CD40L Inhibitor Frexalimab to be Tested in Phase 3 Trials of Relapsing MS and Non-Relapsing Secondary Progressive MS

Frexalimab, an investigational CDL40 inhibitor, will be assessed in 2 phase 3 trials, dubbed FREXALT (NCT06141473) and FREVIVA (NCT06141486), that will assess the efficacy and safety of the agent in patients with relapsing multiple sclerosis (MS) and non-relapsing secondary progressive MS, respectively. Enrollment of both trials has started and recruitment is currently ongoing.¹

The design of the studies were presented at the 2024 Consortium of Multiple Sclerosis Centers (CMSC) Annual Meeting, held May 29-June 2, in Nashville, Tennessee by Stephen Krieger, MD, associate professor of neurology at the Icahn School of Medicine at Mount Sinai. After phase 2 findings provided the rationale for targeting CD40L in MS, these trials hope to further understand frexalimab’s treatment effects in these patient populations, including secondary progressive MS, for whom no approved therapeutic options currently exist.

FREXALT is comprised of 2 independent (FREXALT-1 and FREXALT-2) phase 3, double-blind, double-dummy, active-controlled, parallel group, event-driven trials comparing the efficacy and safety of frexalimab against comparator teriflunomide (Aubagio; Sanofi) in participants with relapsing MS. The trial includes patients aged 18-55 years with Expanded Disability Status Scale (EDSS) scores of less than 5.5 who had at least 1 relapse in the previous year, 2 relapses in previous 2 years, or at least 1 gadolinium-enhancing T1 lesion (Gd+) in the previous year.

Each study includes 700 adults with relapsing MS for treatment duration of 20-40 months, lasting up to 144 weeks. The primary end point is annualized relapse rate (ARR) assessed by protocol-defined adjudicated relapses, while secondary end points include time to onset of 6-month confirmed disability worsening (CDW). Other secondary outcomes include progression independent of relapse activity, new and/or enlarging T2 lesions, and new Gd+ T1 lesions, as well as changes in brain volume loss, cognitive function, quality of life, and plasma neurofilament light and serum immunoglobulin levels. Both studies will also assess the plasma concentration of frexalimab over time.

FREVIVA, similar to FREXALT, assesses doses of frexalimab given every 4 weeks against placebo. Expected to include 858 participants with non-relapsing secondary progressive MS, the study assessed time to onset of 6-month CDP as the primary end point. The trial includes those aged 18-60 years who have an EDSS score of 3.0-6.5, no clinical relapses for at least 24 months, and documented disability progression in the previous 12 months as analyzed by an Eligibility Adjudication Committee.

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The study excludes those with history or presence of disease that can mimic MS symptoms or those with a medical conditions that would adversely impact study participation. Aside from onset of 6-month CDP, the study also looks at changes in brain volume loss, cognitive function, quality of life, and safety. It also assesses new and/or enlarging T2 lesions, plasma NfL and serum immunoglobulin levels, and time to onset in confirmed disability improvement.

Earlier this year, investigators published positive phase 2 data from a study assessing frexalimab in relapsing MS in the New England Journal of Medicine. The double-blind, placebo-controlled trial randomly assigned patients to either 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose), or matching placebos. At the conclusion of the 12-week period, the adjusted mean number of new gadolinium-enhancing T1-weighted lesions relative to week 8 was 0.2 (95% CI, 0.1-0.4) in the 1200 mg frexalimab group, 0.3 (95% CI, 0.1-0.6) in the 300 mg frexalimab group, and 1.4 (95% CI, 0.6-3.0) in the pooled placebo group.²

Of the 129 participants included, 125 (97%) completed the 12-week double-blind period and entered the open-label extension. After 24 weeks of treatment, results from the open-label period showed an unadjusted mean number of 0.1 (95% CI, 0.02-0.2) for new gadolinium-enhancing T1-weighted lesions for those in the 1200 mg group of frexalimab. In addition, 96% of these patients had no new such lesions; however, no definite conclusions were drawn considering it was a nonprespecified analysis.

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REFERENCES
1. Krieger S, Vermersch P, Chitnis T, et al. Frexalimab in relapsing multiple sclerosis and non-relapsing secondary progressive multiple sclerosis: design of phase 3 FREXALT and FREVIVA trials. Presented at: 2024 CMSC Annual Meeting; May 29-June 2; Nashville, TN. ABSTRACT DMT52.
2. Vermersch P, Granziera C, Mao-Draayer Y, et al. Inhibition of CD40L with frexalimab in multiple sclerosis. NEJM. 2024;390:589-600. doi:10.1056/NEJMoa2309439