Safety, tolerability, and efficacy of RIPK1 inhibitor, SAR443820, in amyotrophic lateral sclerosis (HIMALAYA): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.

SAR443820, a CNS-penetrant oral RIPK1 inhibitor, did not improve ALSFRS-R over 24 weeks versus placebo in a phase 2 trial, with no significant difference.

• Why it matters: RIPK1-driven inflammatory signalling and cell death are linked to ALS, but the safety and clinical benefit of inhibiting RIPK1 in people with ALS remained uncertain.
• What they did: In a multicentre, randomised, double-blind, placebo-controlled phase 2 trial across 63 sites in 13 countries, adults with possible to definite ALS received 20 mg SAR443820 twice daily or placebo for 24 weeks.
• The result: ALSFRS-R change from baseline to week 24 was -6·73 (95% CI -7·48 to -5·98) with SAR443820 (n=169) versus -6·32 (95% CI -7·36 to -5·27) with placebo (n=87), with a least squares mean difference of -0·41 (95% CI -1·71 to 0·88). Adverse events were more frequent with SAR443820 (171/202 vs 80/102) and treatment discontinuations were higher (28/202 vs 5/102), with elevated hepatic enzymes most common.

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