US regulators have refused to accept PTC Therapeutics’ application to market its investigational therapy for nonsense mutation Duchenne muscular dystrophy, sending the firm’s stock into nosedive.

The US Food and Drug Administration has issued a Refusal to File letter for PTC’s oral, first-in-class, protein restoration therapy Translarna (ataluren), stating that “the application was not sufficiently complete to permit a substantive review”.

Translarna, which is licensed in Europe for the treatment of patients aged five and above, is designed to enable the formation of a functioning protein in patients with genetic disorders caused by a nonsense mutation, an alteration in the genetic code that prematurely halts the synthesis of an essential protein. 

Primarily affecting males, DMD is a progressive muscle disorder caused by the lack of functional dystrophin protein, which is critical to the structural stability of skeletal, diaphragm, and heart muscles. Patients with DMD lose the ability to walk as early as age 10 and experience life-threatening lung and heart complications in their late teens and twenties, and there is no approved treatment for the condition. It is estimated that nonsense mutations account for around 13% of DMD cases.

While a Phase III trial with Translarna published last Autumn failed to meet its primary endpoint of change from baseline in the six-minute walk test (6MWT) in the overall intent-to-treat study population, a highly significant benefit of 47 meters was demonstrated in the pre-specified patient population of 300m-400 meters at baseline. 

“The totality of the data from our two robust placebo-controlled studies across over 400 patients demonstrate a clinically relevant impact on patients' lives," said Stuart Peltz, the firm’s chief executive, at the time.

PTC said it is now reviewing the content of the Refusal to File letter to determine the appropriate next steps.