Clinical Trial

. 2025 Aug:118:105840.

doi: 10.1016/j.ebiom.2025.105840. Epub 2025 Jul 4.

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

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
PMCID: PMC12271818
DOI: 10.1016/j.ebiom.2025.105840

Clinical Trial

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

Matthew Lynch et al. EBioMedicine. 2025 Aug.

. 2025 Aug:118:105840.

doi: 10.1016/j.ebiom.2025.105840. Epub 2025 Jul 4.

Authors

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
PMCID: PMC12271818
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.

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Conflict of interest statement

Declaration of interests No declarations: DC, PS, KS, EW, AW, AY, NS, GS, GR. JD, KP, MG, SJ, SM, SN, TZ, RW, BX, DHR, JF, MLF, DS. Declarations: CM is a recipient of NHMRC Investigator Grant (2017496). AV, Chief Science Officer of Redenlab Inc. CW, all honoraria paid to institute, not for personal use, Vertex Pharmaceuticals, Nov 2021 SHIFT Steering Committee Medical Education Symposium Event, Nov 2021 SHIFT Symposium, Aug 2022 SHIFT Symposium Steering Committee medical education symposium, Aug 2022 CF Round Table Practical considerations in managing patients with CF, Nov 2022 SHIFT Symposium, Dec 2022 SHIFTing Focus Newsletter Steering Committee, Mar 2023 Round Table Managing Children with Cystic Fibrosis Trikafta 6-11YO, May 2023 Optimising the use of Trikafta in CF patients >6YO, Nov 2023 SHIFT Symposium, Dec 2023 HTA Scientific Webinar Assessing the value of medicines: an introduction for clinicians, Mar 2024 TSANZ Conference Conversation with CF experts on treating pre-school children with CFTR modulators, Aug 2024 SHIFT Symposium, Nov 2021 Trikafta/Kaftrio Evidence Generation Global Advisory Board, Nov 2021–Oct 2023 Lead PI Services in connection with VX20-445-116 and VX20-445-119, Aug 2022 CF < 2YO Study Design Advisory Board, Sep 2022 Trikafta 6–11years old and the rare CFTR gene mutations indication Advisory Board, Feb 2023 Ridgeline Study Investigator Meeting in Feb 2023, Feb 2023–Feb 2026 Lead PI Services in connection with VX22-445-122, Aug 2024—VX Advisory Board Future CFTR Modulators, Deputy Editor Thorax 2020–Dec 2022, Associate Editor ongoing, Associate Editor Respirology, International Advisory Board Vertex Pharmaceuticals.

Figures

**Fig. 1**
Showing increased contactbetween ER and mitochondria in response to nutrient stress. This facilitates the transfer calcium to support energy homeostasis in the mitochondrion. In the absence of ATM this leads to abnormal signal transduction between the organelles. Addition of heptanoate reverses this defect in A-T cells.

**Fig. 2**
Schematic representation of the dosing schedules for each study group. When participants were receiving MCT the study dietitian calculated dose of MCT at 10% TCR. The shaded bars represent the step wise increase in TCR of TC7.

**Fig. 3**
CONSORT flow diagram. Legend: NASH = non-alcoholic steatohepatitis, JRA = juvenile rheumatoid arthritis, IDDM = insulin dependent diabetes mellitus, IP = investigational product.

**Fig. 4**
Boxplots of (a) perfusion defect percentage (QDP), (b) ventilation defect percentage (VDP), and (c) flow-volume loop (FVL)-VDP for baseline and follow-up groups. Significant difference (using Wilcoxon signed-rank test) is marked with an asterisk (p < 0.05). NS indicates non-significant.

**Fig. 5**
Interferon signature gene (ISG) scores for all available patient blood samples at visit 1 and study completion (a) and plotted on a log scale for at both visit 1 and visit 7 (b). (a) ISG score for all available patient blood samples at visit 1 i.e. baseline (n = 16) and visit 7 i.e., study completion (n = 16). Genes examined were IFI27, IFI44L, ISG15, IFIT1, RSAD2, SIGLEC2. ISG score then calculated as (IFI27 + IFI44L + ISG15 + IFIT1 + RSAD2 + SIGLEC2/6). There is a statistically significant reduction in scores between the two visits while on therapy with the mean returning to baseline. (b): ISG score plotted on a log scale for all 12 patients where blood samples were available at both visit 1 and visit 7. Positive control was the ISG score for patients with deficiency of adenosine deaminase 2 deficiency (ADA2). The majority of patients showed a reduction in gene expression between the two visits, but the overall mean did not reach statistical significance. ns = not significant ∗p < 0.05, ∗∗p < 0.01, ∗∗∗p < 0.001.

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References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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Medical