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.

BACKGROUND: Paroxysmal movement disorders are common in Glut1 deficiency syndrome (Glut1DS). Not all patients respond to or tolerate ketogenic diets. OBJECTIVES: The objective was to evaluate the effectiveness and safety of triheptanoin in reducing the frequency of disabling movement disorders in patients with Glut1DS not receiving a ketogenic diet. METHODS: UX007G-CL301 was a randomized, double-blind, placebo-controlled, phase 3 crossover study. After a 6-week run-in, eligible patients 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. The placebo (safflower oil) matched the appearance, taste, and smell of triheptanoin. Open-label triheptanoin was administered in the extension. The frequency of disabling paroxysmal movement disorder events per 4 weeks (recorded by diary during maintenance; primary endpoint) was assessed by Wilcoxon rank-sum test. RESULTS: Forty-three patients (children, n = 16; adults, n = 27) were randomized and treated. There was no difference between triheptanoin and placebo in the mean (interquartile range) number of disabling paroxysmal movement disorder events (14.3 [4.7-38.3] vs. 11.8; [3.2-28.7]; Hodges-Lehmann estimated median difference: 1.46; 95% confidence interval, -1.12 to 4.36; P = 0.2684). Treatment-emergent adverse events were mild/moderate in severity and included diarrhea, vomiting, upper abdominal pain, headache, and nausea. Two patients discontinued the study because of non-serious adverse events that were predominantly gastrointestinal. The study was closed early during the open-label extension because of lack of effectiveness. Seven patients continued to receive triheptanoin compassionately. CONCLUSION: There were no significant differences between the triheptanoin and placebo groups in the frequency of disabling movement disorder events during the double-blind maintenance period. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

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

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.

Exploring triheptanoin as treatment for short chain enoyl CoA hydratase deficiency.

We explored the benefits of triheptanoin as a treatment for Short Chain Enoyl Co-A Hydratase (SCEH) deficiency. One child with early onset, severe SCEH Deficiency was treated with triheptanoin, an odd chain oil with anapleurotic properties, for 37 months. Blood and urine chemistry safety measures, motor skills assessment, physical exam, and neurological assessment were monitored over a 27 month period. Modest sustained gains in motor skills, attention, muscle bulk, and strength were observed without any significant adverse effects. Triheptanoin appears to be a promising effective treatment for SCEH Deficiency.

Effects of dopaminergic medications on psychosis and motor function in dementia with Lewy bodies.

Dopaminergic treatment in dementia with Lewy bodies (DLB) requires balancing risk of worsened psychosis and potential motor benefit. We assessed the effects of increased dopaminergic medication on psychosis and motor function in DLB. We studied 19 subjects fulfilling probable DLB Consensus criteria before and after increased dopaminergic medications. Standard clinical measures included: Thought Disorder score from the Unified Parkinson's disease Rating Scale (UPDRS) Part I, total motor score (UPDRS Part III), and Hoehn-Yahr (H&Y) stage. Motor benefit defined as >10% improvement over baseline UPDRS Part III score, occurred in only one-third of subjects. In this group, worsened hallucinations or psychosis developed in one-third. Considering motor benefit without exacerbation of psychosis as our aim, only 4 DLB subjects (22%) achieved this goal. Our results suggest that dopaminergic medications have limited benefit in DLB because of the low likelihood of motor improvement and the risk of psychosis exacerbation.

Greater impairment of extension movements as compared to flexion movements in Parkinson's disease.

Research on isometric contractions in subjects with Parkinson's disease (PD) has shown that anti-parkinsonian medication results in a greater increase in extensor strength than flexor strength. This finding is consistent with the hypothesis that there is a greater impairment in neural activation of extensor muscles as compared to flexor muscles in subjects with PD. Such a hypothesis is physiologically feasible given the known differences in the neural control of flexor and extensor muscles. If the above hypothesis is true for both phasic and tonic muscle activation, then differences between performance of rapid single-joint flexion and extension movements should exist in subjects with PD. Twelve subjects with PD, "off" and "on" medication, and 12 age-and sex-matched healthy control subjects performed rapid single-joint movements in flexion and extension over three distances. For neurologically healthy subjects, we did not identify any significant differences in either kinematic or EMG parameters between flexion and extension movements. In contrast, in the PD subjects extension movements were slower and associated with more agonist bursts when compared to flexion movements. The results are consistent with the hypothesis that there is a differential impairment of neural activation of extensor muscles of the arm as compared to flexor muscles in subjects with PD.