Phase 3 Randomized, Double-Blind Study of Frexalimab (SAR441344) Versus Teriflunomide in Adults with Relapsing Multiple Sclerosis

The primary objective of this study is to assess the **efficacy** of frexalimab compared to a daily dose of 14 mg teriflunomide, measured by the annualized relapse rate (ARR) in participants with relapsing forms of **multiple sclerosis**. This is clinically relevant as it aims to determine the potential of frexalimab as a more effective treatment option for reducing relapse rates in this patient population.

Secondary objectives include:

• Assessing the efficacy of frexalimab compared to teriflunomide on disability worsening, MRI lesions, cognitive performance, physical function, and quality of life.
• Evaluating the safety and tolerability of frexalimab in participants with relapsing forms of multiple sclerosis.
• Evaluating the pharmacodynamics of frexalimab in participants with relapsing forms of multiple sclerosis.
• Evaluating the pharmacokinetics of frexalimab in participants with relapsing forms of multiple sclerosis.

The clinical trial involves a total of **537 participants** diagnosed with **relapsing forms of multiple sclerosis**. The study population includes both male and female subjects, with an age range of 18 to 65 years. Participants were selected based on specific criteria, including a diagnosis of relapsing multiple sclerosis according to the 2017 revision of the McDonald diagnostic criteria and an Expanded Disability Status Scale (EDSS) score of 5.5 or less at the screening visit. The trial also considers individuals who have experienced at least one documented relapse within the previous year, two documented relapses within the previous two years, or one documented gadolinium-enhancing lesion on an MRI scan within the previous year. The study population includes a vulnerable population, and contraceptive use is required to be consistent with local regulations for clinical study participants. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy and safety of **frexalimab** compared to **teriflunomide** in adult participants with relapsing forms of **multiple sclerosis**. The trial is expected to commence recruitment on September 9, 2024, and conclude by May 6, 2027. Participants will be randomly assigned to receive either frexalimab, administered as a solution for injection, or teriflunomide, provided as film-coated tablets, with matched placebos for each treatment group to maintain blinding. The primary endpoint is the annualized relapse rate (ARR) during the study period, assessed by protocol-defined adjudicated relapses. Secondary endpoints include time to onset of confirmed disability worsening, changes in brain volume, and cognitive function, among others.

The trial will involve several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of relapsing multiple sclerosis according to the 2017 McDonald criteria and an EDSS score of ≤5.5. Participants must have a history of relapses or MRI evidence of disease activity. Following the screening, participants will attend regular follow-up visits to monitor safety and efficacy outcomes, including MRI scans and clinical assessments. The end-of-study visit will occur at the conclusion of the treatment period, which is set for a maximum of 160 weeks.

Participant involvement is expected to last for the entire duration of the trial, approximately 160 weeks, unless early termination is warranted. Conditions for early termination include the occurrence of adverse events, serious adverse events, or any other safety concerns that necessitate discontinuation of the study intervention. Additionally, participants may be withdrawn if they do not adhere to the study protocol or if they choose to withdraw consent at any point during the trial.

The clinical trial involves the administration of **Frexalimab**, a solution for injection, as the experimental medication. Frexalimab is administered via **intravenous infusion** with a maximum daily dose of 1800 mg and a total maximum dose of 48600 mg over a treatment period of 160 days. The active substance in Frexalimab is a protein of other origin, and it is not a paediatric formulation. Participant compliance with the dosing schedule will be monitored throughout the trial.

**Aubagio** 14 mg film-coated tablets, containing the active substance **Teriflunomide**, serve as the comparator treatment. Teriflunomide is a chemical substance administered orally with a maximum daily dose of 14 mg and a total maximum dose of 17038 mg over a treatment period of 160 days. The pharmaceutical form is a film-coated tablet, and it is not a paediatric formulation. Participant adherence to the oral dosing schedule will be closely monitored.

The trial also includes a **matched placebo** for the test product Frexalimab, which is used to maintain the double-blind nature of the study. The placebo is administered in a manner consistent with the experimental medication, although specific details regarding its pharmaceutical form and route of administration are not provided.

Additionally, a **matched placebo** for the comparator Teriflunomide is included in the study. This placebo is designed to mimic the appearance and administration route of the comparator treatment to ensure blinding. Details regarding its pharmaceutical form and route of administration are not specified.

**Colestyramine**, a bile acid sequestrant, is included as a non-experimental treatment. It is administered orally, although the specific dosage and treatment period are not detailed. Colestyramine is not a paediatric formulation and is used to manage potential side effects associated with the trial medications.

The efficacy of frexalimab compared to teriflunomide in adult participants with relapsing forms of multiple sclerosis will be assessed using several parameters. The primary endpoint is the **Annualized Relapse Rate (ARR)**, which will be evaluated through protocol-defined adjudicated relapses during the study period. Secondary endpoints include the time to onset of composite confirmed disability worsening (cCDW), confirmed over 3 or 6 months, and the time to onset of confirmed disability improvement (CDI). Additionally, the study will measure the total number of new and/or enlarging T2 hyperintense lesions and new Gd-enhancing T1 hyperintense lesions per scan, as detected by MRI. Changes in brain volume loss, cognitive function, and patient-reported outcomes will also be assessed.

Data collection will involve MRI scans to detect lesion changes and brain volume loss, as well as the symbol digit modalities test (SDMT) for cognitive function assessment. Patient-reported outcomes will be measured using the Multiple Sclerosis Impact Scale 29 version 2 (MSIS-29v2) and the Patient-Reported Outcome Measurement Information System (PROMIS) Fatigue MS-8. Safety assessments will include monitoring adverse events, serious adverse events, and laboratory test abnormalities. Plasma neurofilament light chain (NfL) levels and frexalimab plasma concentration will be measured over time. The study is designed to provide comprehensive data on the efficacy and safety of frexalimab in comparison to teriflunomide.