Denali Therapeutics halted development of its RIPK1 inhibitor, SAR443820, after a phase 2 clinical trial failed to show meaningful benefits for adults with amyotrophic lateral sclerosis (ALS). The study, known as HIMALAYA (NCT05237284), found that the investigational drug did not slow functional decline over 24 weeks and was linked to a higher rate of adverse events, particularly raised liver enzymes.
Study Design and Participants
Investigators conducted the multicenter, randomized, double-blind, placebo-controlled trial across 63 sites in 13 countries. They enrolled 305 adults aged 18 to 80 who met the revised El Escorial criteria for ALS. Participants received either 20 mg of SAR443820 twice daily or a matching placebo for 24 weeks.
The trial screened 397 potential participants before randomization. The researchers stratified the assignment by geographic region, site of ALS onset, and current use of riluzole, edaravone, or sodium phenylbutyrate and taurursodiol. All parties, including clinicians and outcome assessors, remained masked to treatment allocation throughout the study.
Results on Functional Decline
The primary endpoint measured the change in the ALS Functional Rating Scale–Revised (ALSFRS-R) from baseline to week 24. For participants with evaluable data, the least-squares mean change was −6.73 points in the SAR443820 group and −6.32 points in the placebo group.
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The between-group difference was −0.41 points (95% CI, −1.71 to 0.88). This margin fell outside statistical significance, indicating no clear benefit from RIPK1 inhibition. Function declined by more than 6 points in both groups, with the numerical difference slightly favoring the placebo arm.
Despite the theoretical promise of targeting RIPK1, which regulates inflammatory pathways and cell death, the trial failed to produce a clinically meaningful outcome. The analysis included 169 participants on the experimental drug and 87 on placebo who completed the required assessments.
Safety Profile and Discontinuations
Safety data revealed that treatment with SAR443820 was associated with a higher burden of adverse events. Among the 202 treated participants, 171 (85%) experienced adverse events compared with 80 (78%) of the 102 placebo recipients.
Discontinuation was more common in the experimental group. Twenty-eight participants (14%) stopped taking SAR443820, while only 5 (5%) discontinued placebo. Raised hepatic enzymes were the most frequent reason for stopping treatment.
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During the double-blind period, nine deaths occurred; seven were among SAR443820 recipients and two were among placebo recipients. The investigators did not attribute any of these deaths to the investigational agent.
Implications for ALS Therapy
Merit E. Cudkowicz, MD, MSc, and colleagues concluded that the findings do not support further development of SAR443820 for ALS. The drug failed to demonstrate efficacy and introduced safety concerns that complicate its benefit-risk profile.
Given the absence of clinical efficacy and the increased incidence of liver abnormalities, the data argue against continuing clinical trials for this specific RIPK1 inhibitor in this patient population. Future studies would need to explore different compounds, dosing regimens, or biomarker-defined subgroups to determine if RIPK1 inhibition could eventually offer a therapeutic advantage.
Denali Therapeutics’ decision to halt development of SAR443820 is based on the results of the HIMALAYA trial. The company will likely focus on other potential treatments for ALS. Merit E. Cudkowicz and colleagues’ findings have significant implications for the development of ALS therapies. The study’s results will inform future research into the treatment of ALS.