Never take no for an answer seems to be PTC Therapeutics Inc.'s strategy for bringing its Duchenne muscular dystrophy (DMD) drug to the U.S. market.

Despite two FDA refuse-to-file determinations citing lack of effectiveness, two failed appeals and multiple meetings with agency staff, PTC insisted on filing a new drug application for Translarna (ataluren) over the FDA's protest. The company's next step along the rarely used path is to persuade the agency's Peripheral and Central Nervous System Drugs Advisory Committee Thursday of the merits of the drug, which the EMA approved more than three years ago to treat a small group of DMD patients with a so-called nonsense mutation in the dystrophin gene.

Translarna is a first-in-class protein restoration therapy designed to create a functioning protein in patients who have genetic disorders resulting from a nonsense mutation – about 10 percent to 15 percent of the patients with DMD. The drug is already approved in more than 25 countries worldwide and, if approved by the FDA, it would be the first drug available in the U.S. to treat an underlying cause of the disease.

That means a lot is riding on PTC's ability to convince the FDA advisory committee that its data support the drug's approval. Although adcom recommendations are advisory, they do carry weight with the agency. So far, the FDA appears unimpressed by the data, approvals elsewhere and the company's persistence in trying to turn the agency's no into a yes. Whether it could be swayed by a positive adcom vote looks doubtful.

"The application contains a large number of exploratory analyses that lack interpretability and are often entirely based on unblinded data. . . . Ultimately, no positive results from any prospectively planned analyses that are persuasive have been provided," the agency summarized in its briefing document for Thursday's meeting.

The FDA noted that the results were clearly negative in the one instance where an unblinded post hoc analysis of Study 007 results was prospectively tested in a subsequent study. Its account of the drug's development history is laden with exploratory post hoc manipulations of the unblinded data to find a subgroup that nominally favored the low-dose of Translarna compared with placebo.

Adding to the FDA's negative view of the drug is the fact that a high dose performed worse than a low dose in Study 007. The agency said PTC, like other sponsors facing such failures, attributed it to a "predictable inverted-U shaped dose-response."

"In practice, this pattern of dose-response is extremely rare, and the review team finds that the sponsor's speculative explanation is not supported by the data," the FDA said.

Substantial evidence needed

With a nod toward its controversial accelerated approval last year of Sarepta Therapeutics Inc.'s DMD drug Exondys 51 (eteplirsen), the agency said, "As recent FDA drug approvals indicate, the agency is highly sensitive to the need to exercise regulatory flexibility in the setting of serious diseases like DMD. However, the critical requirement remains that substantial evidence of effectiveness be provided in order to support approval of a new drug." (See BioWorld Today, Sept. 20, 2016.)

Occasionally in adcom meetings, the FDA asks committee members to discuss further studies a sponsor could do to provide data needed for approval. But this time, the FDA has proposed only one question. It's a voting question about the best possible interpretation of the data presented. As the question is drafted, the panelists will have to choose between three possible answers:

  • The data suggest that Translarna is not effective.
  • Although it's possible that Translarna may be effective, the data are inconclusive, and more work would be needed to establish the drug's effectiveness.
  • The data are sufficient to conclude that Translarna is effective.

The drug's PDUFA date is Oct. 24. If it were to succeed in getting a regulatory greenlight, Translarna would strengthen PTC's position in the DMD space, as the South Plainfield, N.J., company already markets Emflaza (deflazacort). It acquired the DMD therapy earlier this year in a $140 million deal from Marathon Pharmaceuticals LLC, after the latter faced public scrutiny over pricing. (See BioWorld Today, March 17, 2017.)

Several groups have pinned their hopes on Translarna. The Muscular Dystrophy Association and the Parent Project Muscular Dystrophy – along with the FDA's Office of Orphan Products Development, the National Center for Research Resources and the National Heart, Lung and Blood Institute – provided grants to help fund the development of the drug.