Article Impact Level: HIGH Data Quality: STRONG Summary of eBioMedicine, 118, 105840. https://doi.org/10.1016/j.ebiom.2025.10584 Dr. Matthew Lynch et al.
Points
- A clinical trial investigated the liquid fat triheptanoin as a potential treatment for Ataxia-telangiectasia by targeting the underlying mitochondrial dysfunction characteristic of the rare neurodegenerative disease.
- The study successfully met its primary endpoint, showing that triheptanoin significantly reduced cell death in the respiratory epithelial cells of patients compared to those who received a placebo.
- Participants receiving the treatment demonstrated notable improvements in motor control, including kinetic function and gait, as well as enhanced speech intelligibility and safer swallowing capabilities during the trial.
- Researchers observed gastrointestinal adverse events like abdominal pain and nausea in about 38% of participants, which necessitated capping the dose for those individuals at a lower level.
- The trial also identified neurofilament light chain and an interferon gene signature as potential biomarkers for tracking disease progression, with future research exploring a dual-therapy approach.
Summary
A Phase 2a/b placebo-controlled, dose-escalation trial evaluated the efficacy of triheptanoin in 31 participants with Ataxia-telangiectasia (A-T), aged 4 to 37 years. The study background established that A-T cells exhibit mitochondrial dysfunction, which is corrected in vitro by the triheptanoin metabolite, heptanoate. The trial involved dose escalations at two-month intervals over a 12-month period, with the primary outcome being the percentage of cell death in respiratory epithelial cells, a marker of mitochondrial function.
At the maximum tolerated dose compared to placebo, the trial met its primary outcome, showing a significant reduction in nasal cell death (mean difference [MD] = −9.7%, 95% confidence interval [CI] = −16.0 to −4.6). Key secondary outcomes also showed significant improvement, including the SARA subscale for kinetic function (MD = −5.8, 95% CI −10.4, −1.2) and ICARS subscales for gait (MD = −0.5, 95% CI −0.9, −0.1) and fine motor disturbance (MD = −2.7, 95% CI −4.3, −1.1). Furthermore, speech intelligibility (MD = −12.8, 95% CI = −21.2 to −4.3) and swallowing safety (−0.9, 95% CI = −1.6 to −0.3) were improved.
Gastrointestinal adverse events, including abdominal pain and nausea, were reported in 12 (38%) participants, requiring dose capping at 20% of caloric intake for those affected. The study concluded that triheptanoin improves mitochondrial function in A-T patients in vivo and identified neurofilament light chain and interferon signature-stimulated gene scores as promising biomarkers for monitoring disease progression and treatment response. Future research will explore a combination therapy with nicotinamide riboside.
Link to the article: https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(25)00284-1/fulltext
References Lynch, M., Manoy, S., Sly, P. D., Wainwright, C. E., Wolvetang, E., Feenstra, J. E., Dowling, J., Ware, R. S., Patel, M. S., Hermith-Ramirez, D., Vogel, A., Preece, K., Zappala, T., Dai, S., Webber, A., Yeo, A., Subramanian, G., Rao, G., Ma, C. S., … Coman, D. J. (2025). Phase 2a/b randomised placebo-controlled dose-escalation trial of triheptanoin for ataxia-telangiectasia: Treating mitochondrial dysfunction with anaplerosis. eBioMedicine, 118, 105840. https://doi.org/10.1016/j.ebiom.2025.10584
