It does not appear additional data and time for review have improved the prospects for Sarepta Therapeutics Inc.'s proposed Duchenne muscular dystrophy treatment eteplirsen.

The product had already appeared to face long odds for approval when FDA released its initial briefing documents for eteplirsen's advisory committee, which had been scheduled for Jan. 22. So when a snowstorm forced postponement of the meeting and Sarepta pledged to offer more data, it seemed like things could only get better for the product.

But as the agency and its advisors prepare to discuss the product on April 25, things may have actually gotten worse. FDA once again found major problems with the clinical trial for the product, indicating almost more convincingly that efficacy has not been shown.

Chief among concerns laid out in FDA's briefing documents was the dependability of the historical control population used to help show eteplirsen's efficacy. Sarepta has asked for an accelerated approval for use in Duchenne patients who have a confirmed dystrophin gene mutation amenable to exon 51 skipping.

"New data and analyses … increase concerns about the reliability, completeness and comparability of the clinical data for eteplirsen-treated patients and external controls," Clinical Team Leader Ronald Farkas, of the Division of Neurology Products, wrote in his memo to the Peripheral and Central Nervous System Drugs Advisory Committee.

"Additional analyses of ambulatory functions such as rise time and 10 meter walk/run appear to suggest that, in the context of a poorly-controlled trial, the rate of [Duchenne muscular dystrophy] progression in eteplirsen-treated patients and external controls was generally similar."

After Sarepta submitted additional clinical data, its user fee goal date also was moved from Feb. 26 to May 26 ([A#14160208002]).

Senior FDA Leaders To Speak

While Sarepta is seeking approval for an orphan indication, eteplirsen is a surprisingly high profile product. FDA is bringing two of its most respected and senior leaders to the meeting, apparently to reinforce its review of the product and deal with the lingering public relations issue.

Robert Temple, Center for Drug Evaluation and Research deputy center director for clinical science, will speak during FDA's presentation on "issues to consider with external control studies," according to the draft agenda.

Temple is considered a leading expert on clinical trials and has helped write many FDA guidances on the subject.

CDER Director Janet Woodcock will close FDA's presentation, which is highly unusual.

Woodcock has appeared at advisory committee meetings previously, but typically to open the meeting or as a spectator. She likely will affirm FDA's commitment to the Duchenne community and remind everyone that no decision has been made on the eteplirsen application.

The meeting is expected to be attended by 800 to 1,000 spectators. More than 80 also are expected to testify during the open public hearing portion of the meeting, which is scheduled to last 2.5 hours, more than double the time reserved during most advisory committee meetings.

Debra Miller, CEO and founder of CureDuchenne, an advocacy group that provided early funding for eteplirsen development, said in an interview with "The Pink Sheet" that she and others will remind FDA that no trial in this setting will be perfect.

"Ultimately, the FDA is basing their decisions on data, but I think as a community it's up to us to help them understand that there may not be any perfect data at this point " Miller said.

Duchenne patients and advocates are highly interested in the potential of eteplirsen and have pressed hard both at FDA and on Capitol Hill for an approval Also see "Sarepta's Eteplirsen Is Centerpiece Of Senate Hearing On Expanded Access" - Pink Sheet, 26 February, 2016..

Eteplirsen is the second Duchenne drug to reach the advisory committee stage in recent months. BioMarin Pharmaceutical Inc.'s drisapersen, proposed trade name Kyndrisa, received a negative FDA review and advisory committee recommendation and later was issued a "complete response" letter Also see "BioMarin's Drisapersen 'Compete Response' Shows FDA Flexibility Still Limited" - Pink Sheet, 14 January, 2016..

Another product in the pipeline has also not progressed as hoped. PTC Therapeutics Inc.' Translarna (ataluren), proposed for the nonsense Duchenne gene mutation, recently received a refuse-to-receive letter ([A#14160223004]).

'Be Prepared To Consider … Efficacy'

As expected, eteplirsen's efficacy will be the main topic for committee members to consider, but no voting questions were mentioned in the briefing package.

The agency also wrote in the briefing document that it wants the committee's opinion on whether the clinical course of those in Sarepta's clinical study differ "appreciably" from the Duchenne natural history and whether the difference is interpretable.

Billy Dunn and Eric Bastings, director and deputy director of the Division of Neurology Products, respectively, along with Ellis Unger, director of the Office of New Drugs' Office of Drug Evaluation I, and Temple, co-wrote in the overall briefing memo to the committee that "FDA is prepared to be flexible with respect to a devastating illness with no treatment options," but "flexibility does not mean approving drugs for which substantial evidence of effectiveness has not been established."

"Be prepared to consider and discuss whether or not you believe that efficacy has been established," the FDAers said in the memo.

Sarepta's briefing document offers numerous examples of FDA's regulatory flexibility in approving drugs for rare diseases with unmet needs, and FDA's instructions to the committee appear to be an effort to put those decisions in context.

The committee also will be asked to consider the "experimental methods" related to dystrophin expression, including their accuracy, reliability and reproducibility. It also will talk about the design and interpretability of the clinical study submitted and the comparison of the open-label experience to natural history.

In addition, the agency wants the committee to "consider the possible design of any future efficacy and safety studies that might be necessary," according to the agency briefing documents.

The company intends to conduct confirmatory trials using the six-minute walk test and other endpoints, should it receive an accelerated approval, according to its briefing document.

Historical Controls 'Not Well Documented'

FDA raised efficacy questions about eteplirsen in January when it issued its first briefing document for the advisory committee meeting. The agency determined that it appeared eteplirsen patients still were following the Duchenne natural history, suggesting little or no treatment effect ([A#14160115002]).

Sarepta responded to the initial FDA briefing with an addendum accompanying its own briefing that pointed out a number of "key inaccuracies" it found ([A#14160208002]).

In the updated briefing, FDA responded to Sarepta's comments and said the additional data the company submitted raised more questions, in particular about the historical control trial.

FDA reviewed source documents on the patients selected from registries to serve as comparators to eteplirsen patients and found several problems.

The agency determined that two or three of the 13 natural history patients used as controls had six-minute walk test distances recorded as zero, "apparently prior to loss of ambulation as documented by ability to perform the 10-meter walk/run test," the agency said in the briefing document.

FDA also said low six-minute walk test values were recorded for control patients "that appear atypical for reasons that are not well documented."

Data showed that several control patients older than 14 had lost ambulation while eteplirsen patients had not, but FDA said "a number of these values appear not to represent the true ambulatory abilities of the patients."

The agency said several of those patients reported six-minute walk test distances of zero, but still were ambulatory, and others who were reported as having a six-minute walk test of zero, but did not appear to have been measured.

Sarepta submitted 10 meter run/walk data to help strengthen the comparison, but the agency said those measurements also may have been conducted differently for eteplirsen patients and control patients.

New Natural History Data Goes Against Eteplirsen

New natural history data also suggests that eteplirsen efficacy may not be established, according to FDA's briefing documents.

The Cooperative International Neuromuscular Research Group gave the agency new data on the ability of Duchenne patients to maintain ambulation. It suggests that 25% of exon-51 skippable patients can maintain ambulation up to age 16, with 15% of patients maintaining it up to age 18.

"The oldest eteplirsen-treated patients are currently about 15 years old, such that it cannot be concluded that the ambulatory function of any eteplirsen-treated patient exceeds the expected range of natural history," the agency wrote. "This is an important point because some of the applicant's analyses give the impression that some, or most, of the eteplirsen patients have maintained ambulation longer than could have been expected compared to natural history."

Indeed, Sarepta noted in its briefing that fewer eteplirsen-treated boys lost ambulation compared to the external control group during a four-year period.

FDA noted that comparisons using the natural history data should take into account that the eteplirsen patients had to meet inclusion criteria to join the study.

"The eteplirsen patients therefore represent a population enriched for patients with a better prognosis than the overall exon-51 skippable population," the agency said in the briefing.

The struggles of eteplirsen illustrate the problems FDA and researchers have had in understanding Duchenne and its potential treatments.

The agency has questioned the viability of dystrophin production as a potential biomarker to predict clinical benefit. It also has said the disease does not appear to consistently worsen over time, which makes it more difficult to determine treatment efficacy Also see "Drisapersen Advisory Committee Is Rough Welcome To FDA For Patient Groups" - Pink Sheet, 21 December, 2015..

Sarepta's Additional Data Doesn't Sway FDA On Eteplirsen

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