RARE Daily

Stealth Bio Receives Refusal to File Letter from the FDA for Barth Syndrome Therapeutic

October 20, 2021

Stealth BioTherapeutics said it received a Refusal to File letter from the U.S. Food and Drug Administration regarding Stealth’s new drug application for elamipretide, a mitochondria-targeted therapy for the treatment of Barth syndrome.

Photo: Reenie McCarthy of Stealth Biotherapeutics

Barth syndrome is an ultra-rare genetic condition characterized by cardiac abnormalities often leading to heart failure and reduced life expectancy, recurrent infections, muscle weakness and delayed growth. Barth syndrome occurs almost exclusively in males and is estimated to affect one in 200,000 to 400,000 individuals worldwide. There are currently no U.S. Food and Drug Administration or European Medicines Agency-approved therapies for patients with Barth syndrome.

Stealth submitted a new drug application at the end of August despite FDA’s recommendation that additional controlled data be generated to support its review, as neither the FDA nor the company had been able to identify a feasible trial design due to the ultra-rare nature of this disease.

The submission was based on results from the SPIBA-001 phase 3 Retrospective Natural History Control Trial, which compared data from the open-label portion of the TAZPOWER phase 2/3 clinical trial to matched natural history controls. SPIBA-001 met its primary and most secondary endpoints, demonstrating elamipretide-mediated improvements in assessments of exercise tolerance, strength, and cardiac function that are unexpected in the natural course of this progressively debilitating disease.

Upon its preliminary review of the application, the FDA determined that it was not sufficiently complete to permit a substantive review.  In the letter, the FDA stated that the NDA does not contain an adequate and well-controlled trial that provides evidence of effectiveness, noting that the SPIBA-201 phase 2 clinical trial of elamipretide for the treatment of Barth syndrome was negative during the randomized, double-blind portion of the study and that the FDA does not consider the open label extension of the SPIBA-201 trial to be adequate and well-controlled. The FDA reiterated its commitment to work with Stealth on a pathway by which a beneficial effect of elamipretide might be demonstrated within the small patient population.

The letter did not explain why SPIBA-001, the company’s positive phase 3 trial comparing SPIBA-201 results to a retrospective natural history control and the primary basis for the NDA submission, would not be considered an adequate and well-controlled trial. Stealth is evaluating the appropriate next steps and anticipates providing an update in early November.

Stealth and the FDA have previously discussed the challenges of conducting additional clinical trials in Barth syndrome, which is an ultra-rare genetic disease affecting fewer than 130 individuals in the United States. “We submitted our NDA at the request of the Barth syndrome patient community, which petitioned us and the FDA to gain access to elamipretide and shared with the FDA its tolerance of risk of uncertainty of benefit based on the data from the small clinical trials we were able to conduct in this ultra-rare disease,” said CEO Reenie McCarthy.  “We deeply value our relationship with the Barth syndrome patient community, and hope to find a way to progress elamipretide as a treatment for Barth syndrome.”

Elamipretide was previously granted Rare Pediatric Disease, Fast Track, and Orphan Drug designations by the FDA, and Orphan Drug designation by the European Medicines Agency (EMA), for the treatment of Barth syndrome.

Author: Rare Daily Staff

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