- A group of 36 doctors associated with treatment of Duchenne’s muscular dystrophy (DMD) sent a letter to the FDA advocating for the approval of Sarepta Therapeutics’ DMD drug eteplirsen. The agency will review the drug’s application at an advisory committee meeting on April 25.
- The letter addresses the FDA’s previous criticism of eteplirsen’s clinical data and asks for the drug to be advanced under accelerated approval with confirmatory trials to follow.
- Last month, 109 members of Congress also sent a letter to the FDA requesting the approval of a Duchenne’s drug, although they did not name eteplirsen. The FDA recently rejected a DMD drug developed by BioMarin.
DMD is a rare genetic disease, which mainly affects boys and young men. In those affected by DMD, muscle tissue does not function properly because the body does not produce dystrophin. This leads to muscle weakening, paralysis, and eventual death. Most patients die before age 30.
Due to DMD’s rarity, it is difficult to enroll a large number of patients in trials—one of the FDA’s criticisms of Sarepta’s application. The core clinical trial in Sarepta’s application involved 12 boys suffering from DMD who were administered eteplirsen over three years. They were evaluated by improvement in a six-minute walk test. In October, 2015, Sarepta announced positive results showing a statistically significant improvement of 151 meters in the walk test. However, the FDA has questioned the reliability of the test.
The letter was signed by physicians from top medical centers across the U.S., as well as from several top Duchenne's researchers at the Western Australia Neuroscience Research Institute affiliated with Murdoch University. Together, they claim collective experience of treating more than 5,000 patients with DMD and argue they are qualified to assess eteplirsen’s efficacy.
A number of the signatories also have ties to Sarepta, as noted by FierceBiotech. Nancy Kuntz, Basil Darras, and Hoda Abdel-Hamid, for example, were principal investigators at local trial sites for Sarepta’s Promovi study.
The FDA has made the case that using an external control group, instead of an actual placebo arm, is questionable science. However, the doctors countered that Sarepta's use of a natural history cohort from Belgium and Italy is scientifically appropriate, because these boys are comparable in terms of age and medical treatment to the boys in the study. They also pointed out that despite the small size of the clinical trials, the strength of the data in terms of 6-minute walk distance (6MWD) and biomarker outcomes is very strong.
Jenn McNary, Director of Outreach and Advocacy at the Jett Foundation, is the mother of two boys with DMD amenable to exon 51 skipping—the specific mutation which responds to treatment with eteplirsen. By the time McNary found out Sarepta was enrolling boys into a clinical trial for eteplirsen, her oldest son Austin (12 at the time) was not eligible for the trial, as his disease had progressed too far. However, her younger son Max was eligible. (Austin and Max are both pictured above.)
McNary watched as Austin, now 17, was forced to use a motorized wheelchair, while Max (now 14) regained his ability to walk without falling down. Max has been receiving the treatment for five years and can now run well enough to play soccer.
McNary is on the front lines of the battle to get eteplirsen approved. "For me this is about validation, patients, and advocates, families have been advocating for this drugs approval for years now,” she said.
“Critics will say we are desperate or don't understand data—but here we finally have experts in Duchenne, who are not desperate, who do certainly understand Duchenne and clinical trial data, poking the same holes in the FDA’s assessment of Eteplirsen that we have seen.”
In the letter, the doctors conclude the aggregate data gives significant evidence of efficacy and supports use in a greater population of boys amenable to exon 51 skipping.
She added: "The support for this drug has grown, from the patient community, to congress and now to the medical professionals, who clearly want to be able to prescribe eteplirsen as a treatment for their patients.”
Pushing for approval
The doctors closed the letter with an emphatic request for approval. “We suggest that the most scientifically robust way forward and the most ethical choice for the Duchenne community is in the context of an accelerated approval followed by a confirmatory trial,” the letter said.
It remains to be seen whether the FDA will agree. The previous advisory committee meeting had been canceled due to bad weather in Washington, D.C. Subsequently, the FDA extended eteplirsen’s review period by three months, from February to May. This could be a positive signal but the FDA’s previous rejection of BioMarin’s drug and earlier criticism of eteplirsen creates some doubt.