Open‐label long‐term treatment of add‐on triheptanoin in adults with drug‐resistant epilepsy

Abstract

Objective: To investigate feasibility, safety, and tolerability of long-term (48 weeks) add-on treatment with triheptanoin (UX007), the triglyceride of heptanoate, in adults with drug-resistant epilepsy. Methods: This extension study was offered to adult participants with drug-resistant epilepsy who completed a 12-week randomized controlled trial of add-on medium-chain triglycerides (MCT) vs triheptanoin. Participants were asked to titrate triheptanoin to their maximum tolerated dose over 3 weeks, followed by 48-week maintenance before tapering or treatment extension. The primary aims were to assess retention and safety of the triheptanoin treatment, and secondary aims to assess the tolerated doses and changes in seizure frequency. Results: Eleven adults were enrolled and ten people were analyzed (because one patient was diagnosed as having nonepileptic seizures while on the study). Two adults finished the study and extended their treatment. Eight participants withdrew from the study, due to lack of efficacy (n = 3), unknown reasons (n = 2), belief of weight gain (n = 1), wanting to try a different treatment (n = 1), and a colonoscopy (n = 1). Diarrhea in two people and bloating in one person were deemed possibly related to treatment, but other adverse events were not. The duration of maintenance treatment dose was 27-513 days (median 247 days, range 27-513 days), and 0.49 -1.1 mL/kg triheptanoin was taken per day (0.77 ± 0.19 mL/kg, mean ± standard deviation, 40-100 mL/d). Two participants experienced >90% and three people >50% reduction in seizure frequency, and all had focal seizures. The median seizure reduction was 48% (average 38%). Significance: Our results indicate antiseizure effects of triheptanoin on focal seizures in 5 out of 10 adults. However, only two people finished and extended the 48week add-on treatment phase, despite lack of safety or tolerability issues.More studies focused on improved treatment formulations, the potential of lower dosages, and efficacy are needed. Trial registration number: ACTRN12615000406505. Pharmaceutical for donating UX007 and providing the funds for the study. We are grateful to James Pitt, Chris French, Mark Cook, Fiona Ellery, and Tina Soulis for support.

Triheptanoin: First Approval

“…An open-label clinical trial using brain magnetic resonance spectroscopy in patients with Huntington's disease found that triheptanoin can improve brain energy metabolism (with apparent improvements in motor function) [39]. Other clinical trials found that triheptanoin may have some efficacy in reducing the frequency of focal seizures in adult patients with refractory epilepsy [14] but does not reduce the occurrence of paroxysmal events in alternating hemiplegia of childhood [15].…”

“…In addition to development in LC-FAOD, phase II trials have been conducted, are ongoing, or are planned (by Ultragenyx and/or other organizations/institutions), to investigate triheptanoin in a range of other indications, including glucose transporter type 1 deficiency syndrome (GLUT1DS; De Vivo disease) [11,12], Huntington's disease [12], glycogen storage disease type V (GSD-V; McArdle's disease) (NCT02919631; NCT02432768), refractory epilepsy [13,14], alternating hemiplegia of childhood [15], adult polyglucosan body disease [16] and Rett syndrome (NCT02696044). After a phase III crossover trial conducted by Ultragenyx to investigate triheptanoin in GLUT1DS failed to meet its primary and key secondary endpoints [17], development of triheptanoin by Ultragenyx in GLUT1DS was discontinued [although phase II trials (NCT03301532 and NCT03181399) by other parties are continuing in this indication].…”

Dietary medium chain triglycerides for management of epilepsy: New data from human, dog, and rodent studies

“…In addition to providing fuel for the TCA cycle, triheptanoin can also provide succinyl‐CoA and refill the intermediates of the TCA cycle (anaplerosis) 48 . Data about triheptanoin treatment for epilepsy in rodent models and clinical trials can be found elsewhere 20,49–54 …”

“…In 2013, a case report reported marked seizure reduction in a man who added four tablespoons of MCT oil twice per day to this regular diet 111 . In a first small controlled randomized double‐blinded clinical trial to test the tolerability of add‐on MCTs versus triheptanoin in Melbourne with 34 adults with treatment‐resistant epilepsy, participants were asked to mix oils into three daily meals and titrate oil doses up slowly over several weeks to their maximal tolerated amount (maximal 35E% or 100 ml/day) while eating to satiety 49 . The oils were tolerated in approximately two thirds of participants.…”

“…In the MCT arm, five of 11 (45%) adults finishing the study, all with focal unaware seizures, showed greater than 50% reduction in seizure frequency. These adults ingested 40–70 ml MCTs per day containing 55% octanoic and 45% decanoic acids (mean = .73 ml/kg body weight) 49 . After cessation of MCTs, seizures returned in all but one adult.…”