Frexalimab phase 2 trial

ClinicalTrials.gov number: NCT04879628

Citation: Vermersch, et al. Frexalimab, a CD40L inhibitor, in relapsing multiple sclerosis: Results from a randomized controlled phase 2 trial. Presented at Consortium of Multiple Sclerosis Centers’ annual meeting, Aurora, Colorado. May 31-June 3 2023

BACKGROUND

• Inflammatory responses in the neural microenvironment of brain or spinal cord involve complex signaling interactions among neurons, astrocytes, microglia, and endothelial cells through cytokines, chemokines, secondary messengers, and neuronal factors. The CD40 receptor and CD40 ligand (also referred as CD40L or CD154) costimulatory pathway is critical for initiating and sustaining neuroinflammatory response and regulates both innate and adaptive immunity (here).
• Hyperactivation or dysregulation of CD40-CD40L signaling is seen in several neurological conditions including traumatic brain injury, Alzheimer’s Disease, Parkinson’s Disease, stroke, epilepsy, nerve injury, multiple sclerosis (MS), amyotrophic lateral sclerosis, myasthenia gravis, and brain tumors. Blocking CD40-CD40L signaling may have a beneficial effect in MS (here)
• Frexalimab (SAR441344) is an anti-CD40L antibody from Sanofi. It modulates both B and T cells without immune (lymphocyte) depletion.
• This was a phase 2, multicenter, randomized, double-blind, placebo-controlled trial to determine the efficacy and safety of frexalimab in people with relapsing MS (pwRMS; including relapsing-remitting MS or secondary progressive MS with relapses).

WHERE AND HOW

• The study is ongoing and as of #CMSC2023 presentation, the study had enrolled 129 pwRMS (aged 18-55 years; EDSS up to 5.5 at screening) at sites (currently 48 listed at ClinicalTrials.gov) across United States, Europe, Russia, and Turkey. The study included both people with relapsing-remitting MS (n=121, 93.8% of total) and secondary progressive MS with superimposed relapses (n=8, 6.2% of total).
• The study participants were randomized 4:4:1:1 to high-dose frexalimab, low-dose frexalimab, high-dose placebo, or low-dose placebo arms.
• The study includes a 12-week placebo-controlled double-blind phase (Part A) followed by an open label phase (Part B) where the high- and low-dose placebo crossover to corresponding frexalimab doses.
• The primary endpoint was the number of new Gd T1 lesions at Week 12 (relative to Week 8), measured by brain MRI.
• The key secondary endpoints were number of new/enlarging T2 lesions at Week 12 relative to Week 8); total number of Gd T1 lesions at Week 12; and safety.
• Key exploratory endpoints were changes in Multiple Sclerosis Impact Scale 29 (MSIS-29) and plasma neurofilament light chain (NfL) at Week 12 compared to baseline.
• Statistics: Analysis of the primary and key secondary endpoints was done in the efficacy population through a negative binomial regression model, with the baseline Gd T1 lesion count as a covariate and treatment as a factor.

RESULTS

• Baseline characteristics were balanced across all groups except age, sex, and Gd T1 lesions: mean ages of ~38 years for frexalimab group (versus ~32 years placebo); 61% and 71% female for low and high dose frexalimab (versus ~65 for placebo); median time from onset of MS symptoms of 7 to 8 years; median EDSS score of 2.5 to 2.8; and ~1 relapse in previous year. Percent of participants with at least 1 Gd T1 lesion were 25% (frexalimab, low dose), 31% (frexalimab, high dose), and 38.5% (pooled placebo group).
• Primary endpoint: The mean number of new Gd T1 lesions in the low- and high-dose frexalimab were 0.3 and 0.2 respectively, versus 1.4 for placebo, at 12 weeks. The relative reduction in new Gd T1 lesions was 79% (95% CI: 44% - 92%, p=0.0021) with low-dose frexalimab and 89% (95% CI: 62% - 97%, p=0.0004) with high-dose frexalimab.

Vermersch et al, #CMSC2023. Fig, new Gd T1 lesions

• Secondary endpoint: The relative reduction in new/enlarging T2 lesions was 86% (95% CI: 59% - 95%) with low-dose frexalimab and 92% (95% CI: 74% - 97% with high-dose frexalimab.
• Exploratory endpoint: MSIS-29 physical impact score significantly improved over 12-weeks in the high-dose frexalimab group vs pooled placebo. At Week 12, the plasma NfL levels also decreased significantly in both frexalimab groups: by 26% (p=0.0020) in high-dose frexalimab and by 20% (p=0.0190) in low dose frexalimab, versus pooled placebo.
• Safety: The most common adverse events were COVID-19 and headache. There was 1 (1.9%) case of isolated asymptomatic alanine aminotransferase elevation (5.9x the upper limit of normal, with no concomitant bilirubin increase) that recovered on treatment in high-dose frexalimab group.

CONCLUSIONS

• Frexalimab significantly reduced the number of Gd T1 lesions, meeting the primary endpoint.
• The study also showed positive effect on the reduction in new/enlarging T2 lesions, MSIS-29 outcome, and the biomarker NfL.
• Frexalimab is the first CD40L blocker to demonstrate efficacy in RMS.
• There are no other frexalimab trials currently listed in ClinicalTrials.gov. However, other anti-CD40L antibodies are also in experimental stage such as toralizumab/IDEC-131 (here).

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SOURCES

• Vermersch, et al. Frexalimab, a CD40L inhibitor, in relapsing multiple sclerosis: Results from a randomized controlled phase 2 trial. Presented at Consortium of Multiple Sclerosis Centers’ annual meeting, Aurora, Colorado. May 31-June 3 2023 [Abstract - archive] [Archive - poster]
• Karnell JL, et al. Targeting the CD40-CD40L pathway in autoimmune diseases: Humoral immunity and beyond. Adv Drug Deliv Rev. 2019 Feb 15;141:92-103. doi: 10.1016/j.addr.2018.12.005. PMID: 30552917.
• Breaking news: we have a new therapeutic target in MS: The phase 2 results of the Frexalimab (anti-CD40L) study are strikingly positive. What does this mean for MS? By Gavin Giovannoni. MS-Selfie Blog. 31 May 2023 [archive]
• 2nd generation CD40L blocker safely reduces new lesions in Phase 2 trial: Frexalimab may control immune activity without side effects of its predecessors. By Lindsey Shapiro. Multiple Sclerosis News Today. 1 June 2023