FDA Advisory Panel Votes BioMarin’s Drisapersen Trials Are Not Persuasive

November 30, 2015

With a mixed bag of results and much at stake for BioMarin Pharmaceutical’s Duchenne muscular dystrophy treatment drisapersen, FDA reviewers overwhelmingly decided the largest, most complete trial in the candidate’s development weakened “promising” findings from earlier studies.

They also were unconvinced of effects of the mechanism of action, reducing dystrophin levels, and the persuasiveness of other research in the candidate’s arsenal.

Uncharacteristic of a typical advisory committee vote, the panel did not vote on whether to recommend approval during last week’s meeting of the Peripheral and Central Nervous System Drugs Advisory Committee. Instead, panelists voted on the persuasiveness of the three trials.

In the end, they were unconvinced about the persuasiveness of the studies used to support the candidate. They pointed to uncertainty about whether the candidate — which, if approved, would be the first DMD-specific treatment — would actually provide a benefit in a real-world setting. Echoing FDA concerns about consistency and statistical significance in relatively small sample sizes, they called for more conclusive research.

Given the hope they saw, panelists suggested additional studies and said there may be a subgroup of “super-responders,” but that needs to be better defined.

Justin Zivin, a Rancho Santa Fe neurologist and committee member, said it gave him no pleasure to vote against the merits of the research because of the serious unmet need. However, “this needs more work,” he added.

In the defining vote, reviewers determined 15 to 2 that BioMarin’s Phase 3 trial weakened the candidate’s case. The other two voters decided it had no effect.

Regarding another key factor, 10 advisory experts thought dystrophin reduction data — the way the drugmaker plans to use drisapersen — did not make a difference in overall interpretation of drug efficacy, while six believed it diminished results.

Drisapersen — an exon skipper designed to target dystrophin protein levels — was studied in 326 patients through two Phase 2 and one Phase 3 trials, as well as long-term extension studies. Each used a six-minute walk test as the primary endpoint, a common measure of muscular strength in the degenerative disease.

The committee concluded that the trials had bright spots but were not a reliable body of evidence.  

Reviewers said that in Phase 1, they saw a trend toward a benefit for many outcomes of continuous treatment. But some saw trouble in the weaker results for the intermittent arm, given that the dosing was the same, and in the “noisy” data set that was not all on the same page. Split on these issues, the committee voted 9 to 7 that the first trial weakened the case.

Support, however, fell as the clinical program wore on.

The weakest case was for the Phase 3 trial, which did not meet primary endpoints and was “disappointing,” the committee said. Although the sponsor defended the trial by showing results over the longer term and pointing to a trial design that accepted weaker, sicker and older patients, reviewers did not feel that made up for the failure. They said this was the most reflective of how the candidate would play out in a clinical setting.

In an emotional plea, dozens of families with children with the disorder showed up to urge the agency to approve the candidate, singing praises of their boys’ improvement — especially in energy and endurance — seen during clinical trials and how those effects went away when they were taken off treatment. Many said drisapersen would be a “first step” for a disease where time is not a luxury and muscles degenerate quickly.

In a departure from the agency’s warnings about drisapersen’s safety profile, many said that if efficacy had been better established, this could have been something better left up to patient-family-doctor teams because of the nature of the debilitating, degenerative and fatal disease.