- Sarepta Therapeutics (SRPT -57.2%) has dropped through the floor in early trading on a 4x surge in volume in response to the harsh nature of the FDA's advisory committee briefing document release today for next week's review of eteplirsen for the treatment of patients with Duchenne muscular dystrophy amenable to exon 51 skipping (~13% of DMD cases). As it reads, there is virtually no chance of a positive vote and, therefore, scant probability of approval.
- The document specifies three areas where the effect of eteplirsen on DMD should be demonstrable: expression of altered messenger RNA in muscle, increased production of dystrophin protein in muscle and improvement or preservation of muscle function.
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Altered RNA: the company used a molecular diagnostic method called RT-PCR to confirm the presence of messenger RNA, but the reviewer states that the PCR signal "provides little support of efficacy" but concedes that it may provide evidence that eteplirsen leads to "at least some degree" of exon 51 skipping.
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Increased production of dystrophin: company used two techniques to confirm dystrophin expression. One, immunofluorescence, can overstate the amount of dystrophin. Also, an on-site inspection at the testing facility identified problems with the way the test was performed. The second, Western blot (the most accurate) showed average dystrophin levels of only 0.9% of normal in patients treated with eteplirsen for 180 weeks. The correlation between the methods was "not strong."
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Muscle function: company's efficacy trial, Study 201/202 failed to achieve its primary endpoint. There was no significant difference in the 30 mg/kg dose, the 50 mg/kg dose and placebo as measured by the 6MWT.
- As an exclamation point, the reviewer states, "Although FDA is prepared to be flexible with respect to a devastating illness with no treatment options, we cannot approve drugs for which substantial evidence of effectiveness has not been established" (page 13).