Phase 3 Randomized, Double-Blind Study of Frexalimab (SAR441344) Versus Placebo in Adults with Nonrelapsing Secondary Progressive Multiple Sclerosis

The primary objective of this study is to assess the **efficacy** of frexalimab compared to placebo in delaying disability progression in patients with nonrelapsing secondary progressive multiple sclerosis (nrSPMS). This is clinically relevant as it aims to address the unmet need for effective treatments in managing the progression of disability in nrSPMS, a condition characterized by a gradual worsening of neurological function.

Secondary objectives include:

• Assessing the efficacy of frexalimab compared to placebo on clinical endpoints, MRI lesions, cognitive performance, physical function, and quality of life.
• Evaluating the safety and tolerability of frexalimab.
• Evaluating the pharmacodynamics of frexalimab in participants with nrSPMS.
• Evaluating the pharmacokinetics of frexalimab in nrSPMS.

The clinical trial involves a total of **626 participants** diagnosed with **multiple sclerosis**, specifically focusing on those with secondary progressive multiple sclerosis (SPMS) who have a history of relapsing-remitting multiple sclerosis (RRMS). The study population includes both male and female subjects, with an age range that corresponds to category code 3, typically representing adults. Participants were selected based on specific criteria, including a documented progression of disability over the past 12 months and an Expanded Disability Status Scale (EDSS) score between 3.0 and 6.5. The trial also considers individuals who have not experienced clinical relapses for at least 24 months. Both genders are included, and the study does not exclude vulnerable populations. Lifestyle factors such as diet and physical activity are not specified, but contraceptive use must align with local regulations for clinical study participants. The selection criteria ensure that participants have either not tolerated or declined siponimod treatment, or have experienced a lack of efficacy with it.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy and safety of **frexalimab** compared to a matched placebo in adult participants with nonrelapsing secondary progressive **multiple sclerosis** (nrSPMS). The primary objective is to assess the efficacy of frexalimab in delaying disability progression. The trial is expected to commence recruitment on October 4, 2024, and conclude by March 24, 2028, with an estimated duration of 51 weeks for each participant's involvement.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a previous diagnosis of relapsing-remitting multiple sclerosis (RRMS) and a current diagnosis of secondary progressive multiple sclerosis (SPMS), among others. Following successful screening, participants will be randomly assigned to receive either frexalimab or placebo via **intravenous infusion**. The study will include multiple follow-up visits to monitor the onset of composite confirmed disability progression (cCDP) and other secondary endpoints, such as changes in brain volume and cognitive function, as well as the occurrence of adverse events.

The end-of-study visit will mark the completion of the participant's involvement, during which final assessments will be conducted to evaluate the long-term effects of the treatment. Participants may be withdrawn from the study early if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The clinical trial involves the administration of **Frexalimab**, a solution for injection, as the experimental medication. Frexalimab is a protein-based therapeutic agent developed by Sanofi Aventis Recherche et Développement (SAR). The pharmaceutical form of Frexalimab is a solution intended for intravenous infusion. The dosing regimen for Frexalimab involves a maximum daily dose of 1800 mg, with a total maximum dose of 61800 mg over a treatment period of up to 51 weeks. The administration of Frexalimab is conducted via intravenous infusion, ensuring precise delivery of the medication into the bloodstream. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

The study also includes a **matched placebo** as a non-experimental treatment to serve as a comparator. The placebo is designed to mimic the appearance and administration route of Frexalimab, ensuring the study remains double-blind. The placebo is administered via intravenous infusion, similar to the experimental medication, to maintain consistency in the treatment experience for all participants. The use of a placebo allows for the assessment of Frexalimab's efficacy and safety in comparison to a control group, providing a robust evaluation of its therapeutic potential in delaying disability progression in nonrelapsing secondary progressive multiple sclerosis (nrSPMS).

The efficacy of Frexalimab in the treatment of nonrelapsing secondary progressive multiple sclerosis (nrSPMS) will be assessed through a randomized, double-blind, Phase 3 clinical trial. The primary endpoint for evaluating efficacy is the time to onset of composite confirmed disability progression (cCDP) confirmed over 6 months. Secondary endpoints include the time to onset of composite cCDP confirmed over 3 months, time to onset of confirmed disability improvement (CDI), and the number of new and/or enlarging T2 hyperintense lesions per scan as detected by MRI. Additional secondary endpoints involve the percent change in brain volume loss as detected by MRI scans, changes in cognitive function assessed by the symbol digit modalities test (SDMT), and changes from baseline in multiple sclerosis impact scale 29 version 2 (MSIS-29v2) questionnaire scores.

Further assessments will include changes from baseline in the patient-reported outcome measurement information system (PROMIS) Fatigue MS-8a, annualized relapse rate, and various safety parameters such as adverse events and serious adverse events. Biomarker evaluations will include changes from baseline in serum immunoglobulin levels, plasma neurofilament light chain (NfL) levels, and Frexalimab plasma concentration over time. These efficacy parameters will be measured and collected at specified timepoints throughout the double-blind treatment period, utilizing validated scales and laboratory tests to ensure accuracy and reliability in the assessment of Frexalimab's efficacy in delaying disability progression in nrSPMS.