Dietary management and major clinical events in patients with long-chain fatty acid oxidation disorders enrolled in a phase 2 triheptanoin study

Abstract

Background & aims: Long-chain fatty acid oxidation disorders (LC-FAOD) are rare, life-threatening, autosomal recessive disorders that lead to energy depletion and major clinical events (MCEs), such as acute metabolic crises of hypoglycemia, cardiomyopathy, and rhabdomyolysis. The aim of this study was to report a post hoc analysis of diet diary data from the phase 2 UX007-CL201 study (NCT01886378).

Methods: In the single-arm, open-label, phase 2 UX007-CL201 study, the safety and efficacy of 78 weeks of treatment with triheptanoin, an odd-carbon, medium-chain triglyceride consisting of three 7-carbon fatty acids on a glycerol backbone, was investigated in subjects with LC-FAOD versus a retrospective 78-week period when subjects were optimally managed under published dietary guidelines. Subject dietary reports were collected to analyze the relationship between diet, triheptanoin treatment, and MCEs. Referring metabolic physicians completed a survey on patient management and clinical outcomes before and after initiation of triheptanoin. Before initiating triheptanoin, subjects received a mean daily caloric intake (DCI) of 17.4% from medium-chain triglycerides (MCT). During the study, subjects received a mean of 27.5% DCI from triheptanoin. Protein (13.7% vs 14.5% DCI), long-chain fat (13.1% vs 10.5% DCI), and carbohydrate (55.3% vs 47.1% DCI) intake were consistent between the pre-triheptanoin and triheptanoin treatment periods, respectively.

Results: Following 78 weeks of treatment, mean annualized MCE rate decreased by 48.1% (p = 0.021) and mean annualized MCE event-day rate decreased by 50.3% (p = 0.028). A weak association existed between improvement in annualized MCE rate and change in percent DCI from MCT (Spearman rank correlation: r = -0.38; 95% CI: -0.675, 0.016). However, there was large variability in the association and no specific pattern of change for larger or smaller changes in dose. Seventy-two percent of physicians reported that triheptanoin had a clinically meaningful benefit on medical management of their patients.

Conclusions: Treatment with triheptanoin at the protocol-specified dose decreased the rate of MCEs in patients with LC-FAOD independently from other dietary changes between the pre-triheptanoin and triheptanoin treatment periods.

Trial registration: ClinicalTrials.gov identifier: NCT01886378.

Keywords: Acute metabolic crises; Cardiomyopathy; Hypoglycemia; Medium-chain triglyceride; Rhabdomyolysis; Triheptanoin.

Conflict of interest statement

Declaration of competing interest JV and NL have served as investigators in a clinical trial sponsored by Ultragenyx Pharmaceutical Inc.; MM, LD, YM, and C-YC are former employees of Ultragenyx Pharmaceutical Inc.; and JC is an employee and shareholder of Ultragenyx Pharmaceutical Inc.

Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Figures

Fig. 1.

Total daily macronutrient distribution before and during triheptanoin therapy. Box and whisker plot shows the minimum, lower quartile, median, upper quartile, and maximum values. The mean is represented with an “x.” Pre-triheptanoin treatment period values are based on available data during the run-in and baseline visits. Triheptanoin treatment period values are based on available data during the week 12, 24, 48, and 78 visits.

Fig. 2.

Change in major clinical events and medium-chain fat intake. Spearman rank correlation: r = −0.38 (95% CI: −0.675, 0.016).