An oral ALS drug aimed at inflammation failed its phase 2 trial

A drug designed to calm a destructive form of inflammation inside dying nerve cells did not slow amyotrophic lateral sclerosis in its first efficacy trial, and its maker is ending the programme [s1]. In the phase 2 HIMALAYA trial, physical function declined almost identically whether patients took the oral RIPK1 inhibitor SAR443820 or a placebo, and the drug caused more liver-enzyme elevations and more dropouts than placebo [s1].

ALS is a fatal neurodegenerative disease in which the motor neurons controlling movement, speech, swallowing and breathing progressively die; the two approved drugs, riluzole and edaravone, slow that course only modestly [s2]. Because inflammation and programmed cell death appear to accompany the neuron loss, drugmakers have looked for ways to interrupt those processes. RIPK1 — receptor- interacting serine/threonine-protein kinase 1 — sits at a control point for both inflammatory signalling and cell death, and SAR443820 is a selective, oral, brain-penetrant, reversible blocker of it [s1]. On paper it was an attractive target; HIMALAYA was built to find out whether hitting it changed anything patients could feel.

What the trial did

HIMALAYA was a multicentre, randomised, double-blind, placebo-controlled phase 2 trial run at 63 sites in 13 countries, funded by Sanofi [s1]. Adults aged 18 to 80 with ALS diagnosed under the revised El Escorial criteria were randomly assigned 2:1 to 20 mg of SAR443820 twice daily or a matching placebo for a 24-week double-blind period, on top of whatever standard ALS treatment they were already taking [s1]. Neither patients nor their clinicians nor the outcome assessors knew who received the drug [s1].

The primary outcome was the change from baseline to week 24 in the ALS Functional Rating Scale– Revised (ALSFRS-R), the standard measure of everyday physical function in ALS, on which scores fall as the disease takes away abilities [s1]. Between April 2022 and July 2023, 397 people were screened and 305 randomly assigned — 203 to SAR443820 and 102 to placebo; six were left out of the primary analysis for missing baseline scores [s1]. The participants' mean age was 56.9 years, and 183 (60%) were male and 122 (40%) female [s1].

What it found

Function declined at essentially the same rate in both groups. The least-squares mean fall in ALSFRS-R over 24 weeks was 6.73 points with SAR443820 (95% confidence interval 5.98 to 7.48, n=169) and 6.32 points with placebo (5.27 to 7.36, n=87) [s1]. The difference between them was 0.41 points in the drug's disfavour, with a confidence interval of −1.71 to 0.88 that comfortably spans zero — no signal of benefit [s1].

Safety ran the wrong way too. Adverse events were reported in 171 (85%) of 202 treated patients versus 80 (78%) of 102 on placebo, and treatment was stopped early in 28 (14%) of the SAR443820 group against five (5%) of the placebo group, most often because of raised liver enzymes [s1]. Nine people died during the double-blind period — seven (3%) of 202 on the drug and two (2%) of 102 on placebo — none of the deaths attributed to SAR443820, a reminder of how quickly ALS itself progresses [s1]. The trial was terminated early, and the authors concluded that further development of SAR443820 in ALS is not warranted [s1].

How to read a null result

A trial that finds nothing is not a wasted trial; it is an answer. HIMALAYA was adequately sized, properly blinded and placebo-controlled, and it measured the outcome that matters — whether people kept more of their physical function [s1]. When two curves of decline overlap this closely, and the confidence interval around their difference straddles zero, the honest reading is that the drug did not work at the dose and duration tested, not that the question is still open [s1]. Charting the two declines side by side, with their intervals, shows the point better than any adjective: the bars are nearly the same height, and their whiskers overlap almost completely.

Two limits are worth naming. A single dose and a 24-week window cannot rule out a small effect that a different dose or a longer trial might have surfaced, and the liver-enzyme problem would have constrained higher dosing anyway [s1]. And a negative result for one RIPK1 inhibitor in ALS does not close the book on inflammation as a driver of the disease; it closes the book on this molecule, at this dose, on this timescale [s1]. That distinction is exactly the one that hype tends to erase in both directions — a failed trial gets read as proof the whole idea was wrong, or gets quietly reframed as "signals worth pursuing." Neither is what the data say.

The result also lands in a field where honest negatives are the norm rather than the exception: most ALS drug candidates that reach efficacy testing do not beat placebo, which is part of why riluzole and edaravone remain the mainstays despite their modest effect [s2]. Related coverage has examined a kidney-disease drug that narrowly missed its primary endpoint and how to weigh a borderline result, a vaccine trial that came back flatly negative, and what brain–computer interfaces can and cannot yet do for people paralysed by conditions like ALS.

What to watch

Sanofi's decision to stop SAR443820 in ALS removes one candidate from a thin pipeline, but RIPK1 inhibitors are still being studied in other inflammatory and neurological conditions, where the balance of benefit and liver risk may fall differently [s1]. For ALS specifically, the open question is not whether to keep testing this drug — the trial answered that — but whether the broader bet on blocking neuroinflammation can be made to pay off with a different target, a different molecule, or patients selected by a marker of active inflammation [s1][s2].

This article describes research and is not medical advice. Treatment decisions in ALS are for patients and their clinicians.

Sources

• Safety, tolerability, and efficacy of RIPK1 inhibitor, SAR443820, in amyotrophic lateral sclerosis (HIMALAYA): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial — The Lancet Neurology, 9 September 2026
• Amyotrophic lateral sclerosis (Seminar) — The Lancet, 15 September 2022