Hilary Vernon, MD, PhD, a professor of pediatrics at Johns Hopkins Hospital, presented the findings in a presentation, titled “An interventional clinical trial to evaluate the role of elamipretide in individuals with Barth syndrome,” at the American Society of Human Genetics (ASHG) 2019 Annual Meeting held recently in Houston.
Barth syndrome is a very rare mitochondrial disease caused by mutations in the tafazzin (TAZ) gene. This gene is needed for cells to make a mature, functional version of cardiolipin, a type of lipid (fatty compound) found at the inner membrane of mitochondria — which provide energy to cells. Cardiolipin is one of the essential lipids involved in energy production, and when its levels are low, mitochondria cannot produce enough energy for the cell, resulting in its death.
Elamipretide, also known as SS-31, enters mitochondria and helps protect cardiolipin. This has the potential to restore normal energy production and decrease oxidative stress in the cell. The U.S. Food and Drug Administration (FDA) granted fast track and orphan drug designations for elamipretide in the treatment of Barth syndrome.
The Phase 2/3 TAZPOWER (NCT03098797) trial, underway in Baltimore, is evaluating the efficacy of daily under-the-skin injections of elamipretide. The trial enrolled 12 patients with genetically confirmed Barth syndrome.
In the first part of the trial, participants received daily under-the-skin injections of 40 mg elamipretide for 12 weeks, followed by a 12-week treatment with placebo, or vice versa, with four weeks of “washout” between each treatment. A washout is a period of time during a clinical study when a participant is taken off the study drug or other medication so as to eliminate its effects on treatment. This type of study design is called a crossover.
The second part of the trial involved an open-label extension for up to 168 weeks, in which 10 of the 12 patients participated.
The primary objective, assessed at week 12, is the change in distance walked by patients during the six-minute walk test. Additional goals included muscle strength, heart performance, patient-reported outcomes, and adverse effects.
It was previously reported that elamipretide showed potential to improve exercise performance, strength and patient- and clinician-reported outcomes in the extension trial. While the changes in the primary objectives were not statistically significant, the researchers detected improvements in the cardiolipin content of the patients’ mitochondria.
The new data show that elamipretide improves cardiac function. Cardiac abnormalities are a key symptom of Barth syndrome, with heart disease being the main cause of early mortality.
Results showed that treatment with elamipretide increased average cardiac stroke volume by 27% — from 40.8 mL at the start of the trial (baseline) to 51.8 mL — at 36 weeks in the open-label extension.
The average cardiac stroke volume is the amount of blood pumped by the heart left ventricle per contraction, and is a key determinant of cardiac output. In healthy adolescent boys, the average stroke volume would normally be 85 mL.
“Based on the data presented showing an increase in stroke volume, treatment with elamipretide appears to have improved heart function, which might indicate cardiac remodeling,” W. Reid Thompson, MD, associate professor of pediatrics at the Johns Hopkins University School of Medicine, said in a press release.
“Most patients with Barth syndrome have underlying heart disease, so a cardiac effect would be an important outcome in this setting that warrants further investigation,” he added.
Improvements in functional measures, quality of life assessments, and cardiolipin content continued to be seen in the open-label-extension.
“We are encouraged to learn that elamipretide may be associated with improvements in cardiac function in Barth patients, in addition to possible improvements in muscle function,” said Reenie McCarthy, CEO of Stealth.
“These changes in well-established biomarkers add to the body of evidence we expect to discuss with regulatory authorities over the next several months, as we progress toward our commitment to bring therapies to patients suffering from this life-limiting disease,” he added.