The FDA’s reviewers pointed out that Stealth’s elamipretide missed its primary efficacy endpoints in the main study used to establish its effectiveness.
The FDA on Tuesday raised substantial doubts about Stealth BioTherapeutics’ data package for its investigational peptide elamipretide, which the biotech is proposing as a treatment for the ultrarare Barth syndrome.
In a briefing document released ahead of an advisory committee meeting, the regulator’s internal reviewers wrote that the “FDA does not believe that the available evidence established the effectiveness of elamipretide” for the treatment for Barth syndrome.
Specifically, the FDA’s staffers pointed out that elamipretide “failed on its primary endpoints” in the first part of the TAZPOWER trial, a Phase II, placebo-controlled, randomized and double-blinded study that assessed the drug’s efficacy according to the 6-minute walk test and participants’ total fatigue score. Stealth positioned part one of TAZPOWER as its adequate and well-controlled study constituting the bulk of the evidence base to support elamipretide.
To further support approval, Stealth also submitted data from the second, open-label extension phase of TAZPOWER and a third, externally-controlled trial. According to the FDA, however, neither study qualifies as an “adequate and well-controlled” trial that can sufficiently establish the effectiveness of elamipretide.
The FDA also suggested that elamipretide would not qualify for accelerated approval based on Stealth’s proposed surrogate biomarker of left ventricle stroke volume (LVSV) because “cardiac hemodynamics and the cardiac effects on functional capacity are based on a complex set of physiological and neurohormonal factors and not LVSV alone,” the briefing document read.
Stealth’s proposed postmarketing observational plan is also “not adequate,” according to the FDA, “and would not be able to confirm clinical benefit.”
The FDA is set to convene its Cardiovascular and Renal Drugs Advisory Committee on Thursday to discuss whether Stealth’s data package for elamipretide sufficiently demonstrates the candidate’s efficacy, and whether accelerated approval is appropriate in this case.
Barth syndrome is caused by a gene mutation that affects the ability of mitochondria to generate energy. It affects multiple systems in the body, including the muscles and heart.
Elamipretide is an investigational peptide therapeutic that works by targeting the inner mitochondrial membrane and reversibly binding to cardiolipin, a phospholipid that plays an important role in maintaining the activity of mitochondria. According to Stealth’s website, preclinical data have shown that elamipretide improves mitochondrial respiration and boosts the production of ATP while also lowering the formation of potentially damaging chemicals.
Stealth had previously tried to secure FDA approval for elamipretide in Barth syndrome, which the FDA rebuffed with a Refusal to File letter. At the time, the regulator said Stealth had not conducted an adequate and well-controlled study to establish the drug’s effectiveness.
