A Randomized, Double-Blind 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 improve the quality of life and long-term outcomes for patients with this chronic neurological condition.

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 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 **545 participants** diagnosed with **Multiple Sclerosis**, specifically relapsing forms such as relapsing-remitting multiple sclerosis (RRMS) or active secondary progressive multiple sclerosis (SPMS). The study population includes both male and female subjects, aged between 18 and 55 years, who are neurologically stable and have an Expanded Disability Status Scale (EDSS) score ranging from 0 to 5.5. Participants were selected based on documented relapses or active lesions within specified timeframes prior to screening. The trial does not specify particular lifestyle considerations such as diet or physical activity. The selection process ensures that participants have provided informed consent and meet the diagnostic criteria according to the 2017 McDonald criteria. The study aims to evaluate the efficacy of remibrutinib compared to teriflunomide in reducing the frequency of confirmed relapses in this population.

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 aims to demonstrate the superiority of remibrutinib in reducing the frequency of confirmed relapses. The study is expected to run until October 2030, with recruitment having commenced in June 2022. Participants will be involved in the trial for a maximum treatment period of 90 days, with the possibility of early termination if they do not meet the inclusion criteria or if adverse events occur.

The trial includes several key study visits. The initial visit is the **screening visit**, where participants provide signed informed consent and undergo assessments to confirm eligibility based on criteria such as age, diagnosis according to the 2017 McDonald diagnostic criteria, and an **Expanded Disability Status Scale (EDSS)** score between 0 and 5.5. Following randomization, participants will attend regular 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 conclude the participant's involvement, assessing overall safety and efficacy outcomes.

Participants will receive either remibrutinib or teriflunomide, with the study employing a double-dummy technique to maintain blinding. The trial will also utilize placebos corresponding to each active treatment. The study's design ensures that neither the participants nor the investigators know which treatment is being administered, thereby minimizing bias. The trial's primary and secondary endpoints will be evaluated through clinical assessments, MRI scans, and laboratory tests, ensuring comprehensive data collection for analysis. Conditions for early termination include non-compliance with the protocol, withdrawal of consent, or the occurrence of significant adverse events. The trial's rigorous methodology and structured visit schedule are designed to ensure the collection of robust and reliable data to assess the comparative efficacy and safety of the investigational treatments.

The clinical trial involves the administration of **remibrutinib**, a low molecular weight compound that covalently binds and inhibits Bruton’s tyrosine kinase. Remibrutinib is provided in the form of a film-coated tablet, with a dosage of 100 mg. The route of administration is oral, and the treatment period extends up to 90 days. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

**Teriflunomide** is used as a comparator in this study. It is an immunomodulatory agent with anti-inflammatory properties, administered as a film-coated tablet. The maximum daily dose is 14 mg, with a total treatment period of 30 days. The administration route is oral, and the tablets are over-encapsulated, repackaged, and relabeled to maintain blinding in the study.

**Colestyramine** is employed as an auxiliary treatment for accelerated elimination procedures as per the protocol and teriflunomide label. It is administered orally, with a maximum daily dose of 24 grams and a total treatment period of 11 days. The pharmaceutical form is designated as PHF00008MIG.

**Activated charcoal** is also used as an auxiliary treatment for accelerated elimination procedures. It is administered orally, with a maximum daily dose of 100 grams and a total treatment period of 11 days. The pharmaceutical form is designated as PHF00245MIG. The active substances include methenamine, magnesium citrate, and activated charcoal.

The study includes a placebo to teriflunomide, provided as a hard capsule, and a placebo to remibrutinib, provided as a film-coated tablet. These placebos are used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators know which treatment is being administered.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the **Annualized Relapse Rate (ARR)** of confirmed relapses in participants with relapsing multiple sclerosis. 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 the concentration of neurofilament light chain (NfL) in serum, the percentage of participants with No Evidence of Disease Activity-3 (NEDA-3), and the time to first confirmed relapse.

Other secondary endpoints include the time to 6-month confirmed disability improvement (6mCDI) on EDSS, changes from baseline in the Symbol Digit Modalities Test (SDMT), and the 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 assess changes from baseline in T2 lesion volume and the Multiple Sclerosis Impact Scale (MSIS-29). Efficacy assessments will be conducted using validated scales and laboratory tests at specified timepoints throughout the trial duration, which is estimated to end on October 30, 2030.