Abstract Details

Title Long-term Treatment Effects of Frexalimab on NfL, CXCL13, and Brain Volume Loss in Relapsing Multiple Sclerosis

Topic Multiple Sclerosis

Presentation(s) P4 - Poster Session 4 (8:00 AM-9:00 AM)

Poster/Presentation
Number 19-009

Objective To report frexalimab’s treatment effects on plasma levels of neurofilament light chain (NfL), chemokine (C-X-C motif) ligand 13 (CXCL13), and brain volume loss (BVL) at year 3 (Week [W] 144) of the phase 2 open-label extension (OLE).

Background Frexalimab, a second-generation anti-CD40L monoclonal antibody, inhibits the costimulatory CD40/CD40L pathway, and may recalibrate immune networks involving adaptive and innate immunity. In the double-blind period of the phase 2 trial (NCT04879628) in participants with relapsing multiple sclerosis (pwRMS), frexalimab-1200mg/intravenous (IV) showed an 89% reduction in new gadolinium-enhancing (Gd+) T1-lesions vs placebo at W12. This was accompanied by 24% and 21% reductions in plasma NfL and CXCL13 levels, respectively.

Design/Methods 129 pwRMS were randomized (4:4:1:1) to frexalimab-1200mg/IV every-4-weeks (q4w), frexalimab-300mg/subcutaneous (SC) q2w, or matching placebo. After W12, placebo recipients switched to frexalimab and entered OLE. The SC dose was increased to 1800mg-q4w to achieve pharmacokinetic comparability with the 1200mg-q4w IV dose. Plasma NfL and CXCL13 (baseline−W144) were measured by Quanterix Simoa® assay and Meso Scale Discovery assay, respectively. BVL (baseline−W144) was estimated using Jacobian integration. Results are summarized as % change of geometric mean from baseline for plasma NfL and CXCL13, and median % change from baseline for BVL.

Results From baseline to W144, frexalimab treatment reduced the plasma NfL levels by 47% (IV), 49% (SC), 35% (placebo»IV), and 45% (placebo»SC). CXCL13 levels decreased by 48%, 61%, 34%, and 28%, respectively. In the IV arm (Phase 3 dose), BVL from baseline was -0.84% (IQR: -1.14 to -0.50) for whole brain, -1.18% (-1.85 to -0.13) for thalamus, and -0.85% (-1.67 to -0.39) for cerebral cortex.

Conclusions Three years of f rexalimab treatment demonstrated marked reductions in NfL and CXCL13, and limited BVL in pwRMS. These data contribute to understanding the effect of frexalimab on neuroinflammation and neurodegeneration, and support further investigations in both RMS and non-relapsing secondary progressive MS.

Authors/Disclosures
Cristina Granziera, MD, PhD (Basel University Hospital) PRESENTER	The institution of Prof. Granziera has received research support from Novartis. The institution of Prof. Granziera has received research support from Hoffmann La Roche. The institution of Prof. Granziera has received research support from Genzyme Sanofi. The institution of Prof. Granziera has received research support from Biogen.
Patrick Vermersch (CHR de Lille)	Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AB Science. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Imcyse. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS-Celgene. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ad Scientiam. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Teva. Patrick Vermersch has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for La revue des microbiotes. The institution of Patrick Vermersch has received research support from Roche. The institution of Patrick Vermersch has received research support from Sanofi.
Biljana Djukic (Sanofi)	Miss Djukic has received personal compensation for serving as an employee of Sanofi.
Svend Geertsen, PhD (Sanofi)	Dr. Geertsen has received personal compensation for serving as an employee of Sanofi.
Andrea T. Shafer, PhD	Dr. Shafer has nothing to disclose.
Nazem Atassi, MD	Dr. Atassi has received personal compensation for serving as an employee of Sanofi. Dr. Atassi has stock in Sanofi.
Gavin Giovannoni, MD (QMUL)	Dr. Giovannoni has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Giovannoni has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi. Dr. Giovannoni has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Merck KGaA. Dr. Giovannoni has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Roche-Genentech. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Moderna. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sandoz. Dr. Giovannoni has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Astoria Biologica. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Zenas. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Giovannoni has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Dr. Giovannoni has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Medscape.

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