On April 25, 2016, the Peripheral and Central Nervous Systems Drugs Advisory Committee (PCNSDAC) voted against the market approval of the Eteplirsen drug. Developed by Sarepta Therapeutics, Eteplirsen is currently under New Drug Application (NDA) review for the treatment of Duchenne muscular dystrophy (DMD) in patients with mutations that can benefit from exon 51 skipping. In DMD, patients contain a defective gene, which inhibits the production of dystrophin, a protein that is essential to the stability and function of muscle fibers. Eteplirsen is a phosphorodiamidate morpholino oligomer (PMO) that targets dystrophin pre-mRNA to induce the skipping of exon 51, which restores and increases dystrophin production.
The advisory committee expressed concerns over the efficacy of Eteplirsen’s clinical trial studies and clinical benefits. The panel voted against the efficacy of Eteplirsen (7 to 3, with three abstentions) because the clinical trial data did not satisfy FDA requirements. Sarepta’s studies consisted of 12 DMD patients without “adequate and well controlled” placebo controls. The panel voted against the accelerated approval of Eteplirsen (7 to 6) as questions were raised over the “substantial evidence” of the drug producing a clinical benefit. The committee considered the dystrophin levels in the trials to review Eteplirsen’s efficiency.
Perhaps the most compelling pieces of evidence used in the meeting were the patient outcomes and perspectives. The video testimonies of the patients used in the clinical trials were supported by the several parents and children of the DMD community in attendance. These patient testimonies had an intense impact on the FDA panel’s decision as stated by pharmacist Richard P. Hoffmann, “I was just basically torn between my mind and my heart.”
In response to this advisory committee meeting, the Muscular Dystrophy Association (MDA) wrote a letter to the director of the Center for Drug Evaluation and Research (CDER) to urge the FDA to go against the recommendation of the panel. The MDA argued that Eteplirsen satisfies the requirements for the Accelerated Approval pathway. Under the premise that DMD is a serious and life-threatening disease, the MDA state that Sarepta’s studies demonstrated meaningful therapeutic benefit, by assessing the primary clinical endpoint of dystrophin in skeletal muscles, and the effect in the 6 Minute Walk Test (6MWT) clinical secondary endpoint. In addition to ongoing clinical safety studies, the MDA argued that the FDA should “consider the totality of the data, including the patient perspective, and to utilize the maximum possible regulatory flexibility via accelerated approval made possible by Food and Drug Administration Safety and Innovation Act (FDASIA) in the review of Eteplirsen.”
Currently, there is no approved therapy for DMD. The FDA originally announced that their decision would be made on May 26; however, the FDA has since stated that they will continue to review the NDA for Eteplirsen and that a final decision will be made in the unforeseeable future.
The Eteplirsen drug for the treatment of DMD in exon 51 amenable patients has the potential to become the first approved DMD therapy and can benefit roughly 13% of patients with this specific dystrophin gene mutation (approximately 1,300 to 1,900 patients in the US).
The agency is not obligated to follow its panel’s recommendation, but normally does so.
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