CD40L Inhibitor Frexalimab Enters Phase 3 FREXITE Trial of Non-Relapsing Secondary Progressive Multiple Sclerosis

At the 2026 Americas Committee for Treatment & Research in Multiple Sclerosis (ACTRIMS) Forum, held February 5-7 in San Deigo, California, investigators shared the design of a new phase 3 trial, dubbed FREXCITE, that tests the efficacy and safety of frexalimab, an investigational CD40L inhibitor, in patients with non-relapsing secondary progressive multiple sclerosis (nrSPMS). This randomized, open-label, multinational study adds to the drug’s clinical program, which includes 2 other ongoing phase 3 trials.¹

Frexalimab is a second-generation investigational anti-CD40L antibody that blocks the CD40/CD40L pathway–key to adaptive and innate immunity–offering a potential best-in-class approach to addressing the acute and chronic neuroinflammation in MS without causing lymphocyte depletion. FREXCITE, a 3-part study, is a bridging study that aims to demonstrate the pharmacokinetic (PK) non-inferiority of subcutaneous (SC) frexalimab using an on-body delivery system (OBDS) compared with intravenous (IV) frexalimab in adults with relapsing MS and nrSPMS.

In part A of the study, approximately 160 participants are randomized 1:1 to receive frexalimab 1800 mg/SC every 4 weeks (q4w) or frexalimab 1200 mg/IV q4w for 24 weeks. In Part B, conducted in the 24-48 weeks following, requires patients to switch or continue frexalimab 1800 mg/SC q4w to further assess long-term safety and tolerability. Of note, home administration of the investigational agent will be allowed in Part B.

Led by Tanuja Chitnis, MD, an associate neurologist at Brigham and Women’s Hospital, FREXCITE uses change in area under the curve of frexalimab plasma concentration over the 20-24-week interval period as the primary end point. Other secondary outcomes of the study include other PK parameters, gadolinium-enhancing T1 lesions, time to onset of confirmed disability worsening/progression (CDW/CDP), patient-reported outcomes, and safety evaluation.

In this bridging study, inclusion criteria involves relapsing MS diagnosis, and Expanded Disability Status Scale (EDSS) scores of 5.5 or less. In addition, patients entering the study must have at least 1 relapse within 1 year or at least 2 relapses within 2 years or at least 1 gadolinium-enhancing lesion within 1 year. For those with nrSPMS, patients must have EDSS between 3.0-6.5, documented evidence of disability progression during the 12 months before screening, and no relapses in the last 24 months.

FREXALT-1 & FREXALT 2

The phase 3 FREXALT program consists of two independent, double-blind, active-controlled trials, FREXALT-1 and FREXALT-2, evaluating frexalimab versus teriflunomide in adults aged 18 to 55 years with relapsing multiple sclerosis and EDSS scores below 5.5.² Eligible participants must have recent inflammatory activity, defined by clinical relapses or at least one gadolinium-enhancing lesion. Each study plans to enroll about 700 patients treated for 20 to 40 months, with annualized relapse rate as the primary end point. Key secondary outcomes include 6-month confirmed disability worsening, progression independent of relapse activity, MRI lesion measures, brain volume loss, cognition, quality of life, and biomarker assessments including neurofilament light and immunoglobulin levels.

FREVIVA is a separate phase 3 trial of frexalimab in non-relapsing secondary progressive MS, comparing dosing every 4 weeks with placebo. The study aims to enroll 858 participants aged 18 to 60 years with EDSS scores of 3.0 to 6.5, no relapses for at least 24 months, and documented recent disability progression. Its primary end point is time to 6-month confirmed disability progression.

Prior Phase 2 Trial of Frexalimab

In a previously completed, double-blind, placebo-controlled phase 2 trial (NCT04879628) published in the New England Journal of Medicine, frexalimab demonstrated a marked reduction in MRI disease activity over 12 weeks. Overall, patients receiving either 1200 mg every 4 weeks (with an 1800 mg loading dose) or 300 mg subcutaneously every 2 weeks (with a 600 mg loading dose) had substantially fewer new gadolinium-enhancing T1 lesions than those on placebo. Adjusted mean lesion counts were 0.2 and 0.3 in the higher- and lower-dose groups, respectively, compared with 1.4 in the pooled placebo group, and roughly 85% of treated patients had no new enhancing lesions versus 50% with placebo.³

Secondary MRI outcomes showed similar separation, with lower total enhancing lesion counts in both frexalimab groups compared with placebo. Exploratory patient-reported outcomes suggested numerically better physical impact scores on the MSIS-29 with frexalimab, though psychological scores and short-term disability, measured by EDSS, remained largely unchanged at 12 weeks. Together, the findings pointed to a strong biologic effect on inflammatory activity without clear early disability differences.

In the open-label extension, frexalimab demonstrated an attenuation of disease activity in patients with relapsing MS over a 2-year period. By week 96, gadolinium-enhancing T1 lesion counts remained low across all frexalimab-treated groups, including patients who switched from placebo at week 12. In the intravenous arms, mean lesion counts were 0.1 in both the continuous 1200 mg group and those who crossed over, while subcutaneous dosing groups maintained mean counts at 0.4 or lower.⁴

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REFERENCES
1. Chitnis T, Mao-Draayer Y, Krieger S, et al. P110 / P110 - Frexalimab in Relapsing Multiple Sclerosis and Non-Relapsing Secondary Progressive Multiple Sclerosis: Design of the Phase 3 FREXCITE Trial. Presented at: 2026 ACTRIMS Forum; February 5-7; San Deigo, CA. Abstract P110
2. 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.
3. 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
4. Vermersch P, Granziera C, Mao-Draayer Y, et al. Safety and Efficacy of Frexalimab from the Phase 2 Open-label Extension in Participants with Relapsing Multiple Sclerosis: 2-year Results. Presented at: 2025 AAN Annual Meeting; April 5-9; San Diego, CA. ABSTRACT 001785