Elamipretide

In this pivotal phase 3, double-blind, placebo-controlled trial, 218 adults with genetically confirmed primary mitochondrial myopathy were randomized 1:1 to subcutaneous elamipretide 40 mg/day or placebo for 24 weeks. The co-primary endpoints—change in 6-minute walk test distance and total fatigue on the Primary Mitochondrial Myopathy Symptom Assessment—were not met in the overall population. A prespecified subgroup with nuclear DNA (nDNA) mutations showed a signal of improvement in 6MWT that the authors described as hypothesis-generating rather than definitive. The drug was generally well tolerated, with injection-site reactions being the most common adverse event.

This large, rigorous trial tested whether a daily under-the-skin injection of elamipretide could help adults with inherited mitochondrial muscle disease walk farther and feel less fatigued. Overall, the drug did not beat placebo on its two main goals. One subset of patients (those with a particular type of genetic mutation) appeared to do somewhat better, but this needs confirmation in future studies. The treatment was safe and mostly caused minor injection-site reactions.

This report covers the 168-week open-label extension of TAZPOWER, a trial in patients with Barth syndrome, a rare X-linked disorder of cardiolipin metabolism. Following an initial 28-week randomized, double-blind, placebo-controlled crossover phase in 12 patients (which did not meet its primary endpoints at 12 weeks), long-term open-label dosing was associated with progressive, statistically significant improvements in 6-minute walk test distance (cumulative +96.1 m at week 168; P=.003), along with gains in muscle strength and measures of cardiac function. Elamipretide showed sustained tolerability over the multi-year period. The uncontrolled open-label design limits causal interpretation, though the durable functional gains supported subsequent regulatory review.

Barth syndrome is a very rare inherited condition affecting the heart and muscles. In the initial short, blinded phase of this small trial, elamipretide did not clearly beat placebo, but when all 12 patients received the drug openly for several years, they showed steady, meaningful improvements in how far they could walk, in muscle strength, and in heart measures. Because everyone knew they were getting the drug in the long-term phase, results should be interpreted with some caution, but the sustained benefits helped support later regulatory approval for this disease.