RIPK1 Inhibitor Fails to Slow Functional Decline in Phase 2 ALS Trial

Findings from the phase 2 HIMALAYA trial (NCT05237284), recently published in The Lancet Neurology, showed that the investigational receptor-interacting protein kinase 1 (RIPK1) inhibitor DNL788 (Denali Therapeutics), also known as SAR443820, did not slow functional decline in adults with amyotrophic lateral sclerosis (ALS). Treatment with the agent was also associated with more adverse events and discontinuations, particularly those related to elevated hepatic enzyme levels.¹

The findings do not support further development of SAR443820 for ALS, according to lead author Merit E. Cudkowicz, MD, MSc, director of the Sean M. Healey & AMG Center for ALS at Massachusetts General Hospital, and colleagues. Although RIPK1 remains a biologically relevant target because of its role in inflammatory signaling and regulated cell death, the results illustrate the challenge of translating mechanistic and preclinical evidence into clinically meaningful benefits for patients.

Study Overview

HIMALAYA was a multicenter, randomized, double-blind, placebo-controlled phase 2 trial conducted at 63 sites across 13 countries. Investigators enrolled adults aged 18 to 80 years who met revised El Escorial criteria for possible, clinically probable, laboratory-supported clinically probable, or clinically definite ALS.^1,2

Between April 2022, and July 2023, investigators screened 397 participants and randomly assigned 305 in a 2:1 ratio to receive oral SAR443820, 20 mg twice daily, or matching placebo for 24 weeks. Randomization was stratified by geographic region, site of ALS onset, and use of riluzole, edaravone, or sodium phenylbutyrate and taurursodiol.

Participants, clinicians, investigators, and outcome assessors remained masked to treatment assignment. The primary end point was change from baseline through week 24 in the ALS Functional Rating Scale–Revised (ALSFRS-R), a measure incorporating bulbar, motor, and respiratory function.³ As a result of the final data, the trial was terminated early.

Key Findings

Among participants with evaluable baseline and week 24 data, the least-squares mean ALSFRS-R change was −6.73 points (95% CI, −7.48 to −5.98) with SAR443820 and −6.32 points (95% CI, −7.36 to −5.27) with placebo. The between-group difference was −0.41 points (95% CI, −1.71 to 0.88), indicating no statistically significant benefit with RIPK1 inhibition.

Function therefore declined by more than 6 points over 24 weeks in both groups, with the numerical difference slightly favoring placebo. The efficacy analysis included 169 participants assigned to SAR443820 and 87 assigned to placebo who had the required ALSFRS-R assessments.

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Adverse events (AEs) occurred in 171 of 202 treated participants (85%) receiving SAR443820 and 80 of 102 participants (78%) receiving placebo. Treatment discontinuation was also more frequent with SAR443820, occurring in 28 participants (14%) compared with 5 participants (5%) receiving placebo. Elevated hepatic enzymes were the most common reason for discontinuation.

Nine deaths occurred during the double-blind period, 7 among SAR443820 recipients and 2 among placebo recipients. Investigators attributed none of the deaths to SAR443820.

Clinical Context and Interpretation

RIPK1 regulates inflammatory pathways and cell death, and experimental research has implicated RIPK1-mediated inflammation and necroptosis in ALS-related axonal degeneration.⁴ SAR443820 was designed as a selective, reversible, orally administered inhibitor capable of penetrating the central nervous system.

Despite that rationale, the trial showed neither a statistically significant nor numerically favorable functional effect. The greater frequency of hepatic enzyme elevations further narrowed the potential benefit-risk profile. These findings are particularly relevant in ALS, where treatment options remain limited and riluzole has provided the longstanding foundation of disease-modifying therapy.⁵

Limitations and Future Research

Early trial termination and missing week 24 assessments reduced the efficacy population relative to the randomized cohort. The 24-week follow-up also limited assessment of longer-term functional, survival, and safety outcomes. In addition, the study evaluated a single dose and regimen, and its findings cannot determine whether RIPK1 inhibition might be effective with another compound, at a different disease stage, or in a biomarker-defined subgroup.

Future research would need to clarify whether target engagement can be linked to measurable changes in neuroinflammation and whether specific ALS phenotypes are more dependent on RIPK1 signaling. For SAR443820 itself, however, the absence of clinical benefit and increased hepatic enzyme abnormalities argue against continued development in ALS.

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REFERENCES
1. Cudkowicz ME, Shefner J, van den Berg LH, et al. Safety, tolerability, and efficacy of RIPK1 inhibitor, SAR443820, in amyotrophic lateral sclerosis (HIMALAYA): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2026;25(10):900-910. doi:10.1016/S1474-4422(26)00277-2
2. Brooks BR, Miller RG, Swash M, Munsat TL; World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;1(5):293-299. doi:10.1080/146608200300079536
3. Cedarbaum JM, Stambler N, Malta E, et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci. 1999;169(1-2):13-21. doi:10.1016/s0022-510x(99)00210-5
4.Ito Y, Ofengeim D, Najafov A, et al. RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science. 2016;353(6299):603-608. doi:10.1126/science.aaf6803
5. Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med. 1994;330(9):585-591. doi:10.1056/NEJM199403033300901