Highlights
- Trehalose, a disaccharide known to activate autophagy, did not significantly alter disease progression in ALS when compared to placebo in the HEALEY ALS Platform Trial.
- The trial demonstrated good tolerability of trehalose, but no clinical or biomarker efficacy was observed at the tested dose.
- Serious adverse events, including deaths, were consistent with ALS natural history and not attributed to the study drug.
Study Background and Disease Burden
Amyotrophic lateral sclerosis (ALS) is a devastating, progressive neurodegenerative disorder characterized by the loss of motor neurons, leading to muscle weakness, paralysis, and ultimately respiratory failure. Despite extensive research, therapeutic options for ALS remain limited, with riluzole and edaravone offering only modest benefits. A major therapeutic target in ALS and other neurodegenerative diseases is the clearance of toxic, misfolded proteins in motor neurons. Trehalose, a naturally occurring disaccharide, has been shown in preclinical studies to activate autophagy pathways, potentially facilitating the removal of aggregated proteins implicated in ALS pathogenesis. However, clinical efficacy in humans remained unproven prior to this trial.
Study Design
The HEALEY ALS Platform Trial is an innovative, perpetual, adaptive, multi-regimen phase 2/3 trial, designed to accelerate the evaluation of potential ALS therapies. Conducted at 60 diverse sites across the USA, the trial enrolled adults meeting the revised El Escorial criteria for possible, probable, laboratory-supported probable, or definite ALS. In this regimen, participants were randomized in a 3:1 ratio to receive either intravenous trehalose (0.75 g/kg weekly for 24 weeks) or a matched placebo, with stratification based on concurrent use of riluzole and edaravone. The primary endpoint was a composite measure of ALS Functional Rating Scale-Revised (ALSFRS-R) rate of decline and survival over 24 weeks, analyzed using a Bayesian shared-parameter model. Interim analyses were planned every 12 weeks, with prespecified stopping rules for futility. The safety population included all participants who initiated treatment, and intention-to-treat analysis was applied to efficacy outcomes. The study also incorporated placebo groups from other regimens to enhance statistical power.
Key Findings
Between February 2022 and February 2023, 1021 individuals were screened, and 171 were assigned to the trehalose arm; 161 met eligibility criteria, with 120 randomized to trehalose and 41 to regimen-specific placebo. An additional 164 placebo recipients from other regimens were included, yielding 205 total placebo participants.
The primary efficacy result showed a disease rate ratio for ALSFRS-R decline and survival of 0.87 (95% credible interval 0.665-1.102), with a posterior probability of superiority of 0.877. This did not meet the prespecified threshold for meaningful clinical benefit. No statistically significant benefit was observed in secondary clinical or biomarker endpoints.
In terms of safety, serious adverse events occurred in 16% of the trehalose group versus 7% in the regimen-only placebo group. Premature treatment discontinuations due to adverse events were more common with trehalose (12%) than placebo (2%). Seven fatal treatment-emergent adverse events occurred in the trehalose group, all deemed unrelated to the study drug—most commonly due to respiratory failure, in line with ALS progression. No new safety signals were identified.
Expert Commentary
The HEALEY ALS Platform Trial represents a methodological advancement for ALS research, offering an efficient framework for testing multiple therapies in parallel. The lack of efficacy for trehalose in this trial underscores the ongoing challenge of translating promising mechanistic insights into clinically meaningful outcomes for ALS. The results also highlight the importance of rigorous, adequately powered trials with robust endpoints for rare and heterogeneous diseases such as ALS.
Mechanistically, while activation of autophagy remains a compelling target, the inability of trehalose to impact clinical or biomarker measures suggests either insufficient central nervous system penetration, inadequate dosing, or that autophagy modulation alone is insufficient to alter ALS progression in humans. The high rate of trial discontinuations in the trehalose arm further emphasizes the need for tolerable, patient-friendly administration routes in a population already facing significant disease burden.
Current clinical guidelines continue to recommend riluzole and edaravone as standards of care, with ongoing trials investigating multi-targeted agents and gene therapies. The adaptive platform design of the HEALEY trial remains a promising approach for accelerating therapy development in ALS.
Conclusion
In summary, intravenous trehalose at the tested dose was safe but did not provide a statistically or clinically significant benefit in slowing ALS progression. No efficacy was demonstrated in secondary outcomes or biomarkers. While the concept of autophagy activation remains biologically plausible, these findings indicate that trehalose is unlikely to be a viable ALS therapy at the current regimen. Ongoing research should focus on alternative targets, improved drug delivery, and precision medicine approaches tailored to ALS subtypes.
References
1. Paganoni S, et al. The HEALEY ALS Platform Trial: design, rationale, and baseline characteristics. Ann Clin Transl Neurol. 2022;9(3):364-375.
2. Hardiman O, et al. Amyotrophic lateral sclerosis. Nat Rev Dis Primers. 2017;3:17071.
3. ClinicalTrials.gov. NCT05136885. Safety and Efficacy of Trehalose in ALS (HEALEY ALS Platform Trial). https://clinicaltrials.gov/ct2/show/NCT05136885
4. Menzies FM, et al. Autophagy and neurodegeneration: pathogenic mechanisms and therapeutic opportunities. Neuron. 2017;93(5):1015-1034.