In two webcasts held Feb. 29 — one for investors and one for Duchenne muscular dystrophy (DMD) patients and families — PTC Therapeutics addressed the Refuse to File letter it received last week from the U.S. Food and Drug Administration (FDA) stating that PTC’s New Drug Application (NDA) for Translarna (ataluren) to treat DMD was not sufficient to permit a substantive review.
Translarna, under development by PTC to treat DMD caused by a “premature stop codon” or “nonsense” mutation, is a “stop codon read-through drug.” It is designed to coax cells to “read through” (ignore) the premature stop codon in the gene for the muscle protein dystrophin, allowing for the production of functional protein. Nonsense mutations are responsible for dystrophin deficiency in 5 to 15 percent of people with DMD.
PTC Therapeutics’ Chief Executive Officer Stuart Peltz noted two concerns raised by the FDA in the Refuse to File letter:
- In the view of the FDA, clinical trial results have not provided substantial evidence of effectiveness as participants who were treated with Translarna did not demonstrate statistically significant benefit compared to those who received a placebo.
- The FDA expressed concern that PTC’s NDA for Translarna does not contain adequate information regarding the abuse (addiction) potential of the drug, which crosses the blood-brain barrier. (The blood-brain barrier, or BBB, is a semi-permeable network of cells that separates blood and its contents from the brain and spinal cord.)
With regard to evidence of effectiveness, Peltz noted that PTC has completed two large, double-blind, placebo-controlled trials in more than 400 nonsense mutation DMD patients, in which the drug has demonstrated clinically meaningful benefits. PTC believes the totality of the data is supportive of effectiveness and demonstrates a strong safety profile.
Peltz also explained that evaluating the potential for abuse is an FDA requirement for new molecules that cross the blood-brain barrier. “We believe, based on the clinical and preclinical work we have done, we should be able to address the FDA’s concern and demonstrate that Translarna has not shown central nervous system effects associated with abuse potential,” he said.
PTC currently is working with the FDA to discuss and clarify the concerns outlined in the letter and determine the best path forward.
“Translarna deserves a full and fair hearing in front of the FDA including an advisory committee with representatives of the DMD community,” Peltz said, adding that PTC believes in the strength of its data and what it represents for patients, and that its main goal remains to obtain regulatory approval for Translarna for DMD in the United States.