Money will go toward a Phase III study in nonsense mutation cystic fibrosis.

PTC Therapeutics obtained a $1.6 million grant from the FDA Office of Orphan Products Development to support a Phase III study of ataluren in patients with nonsense mutation cystic fibrosis (nmCF). The primary goal of the study is to evaluate whether the drug can improve lung function as measured by forced expiratory volume (FEV1).

PTC Therapeutics has an exclusive collaboration with Genzyme for the development and commercialization of ataluren. In July 2008, Genzyme paid $100 million up front and agreed to milestone fees and royalties. PTC, however, will be financially responsible for one ongoing and three additional clinical trials of ataluren. PTC will commercialize the drug in the U.S. and Canada, while Genzyme will commercialize the product in other regions of the world.

Besides improvement in lung function, the Phase III trial will also evaluate whether ataluren can decrease lung infections, reduce the frequency of cough, and improve patient-reported quality of life. The Phase III trial will enroll approximately 200 patients at research centers in North America, Europe, and Israel. They will be randomized to receive either ataluren 40 mg/kg or placebo daily for 48 weeks. Study candidates include patients who are at least six years of age and have CF due to a nonsense mutation.

Patients with CF lack adequate levels of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, a chloride channel necessary for normal function of the lung, pancreas, liver, and other organs.  In nmCF, the nonsense mutation prematurely halts the synthesis of CFTR, causing the protein to be short and nonfunctioning. Nonsense mutations are categorized as Class I mutations that result in little or no production of CFTR. CF patients with Class I mutations typically experience more severe disease symptoms than those with low-risk genotypes, including a greater than two-fold increased risk of death, a higher probability of end-stage lung disease, and a higher prevalence of pancreatic insufficiency. 

Ataluren is a protein restoration therapy designed to allow the ribosome to ignore the premature stop signal and continue translation of the mRNA, resulting in formation of a functioning protein. Ataluren does not cause the ribosomes to read through the normal stop signal.

The drug is also being investigated in a Phase IIa study involving patients with nonsense mutation hemophilia A & B (nmHA/B). The main goals of this multicenter, open-label, dose-escalation study are to determine whether treatment with ataluren can result in an increase in factor VIII or IX levels.

Additionally, the firm has Phase IIa data from trials in nonsense mutation Duchenne/Becker muscular dystrophy (nmDBMD). Results from clinical trials of ataluren in pediatric patients showed that administration of ataluren is associated with production of functional dystrophin.

The development of ataluren has been supported by grants from Cystic Fibrosis Foundation Therapeutics, FDA’s Office of Orphan Products Development, Muscular Dystrophy Association, National Center for Research Resources, National Heart, Lung and Blood Institute, and Parent Project Muscular Dystrophy.

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