Stealth BioTherapeutics announced positive results from the open-label extension of the Phase 2/3 TAZPOWER study of elamipretide, an investigational drug, in patients with genetically confirmed Barth syndrome. Barth syndrome is an ultra-rare mitochondrial disease in which reduced levels of the mitochondrial phospholipid cardiolipin are associated with skeletal muscle weakness, debilitating fatigue, cardiac abnormalities, recurrent infections, delayed growth and reduced life expectancy. The TAZPOWER open-label results, presented at the 2019 MDA Clinical & Scientific Conference, demonstrated potential for elamipretide to improve the relative levels of normal to abnormal cardiolipin which are diagnostic for the disease, as well as measures of exercise performance and patient-reported outcomes.
"These Phase 2/3 results support previous pre-clinical findings suggesting that elamipretide may help improve cardiolipin levels," said Dr. Hilary Vernon, TAZPOWER trial investigator, Associate Professor of Pediatrics at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine and Director, Barth Syndrome Clinic at Kennedy Krieger Institute, Baltimore, MD. "Based on the correlation of the cardiolipin ratio with disease severity, these changes in the cardiolipin ratio data may suggest that elamipretide has the potential to modify the course of disease in Barth syndrome rather than merely addressing the symptoms."
TAZPOWER was a Phase 2/3 crossover study of elamipretide in 12 patients with Barth syndrome followed by an open-label extension in which 10 of the 12 patients participated. Although statistical significance was not achieved in the intent-to-treat population during the blinded, placebo-controlled portion of the study, a pre-specified analysis of subjects with relatively higher levels of normal cardiolipin showed improvement on several endpoints.
The presentation of the open-label extension data, demonstrating improvements in various endpoints irrespective of baseline cardiolipin levels, suggests that a longer duration of elamipretide therapy is particularly important for patients with lower baseline levels of normal cardiolipin. Overall, a significant (almost 40%) decrease in the average ratio of abnormal to normal cardiolipin was observed from the start of the study to week 12 of the open-label extension.
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Additionally, significantly increased exercise performance in the Six Minute Walk Test (6MWT) was observed both in patients with relatively more normal cardiolipin as well as in those with relatively less normal cardiolipin. Reductions in fatigue, measured through the BarTH Syndrome Symptom Assessment (BTHS-SA) tool, a novel patient-reported outcome assessment measure, were also observed, with greater improvements observed with longer duration of elamipretide treatment. Improvements were also seen across additional secondary and exploratory endpoints including functional assessments and patient-reported outcomes.
Patients reported improvements in various symptoms, including fatigue/energy levels (90% of patients reported improvement), stamina/endurance (90%), muscle strength (80%) and appetite (70%). In addition, most patients reported improvement in daily life activities (90%), physical activities (90%) and quality of life (80%).
"Our patient community is in dire need of a therapy that addresses the complex, multi-system challenges that occur in Barth syndrome," said Emily Milligan, Barth Syndrome Foundation Executive Director. "The positive findings presented today that elamipretide may improve fatigue and overall quality of life for people living with this devastating disease are encouraging that a potential therapy could finally be on the horizon."
In the placebo-controlled and open-label extension portions of the study, most adverse events were mild to moderate in severity. The most commonly reported adverse events included injection site reactions.
"We are encouraged by these signals that elamipretide may benefit individuals affected by the severe cardiolipin deficiency characteristic of Barth syndrome, which we believe to be one of the most challenging mitochondrial diseases for elamipretide due to reduced opportunity for elamipretide to engage with its target, cardiolipin," said Reenie McCarthy, Chief Executive Officer of Stealth BioTherapeutics. "These findings, which align with the improvements in activities of daily living reported by TAZPOWER subjects in our patient and caregiver perception of change video protocols, will inform our upcoming discussions on a regulatory path forward."
The U.S. Food and Drug Administration (FDA) has granted Fast Track and Orphan Drug designations for elamipretide for the treatment of Barth syndrome. Last summer, the Barth Syndrome Foundation (BSF) hosted a patient-focused drug development meeting with the FDA, from which the organization published a Voice of the Patient Report. The BSF recently shared the report with the FDA during a Professional Affairs and Stakeholder Engagement meeting.