The FDA's Cardiovascular and Renal Drugs Advisory Committee (CRDAC) has voted in favor of Stealth BioTherapeutics' elamipretide for the treatment of Barth syndrome, a rare and life-threatening genetic disorder. The committee's decision, while not binding, signals a potential path forward for the drug despite concerns raised about the robustness of the supporting clinical data. The vote was 10 in favor and 6 against, reflecting the complexities and uncertainties surrounding the evidence presented.
The CRDAC's decision was based on a review of data from several studies, including the TAZPOWER Part 2 baseline-controlled extension study and the SPIBA-001 Phase 3 natural history control study. While the SPIBA-001 trial met its primary endpoint, the FDA expressed concerns regarding the study design, particularly the use of natural history controls and potential biases. Specifically, the FDA noted the potential for selection bias and confounding bias due to the lack of randomization.
Concerns Over Trial Design and Data Interpretation
One of the key issues raised by the FDA was the difficulty in attributing the findings from the SPIBA-001 trial and the open-label extension study (SPIBA-201 Part 2) solely to elamipretide, citing significant limitations in the study designs. Ann Punnoose, M.D., clinical reviewer for the FDA’s division of cardiology and nephrology, stated that the agency had difficulty interpreting the data due to these limitations.
Notably, the SPIBA-201 trial, a phase 2/3 study, failed to meet its primary endpoint of improving average distance walked. The data showed a non-statistically significant difference in walking distance between the elamipretide group (443.1 meters) and the placebo group (443.9 meters), with a p-value of 0.5. Despite these concerns, some committee members were swayed by the overall trend toward positive outcomes and the urgent need for a treatment option for Barth syndrome.
Patient Advocacy and Unmet Need
During the advisory committee meeting, the panel heard compelling testimonies from patients, caregivers, and healthcare providers who shared their experiences with elamipretide. Many described improvements in strength, stamina, and overall quality of life. Jacob Wilson, a 24-year-old man with Barth syndrome, shared that elamipretide made him feel like a "new person," enabling him to gain weight, strength, and stamina.
Emily Milligan, executive director of the Barth Syndrome Foundation, emphasized the significant unmet medical need and urged the FDA to swiftly approve elamipretide. She stated that approving elamipretide would set an important precedent for addressing the unmet needs of patients and families affected by rare diseases.
Elamipretide: A Potential First-in-Class Therapy
Elamipretide is a first-in-class mitochondria-targeted therapeutic. Barth syndrome is an ultra-rare genetic condition primarily affecting males, characterized by cardiac abnormalities, muscle weakness, fatigue, and growth delays. It is estimated to affect approximately 1 in 1,000,000 males worldwide, with about 150 individuals affected in the United States. Currently, there are no FDA- or EMA-approved therapies for Barth syndrome.
Reenie McCarthy, Chief Executive Officer of Stealth BioTherapeutics, expressed gratitude to the patients, caregivers, advocates, and healthcare providers who shared their perspectives with the advisory committee. She stated that the company looks forward to collaborative conversations with the FDA as the agency completes its review of elamipretide.
FDA Decision and Future Implications
The FDA is expected to make its final decision on the approval of elamipretide by January 29, 2025. While the advisory committee's vote is not binding, the FDA typically follows its recommendations. If approved, elamipretide would be the first therapy for Barth syndrome, offering hope to patients and families affected by this devastating disease. The case highlights the challenges and complexities of developing therapies for ultra-rare diseases, where traditional clinical trial designs may not be feasible and regulatory flexibility is essential.
