Triheptanoin Shows No Significant Effect on Movement Disorder Events in Glut1 Deficiency Syndrome

Valentina De Giorgis, PhD

Recently published data from UX007G-CL301, a randomized, double-blind, placebo-controlled, phase 3 crossover study (NCT02960217) revealed that treatment with triheptanoin did not have a significant impact vs placebo in the frequency of disabling movement disorders among patients with glucose transporter type 1 deficiency syndrome (Glut1DS). All told, the study was closed during the open-label extension because of lack of effectiveness.¹

Published in Movement Disorders, 43 patients with Glut1DS were randomized 1:1 to the first sequence (triheptanoin/placebo or placebo/triheptanoin) titration plus maintenance, followed by washout and the opposite sequence titration plus maintenance after an initial 6-week run-in. The placebo (safflower oil) matched the appearance, taste, and smell of triheptanoin. Coming into the study, most patients had previously received a prescribed high-fat diet (classic ketogenic: 51.2%; modified Atkins: 11.6%).

Led by Valentina De Giorgis, PhD, doctor of philosophy at the University of Pavia, there was no significant difference between the triheptanoin and placebo groups in the frequency of movement disorder events during the double-blind maintenance, as recorded by patients/caregivers in the daily Glut1DS symptom diary. The median number of movement disorder events per 4 weeks was 14.3 (IQR, 4.7-38.3) with triheptanoin versus 11.8 (IQR, 3.2-28.7) with placebo (Hodges-Lehmann estimated median difference, 1.46; 95% CI, –1.12 to 4.36; P = .2684).

From baseline to week 10, there was no between-group different in change on 12-meter walk time distance (Hodges-Lehmann estimated median difference, 25.00; 95% CI, –62.5 to 91.5; P = .6419). In addition, these 2 groups demonstrated no significant difference on Clinician Global Impression-Improvement scale when reported by patients/caregivers (ANCOVA least-square mean difference, –0.1; 95% CI, –0.6 to 0.5; P = .8329) or by physicians (Hodges-Lehmann estimated median difference, 0.5; 95% CI, 0-1.0; P = .1982).

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In terms of safety, treatment-emergent adverse events (TEAEs) were more frequent in the triheptanoin (93.0%) group than placebo (81.0%). Most TEAEs were mild or moderate in severity, with the most common being diarrhea (53.5%), vomiting (37.2%), upper abdominal pain (34.9%), headache (25.6%), and nausea (23.3%). During the double-blind period, gastrointestinal TEAEs were more frequent among patients who received triheptanoin than placebo (74.4% vs 40.5%). Notably, 2 patients in the triheptanoin group discontinued treatment and left the study because of non-serious AEs (patient one: treatment-related upper abdominal pain, aggressive behavior, headache, and vomiting; patient two: possibly treatment-related abdominal pain and diarrhea).

In the discussion, the investigators noted that the failure to meet the primary end point may have been attributed to factors such as insufficient dietary adherence, patient compliance with triheptanoin dosage, and inadequate sugar intake monitoring. While dietary instructions and ketosis monitoring were part of the protocol, noncompliance with a low-sugar diet persisted. Notably, stricter sugar intake might have enhanced triheptanoin’s efficacy, though this hypothesis is primarily supported by open-label studies, lacking confirmation from randomized, placebo-controlled trials.

The study authors also wrote that the study’s crossover design and selected clinical assessments may have been suboptimal for evaluating the primary end point in Glut1DS-related movement disorders. They wrote that factors such as the 12MWT's inability to reliably elicit dyskinesia, a small sample size, and insufficient study duration may have impacted the results. Additionally, allowing personalized dosing, dietary adaptations, or younger patient enrollment could have improved efficacy insights.

"In the absence of alternatives to a KD, which may be ineffective or not tolerated, early open-label uncontrolled studies of triheptanoin in Glut1DS were promising, but unfortunately, were not confirmed by our placebo-controlled randomized double blind study,” Giorgis et al wrote. “When designing future clinical studies of Glut1DS, it will be important to consider the complexity and heterogeneity of the disabling movement disorders, as well as elements of study design, such as dietary monitoring (especially simple sugar intake), sample size, and randomized treatment period length."

REFERENCE
1. De Giorgis V, Bhatia KP, Boespflug-Tanguy O, et al. Triheptanoin Did Not Show Benefit versus Placebo for the Treatment of Paroxysmal Movement Disorders in Glut1 Deficiency Syndrome: Results of a Randomized Phase 3 Study. 2024;39(8):1386-1396. doi:10.1002/mds.29822