Phase 3 Randomized, Double-Blind Study of Frexalimab 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 **541 participants** diagnosed with **multiple sclerosis**, specifically focusing on relapsing forms of the disease. The study population includes both male and female subjects, with an age range that corresponds to adults. 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. Additionally, participants must 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 trial also considers lifestyle factors such as contraceptive use, which must align with local regulations for clinical study participants. The study includes a vulnerable population, ensuring comprehensive representation of the disease's impact across different demographics.

The clinical trial is designed as a **randomized**, **double-blind**, Phase 3 study to evaluate the efficacy and safety of frexalimab compared to teriflunomide in adult participants with relapsing forms of **multiple sclerosis**. The trial aims to assess the annualized relapse rate (ARR) during the study period, with secondary endpoints including time to onset of confirmed disability worsening, changes in cognitive function, and adverse events. The trial is expected to commence recruitment on February 29, 2024, and conclude by May 6, 2027, with an estimated duration of 160 weeks for participant involvement.

Participants will undergo a series of 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 Expanded Disability Status Scale (EDSS) score of ≤5.5. The screening visit will also verify the presence of at least one documented relapse or gadolinium-enhancing lesion within the specified timeframe. Following the screening, participants will be randomly assigned to receive either frexalimab or teriflunomide, with matched placebos used to maintain blinding.

Subsequent follow-up visits will be scheduled at regular intervals to monitor the participants' health status, assess the primary and secondary endpoints, and ensure adherence to the study protocol. These visits will include clinical assessments, MRI scans, and laboratory tests to evaluate the progression of the disease and any potential side effects of the treatment. The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted to gather comprehensive data on the treatment's efficacy and safety.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. Such conditions may include the occurrence of serious adverse events, non-compliance with the study protocol, or withdrawal of consent. The trial's design ensures that all data collected will contribute to a robust evaluation of frexalimab's potential as a treatment for relapsing multiple sclerosis, with the ultimate goal of improving patient outcomes.

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 the product is developed by Sanofi Aventis Recherche et Développement (SAR). 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. The tablets are administered orally with a daily dose of 14 mg, and the treatment period extends up to 160 days. The total maximum dose is 17038 mg. Aubagio is manufactured by Sanofi Winthrop Industrie and is classified under the ATC code L04AA31.

The trial also includes a matched placebo for the comparator Teriflunomide, which is administered in a similar manner to maintain the double-blind nature of the study. The placebo is designed to match the pharmaceutical form and appearance of the active comparator.

Additionally, a matched placebo for the test product Frexalimab is included in the study. This placebo is used to ensure blinding and is administered in a manner consistent with the experimental medication.

**Colestyramine**, a bile acid sequestrant, is used as an auxiliary treatment in the trial. It is administered orally, although specific dosing details are not provided. Colestyramine is classified under the ATC code C10AC01.

**Gadobutrol**, a paramagnetic contrast media, is also used as an auxiliary treatment. It is administered intravenously, and its use is limited to a single treatment period. Gadobutrol is classified under the ATC code V08CA.

Participant compliance with the administration of all treatments will be closely monitored to ensure adherence to the study protocol. The trial is designed to assess the efficacy and safety of Frexalimab compared to Teriflunomide in adult participants with relapsing forms of multiple sclerosis.

The efficacy of the investigational product, **frexalimab**, will be assessed in a randomized, double-blind, Phase 3 clinical trial comparing its effects to those of teriflunomide in adult participants with relapsing forms of multiple sclerosis. The primary endpoint for evaluating efficacy is the **Annualized Relapse Rate (ARR)**, which will be measured by protocol-defined adjudicated relapses during the study period. Secondary endpoints include various measures of disability and disease progression, such as the time to onset of composite confirmed disability worsening (cCDW), time to onset of confirmed disability improvement (CDI), and progression independent of relapse activity. Additionally, the trial will assess the total number of new and/or enlarging T2-hyperintense lesions and new Gd-enhancing T1-hyperintense lesions as detected by MRI scans.

Other secondary endpoints involve changes in brain volume loss, cognitive function, and patient-reported outcomes, including the Multiple Sclerosis Impact Scale 29 version 2 (MSIS-29v2) and the Patient Reported Outcome Measurement Information System (PROMIS) Fatigue MS-8. Safety and tolerability will also be monitored through adverse events, serious adverse events, and laboratory test abnormalities. The trial will further evaluate changes in plasma neurofilament light chain (NfL) levels and frexalimab plasma concentration over time. These efficacy parameters will be collected and analyzed at various timepoints throughout the study, with specific assessments conducted at the end of the study (EOS) and compared to baseline measurements.