Translarna’s Future Uncertain After FDA Panel Finds Its Efficacy as DMD Treatment ‘Inconclusive’

A U.S. Food and Drug Administration (FDA) advisory board concluded that evidence supporting the effectiveness of Translarna (ataluren), by PTC Therapeutics, as a treatment for Duchenne muscular dystrophy is inconclusive.

The opinion, which was endorsed by 10 of the 11 advisory board members at its Sept. 28 meeting, also stated that more research is needed to establish if the treatment is effective. This indicates the board is open to the possibility that Translarna might work.

The panel’s vote adds uncertainty to the treatment’s future, as the FDA’s action date — Oct. 24 — to decide whether the treatment should be approved is nearing. The board meeting was an independent review of the data supporting what’s known as a marketing application, or request for approval.

Indeed, the vote makes it unlikely that the FDA will approve Translarna later this month. But, while  advisory board recommendations weigh heavily in the approval process, FDA scientists are free to disregard that advice when making final decisions.

An earlier FDA memo intended to brief the advisory board on the therapy, however, also took a harsh tone when summarizing the status of the Translarna research. In it, the agency argued that PTC had failed to show that the treatment works.

“The approach of attempting to retrospectively support an exploratory result in a negative trial with a post hoc analysis of unblinded data from an earlier negative trial substantially lacks scientific rigor,” the FDA briefing document read.

“The application contains a large number of exploratory analyses that lack interpretability and are often entirely based on unblinded data. The presentation of the data in the application is often unclear as to which analyses were used by the applicant,” it continued. “Ultimately, no positive results from any prospectively planned analyses that are persuasive have been provided with this application.”

According to an article by Toni Clarke in Reuters, the FDA director of neurology products, Billy Dunn, suggested that this analytic approach is troubling.

“We are not arguing about the numbers,” Dunn said in the article. “Our concern is much more fundamental and concerns the basis of the scientific method.”

When analyzing scientific data, it is well-known that making a large number of analyses of various aspects of information brings with it a risk of false positive findings — findings of an outcome that doesn’t actually exist, particularly when analyzing unblinded data. That appears to concern the FDA.

The document reviewed the results of two Translarna clinical trials (NCT00847379 and NCT01826487), which both failed to meet their primary goal of a change in the six-minute walk test, as well as key secondary outcome measures.

To support the therapy’s effectiveness, PTC instead provided numerous post-hoc analyses examining aspects of data after a trial. PTC provided the advisory board with a briefing document of its own, in which the company explained the rationale for these various analyses.

PTC also gave the board additional information regarding the regulatory history of Translarna, for which PTC opted to use a “file-over-protest” approach. This rarely used regulatory pathway allows a developer to file a New Drug Application (NDA) against the recommendations of the FDA.

Twice previously, the FDA refused to file Translarna applications — in 2011 and 2016 — a fact that the agency noted in its memo to the advisory board. PTC’s filed-over-protest application came about after two unsuccessful appeals to the rejections.

But the company argued that the FDA only provided the board with its part of the communications regarding regulatory issues, and so PTC added information that it had given the agency.

Among other things, the document held a list of other treatments approved by the FDA despite negative findings in primary outcome measures in pivotal clinical trials. These drugs had been approved based on findings in post-hoc analyses and secondary outcome measures.

A single question was asked of the advisory board:

“The best interpretation of the information presented today regarding the use of ataluren [Translarna] for the treatment of dystrophinopathies resulting from nonsense mutations in the dystrophin gene is that:

• the data suggest that ataluren is not effective.
• although it is possible that ataluren may be effective, the data are inconclusive, and more work would be needed to establish whether ataluren is effective.
• the data are sufficient to conclude that ataluren is effective.”

No board member suggested that ataluren is ineffective, PTC reported. Ten stated that data is inconclusive, and one found data to be convincing of Translarna’s effectiveness. This vote suggests that the advisory board did not share the FDA’s view that PTC had provided no persuasive positive results.

Translarna is designed to bypasses a stop-sign in the form of a so-called nonsense mutation in the dystrophin gene. This should allow the production of dystrophin protein, but so far, it is not clear if this happens in patients.

Europe has taken a different approach compared to Translarna’s regulatory turns in the U.S. In the EU, the treatment was awarded conditional approval, and that approval status was recently renewed. This means Translarna may be used there in ambulatory patients, ages 5 and older, who have nonsense mutation Duchenne muscular dystrophy (nmDMD).