Phase 2a/b randomised placebo-controlled dose-escalation trial of triheptanoin for ataxia-telangiectasia: treating mitochondrial dysfunction with anaplerosis

Matthew Lynch; Sophie Manoy; Peter D Sly; Claire E Wainwright; Ernst Wolvetang; John E Feenstra; Jason Dowling; Robert S Ware; Maharshi S Patel; Diana Hermith-Ramirez; Adam Vogel; Kahn Preece; Tania Zappala; Shuan Dai; Ann Webber; Abrey Yeo; Goutham Subramanian; Geetha Rao; Cindy S Ma; Sara Jose; Magtouf Gatei; Bowen Xin; Nicoletta Sandona; Peter Lewindon; Katherine G Sinclair; Sam Nayler; Martin F Lavin; David J Coman

doi:10.1016/j.ebiom.2025.105840

Phase 2a/b randomised placebo-controlled dose-escalation trial of triheptanoin for ataxia-telangiectasia: treating mitochondrial dysfunction with anaplerosis

EBioMedicine. 2025 Jul 4:118:105840. doi: 10.1016/j.ebiom.2025.105840. Online ahead of print.

Authors

Matthew Lynch¹, Sophie Manoy², Peter D Sly³, Claire E Wainwright⁴, Ernst Wolvetang⁵, John E Feenstra⁶, Jason Dowling⁷, Robert S Ware⁸, Maharshi S Patel⁹, Diana Hermith-Ramirez⁹, Adam Vogel¹⁰, Kahn Preece¹¹, Tania Zappala¹², Shuan Dai¹³, Ann Webber¹⁴, Abrey Yeo¹⁵, Goutham Subramanian¹⁶, Geetha Rao¹⁷, Cindy S Ma¹⁸, Sara Jose¹⁵, Magtouf Gatei¹⁶, Bowen Xin⁷, Nicoletta Sandona¹⁹, Peter Lewindon²⁰, Katherine G Sinclair²¹, Sam Nayler²², Martin F Lavin¹⁵, David J Coman²³

Affiliations

¹ Department of Metabolic Medicine, Queensland Children's Hospital, South Brisbane, QLD, 4101, Australia; Department of Paediatrics, Wesley Medical Research, Auchenflower Brisbane, QLD, 4066, Australia; Child Health Research Centre, Faculty of Medicine, University of Queensland, South Brisbane, QLD, 4101, Australia; Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Saint Lucia Brisbane, QLD, 4067, Australia.
² Department of Metabolic Medicine, Queensland Children's Hospital, South Brisbane, QLD, 4101, Australia; Child Health Research Centre, Faculty of Medicine, University of Queensland, South Brisbane, QLD, 4101, Australia.
³ Child Health Research Centre, Faculty of Medicine, University of Queensland, South Brisbane, QLD, 4101, Australia.
⁴ Child Health Research Centre, Faculty of Medicine, University of Queensland, South Brisbane, QLD, 4101, Australia; Department of Respiratory and Sleep Medicine, Queensland Children's Hospital, South Brisbane, QLD, 4101, Australia.
⁵ Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Saint Lucia Brisbane, QLD, 4067, Australia.
⁶ Faculty of Medicine, University of Queensland, South Brisbane, QLD, 4101, Australia; Department of Adult Respiratory and Sleep Medicine, Wesley Medical Research, Auchenflower Brisbane, QLD, 4066, Australia.
⁷ Australian e-Health Research Centre, CSIRO, Herston, Brisbane, QLD, 4006, Australia.
⁸ School of Medicine and Dentistry, Griffith University, Gold Coast, 4222, Australia; Griffith Biostatistics Unit, Griffith University, Nathan Campus, Brisbane, QLD, 4111, Australia.
⁹ Griffith Biostatistics Unit, Griffith University, Nathan Campus, Brisbane, QLD, 4111, Australia.
¹⁰ School of Health Sciences, The University of Melbourne, Parkville, Melbourne, 3010, Australia; Redenlab Inc., Melbourne 3000, Australia.
¹¹ Department of Immunology and Allergy, John Hunter Children's Hospital, New Lambton Heights, Newcastle, NSW, 2305, Australia.
¹² Department of Paediatrics and Dermatology, Queensland Children's Hospital, South Brisbane, QLD, 4101, Australia.
¹³ Child Health Research Centre, Faculty of Medicine, University of Queensland, South Brisbane, QLD, 4101, Australia; Department of Ophthalmology, Queensland Children's Hospital, South Brisbane, QLD, 4101, Australia.
¹⁴ Department of Ophthalmology, Queensland Children's Hospital, South Brisbane, QLD, 4101, Australia.
¹⁵ University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, Herston Brisbane, QLD, 4029, Australia.
¹⁶ Department of Gastroenterology and Hepatology, Queensland Children's Hospital, South Brisbane, QLD, 4101, Australia.
¹⁷ Human Immune Disorders Laboratory, Garvan Institute of Medical Research, NSW, 2010, Australia.
¹⁸ Human Immune Disorders Laboratory, Garvan Institute of Medical Research, NSW, 2010, Australia; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, NSW, Australia.
¹⁹ Department of Paediatrics, Wesley Medical Research, Auchenflower Brisbane, QLD, 4066, Australia.
²⁰ Child Health Research Centre, Faculty of Medicine, University of Queensland, South Brisbane, QLD, 4101, Australia; Department of Gastroenterology and Hepatology, Queensland Children's Hospital, South Brisbane, QLD, 4101, Australia.
²¹ Department of Paediatrics, Wesley Medical Research, Auchenflower Brisbane, QLD, 4066, Australia; Child Health Research Centre, Faculty of Medicine, University of Queensland, South Brisbane, QLD, 4101, Australia; Neurosciences Department, Queensland Children's Hospital, South Brisbane, QLD, 4101, Australia.
²² QIMR-Berghofer Research Institute, QLD, 4006, Australia.
²³ Department of Metabolic Medicine, Queensland Children's Hospital, South Brisbane, QLD, 4101, Australia; Department of Paediatrics, Wesley Medical Research, Auchenflower Brisbane, QLD, 4066, Australia; Child Health Research Centre, Faculty of Medicine, University of Queensland, South Brisbane, QLD, 4101, Australia; School of Medicine and Dentistry, Griffith University, Gold Coast, 4222, Australia; Faculty of Medicine, University of Queensland, South Brisbane, QLD, 4101, Australia. Electronic address: david.coman@health.qld.gov.au.

PMID: 40616902
DOI: 10.1016/j.ebiom.2025.105840

Abstract

Background: Ataxia-telangiectasia (A-T) is a rare multisystem disease characterised by neurodegenerative cerebellar ataxia, lung disease, immune deficiency, high cancer risk, and mitochondrial dysfunction. A-T cells demonstrate defective endoplasmic reticulum-mitochondrial connectivity disrupting calcium homoeostasis and mitochondrial fusion, which are corrected in vitro by the triheptanoin metabolite, heptanoate.

Methods: We performed a Phase 2a/b trial of triheptanoin with a three-arm placebo-controlled dose-escalation design. Doses escalated at 2-month intervals for 12 months in the sequence 0%, 10%, 20%, 35% of calculated caloric intake. The primary outcome was cell death in respiratory epithelial cells. Key secondary outcomes included scales for assessment and rating of ataxia (SARA), international cooperative ataxia rating scale (ICARS), speech and swallowing function, and novel biomarker discovery.

Findings: 31 participants with A-T were enrolled aged from 4 to 37 years (median 16-years). For the maximum dose vs. placebo or no dose, significant improvements was observed for the primary outcome percent nasal cell death (mean difference (MD) = -9.7%, 95% confidence interval (CI) -16.0, 4.6). The SARA subscale kinetic function improved (MD = -5.8, 95% CI -10.4, -1.2), as did ICARS subscales gait (MD = -0.5, 95% CI -0.9, -0.1) and fine motor disturbance (MD = -2.7, 95% CI -4.3, -1.1). Speech intelligibility (MD = -12.8, 95% CI -21.2, -4.3) and swallowing safety (-0.9, 95% CI -1.6, -0.3) improved. Adverse events including abdominal pain, nausea, vomiting, and diarrhoea, requiring dose capping at 20%, were observed in 12 (38%) participants.

Interpretation: Improvements in mitochondrial function in A-T cells in vivo in patients occurred after triheptanoin. The biomarkers neurofilament light chain and interferon signature stimulated gene scores may allow for monitoring of disease progression and treatment response.

Funding: Funded by Medical Researcher Futures Fund Australia (GA89314), The University of Queensland, Wesley Research Institute, and BrAshA-T.

Keywords: Ataxia-telangiectasia; Cell death; Drug repurposing; Interferon signature gene scores; Neurofilament light chain; Triheptanoin.