FDA Rejects PTC’s New Drug Application for Translarna as a Nonsense Mutation DMD Treatment

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by Charles Moore |

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Duchene muscular dystrophy drug candidate

PTC Therapeutics, Inc. announced Wednesday that it has received a Refuse to File letter from the U.S. Food and Drug Administration (FDA) with regard to its New Drug Application (NDA) for ataluren (trade name, Translarna), an oral, first-in-class, protein restoration therapy for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD).

The FDA states in its letter that the drug application was not sufficiently complete for the agency to conduct a substantive review. PTC is reviewing the letter’s content to determine the appropriate next steps to take, the company said in a press release.

PTC, a South Plainfield, New Jersey-based biopharmaceutical company, is focused on the discovery, development, and commercialization of proprietary, orally administered, and small molecule drugs targeting the area of RNA biology called ‘post-transcriptional control’ — referring to regulatory event processes that occur in cells during and after a messenger RNA, or mRNA, molecule is copied via the mechanism known as DNA transcription.

Ataluren is a small-molecule protein restoration therapy compound in clinical development for the treatment of Duchenne muscular dystrophy (DMD) caused by a nonsense mutation (nmDMD), cystic fibrosis caused by a nonsense mutation (nmCF), and other genetic disorders caused by nonsense mutations. The company explains that such mutations are alterations in the genetic code that create a premature ‘stop signal’ in the translation of code contained in mRNA, prematurely halting synthesis of an essential protein and preventing production of full-length, functional proteins. Nonsense mutations are associated with a variety of genetic disorders, the specificity of which is determined by which protein cannot be expressed in its entirety and is no longer functional, such as dystrophin in Duchenne muscular dystrophy, a progressive muscle disorder primarily affecting males. Dystrophin is critical for maintaining structural stability of the skeletal, diaphragm, and heart muscles, and DMD patients typically lose their ability to walk as early as age 10, and experience serious lung and heart complications in their late teens and 20s. It is estimated that nonsense mutations account for about 13 percent of DMD cases and, in the United States, affect roughly 2,000 people.

Translarna has been granted conditional marketing authorization in the European Union for the treatment of nmDMD in ambulatory patients ages 5 and older.

PTC notes that translarna is the first treatment given conditional approval that addresses the underlying cause of DMD. The European Medicines Agency, or EMA, has designated ataluren an orphan medicinal product. and the FDA has granted orphan drug designation to ataluren for the treatment of both nmDMD and nmCF.

PTC researchers believe that ataluren interacts with the ribosome — the cell component that decodes mRNA molecules and manufactures proteins — thus enabling it to read past the mutation-caused premature nonsense stop signals on mRNA, and allowing the cell to produce a full-length, functional protein. They maintain that ataluren has potential as an important therapeutic agent for treating muscular dystrophy, cystic fibrosis, and other genetic disorders for which nonsense mutations are causative.

Translarna’s development of has been supported by grants from Cystic Fibrosis Foundation Therapeutics Inc. (the nonprofit affiliate of the Cystic Fibrosis Foundation); the Muscular Dystrophy Association (MDA); the FDA’s Office of Orphan Products Development, the National Center for Research Resources; the National Heart, Lung, and Blood Institute; and the Parent Project Muscular Dystrophy.

For more information about PTC and its drug candidate pipeline, visit www.ptcbio.com

PTC Therapeutics, Inc.