The FDA's technical staff had little good to say about eteplirsen, Sarepta Therapeutics' candidate for Duchenne muscular dystrophy, ahead of an advisory committee meeting next week.
FDA reviewers were wary that studies couldn't produce an accurate measurement of dystrophin levels -- the protein whose production the drug is supposed to increase -- and that the use of historical controls in its only clinical trial made the results susceptible to bias.
Sarepta is seeking accelerated approval for eteplirsen, given as a weekly dose of 30 mg/kg intravenous infusion, for patients with DMD who have a mutation in the dystrophin gene that makes them amenable to exon 51 skipping. The drug works by removing exon 51 of premessenger RNA, restoring the mRNA "reading frame" to enable production of a truncated dystrophin protein. Although the protein would still be abnormal, the hope is that the increased quantity will slow or prevent progression of DMD.
A similar exon 51 skipping drug, drisapersen by BioMarin Pharmaceuticals, recently received a following a negative response from an advisory committee in November. In it, the FDA told BioMarin that the firm hadn't satisfied "the standard of substantial evidence of effectiveness."
The agency's briefing documents for the eteplirsen review suggest a similar attitude toward that drug as well.
In its own briefing documents posted ahead of the meeting, Sarepta noted that the accelerated approval pathway "means that there will be an acceptable degree of uncertainty about whether the therapy will actually result in the anticipated clinical benefit."
The company holds that its lone placebo-controlled clinical trial of 12 patients, which ultimately ended up using a comparison with historical controls, showed a 151-meter advantage at 3 years on the 6-minute walk test (6MWT) for those on the drug compared with the natural history of the disease.
In the FDA's clinical review, Ronald Farkas, MD, PhD, said the two exploratory studies of dystrophin expression, Study 28 and Study 33, could not reliably demonstrate whether or not the drug increased dystrophin levels.
In Study 33, Farkas noted that increased dystrophin expression following a localized injection didn't reveal anything about what effects intravenous eteplirsen might have. In Study 28, methods for dystrophin quantification weren't reviewed by the FDA before the study, and the agency had several concerns about the reliability of the methods and procedures used.
The lone clinical study, Study 201/202, evaluated 12 patients randomized to either placebo or to one of two doses of eteplirsen. Farkas wrote that the clinical endpoints were "essentially uniformly negative, without trends supportive of efficacy."
The company ultimately compared the results from the open-label phase of the study with historical controls to find a benefit, but the FDA said the effects of bias in this type of design "can be considerable ... with many factors potentially favoring the treatment arm."
Even so, the agency said the results of this comparison "suggest that eteplirsen does not have the type of large beneficial effect that would be possible to reliably detect in even a well-designed historically controlled trial."
Farkas also highlighted several problems with the first three biopsies from the clinical trial done to assess dystrophin biomarkers, challenging whether the findings are "reliable or interpretable." A fourth biopsy was criticized for not matching controls by muscle group or by patient.
"Based on the data submitted by the applicant, considerable doubt remains about how much, or perhaps even whether, dystrophin levels were increased by eteplirsen," Farkas wrote. "The degree of uncertainty about the dystrophin data hinders discussion of its use as a surrogate endpoint for eteplirsen."
The agency's statistical review concluded that there were no differences in the original primary endpoint of the 6-minute walk test, and that the comparison with historical controls is "statistically uninterpretable," concluding that the data don't provide statistical evidence to support the efficacy of eteplirsen in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping.
The Peripheral and Central Nervous Systems Drugs advisory committee will meet on Friday, Jan. 22, to decide whether or not to recommend accelerated approval for eteplirsen. The FDA is not obliged to follow its committees' recommendations but it often does.