Rare Disease Report

FDA Rejects PTC Therapeutics' Application for Duchenne Drug

OCTOBER 25, 2017
James Radke
PTC Therapeutics, Inc. announced that the U.S. Food and Drug Administration (FDA) has issued a complete response letter for its New Drug Application (NDA) assessing the safety and efficacy of ataluren to treat Duchenne muscular dystrophy in patients who have a nonsense mutation (nmDMD).

A complete response letter means the FDA is unable to approve the NDA in its current form.

The announcement does not come as a surprise to those who have followed the story. Last month, the FDA provided its assessment of the drug before an Advisory Committee Meeting on September 28, 2017, stating: “Overall, the data intended by the applicant to establish the effectiveness of ataluren for the treatment of nmDMD are not persuasive.”

DMD is a progressive degenerative muscle disease caused by low levels of dystrophin protein which acts as a shock-absorber for muscles. Without a functional dystrophin protein, 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.

According to PTC Therapeutics, the letter from the FDA indicated that additional ‘adequate and well-controlled’ clinical trial(s) will be necessary, at a minimum, to indicate that the drug is effective in DMD patients with nonsense mutations.

In a short press release, Stuart Peltz, PhD, chief executive officer of PTC Therapeutics shared his thoughts: "We are extremely disappointed for the Duchenne community and strongly disagree with the agency's conclusions," said Peltz. "We believe that this decision fails to consider the benefit-risk of ataluren and the high unmet medical need. Therefore, we plan to file a formal dispute resolution request next week."

This is not the first time the FDA has told the company that the data was not very persuasive. In 2016, the FDA originally declined to review the clinical data stating the application was not sufficiently completed to permit a proper review. Then in March 2017, the FDA accepted the drug for review with a PDUFA date set for October 24, 2017.

The pivotal data in the application to the FDA is from the ACT-DMD study – 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 24 21 -1.0 .749
     300 < 400 m 47 52 47.2 .007
     400 m 45 41 09.6 .560

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 and PTC Therapeutics were hopeful that the FDA would be more lenient in assessing post-hoc data. The FDA was not.

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