Elamipretide Improves Physical Fitness Compared to Natural Disease Course in Barth Syndrome, Analysis Shows

Elamipretide (MTP-131) improves physical fitness in people with Barth syndrome, as compared to the natural course of the disease, according to a new comparison using data from the Phase 2/3 TAZPOWER clinical trial.

Stealth BioTherapeutics, the company that is developing elamipretide and which funded TAZPOWER, plans to meet with the FDA later this quarter to discuss these findings.

Barth syndrome is a rare mitochondrial disease caused by mutations in the gene tafazzin (TAZ). Such mutations lead to low levels of cardiolipin, a lipid (fatty compound) that is necessary for mitochondria to produce energy. As such, common symptoms of Barth syndrome include muscle weakness and fatigue.

Elamipretide can enter mitochondria and protect cardiolipin, which can restore cellular energy production. It is administered via subcutaneous (under-the-skin) injection.

The TAZPOWER clinical trial (NCT03098797) enrolled 12 people with genetically confirmed Barth syndrome. The trial was conducted in two parts: in the first, participants were given daily under-the-skin injections of 40 mg elamipretide for 12 weeks, then 12 weeks of placebo, or vice versa, with a four-week “wash-out” period between. This trial design is called a crossover study, and it allows for greater statistical power because there is both treatment and placebo data for all participants.

Following the crossover portion of the trial, 10 of the participants enrolled in an open-label extension, at which time they were all given elamipretide and followed for up to 168 weeks (3.2 years).

Previously reported findings from TAZPOWER suggested that elamipretide improved heart function.

In the new analysis, data from the trial were compared with data on 19 untreated people with Barth syndrome, which was collected from 2012 to 2019 by investigators at Johns Hopkins Kennedy-Krieger Institute in Baltimore, Maryland. This data was used to create a model of the natural course of Barth syndrome.

To minimize bias, Stealth was not given access to this natural course data while the TAZPOWER trial was ongoing, and the statistical team that developed the natural course model was separate from the team that analyzed the TAZPOWER results.

The primary goal of TAZPOWER was the six-minute walk test (6MWT), which, as its name suggests, measures the distance a person can walk in six minutes. This is commonly used to assess physical fitness in ambulatory people.

Participants in TAZPOWER (including the open-label extension) receiving elamipretide for up to one year had an average 6MWT improvement of more than 80 meters (about 260 feet). In contrast, in the natural course of the disease, the improvement was less than one meter (less than three feet). This difference was statistically significant, meaning it was unlikely to be attributable to random chance.

There also were statistically significant improvements, relative to the natural course, in tests of muscle strength and in sit-to-stand evaluations (ease of standing up from a seated position).

According to Stealth, more detailed results will be presented at upcoming medical meetings.

“We are grateful to have access to such recent and carefully collected natural history data to serve as a control for our TAZPOWER open-label extension, demonstrating the tremendous potential of elamipretide,” Reenie McCarthy, CEO of Stealth, said in a press release. “Thanks to the foresight and commitment of our investigators at Johns Hopkins and the Barth Syndrome Foundation, we have been able to show that elamipretide’s effect on important functional parameters associated with Barth is not only striking but well-beyond what would be expected based on the natural course of disease progression.”

“Our patient community is in dire need of a therapy that addresses the complex, multi-system challenges that occur as a result of Barth syndrome,” said Emily Milligan, executive director of the Barth Syndrome Foundation. “In our meetings with FDA, the Agency has emphasized the importance of natural history data to support therapeutic development in this ultra-rare disease, and we are optimistic to see elamipretide demonstrate such measurable improvements in several key markers of disease that have otherwise been shown to persist over time.”