Eteplirsen (to be marketed as ExonDys 51), an antisense oligonucleotide developed by Sarepta Therapeutics, was just recently approved by the FDA as the first therapy targeting the underlying cause of Duchenne muscular dystrophy (DMD), though only for a small segment of DMD patients. DMD, which results from the absence or reduction in levels of the dystrophin protein in muscle tissues, manifests as muscle degeneration and weakness, and progresses quickly to loss of ambulation in the early teenage years and subsequent early death.

With no approved therapies for the disease in the United States, eteplirsen’s approval had been heavily advocated for and welcomed by patients, their families, and advocacy organizations despite limited clinical evidence for the efficacy and safety of the drug. Within the FDA, contentious deliberations on whether the amount of dystrophin produced by eteplirsen was “reasonably likely to predict clinical benefit” resulted in an appeal to the FDA Commissioner Robert Califf. He upheld the right of Dr. Janet Woodcock, Director of the Center for Drug Evaluation, to overrule her staff and grant eteplirsen accelerated approval.

The approval was touted by many, both within and outside the DMD community, as a win for patients and as evidence of a new, more flexible FDA. However, the level of disagreement concerning whether the changes observed in dystrophin levels are likely to translate into a clinical benefit may inject some uncertainty regarding the benefits of eteplirsen’s approval and the consequences it may have on future drug development in DMD. Let’s explore some of the potential lingering questions following the FDA’s decision and the anticipated commercial availability of eteplirsen:

Is eteplirsen effective at the approved dose? Preliminary data from an ongoing trial of eteplirsen, PROMOVI, were submitted in response to the FDA’s request—one that came after the FDA completed its review of the original application for eteplirsen’s approval. According to FDA documents, the data provided demonstrated a statistically significant increase in average dystrophin production amongst DMD patients of 0.22-0.32% of normal healthy dystrophin production. The central argument is whether this statistically significant increase is reasonably likely to predict clinical benefit. A commonly cited assumption from leading DMD experts is that 10% of normal dystrophin production might be required to display a clinical benefit. There is broad agreement across the FDA, supported by preclinical studies, that higher doses of eteplirsen than the one approved may achieve the 10% increase. As part of the confirmatory trial required under the accelerated approval, the FDA has mandated that Sarepta test a higher dose of eteplirsen. Traditionally, dose investigation would be conducted in early phase trials, and conducting such an investigation as part of a confirmatory trial may prevent Sarepta from identifying a therapeutically effective dose.

What may be the impact of eteplirsen’s approval on patients and caregivers? An assumption of efficacy with limited supporting evidence may lead patients to assume that improvement in their condition is due to eteplirsen, when it may more properly be ascribed to the standard of care glucocorticoids. Glucocorticoids have proven efficacy in slowing DMD progression but are also associated with undesirable side effects such as weight gain and behavior alterations. In the situation of a patient taking both eteplirsen and glucocorticoids it may be possible for the patient and/or their caregivers to falsely assign any slowing of the patient’s deterioration to eteplirsen when it may be more properly assigned to the glucocorticoids. In an effort to improve the patient’s quality of life by limiting side effects, it is conceivable that parents and patients may opt to stop glucocorticoid treatment and thus, by removing an efficacious therapy from a treatment regimen, unintentionally accelerate disease progression. The burden eteplirsen places on patients and their care givers is not insignificant either, requiring a substantial time commitment with weekly intravenous injections necessitating doctor’s visits; the financial strain that may be caused by adding a $300,000 per year (an average price quoted by Sarepta) therapy to already sizeable medical bills families bear should be taken into account as well.

Does eteplirsen have unknown side effects? Thus far the safety and tolerability profile of eteplirsen has not included significant adverse events. However, the primary pivotal trial in support of eteplirsen’s NDA consisted of just 12 patients, greatly limiting the study’s power to identify potential side effects and complications from treatment. For example, administration of BioMarin’s antisense oligonucleotide drisapersen, previously in development for DMD, resulted in thrombocytopenia in 7% of patients, a concerning rate, but one which would not have necessarily been detected in a study of only 12 patients. Any potential side effects may be detected in confirmatory trials of eteplirsen, but eteplirsen will be available to over 1,000 patients for several years before confirmatory study results become available, and during that time providers, patients and their caregivers could lack valuable clinical information that could help guide treatment decisions and choices. However, given the devastating nature of the disease and the lack of available therapeutics, some patients and their families may be willing to risk potential unknown side effects.

What impact will eteplirsen’s approval have on future drug development in DMD? An inherent complexity of orphan drug development is the limited patient population, which confounds clinical trial design and enrollment. In his scientific appeal of Dr. Woodcock’s approval of eteplirsen, Dr. Unger of the FDA’s Office of Drug Evaluation I makes the compelling theoretical case of a new DMD drug with the potential to produce dystrophin at a much higher rate than eteplirsen. Such a drug could face significant barriers to fulfilling its clinical trial enrollment because it could require patients to discontinue eteplirsen treatment, something which patients with a devastating disease and limited time might not be willing to do.


While eteplirsen is being heralded by many as significant advancement for the Duchenne muscular dystrophy field, it remains to be seen to what degree it would benefit DMD patients as its efficacy has yet to be fully proven and its safety profile is not fully known; moreover, it introduces the potential for efficacious glucocorticoids to be discontinued, and may increase the challenges in future DMD drug development. Many will look to the confirmatory trials with the hope for more evidence of eteplirsen’s efficacy in treating DMD.

For additional analysis of Duchenne muscular dystrophy, please see here.

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