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.

Triheptanoin in the management of long-chain fatty acid oxidation disorders: a profile of its use

“…From the 18-month pre-triheptanoin period to the 36-month triheptanoin period, the mean annualized total MCE rate decreased 45% (from 1.76 events/year to 0.96 events/ year; p = 0.0319), and the mean annualized hospitalization event rates decreased by 46.9% (from 1.43 to 0.76 events/ year; p = 0.0429). In addition, the improvements with triheptanoin in the physical health summary score seen in CL201 were maintained in CL202 [15].…”

“…The therapeutic effect of triheptanoin appeared to be sustained during longer-term therapy [15]. From the 18-month pre-triheptanoin period to the 36-month triheptanoin period, the mean annualized total MCE rate decreased 45% (from 1.76 events/year to 0.96 events/ year; p = 0.0319), and the mean annualized hospitalization event rates decreased by 46.9% (from 1.43 to 0.76 events/ year; p = 0.0429).…”

“…Following the completion of study CL201, 24 patients entered an open-label, long-term, phase 2 extension study (CL202) [15]. Patients transitioned into the extension study at the same dose of triheptanoin that they were taking in CL201, and the dose was titrated per investigator discretion (the target dose was 25-35% of total DCI).…”

“…Of note, the study also included a triheptanoin-naive treatment arm and rollover patients from investigator-sponsored trials/expanded access programs. Results compare the 18-month pre-triheptanoin period with the 36-month triheptanoin period (18 months each from CL201 and CL202) [15].…”

Lipidomic and Proteomic Alterations Induced by Even and Odd Medium-Chain Fatty Acids on Fibroblasts of Long-Chain Fatty Acid Oxidation Disorders

“…In particular, C7 resulted in a higher ratio also for the species 40:2 of CER/HEX and for 42:1 of SM/HEX ( Figure 5 E,F). It is therefore conceivable that C7 may improve neuropathic symptoms via remodeling of complex lipids [ 31 , 32 , 33 , 34 ]. On the other hand, C8 showed a similar effect on the ratio for the species 34:1; however, all other species remained unaffected ( Figure 5 E,F).…”