Comment to: “Randomized Phase 3 Study of Triheptanoin for Glut1 Deficiency Syndrome–Associated Paroxysmal Movement Disorders”

Abstract

The Ultragenyx@-sponsored phase 3 randomized controlled study evaluating the effect of triheptanoin to treat paroxysmal episodes of movement disorders related to Glut1 deficiency syndrome (Glut1-DS) failed to demonstrate efficacy.¹ This was unexpected considering the rationale supporting the use of triheptanoin,² and the striking results of preliminary investigator-driven open-label studies that showed over 90% reduction of paroxysmal movement disorders in patients with Glut1-DS,^{3, 4} a clinical benefit sustainable over years of treatment.⁵

Triheptanoin is an odd medium C7 chain triglyceride that is metabolized into acetyl-CoA and propionyl-CoA, two key entries of the tricarboxylic acid cycle, making it a unique molecule to address defective brain energy metabolism.⁶ Importantly, treatment of Glut1-DS with triheptanoin must comprise a restriction of dietary carbohydrates, especially those with a high glycemic index.⁷ Indeed, the brain always prefers simple sugars to any alternative source of energy fuel,⁸ and patients with Glut1-DS tend to spontaneously increase their sugar intakes when experiencing paroxysmal manifestations. We documented in two distinct patient populations that increased sugar intake in patients with Glut1-DS treated with triheptanoin led to a prompt recurrence of movement disorders.^{4, 5} In the present Ultragenyx@-sponsored negative study, most patients did not follow this basic principle. In fact, De Giorgis et al¹ indicated that “patients/caregivers were instructed to avoid simple sugars at the end of the inclusion period (December 2017).” Given that almost all patients had by then completed the 8-week treatment periods, this is a major issue regarding the study conduct and the validity of the authors' conclusions. Other factors that may have affected the study results comprise short study periods in a highly fluctuating disease, absence of an optimal placebo, and lack of a tailored treatment schedule (ie, fixed daily pattern of drug administration despite variable energy needs depending on energy expenditure in patients with Glut1-DS).

There are several reasons for a potentially efficacious drug to fail to demonstrate efficacy such as flawed study designs, inappropriate statistical endpoints, or underpowered studies.⁹ Pharmaceutical companies must deal with the high cost of clinical trials, but their desire to move experimental drugs forward into clinical applications may have deleterious consequences on important aspects of study design such as too short study periods or the lack of appropriate dietary instructions for a study drug that mainly consisted into a dietary intervention as it was the case in De Giorgis study.¹ Ultimately, this may hamper the possibility for patients to get access to a drug that could help at least some of them, especially in the field of rare diseases. We suspect this is what is happening there. We, therefore, advocate that it is critical from the patients' perspective to openly analyze mistakes in the field of therapeutic trials instead of trying to minimize them. In our opinion, this phase 3 study should be considered as “unconclusive” rather than “negative,” and it should be acknowledged that treatment with triheptanoin still represents a credible treatment option for Glut1-DS patients that warrants further investigations.

E.R. has received honorarium for speech from Orkyn, Elivie, Merz-Pharma, Janssen, Teva, and for participating in advisory boards from Elivie, Merz-Pharma, Teva, and BIAL. He has received research support from Elivie, Merz-Pharma, Orkyn, Ipsen, Everpharma, AMADYS, ADCY5.org, Fonds de dotation Patrick Brou de Laurière, Agence Nationale de la Recherche, Dystonia Medical Research Foundation, Hope for Annabel, and Alternating Hemiplegia foundations. A.M. has received honorarium for speech from Merz-Pharma and Teva and travel funding from Merz-Pharma and Elivie. E.H. has received honorarium for speech from Boston Sci and travel funding from Boston Sci and Insightec. F.M. has received consultancy fees from Minoryx Therapeutics and honorarium for participating in advisory boards from Minoryx Therapeutics and Vigil Neuroscience. She has received research support from Minoryx Therapeutics, Vigil Neuroscience, Leadiant Biosciences, Agence Nationale de la Recherche, and Paris Brain Institute.

(1) Manuscript: A. Writing of the First Draft, B. Review and Critique.

E.R.: 1A

A.M.: 1B

E.H.: 1B

F.M.: 1B