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

Abstract

Long-chain fatty acid oxidation disorders (LC-FAOD) are autosomal recessive conditions that impair conversion of long-chain fatty acids into energy, leading to significant clinical symptoms. Triheptanoin is a highly purified, 7-carbon chain triglyceride approved in the United States as a source of calories and fatty acids for treatment of pediatric and adult patients with molecularly confirmed LC-FAOD. CL202 is an open-label, long-term extension study evaluating triheptanoin (Dojolvi) safety and efficacy in patients with LC-FAOD. Patients rolled over from the CL201 triheptanoin clinical trial (rollover); were triheptanoin-naïve (naïve); or had participated in investigator-sponsored trials/expanded access programs (IST/other). Results focus on rollover and naïve groups, as pretreatment data allow comparison. Primary outcomes were annual rate and duration of major clinical events (MCEs; rhabdomyolysis, hypoglycemia, and cardiomyopathy events). Seventy-five patients were enrolled (24 rollover, 20 naïve, 31 IST/other). Mean study duration was 23.0 months for rollover, 15.7 months for naïve, and 34.7 months for IST/other. In the rollover group, mean annualized MCE rate decreased from 1.76 events/year pre-triheptanoin to 0.96 events/year with triheptanoin (P = .0319). Median MCE duration was reduced by 66%. In the naïve group, median annualized MCE rate decreased from 2.33 events/year pre-triheptanoin to 0.71 events/year with triheptanoin (P = .1072). Median MCE duration was reduced by 80%. The most common related adverse events (AEs) were diarrhea, abdominal pain/discomfort, and vomiting, most mild to moderate. Three patients had serious AEs (diverticulitis, ileus, rhabdomyolysis) possibly related to drug; all resolved. Two patients had AEs leading to death; neither drug related. Triheptanoin reduced rate and duration of MCEs. Safety was consistent with previous observations.

Keywords: cardiomyopathy; long-chain fatty acid oxidation disorders (LC-FAOD); rhabdomyolysis; triheptanoin (UX007).

Conflict of interest statement

J. C. and X. L. are an employee and shareholder of Ultragenyx Pharmaceutical Inc. J. V., B. B., G. B., N. L., J. P., A. S.‐V., K. C., P. T., S. G., and E. M. have served as a clinical investigator in clinical trials with the product manufactured by Ultragenyx Pharmaceutical Inc.

© 2020 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.

Figures

FIGURE 1

Reduction in major clinical events (MCEs) with triheptanoin. Significant P‐values provided on the graph. Event rate (triheptanoin‐naïve) and duration (both groups) for hypoglycemia and cardiomyopathy were <1 events/year and days/year for both the pre‐triheptanoin and with‐triheptanoin periods, and, therefore, were not graphed. In the CL201 rollover group, the with‐triheptanoin period is comprised of the first 36 months following triheptanoin initiation in studies CL201 and CL202, or from triheptanoin initiation to discontinuation for patients who discontinued. In the triheptanoin‐naïve group, the with‐triheptanoin period is the first 18 months following triheptanoin initiation during CL202, or from triheptanoin initiation to discontinuation for patients who discontinued

FIGURE 2

Improvement in physical functioning with triheptanoin. Shaded gray area indicates normal range (40‐60)