Trehalose Fails to Slow ALS Progression in Major Phase 2/3 Trial
A large adaptive trial finds trehalose, a sugar that activates autophagy, showed no benefit over placebo in slowing ALS disease progression.
Summary
The HEALEY ALS Platform Trial tested whether trehalose — a natural disaccharide known to activate autophagy and clear toxic misfolded proteins — could slow progression of amyotrophic lateral sclerosis (ALS). In this rigorous phase 2/3 adaptive trial across 60 US sites, 120 patients received weekly intravenous trehalose and 205 received placebo over 24 weeks. The primary composite outcome measuring disease progression via ALSFRS-R and survival showed no meaningful difference between groups (disease rate ratio 0.87, posterior probability of superiority 0.877). Secondary clinical and biomarker measures also showed no benefit. While trehalose was generally well tolerated, more serious adverse events and treatment discontinuations occurred in the trehalose group. Researchers concluded that trehalose at this dose is unlikely to be an effective ALS treatment.
Detailed Summary
Amyotrophic lateral sclerosis (ALS) remains one of the most devastating and rapidly fatal neurodegenerative diseases, with very limited treatment options. Researchers have been exploring autophagy activation — the cellular process of clearing toxic, misfolded proteins — as a potential therapeutic strategy. Trehalose, a naturally occurring disaccharide, had shown promise in animal models of neurodegeneration by stimulating autophagy pathways in motor neurons, making it a compelling candidate for human trials.
The HEALEY ALS Platform Trial is an innovative perpetual adaptive platform design allowing multiple treatment regimens to be tested simultaneously against shared placebo controls. In the trehalose regimen, 161 eligible adults with ALS were randomized 3:1 to receive 0.75 g/kg intravenous trehalose weekly or matching placebo for 24 weeks across 60 geographically diverse US sites. Screening occurred between February 2022 and February 2023, with 1,021 patients screened in total.
The primary composite outcome — combining the rate of ALSFRS-R functional decline and survival over 24 weeks in a Bayesian shared-parameter model — showed a disease rate ratio of 0.87 (95% credible interval 0.665–1.102) with a posterior probability of superiority of 0.877, falling well short of the threshold for meaningful benefit. No secondary clinical outcomes or biomarker measures showed significant improvement with trehalose.
On the safety side, serious adverse events were more frequent in the trehalose group (16%) compared to regimen-only placebo (7%), and premature discontinuations were higher (12% vs. 2%). Seven fatal treatment-emergent adverse events occurred in the trehalose group, though none were considered drug-related; most deaths were attributed to respiratory failure consistent with ALS natural history.
These results indicate that trehalose at this intravenous dose and schedule is unlikely to benefit people with ALS. While the autophagy hypothesis remains scientifically plausible, this trial highlights the challenge of translating animal model findings into human therapies and underscores the need for better biomarkers and dosing strategies in future ALS drug development.
Key Findings
- Trehalose showed no significant benefit over placebo on the primary composite of ALSFRS-R progression and survival (rate ratio 0.87).
- Posterior probability of superiority was 0.877, below the threshold needed to demonstrate efficacy.
- No secondary clinical or biomarker outcomes favored trehalose over placebo.
- Serious adverse events were more common in the trehalose group (16%) versus placebo (7%), with more discontinuations.
- Seven fatal adverse events occurred in the trehalose group, none considered drug-related; respiratory failure was the primary cause.
Methodology
This was a phase 2/3 adaptive, double-blind, randomized, placebo-controlled platform trial conducted at 60 US sites, using a Bayesian shared-parameter model to assess a composite primary outcome of ALSFRS-R decline and survival over 24 weeks. Randomization was 3:1 (trehalose:placebo) with prespecified interim analyses every 12 weeks and futility stopping rules; placebo participants from other platform regimens were pooled to increase statistical power.
Study Limitations
The trial was limited to a single dose and route of administration (IV weekly), so alternative dosing strategies or oral formulations cannot be ruled out as potentially effective. The 24-week follow-up period may be insufficient to detect slower-acting biological effects, and only abstract data were available for this summary, limiting full assessment of subgroup analyses or biomarker details.
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