Eteplirsen Approved for Duchenne Muscular Dystrophy: The FDA Faces a Difficult Choice

Eeplirsen (Sarepta Inc., Boston, MA) is a 30-mer phosphomorpholidate oligonucleotide that has been evaluated in young male patients with the devastating disease known as Duchenne muscular dystrophy (DMD). This X-linked disease, found in approximately 1/3,500–1/5,000 live male births,¹ is characterized by mutations in the dystrophin gene that take the messenger RNA (mRNA) reading frame out of frame. These mutations can produce premature stop codons¹ in the dystrophin mRNA, leading to mRNA degradation and the loss of protein synthesis^2,3 in striated muscle, resulting in catastrophic clinical consequences.

The dystrophin protein is located beneath the sarcolemma (the muscle cell membrane). Through N-terminal binding to F-actin and C-terminal binding to β-dystroglycan (a protein that forms a complex with dystrophin), it connects the cellular cytoskeleton to the sarcolemma. The loss of dystrophin results in inflammation and degeneration of muscle, and its replacement with fibrotic tissue and fat.⁴

Sufferers from DMD progressively lose neuromuscular function as they age, culminating in their inability to walk by their mid-teens. Sadly, muscle deterioration continues unabated, resulting in cardiomyopathy, respiratory failure, and death by the time DMD patients are in their third decade.⁵ As I can assure you from personal experience in caring for such patients, words cannot adequately express either the heartbreak of the parents of DMD patients or the suffering patiently endured by those who are afflicted by this terrible ailment.

In roughly 13% of patients with DMD, the molecular lesion, an out-of-frame deletion as mentioned above, can be found in exons 47–63 (ref. 6). Eteplirsen, targeted to the splice-donor region of exon 51, induces skipping of exon 51 (ref. 7). This yields an in-frame, truncated, yet partially functional dystrophin protein, similar to what is found in Becker muscular dystrophy, a much less severe form of the disease.

According to van Deutekom et al.,² as of 2013 more than 100 in vitro and in vivo studies had demonstrated restoration of dystrophin protein via an exon-skipping strategy. Perhaps the most critical of these studies was published by Mendell et al. in early 2016 (ref. 5), in which patients with DMD were treated with eteplirsen. In this study, the primary functional assessment was the six-minute walk test (6MWT), the “only primary validated efficacy endpoint that has been accepted by regulatory authorities.”² Treatments were double-blinded and patients randomly assigned to three cohorts (n = 4 each): placebo; eteplirsen 30 mg/kg or 50 mg/kg weekly for 24 weeks. Subsequently, patients received drug on an open-label basis, while placebo patients also received open-label drug (30 or 50 mg/kg) for a span of over three years. Because all placebo patients had crossed over to active drug treatment, a group of pooled historical controls were employed for purposes of comparison. The results demonstrated that the distance lost on the 6MWT test at 36 months was 151 m less than that lost in the historical controls (P < 0.01; from about 350 to 250 m in the eteplirsen-treated patients, compared to about 350 to 100 m in the historical controls). After three years, 16.7% of the eteplirsen-treated patients lost ambulation, compared with 46.2% of the historical control patients. There were no reports of serious adverse advents related to treatment, and none of the observed adverse events led to treatment interruptions or dose adjustments.

You might think this story would quickly end happily—for patients, for their parents, and for the doctors who treat DMD—as a joyful US Food and Drug Administration (FDA) overwhelmingly approved Sarepta's application for marketing. In the short term, it was not to be. Despite a “legion” of eteplirsen advocates—including over 100 members of Congress—an FDA advisory panel, by a 6–7 vote, wasn't convinced. It seems that Sarepta had not heeded repeated FDA advice not to perform a trial based on such a small number (n = 11) of historical controls. In fact, according to the FDA, the entire study was too small; a larger, placebo-controlled trial would be necessary to determine if eteplirsen had truly helped anyone.⁸ Moreover, Sarepta had apparently never demonstrated much of an increase in dystrophin production in affected muscle tissue (0.28%, to be precise, far less than the 10% deemed necessary for a clinical impact), even in patients who had been clinically helped by their drug. Fortunately, by June 2016 Sarepta and the FDA had come to terms; the company will submit biopsy results to the FDA from treated patients as part of an additional, larger placebo-controlled trial that is currently accruing patients. How much dystrophin production will be sufficient to convince the FDA that eteplirsen is doing what Sarepta claims it does? Perhaps, as has been suggested,⁹ only 0.9% of the amount of protein found in normal muscle cells will be necessary. This should not be an insurmountable barrier for an “active” oligonucleotide.

As one could imagine, the FDA's initial position was not popular among the advocacy set. In a recent opinion piece, as learned a media organ as the Wall Street Journal¹⁰ berated the agency, saying that it would rather “check off procedural boxes than confront…realities.”

Nevertheless, numerous FDA scientists adhered to their original analysis. There was not sufficient scientific information, they emphatically stated, to justify the marketing of a drug that retailed for $300,000/patient/year. (Anthem, a leading carrier, agreed and eventually refused to cover eteplirsen's cost for their insured patients, although other carriers have been willing to approve coverage.)

On 19 September, Janet Woodcock, Director of the FDA's Drug Division, overruled her own scientists, and Robert Califf, the FDA commissioner, agreed with her. Eteplirsen, now renamed Exondys 51, was approved,¹¹ to the delight of many and the fury of some, who lamented the FDA's decision as “this isn't even science.”¹¹ But in having to deal with such a politically charged question, perhaps Dr. Woodcock took the optimal course of action by kicking the can down the road a bit; Sarepta must produce data on more than 12 patients or run the risk of losing its hard-won FDA approval. We should know if Exondys 51 will produce in about the year 2020. My belief is that it ultimately will.