Amlitelimab (SAR445229): A Comprehensive Clinical and Strategic Analysis of a First-in-Class OX40 Ligand Inhibitor

Executive Summary

Amlitelimab (SAR445229) is an investigational, fully human, non-depleting monoclonal antibody poised to establish a new therapeutic class as a first-in-class inhibitor of the OX40 ligand (OX40L). Developed by Sanofi following its strategic acquisition of Kymab Ltd., Amlitelimab represents a significant advancement in immunomodulatory therapy, with its primary development focus on moderate-to-severe atopic dermatitis (AD). Its novel mechanism of action, which involves targeting an upstream co-stimulatory pathway critical for T-cell activation and memory, distinguishes it from existing treatments that target more downstream inflammatory mediators. By binding to OX40L on antigen-presenting cells, Amlitelimab blocks the activation of multiple T-helper cell subsets (Th2, Th1, Th17, and Th22) implicated in AD pathogenesis. Critically, this approach spares regulatory T-cells, suggesting a potential to restore immune homeostasis rather than inducing broad immunosuppression.

The clinical development program has yielded compelling evidence of Amlitelimab's efficacy and a favorable safety profile. The pivotal Phase IIb STREAM-AD study in adults with moderate-to-severe AD met its primary and key secondary endpoints, demonstrating statistically significant and clinically meaningful improvements in skin lesions and pruritus across all doses tested. The most profound finding from this trial was the unprecedented durable response observed in patients after treatment cessation; a majority of clinical responders maintained significant improvements for at least 28 weeks off-drug. This durable effect is supported by biomarker data showing sustained suppression of key inflammatory mediators long after the drug was withdrawn, lending credence to its potential for long-term disease modification.