Reply to: Comment on De Giorgis et al. “Randomized Phase 3 Study of Triheptanoin for Glut1 Deficiency Syndrome–Associated Paroxysmal Movement Disorders”

From a metabolic and basic science point of view, triheptanoin was an excellent therapeutic candidate for patients with Glut1DS. Earlier studies in humans were promising; however, these studies were open-label, observational studies with a small number of participants.^1-4 Two randomized placebo-controlled trials have failed to demonstrate triheptanoin efficacy to control seizure frequency and movement disorders in GLUT1DS.^{5, 6} To our knowledge, no other double-blind, placebo-controlled trials have been conducted. Additionally, triheptanoin has been tested in many other metabolic and mitochondrial pathologies but has demonstrated efficacy in only one disease: long-chain fatty acid oxidation disorders (LC-FAOD).^{7, 8}

Dr. Mochel and colleagues⁹ point out some limitations of our trial. These same limitations were described in detail in our article.⁵ Briefly, the dietary restrictions, dietary instructions, and dosing schedules used in our study mimic those used in earlier studies by Dr. Mochel and others.^1-4 These earlier open-label studies did show a strong effect for triheptanoin, whereas in the more demanding clinical trials we did not. As these factors are similar among studies with different outcomes, it is unlikely that these factors are driving the differences.

Safflower oil was used as a placebo to match the appearance, taste, and smell of triheptanoin. This was necessary to maintain blinding, though as discussed in the article, “any oil, in a condition such as Glut1DS that may respond to additional dietary fat, may have a treatment effect, and therefore, may not function as a true placebo.”

Finally, treatment duration was 10–12 weeks of titration and 8 weeks of maintenance. This was followed by an open-label extension period of up to 3 years. No differences were seen during the double-blind portion of the study. No differences were seen during the open-label extension. Therefore, it seems unlikely that a longer duration of follow-up would reveal belated results.

In summary, triheptanoin failed to meet the primary endpoint, or any other endpoints in this clinical trial. While some patients may have benefited from triheptanoin, perhaps those with more subtle symptoms, these are single, anecdotal results that cannot be generalized without solid evidence of efficacy. The trial was, unfortunately, negative. We hope the details provided in our article⁵ and in this discussion are helpful to patients, caregivers, and other researchers working on therapies for this challenging disease.

(1) Conception; (2) A. Writing of the First Draft, B. Review and Critique.

V.D.G.: 1, 2A, 2B

D.C.D.: 1, 2B

V.D.G. has received speaker honoraria from Nutricia, Vitaflo, Kanso; has served as advisor/consultant for Vitaflo and Longboard Pharmaceuticals; has been an investigator for clinical trials for Eisai, UCB Pharma, and Marinus; and received travel reimbursement from GW Pharmaceuticals, Lusofarmaco. D.C.D. is an advisor/consultant for AveXis, Biogen, Cytokinetics, Ionis Pharmaceuticals, Metafora Biosystems, Roche, Sanofi, Sarepta, and SMA Foundation; has received research grants from Hope for Children Research Foundation, National Institutes of Health, SMA Foundation, Cure SMA, Glut1 Deficiency Foundation, and United States Department of Defense; has received clinical trial funding from Biogen, Mallinckrodt, PTC Therapeutics, Sarepta, Scholar Rock, and Ultragenyx Pharmaceutical; and has received compensation as a member of a data and safety monitoring board (Canavan disease) for Aspa Therapeutics. The phase III trial of triheptanoin in Glut1DS was funded by Ultragenyx Pharmaceutical Inc. Drs. De Giorgis and De Vivo were principal investigators in the trial.