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SAR443820 RIPK1 Inhibitor Shows No Functional Benefit in ALS at 24 Weeks
A phase 2 randomised controlled trial found no clinically meaningful or statistically significant difference in ALS functional decline between SAR443820 and placebo over 24 weeks, with the least squares mean difference in ALSFRS-R score amounting to just -0.41 points (95% CI -1.71 to 0.88). The drug was also associated with higher rates of adverse events and hepatic enzyme elevations, prompting early trial termination and leading investigators to conclude that further clinical development of this compound in ALS is not warranted.
What Was Studied
The trial examined whether SAR443820, a selective, orally administered, CNS-penetrant, and reversible inhibitor of RIPK1 — a protein involved in inflammatory signalling and cell death pathways implicated in ALS pathophysiology — could slow functional decline in people living with ALS. The primary outcome was change in the ALS Functional Rating Scale Revised (ALSFRS-R) total score from baseline to 24 weeks, a validated measure of disease progression tracking motor and respiratory function.
How It Was Studied
The HIMALAYA trial was a multicentre, randomised, double-blind, placebo-controlled phase 2 study conducted across 63 clinical sites in 13 countries. Adults aged 18 to 80 years with a diagnosis spanning the spectrum from possible to clinically definite ALS, as defined by the revised El Escorial World Federation of Neurology criteria, were eligible to participate. A total of 305 participants were randomly assigned in a 2:1 ratio — 203 to SAR443820 at 20 mg orally twice daily and 102 to matching placebo — using a stratified block design that accounted for geographic region, site of ALS onset, and use of concomitant ALS therapies including riluzole, edaravone, and sodium phenylbutyrate with taurursodiol. Participants, investigators, care providers, and outcomes assessors were all masked to treatment allocation throughout the 24-week double-blind period.
What Was Observed
- No difference in functional decline between groups: Both groups experienced substantial worsening on the ALSFRS-R over 24 weeks. The SAR443820 group declined by a least squares mean of -6.73 points (95% CI -7.48 to -5.98) and the placebo group by -6.32 points (95% CI -7.36 to -5.27). The between-group difference of -0.41 points (95% CI -1.71 to 0.88) was not statistically significant, indicating that the drug provided no measurable functional benefit over placebo.
- Higher rate of adverse events in the treated group: Adverse events occurred in 85% of participants receiving SAR443820 (171 of 202) compared with 78% in the placebo group (80 of 102), suggesting a modestly higher burden of side effects with active treatment.
- Notable hepatic safety signal and treatment discontinuations: Treatment discontinuations were nearly three times more frequent in the SAR443820 group (14%, 28 of 202) than in the placebo group (5%, 5 of 102), with elevated hepatic enzymes identified as the most common driver of discontinuation.
- Deaths during the double-blind period were numerically higher in the treated arm but not attributed to drug: Nine deaths occurred in total — seven (3%) in the SAR443820 group and two (2%) in the placebo group — and none was considered causally related to study treatment by investigators.
Why This Matters
ALS remains a disease with very limited treatment options, and SAR443820 was designed to target RIPK1-mediated neuroinflammation and cell death, a biologically plausible mechanism in the disease. The complete absence of functional benefit alongside a hepatic safety signal suggests that RIPK1 inhibition through this particular compound does not translate into clinical disease modification, and the tolerability profile further constrains its therapeutic viability. These results directly inform the field’s evaluation of this mechanistic target and dosing approach in ALS.
How to Read This Result
Although the trial used a rigorous double-blind design across a large international network, early termination may have reduced statistical power to detect small but potentially meaningful treatment effects, and the 24-week observation window may be insufficient to capture disease-modifying signals in a slowly progressive condition like ALS.
Limitations
The trial was terminated before reaching its planned enrolment, which constrains the ability to draw definitive conclusions about efficacy and increases uncertainty around the precision of the estimates. Additionally, six participants were excluded from the primary analysis due to missing baseline ALSFRS-R values, introducing a minor potential for incomplete representation of the full randomised population.