---
title: "Frexalimab: The Anti-CD40L Antibody That Came Back From a 20-Year Safety Problem (September 25, 2026) | PepTracker Pro Blog"
url: https://peptrackerpro.com/blog/frexalimab-sar441344-sanofi-second-generation-anti-cd40l-cd154-monoclonal-antibody-relapsing-multiple-sclerosis-nonrelapsing-secondary-progressive-ms-frexalt-freviva-fabulinus-type-1-diabetes-lupus-gadolinium-enhancing-lesions-neurofilament-light-costimulation-teriflunomide-phase-3-september-25-2026
description: "Frexalimab is Sanofi's second-generation anti-CD40L antibody for multiple sclerosis - an upstream, non-depleting way to switch off autoimmunity that revives a target abandoned for two decades over blood-clot risk. Here's what the Phase 2 and long-term data actually show, why the re-engineered antibody matters, and what the Phase 3 FREXALT and FREVIVA trials still have to prove."
lang: en
---

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Research & Compounds

Research & Compounds

# Frexalimab: The Anti-CD40L Antibody That Came Back From a 20-Year Safety Problem (September 25, 2026)

PepTracker Pro Research Team September 25, 2026 9 min read

## Table of Contents

- What frexalimab is, in one line
- Why CD40L, and why this target has a long, difficult history
- The fix that made the target usable again
- The Phase 2 MS results, in plain numbers
- Does the benefit last? Two- and three-year data
- What Phase 3 still has to prove
- Beyond MS - and a reality check, plus the bottom line

## What frexalimab is, in one line

Frexalimab (development code SAR441344) is an investigational antibody from Sanofi being developed mainly for multiple sclerosis (MS). Instead of blocking one inflammatory messenger or wiping out immune cells, it blocks a costimulatory switch called CD40 ligand (CD40L, also written CD154) that immune cells use to talk to each other and turn autoimmunity on. It is given by infusion or by injection under the skin, is not approved anywhere yet, and is in late-stage (Phase 3) testing for relapsing MS and for a harder-to-treat form called nonrelapsing secondary progressive MS.

## Why CD40L, and why this target has a long, difficult history

CD40L sits mostly on activated T cells (and on platelets); its partner, CD40, sits on B cells and the antigen-presenting cells that kick off immune responses. When CD40L engages CD40, it acts like a 'second signal' that licenses dendritic cells, activates B cells, and drives antibody production and immune memory. Shut that signal down and you can, in theory, quiet many arms of an autoimmune disease at once - without depleting the immune cells themselves. Immunologists have wanted to drug this target since the 1990s. The problem: the first anti-CD40L antibodies caused dangerous blood clots (thromboembolism), because the tail (Fc region) of the antibody grabbed a receptor on platelets and made them clump. That safety disaster shelved the whole approach for roughly two decades.

## The fix that made the target usable again

Frexalimab is a 'second-generation' anti-CD40L antibody, and the key word is the engineering. Its Fc region is modified so it does not activate platelets - the exact mechanism behind the old clotting problem. In the trials run so far, no thromboembolic safety signal has appeared. That single design change is what separates frexalimab from its failed predecessors and is why the CD40-CD40L pathway is back in serious clinical development, not just for MS but potentially across autoimmune disease.

## The Phase 2 MS results, in plain numbers

In the Phase 2 relapsing-MS study (NCT04879628), 129 adults were randomized to higher-dose intravenous frexalimab (1200 mg every 4 weeks after an 1800 mg loading dose), lower-dose subcutaneous frexalimab (300 mg every 2 weeks after a 600 mg loading dose), or placebo. The main measure was the number of new 'gadolinium-enhancing' brain lesions on MRI at week 12 - fresh spots of active inflammation. The higher dose cut new lesions by 89% and the lower dose by 79% versus placebo. The drug was well tolerated; the most common side effects were COVID-19 (generally mild to moderate) and headache, and 97% of participants finished the study. These results were published in the New England Journal of Medicine in 2024.

## Does the benefit last? Two- and three-year data

Short MRI wins do not always translate into lasting control, so the open-label extension matters. By week 48, roughly 96% of higher-dose participants had no gadolinium-enhancing lesions, and blood neurofilament light - a marker of ongoing nerve-cell damage - went down. Follow-up presented at AAN 2025 (two years) and CMSC 2026 (three years) showed the low disease activity held up over time. Durability is exactly the kind of signal that justified moving into a large Phase 3 program.

## What Phase 3 still has to prove

The pivotal program is big and pointed. FREXALT is two independent studies (under master protocol NCT06141473) that pit frexalimab against an active oral drug, teriflunomide, in relapsing MS - about 700 patients each - so it must beat a real comparator, not just placebo. FREVIVA (NCT06141486) tests frexalimab against placebo in nonrelapsing secondary progressive MS, a population where almost nothing works, with roughly 858 patients. A separate bridging study, FREXCITE, checks a subcutaneous on-body delivery system against the intravenous version. The open questions are the ones MRI can't fully answer: does frexalimab actually reduce relapses and slow disability, and does the clean safety record hold at scale and over years?

## Beyond MS - and a reality check, plus the bottom line

Because CD40L blockade is upstream and broad, Sanofi is testing frexalimab in other autoimmune diseases: the Phase 2 FABULINUS trial (NCT06111586) asks whether it can preserve insulin-producing beta cells in people with recent-onset type 1 diabetes, and there is a parallel systemic lupus program. But not every door has opened - a Phase 2 study in Sjogren's syndrome was discontinued in 2024 after it confirmed the drug's activity and safety yet missed its efficacy endpoint, a useful reminder that a shared mechanism does not guarantee results in every disease. The bottom line: frexalimab is one of the more scientifically interesting immunology assets in development - a revived, re-engineered take on a classic target with genuinely strong MS biomarker data - but it remains investigational, unapproved, and dependent on the Phase 3 readouts to show that lesion suppression becomes durable, real-world benefit. Anything sold as 'frexalimab' outside a clinical trial is unverified and should not be used.

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## Citations

1. [1] Inhibition of CD40L with Frexalimab in Multiple Sclerosis - New England Journal of Medicine (2024) Source (https://www.nejm.org/doi/full/10.1056/NEJMoa2309439)
2. [2] Phase 2 data published in NEJM show potential of frexalimab as high-efficacy therapy in relapsing MS (February 2024) - Sanofi Source (https://www.sanofi.com/en/media-room/press-releases/2024/2024-02-15-13-00-00-2829933)
3. [3] New 48-week frexalimab Phase 2 data support potential for high sustained efficacy in multiple sclerosis (April 2024) - Sanofi Source (https://www.sanofi.com/en/media-room/press-releases/2024/2024-04-17-05-00-00-2864225)
4. [4] Efficacy and Safety Studies of Frexalimab (SAR441344) in Relapsing Forms of MS (FREXALT master protocol) - ClinicalTrials.gov NCT06141473 Source (https://clinicaltrials.gov/study/NCT06141473)
5. [5] Efficacy and Safety Study of Frexalimab in Nonrelapsing Secondary Progressive MS (FREVIVA) - NCT06141486 / Sanofi Source (https://www.sanofi.com/en/clinical-trials/nct06141486)
6. [6] A Phase 2 Trial of Frexalimab in Recent-Onset Type 1 Diabetes (FABULINUS): Rationale and Study Design - Diabetes, Obesity and Metabolism (2026) Source (https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.70785)
7. [7] Sanofi crosses Sjogren's off frexalimab's hit list after Phase 2 data disappoint (2024) - Fierce Biotech Source (https://www.fiercebiotech.com/biotech/sanofi-crosses-sjogrens-5b-drugs-hit-list-after-phase-2-data-disappoint)
8. [8] CMSC 2026: trial data show frexalimab benefits lasting 3 years in relapsing MS - Multiple Sclerosis News Today Source (https://multiplesclerosisnewstoday.com/news-posts/2026/06/01/cmsc-2026-trial-data-show-frexalimab-benefits-lasting-3-years/)

**Disclaimer:** This article is for educational purposes only and does not constitute medical advice. Always consult a licensed healthcare provider. Read full research disclaimer → (https://peptrackerpro.com/research-disclaimer)

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