A Randomized, Double-Blind, Parallel-Group Study Comparing Remibrutinib and Teriflunomide in Relapsing Multiple Sclerosis Patients, with Open-Label Remibrutinib Extension

The primary objective of this study is to demonstrate that **remibrutinib** is superior to **teriflunomide** in reducing the frequency of confirmed relapses in participants with relapsing **multiple sclerosis**. This is clinically relevant as reducing relapse frequency can significantly impact the disease progression and quality of life for patients with multiple sclerosis.

Secondary objectives include:

• Assessing whether remibrutinib is superior to teriflunomide in delaying disability progression based on pooled data from both identical pivotal studies.
• Evaluating the superiority of remibrutinib over teriflunomide in reducing new inflammatory activity on Magnetic Resonance Imaging (MRI), based on MRI cohort data.
• Determining if remibrutinib is superior to teriflunomide in reducing neuronal damage, as measured by neurofilament light chain (NfL).
• Assessing whether remibrutinib is superior to teriflunomide in achieving a disease-activity-free status based on pooled data from both identical pivotal studies (MRI Cohort).
• Evaluating the effects of remibrutinib relative to teriflunomide on additional clinical and MRI endpoints.
• Assessing the effect of remibrutinib relative to teriflunomide on the physical and psychological impact of multiple sclerosis.
• Evaluating the safety and tolerability of remibrutinib compared to teriflunomide.
• Assessing the pharmacokinetics (PK) of remibrutinib.
• In the extension part, assessing long-term safety, tolerability, and efficacy parameters in participants treated with remibrutinib.

The clinical trial involves a total of **495 participants** diagnosed with **Multiple Sclerosis**. The study population includes both male and female subjects, aged between 18 to 55 years, who meet the 2017 McDonald diagnostic criteria for Relapsing Multiple Sclerosis (RMS), which encompasses Relapsing-Remitting Multiple Sclerosis (RRMS) or active Secondary Progressive Multiple Sclerosis (SPMS). Participants were selected based on their documented history of relapses or the presence of active Gadolinium-enhancing lesions within specified timeframes prior to screening. The trial population is neurologically stable, with an Expanded Disability Status Scale (EDSS) score ranging from 0 to 5.5. The selection process ensures that participants are not experiencing a relapse within one month prior to screening and randomization. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, as indicated by the selection criteria.

The clinical trial is designed as a **randomized**, **double-blind**, double-dummy, parallel-group study to evaluate the efficacy and safety of **remibrutinib** compared to **teriflunomide** in participants with relapsing **multiple sclerosis**. The trial will be conducted in two phases: an initial comparative phase followed by an extended treatment phase with open-label remibrutinib. The primary objective is to demonstrate the superiority of remibrutinib in reducing the frequency of confirmed relapses. The trial is expected to conclude by October 30, 2030, with recruitment having commenced on June 20, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and disease stability. The trial will include follow-up visits to monitor the primary endpoint, which is the annualized relapse rate of confirmed relapses, and secondary endpoints, including time to confirmed disability progression and changes in MRI lesion counts. The end-of-study visit will assess the overall outcomes and safety of the treatments. The expected duration of participant involvement is up to 90 days for the initial treatment phase, with additional time for the open-label extension.

Participants may be withdrawn from the study early if they experience significant adverse events, fail to adhere to the study protocol, or withdraw consent. The trial will utilize a placebo to remibrutinib and a placebo to teriflunomide to maintain blinding. The study will ensure rigorous monitoring of safety and efficacy through regular assessments, including laboratory tests, vital signs, and imaging studies. The trial's design and procedures are structured to provide robust data on the comparative effectiveness of remibrutinib and teriflunomide in managing relapsing multiple sclerosis.

The clinical trial involves the administration of **remibrutinib**, an experimental medication identified by the product code LOU064. Remibrutinib is provided in the form of a **film-coated tablet** and is administered orally. The compound is a low molecular weight chemical that covalently binds and inhibits Bruton’s tyrosine kinase. The maximum treatment period for remibrutinib is 90 days. The specific dosage and frequency of administration are not detailed in the provided data.

In addition to the experimental treatment, the study includes a **placebo** to remibrutinib, which is also in the form of a 100 mg film-coated tablet. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know who is receiving the active treatment versus the placebo.

The trial also involves the use of **teriflunomide**, a comparator treatment. Teriflunomide is an immunomodulatory agent with anti-inflammatory properties, provided as a film-coated tablet for oral use. The maximum daily dose is 14 mg, with a total maximum dose of 12,775 mg over a treatment period of 30 days. Teriflunomide is over-encapsulated, repackaged, and relabeled for the study.

A placebo to teriflunomide is also included in the study, provided as a 14 mg hard capsule. This placebo serves a similar purpose as the placebo to remibrutinib, ensuring the integrity of the double-blind study design.

Auxiliary treatments in the study include **medicinal charcoal** and **colestyramine**. Medicinal charcoal, composed of methenamine, magnesium citrate, and activated charcoal, is used for accelerated elimination procedures as per protocol and teriflunomide label. It is administered orally, with a maximum daily dose of 100 g and a total maximum dose of 1,100 g over 11 days. Colestyramine, a polymer-based compound, is also used for accelerated elimination procedures. It is administered orally, with a maximum daily dose of 24 g and a total maximum dose of 264 g over 11 days.

The efficacy of the clinical trial will be assessed by comparing the effects of **remibrutinib** versus teriflunomide in participants with relapsing multiple sclerosis. The primary endpoint for evaluating efficacy is the Annualized Relapse Rate (ARR) of confirmed relapses. Secondary endpoints include the time to 3-month and 6-month confirmed disability progression (3mCDP and 6mCDP) on the Expanded Disability Status Scale (EDSS), the number of new or enlarging T2 lesions on MRI per year, and the total number of Gd-enhancing T1 lesions per MRI scan. Additional secondary endpoints involve measuring neurofilament light chain (NfL) concentration in serum, the percentage of participants with No Evidence of Disease Activity-3 (NEDA-3), and the time to first confirmed relapse.

Further assessments will include changes from baseline in the Symbol Digit Modalities Test (SDMT), time to 6-month confirmed disability improvement (6mCDI), and time to 6-month confirmed worsening by at least 20% in the Timed 25-foot walk test (T25FW) and Timed 9-hole peg test (9HPT). The trial will also evaluate changes from baseline in T2 lesion volume and the Multiple Sclerosis Impact Scale (MSIS-29). Efficacy parameters will be collected and analyzed at various timepoints throughout the study, including baseline, during treatment, and at the end of the treatment period. The trial will utilize validated scales and laboratory tests to ensure accurate and reliable measurement of these endpoints.