Participants must have been on stable standard of care (SOC) treatments for gMG for at least six months prior to the baseline, which may include non-steroidal immunosuppressive therapies (NSISTs), plasmapheresis, plasma exchange, or intravenous immunoglobulin. Vaccination against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae is mandated before the commencement of the study treatment. The trial includes a vulnerable population, ensuring comprehensive safety and ethical considerations are in place.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** phase III study to evaluate the efficacy, safety, and tolerability of **iptacopan** in patients with **generalized Myasthenia Gravis** (gMG). The trial will be conducted over a period of approximately 66 months, with an estimated recruitment start date in July 2024 and an estimated end date in April 2032. The study will include an initial treatment phase followed by an open-label extension phase.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as age between 18-75 years, positive serology testing for AChR+ antibody, and a baseline MG-ADL score of at least 6. The screening visit will also ensure that participants have been vaccinated against Neisseria meningitidis, Streptococcus pneumoniae, and Haemophilus influenzae infections, as per local regulations. Following the screening, eligible participants will be randomized to receive either iptacopan or a placebo in the form of hard gelatin capsules, administered orally.

Throughout the trial, participants will attend regular follow-up visits to monitor changes in the Myasthenia Gravis Activity of Daily Living (MG-ADL) total score, as well as other secondary endpoints such as the Quantitative MG (QMG) total score and the Myasthenia Gravis Composite (MGC) total score. These visits will also assess the incidence of adverse events, changes in clinical laboratory values, vital signs, and electrocardiograms. The primary endpoint is the change from baseline to Month 6 in the MG-ADL total score.

The end-of-study visit will occur at the conclusion of the treatment phase, where final assessments will be conducted to evaluate the long-term effects of the treatment. Participants are expected to be involved in the study for the entire duration unless conditions arise that necessitate early termination, such as significant adverse events or withdrawal of consent. The trial aims to provide comprehensive data on the efficacy and safety of iptacopan in managing symptoms of generalized Myasthenia Gravis.

The clinical trial involves the administration of **Iptacopan**, a chemical compound with the active substance name **Iptacopan**. It is provided in the form of hard gelatin capsules. The pharmaceutical form is specifically designed for oral administration. The trial aims to evaluate the efficacy, safety, and tolerability of Iptacopan in patients with generalized **Myasthenia Gravis**. The dosage and frequency of administration are determined by the study protocol, with a maximum treatment period of 66 days. The active substance is chemically synthesized and is identified by the sponsor product code LNP023. The trial is conducted under the sponsorship of Novartis Pharma AG.

In addition to the experimental treatment, a **placebo** is used as a comparator in this double-blind, placebo-controlled study. The placebo is a 0 mg hard gelatin capsule, identical in appearance to the Iptacopan capsules, ensuring blinding of the study participants and investigators. The placebo is administered orally, following the same dosing schedule as the active treatment. This design allows for the assessment of the true efficacy of Iptacopan by comparing it against the placebo group. Compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

The efficacy of iptacopan in patients with generalized **Myasthenia Gravis** (gMG) will be assessed through a randomized, double-blind, placebo-controlled phase III study. 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, Myasthenia Gravis Composite (MGC) total score, and revised MG Quality of Life Questionnaire (MG-QOL15r) survey score. Additionally, the proportion of participants achieving specific reductions in MG-ADL and QMG scores without the use of rescue medication will be measured.

Efficacy parameters will be collected and analyzed at specified timepoints, including baseline and Month 6. The MG-ADL scale, a validated tool, will be used to assess daily living activities affected by gMG. The QMG and MGC scores will provide quantitative measures of disease severity, while the MG-QOL15r survey will evaluate the impact on quality of life. The study will also monitor the incidence of adverse events and changes in clinical laboratory values, vital signs, and electrocardiograms. The proportion of participants achieving a reduction in oral corticosteroids dose and maintaining it up to the end of the extension part will be evaluated. The study aims to demonstrate the efficacy of iptacopan compared to placebo in reducing the MG-ADL score at 6 months of treatment.