FDA Won’t Approve Ataluren; PTC Therapeutics to Appeal

Duchenne muscular dystrophy drug fared poorly in trials

PTC Therapeutics plans an appeal after the FDA declined to approve its proposed Duchenne muscular dystrophy drug without an additional clinical trial. The agency has issued a complete response letter (CRL) for ataluren, an investigational medicine intended to treat nonsense mutation dystrophinopathies.

"We are extremely disappointed for the Duchenne community and strongly disagree with the agency's conclusions," said Stuart W. Peltz, PhD, Chief Executive Officer of PTC Therapeutics. "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."

The letter from the FDA’s Office of Drug Evaluation I stated that it is unable to approve the application in its current form. Specifically, the letter indicated that evidence of effectiveness from one or more additional adequate and well-controlled clinical trials will be necessary to provide substantial evidence of effectiveness. PTC Therapeutics said the letter also raised other nonclinical and chemistry, manufacturing, and controls matters that the company is addressing.

Last month, an FDA advisory panel voted 10-1 against recommending approval of the drug, saying that it did not work in two major patient tests while calling the provided data inconclusive.

Ataluren is a protein restoration therapy designed to enable the formation of a functioning protein in patients with genetic disorders caused by a nonsense mutation. A nonsense mutation is an alteration in the genetic code that prematurely halts the synthesis of an essential protein. The resulting disorder is determined by which protein cannot be expressed in its entirety and is no longer functional, such as dystrophin in Duchenne muscular dystrophy (DMD).

Ataluren, traded under the name Translarna, has a conditional approval in Europe, where its license must be renewed every year. The approval is for the treatment of nonsense-mutation DMD in ambulatory patients 5 years of age and older.

Primarily affecting males, DMD is a rare and fatal genetic disorder that results in progressive muscle weakness from early childhood and leads to premature death in the mid-20s due to heart and respiratory failure. It is a progressive muscle disorder caused by the lack of functional dystrophin protein. Dystrophin is critical to the structural stability of skeletal, diaphragm, and heart muscles.

Patients with DMD can lose the ability to walk as early as age 10, followed by loss of the use of their arms. DMD patients subsequently experience life-threatening lung complications, requiring the need for ventilation support, and heart complications in their late teens and 20s. It is estimated that a nonsense mutation is the cause of DMD in approximately 13% of patients.

Sources: PTC Therapeutics; October 25, 2017; Pharmaceutical Business Review; October 26, 2017.