1100 - Frexalimab, a Second-Generation Anti-CD40 Ligand Antibody: Prolonged Kidney Allograft Survival in Non-Human Primates with Subcutaneous Maintenance Administration

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Author Block: P. Severy¹, J. L. Vela¹, I. Mochkin², J. Voss³, E. Poulton¹, A. Vergani¹, C. Radosti³, ¹Sanofi, Cambridge, MA, ²Sanofi, Paris, France, ³Sanofi, Morristown, NJ
*Purpose: Frexalimab, a 2^nd generation anti-CD40L monoclonal antibody with an Fc region engineered to prevent platelet aggregation and mitigate thromboembolic risks, inhibits the CD40/CD40L costimulatory pathway critical for alloimmune responses. It is being investigated in Phase 3 (multiple sclerosis) and Phase 2 trials (type 1 diabetes, systemic lupus erythematosus, glomerulonephritis). This study presents non-human primate (NHP) data on frexalimab's efficacy and safety in kidney transplantation, supporting its clinical development for this indication.
*Methods: Male cynomolgus monkeys with major histocompatibility complex mismatch in ≥6/7 major antigens underwent life-sustaining kidney transplantation with remaining native kidney removed and administered vehicle control (n=2) or frexalimab 100 mg/kg weekly: intravenous (IV; n=6) or 1^st dose IV then subcutaneous (SC; n=6). They did not receive any induction therapy, steroids, other immunosuppressants, or any prophylaxis for viral infections. Survival, renal function, pharmacokinetics, clinical signs, donor-specific antibodies, and histopathology were monitored for 120 days.
*Results: In this NHP model, frexalimab significantly prolonged graft survival vs. control (median 68 vs. 10 days, p=0.0152); 4/12 frexalimab-treated NHPs had functioning allografts through 120 days. One NHP (SC/IV group) with surgical infarct was excluded (Figure 1). SC formulation showed comparable efficacy to IV. Frexalimab-treated NHPs reaching the 120-day endpoint (n=4) maintained stable serum creatinine and adequate urine output, with milder mononuclear-cell infiltration and tubular degeneration per histology vs. the severity seen in untreated and treated NHPs not reaching 120 days. Donor-specific antibody development was suppressed in frexalimab-treated NHPs: <1.5-fold change from baseline on donor T and B cells (except 1 NHP had >2-fold change on B cells while maintaining graft function). Transient cytomegalovirus levels were detected in a few NHPs, which resolved without treatment with no symptomatic infections. No major adverse events related to frexalimab were observed, confirming its positive safety profile.
*Conclusions: These data demonstrate that frexalimab, an anti-CD40L, without other immunosuppressive agents, is effective and safe at preventing rejection in a NHP transplantation model. This supports the advancement of frexalimab’s clinical development program in kidney transplantation.