A randomized, double-blind trial of triheptanoin for drug-resistant epilepsy in glucose transporter 1 deficiency syndrome

Pasquale Striano, Stéphane Auvin, Abigail Collins, Rita Horvath, Ingrid E Scheffer, Michal Tzadok, Ian Miller, Mary Kay Koenig, Adrian Lacy, Ronald Davis, Angela Garcia-Cazorla, Russell P Saneto, Melanie Brandabur, Susan Blair, Tony Koutsoukos, Darryl De Vivo, Pasquale Striano, Stéphane Auvin, Abigail Collins, Rita Horvath, Ingrid E Scheffer, Michal Tzadok, Ian Miller, Mary Kay Koenig, Adrian Lacy, Ronald Davis, Angela Garcia-Cazorla, Russell P Saneto, Melanie Brandabur, Susan Blair, Tony Koutsoukos, Darryl De Vivo

Abstract

Objective: This study was undertaken to evaluate efficacy and long-term safety of triheptanoin in patients >1 year old, not on a ketogenic diet, with drug-resistant seizures associated with glucose transporter 1 deficiency syndrome (Glut1DS).

Methods: UX007G-CL201 was a randomized, double-blind, placebo-controlled trial. Following a 6-week baseline period, eligible patients were randomized 3:1 to triheptanoin or placebo. Dosing was titrated to 35% of total daily calories over 2 weeks. After an 8-week placebo-controlled period, all patients received open-label triheptanoin through Week 52.

Results: The study included 36 patients (15 children, 13 adolescents, eight adults). A median 12.6% reduction in overall seizure frequency was observed in the triheptanoin arm relative to baseline, and a 13.5% difference was observed relative to placebo (p = .58). In patients with absence seizures only (n = 9), a median 62.2% reduction in seizure frequency was observed in the triheptanoin arm relative to baseline. Only one patient with absence seizures only was present in the control group, preventing comparison. No statistically significant differences in seizure frequency were observed. Common treatment-emergent adverse events included diarrhea, vomiting, abdominal pain, and nausea, mostly mild or moderate in severity. No serious adverse events were considered to be treatment related. One patient discontinued due to status epilepticus.

Significance: Triheptanoin did not significantly reduce seizure frequency in patients with Glut1DS not on the ketogenic diet. Treatment was associated with mild to moderate gastrointestinal treatment-related events; most resolved following dose reduction or interruption and/or medication for treatment. Triheptanoin was not associated with any long-term safety concerns when administered at dose levels up to 35% of total daily caloric intake for up to 1 year.

Trial registration: ClinicalTrials.gov NCT01993186.

Keywords: diet treatment; drug resistance; epilepsy; glucose transporter 1 deficiency syndrome; triheptanoin.

Conflict of interest statement

P.S. has received fees from Ultragenyx Pharmaceutical Inc, Zogenix, BioMarin, PTC Therapeutics, GW Pharma, and Neuraxpharm, and research grants from GW Pharma, PTC Therapeutics, Enecta, and Kolfarma. He has been an investigator for clinical trials for Ultragenyx Pharmaceutical Inc and Zogenix. He has served on a scientific advisory board for the Italian Medicines Agency; has received honoraria from GW Pharma, Kolfarma, and Eisai; and has received research support from the Italian Ministry of Health and San Paolo Foundation. S.A. has served as a consultant or received honoraria for lectures from Biocodex, BioMarin, Eisai, GW Pharma, Neuraxpharm, Nutricia, UCB Pharma, Ultragenyx Pharmaceutical Inc, and Zogenix. He has been an investigator for clinical trials for Eisai, UCB Pharma, Ultragenyx Pharmaceutical Inc, and Zogenix. I.E.S. has served on scientific advisory boards for UCB, Eisai, GlaxoSmithKline, BioMarin, Nutricia, Rogcon, Chiesi, Encoded Therapeutics, Knopp Biosciences, and Xenon Pharmaceuticals; has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, Chiesi, LivaNova, and Eisai; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, BioMarin, and Eisai; has served as an investigator for Zogenix, Zynerba, Ultragenyx Pharmaceutical Inc, GW Pharma, UCB, Eisai, Xenon Pharmaceuticals, Anavex Life Sciences, Ovid Therapeutics, Epygenix Therapeutics, Encoded Therapeutics, and Marinus; and has consulted for Zynerba Pharmaceuticals, Atheneum Partners, Ovid Therapeutics, Care Beyond Diagnosis, Epilepsy Consortium, and UCB. She may accrue future revenue on pending patent WO61/010176 (filed 2008; Therapeutic Compound); has a patent for SCN1A testing held by Bionomics and licensed to various diagnostic companies; and has a patent "Molecular Diagnostic/Theranostic Target for Benign Familial Infantile Epilepsy (BFIE)" (PRRT2; 2011904493, 2012900190 and PCT/AU2012/001321; TECH ID: 2012–009). D.C.D. has served as 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 US Department of Defense; has received clinical trial funding from Biogen, Mallinckrodt, PTC Therapeutics, Sarepta, Scholar Rock, and Ultragenyx Pharmaceutical Inc; and has received compensation as a member of a data and safety monitoring board (Canavan disease) for Aspa Therapeutics. M.T. has served as consultant for or received honoraria from Novartis and LivaNova; he has served on a scientific advisory board for Novartis and has been an investigator for clinical trials for LivaNova, Ovid Therapeutics, Novartis, GW Pharma, Ultragenyx Pharmaceutical Inc, and Pfizer. R.H. has served on a scientific advisory board for Zogenix. R.P.S. has received speaker honoraria from GW Pharma and has been an investigator for clinical trials for GW Pharma, Zogenix, Ultragenyx Pharmaceutical Inc, UCB Pharma, and Lundbeck. M.K.K. has served on advisory boards for Novartis and Taysha Gene Therapies; has received speaker honoraria from Novartis Pharmaceuticals, Greenwich Pharmaceuticals, and Lundbeck; serves on a data and safety monitoring board for Zogenix; and has received research funding from GW Research, Reneo Pharmaceuticals, Astellas Pharma, PTC Therapeutics, Marinus Pharmaceuticals, Stealth Biotherapeutics, EryDel, Ultragenyx Pharmaceutical Inc, Retrophin, LAM Therapeutics, Pfizer, Vtesse, Reata Pharmaceuticals, and Novartis Pharmaceuticals. None of the other authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Figures

FIGURE 1
FIGURE 1
Study design of UX007G‐CL201, a randomized, double‐blind, placebo‐controlled, parallel‐group trial. *SOC, standard of care
FIGURE 2
FIGURE 2
CONSORT (Consolidated Standards of Reporting Trials) diagram and patient disposition
FIGURE 3
FIGURE 3
Treatment‐emergent adverse events by system organ class and age subgroup during the double‐blind period (placebo and triheptanoin treated) and extension period (open‐label triheptanoin). Children: 2 to

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