Multiple sclerosis

Frexalimab, a second-generation anti-CD40L antibody, has shown “strikingly positive” effects in treating relapsing multiple sclerosis (MS), significantly reducing disease activity without depleting B cells. The drug is a novel, second-generation monoclonal antibody designed to block the costimulatory CD40/CD40L cellular pathway, the mechanism of which is believed to potentially modify T-and B-cell activation and innate immune cell function. In a phase 2, multicenter trial, 129 participants with relapsing MS were randomly assigned to one of four groups – high-dose frexalimab (n = 52), low-dose frexalimab (n = 51), or placebo (n = 12 high-dose, n = 14 low-dose) for the 12-week placebo-controlled period. Those receiving high-dose frexalimab had an 89% greater reduction in the number of new gadolinium-enhancing T1-lesions compared with the pooled placebo group after 12 weeks. Furthermore, after 24 weeks, 96% of the high-dose frexalimab group were free of gadolinium-enhanced T1 lesions.

Gavin Giovannoni, MD, PhD, chair of neurology at the Blizard Institute of Barts and the London School of Medicine and Dentistry in the United Kingdom, said these results were “better than expected” and have helped “fundamentally tackle autoimmunity”. He also added that it will be interesting to see if this treatment re-establishes immune tolerance and induces long-term remission. In his newsletter, Giovannoni characterized the study’s results as “strikingly positive,” adding that they “are the most exciting to emerge in MS in the last 12-24 months.”

Salim Chahin, MD, assistant professor of Neurology at Washington University in St. Louis, Missouri, commented that frexalimab represents an intriguing mechanistic approach to MS, “In the world of MS and neuroimmunology, this is indeed a unique mechanism that has not been explored before.” He noted that therapies targeting CD40 and CD40L are not new but were previously associated with unfavorable side effects, mainly thromboembolic events that halted their development. The drug appears to avoid these side effects, providing good phase 2 efficacy data. Additionally, the study found frexalimab to be well-tolerated over the 12-week study, with headache and COVID-19 reported among 4% or fewer participants and no serious adverse events were reported.

However, it remains to be seen whether the drug will be associated with a more favorable safety profile than some of the currently approved MS treatments, and further safety and efficacy issues will be watched closely in the phase 3 trial data. Despite this, the investigators note that this drug has the potential for further development as a high-efficacy therapy that can prevent inflammation in MS.

In summary, the potential of frexalimab in treating relapsing multiple sclerosis is significant, and the drug has demonstrated impressive results in its reduction of gadolinium-enhanced T1 lesions compared to the placebo. Given these results, the importance of developing a drug with limited side effects that can support MS patients is more critical than ever. The study paves the way for the development of new therapies that can control MS effectively.