PTC Therapeutics Announces Encouraging Phase 2 Results Of PTC124 In Cystic Fibrosis

Armen Hareyan's picture

PTC Therapeutics announced encouraging data from a Phase 2 clinical trial of PTC124 in pediatric patients with cystic fibrosis (CF) due to a nonsense mutation. These pediatric results and additional information emerging from long-term studies support the existing data from prior short- term studies in adult CF patients. These studies show that treatment with PTC124 results in statistically significant improvements in a measure of the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. These data were highlighted today in a plenary session entitled "CF Drug Development: What's New?" given by Dr. Felix Ratjen, University of Toronto Professor of Pediatrics and Respiratory Medicine Division Chief, at the 21st North American Cystic Fibrosis Conference in Anaheim, California.

Patients with CF lack the CFTR protein, a chloride channel that maintains proper hydration of epithelial cells in the lung, pancreas, and liver. PTC has completed multi-site, open-label, dose-ranging Phase 2 clinical trials in adult CF patients to determine whether PTC124 can induce production of active CFTR protein. Studies in the U.S. and Israel evaluated nasal transepithelial potential difference (TEPD) as a surrogate for CFTR protein production in adult CF patients. Across the two studies, at both PTC124 dose levels tested, TEPD assessments showed statistically significant (p<0.03) improvements of mean CFTR-dependent chloride secretion in the airways.

PTC is currently conducting a third, open-label, dose-ranging Phase 2 clinical trial in pediatric CF patients at l'Hopital Necker-Enfants Malade, Paris, France to determine whether PTC124 can induce production of active CFTR protein. In the trial, patients receive two sequential two-week courses of treatment. Patients have been randomized to receive either a low or high dose of PTC124 followed by two weeks of rest and then are crossed over to the other dose level for an additional two weeks of therapy. Eleven patients have completed the study and data from these patients were available for inclusion in the initial analysis. Across both dose levels, statistically significant improvements (p<0.05) were seen in CFTR chloride-channel function as measured by TEPD.

"Our initial observations in a pediatric population confirm the findings from the previous studies in older CF patients," said Isabelle Sermet- Gaudelus, M.D., Ph.D., principal investigator at l'Hopital Necker-Enfants Malade, Paris, France. "Normalization of CFTR-mediated chloride secretion was observed in several of the children, indicating that PTC124 continues to demonstrate significant potential as a treatment for patients with CF. Based on the enthusiasm generated by these data, we have recently added two new study sites in Belgium in order to expand the evaluation of PTC124 across a larger pediatric population."

Eitan Kerem, M.D., Head of Pediatrics and the CF Center at the Hadassah University Hospital in Mount Scopus, Jerusalem also commented on longer-term studies that he has been leading in Israel. "Based on the positive results we observed during our initial study with two-week treatment periods, we have analyzed preliminary data from a three-month extension study evaluating the longer-term effect of PTC124 in patients with nonsense-mutation-mediated CF. We have seen encouraging evidence of sustained CFTR chloride-channel function and improvements in symptoms of CF, such as coughing, which we believe may be predictive of longer-term clinical benefit. We look forward to presenting the full data from this trial next year."


"We are very pleased to see the evidence of drug activity reported at last year's North American Cystic Fibrosis Conference reproduced by additional investigators in a pediatric population," said Langdon Miller, M.D, Chief Medical Officer of PTC. "We are also encouraged by the findings of the Israeli three-month study. We believe these confirmatory results, coupled with supportive safety data in more than 50 patients participating in the Phase 2 trial program, can lead to initiation of longer-term trials to evaluate the clinical benefit of PTC124 in patients with CF."

About Cystic Fibrosis

Cystic fibrosis (CF) is among the most common life-threatening genetic disorders worldwide. According to the Cystic Fibrosis Foundation, CF affects approximately 30,000 adults and children in the United States and, according to the European Cystic Fibrosis Foundation, it affects a similar number of patients in Europe. CF occurs in approximately one of every 3,500 live births, with approximately 1,000 new cases diagnosed each year in the United States. There is a commercially available genetic test to determine if a patient's CF is caused by a nonsense mutation and it is estimated that nonsense mutations are the cause of CF in approximately 10% of patients in the United States. There is currently no available therapy to correct defective CFTR production and function. Instead, available treatments for CF are designed to alleviate the symptoms of the disease. These treatments include chest physical therapy to clear the thick mucus from the lungs, antibiotics to treat lung infections and a mucus-thinning drug designed to reduce the number of lung infections and improve lung function. In addition, the majority of cystic fibrosis patients take pancreatic enzyme supplements to assist with food absorption in digestion. There is a significant unmet medical need for a treatment for the underlying cause of CF.

About PTC124

PTC124 is an orally delivered investigational new drug in Phase 2 clinical development for the treatment of genetic disorders due to nonsense mutations. Nonsense mutations are single-point alterations in the genetic code that prematurely halt the translation process, producing a shortened, non- functional protein. PTC124 has restored production of full-length, functional proteins in preclinical genetic disease models harboring nonsense mutations. In Phase 1 clinical trials, PTC124 was generally well tolerated, achieved target plasma concentrations that have been associated with activity in preclinical models and did not induce ribosomal read through of normal stop codons. PTC is currently conducting Phase 2 clinical trials of PTC124 in nonsense-mutation-mediated cystic fibrosis (CF) and Duchenne muscular dystrophy (DMD).

It is estimated that 10% of the cases of CF and 13% of the cases of DMD are due to nonsense mutations. PTC believes that PTC124 is potentially applicable to a broad range of other genetic disorders in which a nonsense mutation is the cause of the disease. The FDA has granted PTC124 Fast-Track designations and Orphan Drug designations for the treatment of CF and DMD due to nonsense mutations. PTC124 has also been granted orphan drug status for the treatment of CF and DMD by the European Commission. PTC124's development is supported by grants from the Muscular Dystrophy Association (MDA), Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT), Parent Project Muscular Dystrophy (PPMD), FDA's Office of Orphan Products Development (OOPD) and by General Clinical Research Center grants from the National Center for Research Resources (NCRR).