Response to triheptanoin therapy in critically ill patients with LC-FAOD: Report of patients treated through an expanded access program

Long-chain fatty acid oxidation disorders (LC-FAOD) are a group of inborn errors of metabolism wherein patients are unable to process long-chain fatty acids into useable energy in the mitochondria. LC-FAOD commonly affects organ systems with high energy demand, manifesting as hypoketotic hypoglycemia, liver dysfunction, cardiomyopathy, rhabdomyolysis, and skeletal myopathy, as well as peripheral neuropathy and retinopathy in some subtypes. Collectively, LC-FAOD have a high mortality rate, especially in cases of early onset disease, and in the presence of cardiomyopathy. Triheptanoin is a synthetic medium-odd chain triglyceride, produced using a GMP-compliant process, which was designed to replenish mitochondrial metabolic deficits and restore energy homeostasis. Prior to its approval, triheptanoin was only available through clinical trials or to seriously ill patients as part of an expanded access program (EAP) following physician request. This retrospective study examined the impact of triheptanoin on cardiovascular parameters, in critically ill patients who participated in the EAP from February 2013 to January 2018. These patients persisted in critical condition despite receiving standard treatment in highly qualified centers by expert metabolic physicians and dietitians. Physician-completed questionnaires and narrative summaries were used to evaluate the disease presentation and management prior to the trigger event leading to triheptanoin request and use, and the response to triheptanoin treatment. Following triheptanoin initiation, most patients survived the initial trigger event (e.g., severe urinary tract infection, pneumonia) and demonstrated improvements in both short-term and long-term LC-FAOD manifestations. In patients with cardiomyopathy, stabilization or improvement from pretreatment levels was reported in left ventricular ejection fraction and left ventricular mass, in particular, all infants with cardiomyopathy showed improvement in cardiac function during triheptanoin therapy. Triheptanoin therapy was generally well tolerated. The study results are consistent with the existing positive benefit/risk profile of triheptanoin and reflect the effect of triheptanoin improving cardiac function in patients experiencing severe episodes of metabolic decompensation despite standard therapy.