Non-Inferiority Study of Remibrutinib Versus Ocrelizumab in Relapsing Multiple Sclerosis Patients Transitioning to Remibrutinib Therapy

The primary objective of this study is to demonstrate that **remibrutinib** is non-inferior to **ocrelizumab** in controlling inflammatory activity on magnetic resonance imaging (MRI) after switching from ocrelizumab in participants with **relapsing multiple sclerosis**. This is clinically relevant as it evaluates the potential of remibrutinib to maintain disease control, which is crucial for managing relapsing multiple sclerosis and improving patient outcomes.

Secondary objectives include:

• Assessing whether remibrutinib is non-inferior to ocrelizumab in maintaining disease-activity free status after switching from ocrelizumab.
• Evaluating the safety and tolerability of remibrutinib after switching from ocrelizumab and compared to ocrelizumab.
• In the extension part, assessing long-term safety and tolerability in participants treated with remibrutinib after ocrelizumab.
• In the extension part, evaluating long-term efficacy parameters in participants treated with remibrutinib after ocrelizumab.

The clinical trial involves a total of **183 participants** diagnosed with **relapsing multiple sclerosis**. The study population includes both male and female subjects aged 40 years or older. Participants were selected based on their prior treatment with ocrelizumab and their suitability to switch to remibrutinib, as determined by physician judgment or patient preference. The trial population is characterized by individuals who are neurologically stable, with no multiple sclerosis relapse within 30 days 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, although specific details regarding this aspect are not provided by the sponsor.

The clinical trial is designed as a **randomized**, open-label, parallel-group, non-inferiority study to evaluate the efficacy, safety, and tolerability of **remibrutinib** after switching from **ocrelizumab** in participants with **relapsing multiple sclerosis**. The trial will be conducted over an estimated duration from October 2025 to June 2031, with the primary objective to demonstrate that remibrutinib is non-inferior to ocrelizumab in controlling inflammatory activity on magnetic resonance imaging (MRI) after the switch. The study will include a series of visits, starting with a screening visit to confirm eligibility based on criteria such as age, diagnosis, and previous treatment with ocrelizumab. Participants must be neurologically stable and suitable for switching to remibrutinib.

Following the screening, participants will be randomized into treatment groups and will undergo regular follow-up visits to monitor the annualized rate of new or enlarging T2 lesions on MRI at Month 24, which serves as the primary endpoint. Secondary endpoints include the percentage of participants with no evidence of disease activity-3 (NEDA-3) and the assessment of adverse events, laboratory data, and vital signs. The trial will also include an extension part to further evaluate these parameters. The end-of-study visit will conclude the participant's involvement, which is expected to last up to 48 months, depending on the treatment group.

Participants may be withdrawn from the study early due to reasons such as adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial is categorized as a Phase IIIb study, and it is not considered a low-intervention trial. The investigational product, remibrutinib, is administered orally as a film-coated tablet, while ocrelizumab is provided as a comparator in the form of a solution for injection or concentrate for solution for infusion. The study aims to provide valuable insights into the management of relapsing multiple sclerosis and the potential benefits of switching therapies.

The clinical trial involves the administration of **remibrutinib**, an experimental medication, in the form of a **film-coated tablet**. The active substance, remibrutinib, is a low molecular weight compound that covalently binds and inhibits Bruton’s tyrosine kinase. The pharmaceutical form is designed for **oral use**. The maximum treatment period for remibrutinib is 48 weeks. The dosage and frequency of administration are determined based on the study protocol, with compliance monitored throughout the trial duration. Remibrutinib is not a paediatric formulation and is not classified as an orphan drug.

In addition to the experimental treatment, the study includes a comparator treatment with **ocrelizumab**, a monoclonal antibody. Ocrelizumab is administered in two different pharmaceutical forms: as a **solution for injection** and as a **concentrate for solution for infusion**. The solution for injection is administered via the **subcutaneous route**, with a maximum daily dose of 920 mg and a total dose of 3.68 g over a 24-week period. The concentrate for solution for infusion is administered **intravenously**, with a maximum daily dose of 600 mg and a total dose of 2.40 g over the same period. Both forms of ocrelizumab are not paediatric formulations and are not classified as orphan drugs. The administration of ocrelizumab is subject to packaging and labeling requirements as per local regulations and sourcing strategies.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the **Annualized Rate of New or Enlarging T2 Lesions (AR-NELT2)** on magnetic resonance imaging (MRI) at Month 24, relative to the baseline MRI scan. This endpoint will provide a measure of the inflammatory activity in participants with relapsing multiple sclerosis after switching from ocrelizumab to remibrutinib.

Secondary endpoints include the percentage of participants with no evidence of disease activity-3 (NEDA-3), which is assessed by the absence of confirmed multiple sclerosis relapses, 6-month confirmed disability progression (6mCDP), and new/enlarging T2 lesions on MRI between baseline and Month 24. Additional secondary endpoints involve the monitoring of adverse events, laboratory data, vital signs, and electrocardiograms (ECGs) throughout the study. These assessments will be conducted at specified intervals to ensure comprehensive data collection and analysis.