A New Dawn: Frexalimab’s Quest to Redefine Multiple Sclerosis Therapy

• Frexalimab (SAR441344) is a novel anti-CD40L antibody in development, designed to inhibit the CD40/CD40L pathway, a crucial element in activating both adaptive and innate immune responses. Its distinctive mode of action targets neuroinflammation in multiple sclerosis, offering potential benefits for both acute and chronic inflammation without depleting lymphocytes.
• Sanofi’s 48-week data reveals Frexalimab’s sustained safety, effectiveness, and remarkable tolerability in relapsing multiple sclerosis (RMS), emphasizing its enduring therapeutic potential and patient-centric approach.

Relapsing Multiple Sclerosis (RMS) manifests as intermittent flare-ups, known as relapses or exacerbations, followed by periods of partial or complete symptom remission. Addressing the complexities of RMS treatment encompasses various challenges, including prognostication, initial therapy selection, diligent monitoring of treatment efficacy, and adept management of potential side effects. 

At the American Academy of Neurology conference 2024, Sanofi unveiled fresh 48-week data from the Phase II trial (NCT04879628) of Frexalimab, underscoring its promising potential for sustained efficacy in the treatment of multiple sclerosis. Frexalimab, a second-generation anti-CD40L monoclonal antibody, disrupts the pivotal CD40/CD40L pathway crucial for both adaptive and innate immune system activation. In the initial 12-week double-blind period (DBP), Frexalimab showcased both safety and efficacy, particularly with the high-dose regimen demonstrating an impressive 89% reduction in new gadolinium-enhancing (Gd+) T1-lesions compared to the placebo group. Throughout the subsequent 24-week Open Label Extension (OLE) phase, Frexalimab exhibited continued tolerability, with a further decrease observed in lesion numbers.

Following the initial 12-week double-blind period, 97% of participants transitioned into the OLE phase of the Phase II study. At the 48-week mark, 87% of all participants receiving Frexalimab, whether on high- or low-dose regimens, or those who switched from placebo, remained engaged in the study. Throughout the OLE, individuals received consistent dosages of Frexalimab tailored to their initial treatment arms, ensuring continuity and sustained therapeutic benefit. 

Results of the Phase II OLE at week 48 showed at the 48-week mark, 96% of patients on high-dose Frexalimab and 87% on low-dose remained free of Gd+ T1 lesions. Those switching from placebo to either high or low-dose saw significant improvements, with 90% and 92% lesion-free, respectively, at Week 48. The mean number of Gd+ T1 lesions remained minimal across all groups, while new or enlarging Gd+ T2 lesions remained low. High-dose Frexalimab resulted in a low annualized relapse rate (ARR) of 0.04, with 96% free of relapses. These findings underscore the promising efficacy and potential of Frexalimab in treating multiple sclerosis.

Conclusion: The 48-week data for Frexalimab demonstrate notable reductions in lesion numbers and sustained disease activity decline, with a remarkably low annual relapse rate, showcasing its potential as a pioneering therapy in relapsing multiple sclerosis. These promising preliminary clinical outcomes underscore the rationale for targeting CD40L and bolster the case for advancing Frexalimab’s development as a high-efficacy treatment for multiple sclerosis. As a novel potential first-in-class therapy, Frexalimab addresses critical unmet needs in multiple sclerosis treatment, leveraging our expertise to combat neuroinflammation and neurodegeneration comprehensively, aiming to enhance the quality of life for multiple sclerosis patients.