MedicineEurope PMC
Heuristic editor, no API keyVerdict: MajorSafety, tolerability, and efficacy of RIPK1 inhibitor, SAR443820, in amyotrophic lateral sclerosis (HIMALAYA): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial
Background RIPK1, a protein regulating inflammatory signalling and cell death, is implicated in amyotrophic lateral sclerosis (ALS) pathophysiology.
Key numbers
- 95% CI
VerdictA leading story on any desk.
Abstract
Background RIPK1, a protein regulating inflammatory signalling and cell death, is implicated in amyotrophic lateral sclerosis (ALS) pathophysiology. SAR443820 is a selective, oral, CNS-penetrant, reversible RIPK1 inhibitor. We aimed to evaluate the safety, tolerability, and efficacy of SAR443820 in participants with ALS. Methods This multicentre, randomised, double-blind, placebo-controlled, phase 2 trial was conducted at 63 clinical sites in 13 countries (Belgium, Canada, China, France, Germany, Italy, Japan, the Netherlands, Poland, Spain, Sweden, the UK, and the USA). Adults (aged 18-80 years) with a diagnosis of possible ALS, clinically probable ALS, clinically probable laboratory-supported ALS, or clinically definite ALS, in accordance with the revised El Escorial World Federation of Neurology criteria, were randomly assigned (2:1) by use of a stratified block design (blocks of three) to receive either 20 mg SAR443820 orally twice per day or matching placebo in the 24-week double-blind period. Randomisation was done centrally using interactive response technology and stratified by geographical region of trial site, region of ALS onset, use of riluzole, use of edaravone, and use of the combination of sodium phenylbutyrate and taurursodiol. Participants, care providers, investigators, and outcomes assessors were masked to trial intervention. The primary outcome was a change in ALS Functional Rating Scale Revised (ALSFRS-R) total score from baseline to week 24 and was calculated for all participants who had an ALSFRS-R total score available at baseline and at week 24. Safety analyses included all randomly assigned participants receiving one dose or more of trial intervention. This trial is registered with ClinicalTrials.gov (NCT05237284) and was terminated early. Findings Between April 13, 2022, and July 17, 2023, 397 participants were screened and 305 randomly assigned to SAR443820 (n=203) or placebo (n=102); six were excluded from the primary analysis due to missing baseline ALSFRS-R values. Mean age was 56·9 years (SD 11·5); 183 (60%) participants were male and 122 (40%) were female. Least squares mean change in ALSFRS-R from baseline to week 24 was -6·73 (95% CI -7·48 to -5·98) for SAR443820 group (n=169) and -6·32 (-7·36 to -5·27) for placebo group (n=87). There was no statistically significant difference between the study groups (least squares mean difference -0·41 [95% CI -1·71 to 0·88]). Participants in the SAR443820 group had higher incidence of adverse events (171 [85%] of 202 vs placebo 80 [78%] of 102) and treatment discontinuations (28 [14%] of 202 vs placebo five [5%] of 102), with elevated hepatic enzymes being the most common cause. Nine deaths occurred in the double-blind period (seven [3%] of 202 in the SAR443820 group and two [2%] of 102 in the placebo group); none was attributed to SAR443820. Interpretation SAR443820 did not show clinical benefit and was associated with higher hepatic enzyme increase, indicating that further clinical development of SAR443820 in ALS is not warranted. Funding Sanofi.
The editor's rubric
| Dimension | Level | Weight | What that level means |
|---|---|---|---|
| Leverage | ███░░ 3 | 10% | A method or resource many groups across the field will adopt within a year. |
| Magnitude | ███░░ 3 | 20% | Large gain: roughly 2x, or a clear new state of the art on a hard, unsaturated problem. |
| Evidence | █████ 5 | 32% | Definitive: phase 3 randomized evidence on hard endpoints, multi-lab replication, or community verification at scale. |
| Novelty | ██░░░ 2 | 8% | A new combination of known ideas. |
| Trajectory | ███░░ 3 | 5% | A clear path to scale. |
| Stakes | ███░░ 3 | 25% | Meaningful benefit to many people within a few years. |
Editor’s rationale
Heuristic triage from title and abstract text only, not a reading of the paper. Cues found: breadth (many tasks); gains (versus baseline); novelty (open problem); design (randomized, blinded, placebo-controlled); verification (confidence interval); scale (scalable); stakes (mortality, prevention or cure).
How the score was computed
- Merit
- 7.1 / 10
- Adjusted merit
- 5.6 / 10
- Attention
- 35%
- Freshness
- 98%
- Citations1 (reference 20, via openalex, Oct 1, 2026, 06:17 UTC)
- Field-weighted citation impact5.0 (reference 3, via openalex, Oct 1, 2026, 06:17 UTC)