Results from a 78‐week, single‐arm, open‐label phase 2 study to evaluate UX007 in pediatric and adult patients with severe long‐chain fatty acid oxidation disorders (LC‐FAOD)

Abstract

Summary Long-chain fatty acid oxidation disorders (LC-FAOD) are rare disorders characterized by acute crises of energy metabolism and severe energy deficiency that may present with cardiomyopathy, hypoglycemia, and/or rhabdomyolysis, which can lead to frequent hospitalizations and early death. An open-label Phase 2 study evaluated the efficacy of UX007, an investigational odd-carbon medium chain triglyceride, in 29 subjects with severe LC-FAOD. UX007 was administered over 78 weeks at a target dose of 25%–35% total daily caloric intake (mean 31%).The frequency and duration of major clinical events (hospitalizations, emergency room visits, and emergency home interventions due to rhabdomyolysis, hypoglycemia, and cardiomyopathy) occurring during 78 weeks of UX007 treatment was compared with the frequency and duration of events captured retrospectively from medical records for 78 weeks before UX007 initiation. The mean annualized event rates decreased from 1.69 to 0.88 events/year following UX007 initiation (p=0.021; 48.1% reduction). The mean annualized duration rate decreased from 5.96 to 2.96 days/year (p=0.028; 50.3% reduction). Hospitalizations due to rhabdomyolysis, the most common event, decreased from 1.03 to 0.63 events/year (p=0.104; 38.7% reduction). Initiation of UX007 eliminated hypoglycemia events leading to hospitalization (from 11 pre-UX007 hospitalizations, 0.30 events/year vs. 0; p=0.067) and ICU care (from 2 pre-UX007 ICU admissions, 0.05 events/year vs. 0; p=0.161) and reduced cardiomyopathy events (3 events vs. 1 event; 0.07 to 0.02 events/year, 69.7% decrease). The majority of treatment-related AEs were mild to moderate GI symptoms including diarrhea, vomiting, abdominal or gastrointestinal pain, which can be managed with smaller, frequent doses mixed with food.

Effects of triheptanoin (UX007) in patients with long‐chain fatty acid oxidation disorders: Results from an open‐label, long‐term extension study

“…The results of this clinical trial are consistent with findings from previous triheptanoin studies 7,16,21,22 . Results from the previous triheptanoin study CL201 showed a 48.1% reduction in mean annualized total MCE event rate and a 50.3% reduction in mean annualized total MCE event duration (days/year) compared to an 18‐month pre‐triheptanoin period.…”

“…For MCE event type, mean annualized event rate decreased 32% for rhabdomyolysis (mean [SD] events/year: 1.30 [1.53] pre‐triheptanoin to 0.89 [1.05] with triheptanoin), 96% for hypoglycemia (0.383 [0.98] to 0.014 [0.07]), and 33% for cardiomyopathy (0.083 [0.30] to 0.056 [0.21]). More specifically for hypoglycemia, 12 events occurred in four patients during the pre‐triheptanoin period and only one event occurred during the with‐triheptanoin period on the patient's first day of triheptanoin treatment in CL201 16 . No hypoglycemia events occurred in the CL201 rollover group during CL202.…”

Long-term experience with triheptanoin in 12 Austrian patients with long-chain fatty acid oxidation disorders

“…Despite these measures, morbidity and mortality remain high [ 5 ]. With no approved specific medication for treatment of LC-FAODs available, triheptanoin constitutes a promising agent that is currently used in compassionate care programs [ 6 , 7 ]. Triheptanoin is a highly purified, synthetic seven odd-chain fatty acid triglyceride that can bypass the deficient long-chain oxidation.…”

Recent Advances in the Pathophysiology of Fatty Acid Oxidation Defects: Secondary Alterations of Bioenergetics and Mitochondrial Calcium Homeostasis Caused by the Accumulating Fatty Acids

“…Further studies performed preferentially in vivo in animal models and in patients affected by FAOD are therefore necessary to further clarify the underlying mechanisms of tissue damage in these disorders. Finally, it is expected that, besides restricting fat dietary intake and avoiding fasting, drugs that stimulate mitochondrial function such as bezafibrate and the anaplerotic compound triheptanoin may hopefully improve the clinical outcome of the affected patients (Gillingham et al, 2017;Vockley et al, 2017Vockley et al, , 2019Yamada et al, 2018;Shiraishi et al, 2019;Suyama et al, 2020).…”

“…However, the clinical efficacy of bezafibrate is still disputed and needs to be further confirmed (Ørngreen et al, 2014, 2015). Furthermore, replacement of longchain triglycerides by MCT and replenishment of citric acid cycle (CAC) intermediates by the seven-carbon fatty acid triglyceride (C7) triheptanoin to support ATP production have been recently demonstrated to improve the clinical outcome of these patients (Gillingham et al, 2017;Vockley et al, 2017Vockley et al, , 2019.…”