Rare Disease Report

FDA Critical of Duchenne Drug by PTC Therapeutics

SEPTEMBER 26, 2017
James Radke
Today, the U.S. Food and Drug Administration (FDA) posted their assessment of ataluren to treat boys with Duchenne muscular dystrophy who have nonsense mutations (nmDMD).

The assessment will be presented by the Advisory Committee during a meeting on Thursday September 28, 2017.

DMD, or Duchenne muscular dystrophy, is a progressive degenerative muscle disease caused by low levels of dystrophin protein. The low levels are the result of mutations along the Dystrophin gene, and without dystrophin, which acts as a shock-absorber, affected muscles gradually die.  Symptoms typically begin in patients around 4-to-5 years old, and those with the condition are commonly non-ambulatory by their teenage years.

Approximately 13% of all patients with DMD have the nonsense mutation, and ataluren allows RNA to read over the nonsense mutations while synthesizing dystrophin.

The path to FDA approval of the drug has had been a rocky one. In 2016, the FDA declined to review the clinical data for it, stating the application was not sufficiently completed to permit a proper review. In March, the FDA accepted the drug for review with a PDUFA date set for October 24, 2017 and there is an Advisory Committee Meeting set for September 28, 2017 to examine the data. The FDA and the developer of the drug submitted their assessment of the data for the Advisory Committee to review. And the 2 reports differ greatly in their conclusions.

The FDA concluded in their report that, “Overall, the data intended by the applicant to establish the effectiveness of ataluren for the treatment of nmDMD are not persuasive.”

The key word in that sentence is ‘overall’ since PTC Therapeutics,  the developers of ataluren, have asked the Advisory Committee to ‘consider the totality of data,’ when assessing the drug’s efficacy and safety in their report.

Unfortunately for PTC Therapeutics, the FDA thinks the totality of the data is not very impressive. In their briefing document, the FDA concluded “no positive results from any prospectively planned analyses that are persuasive have been provided with this application. The applicant has presented only the results from numerous post hoc and exploratory analyses that are intended to mitigate two negative clinical trials.”

And while the FDA acknowledges that it is “arguable that some trends observed in the applicant’s data may warrant further prospective investigation,” but the FDA also states they have consistently encouraged the applicant to consider further studies. Something the company has not done. Rather, they have relied on exploratory post hoc analyses to convey to the FDA that their drug is effective.

The key data in the application to the FDA is from the ACT-DMD study – a pivotal clinical trial for the drug – which failed to meet its primary endpoint of a change from baseline in the 6-minute walk test (6MWT). In the study, patients given ataluren demonstrated a 13-meter benefit over placebo but the difference was not statistically significant (P = .21).

Table: 6MWT Data from Pivotal Clinical Trial
Difference between
groups (meters)
  All  Patients
114 114 13 .21
  Baseline 6MWT
    < 300 m
    300 < 400 m
    400 m





Post hoc analysis did show that the 6MWT was improved in pre-specified patient populations (patients who had baseline 6MWT results of 300-400 meters) given ataluren.
For more from the FDA, including applications, designations and approvals, follow Rare Disease Report on Facebook and Twitter.

Stay informed on the latest rare disease news and developments by signing up for our newsletter.
Copyright © RareDR 2013-2018 Rare Disease Communications. All Rights Reserved.