PTC Therapeutics, Inc., a biopharmaceutical company, announced the findings from two phase 2 clinical trials of PTC124 in patients with cystic fibrosis (CF) due to a nonsense mutation.

The results suggest that PTC124 can restore function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein in airway cells and significantly reduce blood neutrophil counts that are a hallmark of the CF disease process. The initial data were presented at the North American Cystic Fibrosis Conference in Denver, Colorado.

"These results are very exciting because they provide the first indication that an oral therapy may address the underlying cause of CF through restoration of CFTR function," said J.P. Clancy, M.D., director of the Paediatric Pulmonary Division, University of Alabama at Birmingham, and the lead investigator of the US phase 2 PTC124 trial. "These data indicate that PTC124 warrants further clinical investigation in this patient population, which currently can only be treated with supportive therapies."

"We are encouraged that PTC124 provides hope for a particular group of individuals with CF, as well as offering important scientific information that may have broader implications for pharmacological approaches to CF," said Robert J. Beall, Ph.D., president and CEO of the Cystic Fibrosis Foundation. "It is gratifying to see the Cystic Fibrosis Foundation Therapeutics' support of this drug yield encouraging results."

Patients with CF lack the CFTR protein, a chloride channel that maintains proper hydration of epithelial cells in the lung, pancreas, and liver. Patients with CF develop highly viscous secretions in these organs that result in inflammation, chronic colonization of pathogenic bacteria and progressive organ destruction. Pulmonary involvement usually causes the greatest disability as blood neutrophils migrate into the lungs, contributing to clogging of the airways. Patients experience chronic shortness of breath, coughing and production of thick, sticky sputum filled with neutrophils and bacteria.

PTC sponsored a multi-site, open-label, dose-ranging phase 2 clinical trial programme to determine whether PTC124 can induce production of active CFTR protein. Identical studies in the U.S. and Israel evaluated nasal transepithelial potential difference (TEPD) as a surrogate for CFTR protein production. A change in CFTR-mediated chloride transport toward normal during PTC124 treatment would suggest that PTC124 is inducing the cells to make full-length, functional CFTR protein. TEPD is measured using a small plastic catheter to assess electrical differences across the cell membrane in each nostril. Also assessed were circulating blood neutrophil and liver enzyme values, lung function, and body weight, as well as safety, compliance, and pharmacokinetics. Patients received two sequential 14-day courses of treatment of PTC124, first at a lower and then at a higher dose level.

All patients were adults with a nonsense mutation in one of their CFTR genes. Over 90 per cent had severe CF as characterized by colonization of the lung with Pseudomonas aeruginosa bacteria, pancreatic insufficiency requiring pancreatic enzyme replacement to prevent malabsorption of food, and relative elevations of neutrophil levels in blood. Patients tended to be underweight due to complications of CF.

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. By the end of the first cycle of treatment, 43 per cent (18/42) had responded with a change of at least -5 mV in chloride secretion TEPD and 36 per cent (15/42) had chloride secretion TEPD values in the generally accepted normal range (more electrically negative than -5 mV). CFTR chloride secretion responses were observed in both the US and Israel among several of the most common nonsense mutation genotypes affecting patients with CF.

In evaluating the studies separately, the results from the Israeli study demonstrated statistical significance for chloride secretion TEPD response for the population as a whole while the interim results from the US study demonstrated such responses in several patients but the trends did not reach statistical significance. The differences in detection of chloride secretion response between the studies may result from a number of factors, including differences in use of concomitant inhaled medications. Blood neutrophil counts were also monitored before and during PTC124 treatment because CF is a neutrophil-mediated disease, and reductions in blood neutrophil counts may be consistent with PTC124 activity. Statistically significant reductions (p<0.02) in blood neutrophil counts were observed in both the U.S. and Israeli studies. Furthermore, improvements in circulating levels of liver enzymes in the blood were seen in both trials, supporting the hypotheses that PTC124 would offer systemic benefits to patients with multiorgan compromise due to CF. Trends toward improved pulmonary function and body weight were also observed in patients participating in the Phase 2 program. Although a formal symptom assessment was not a component of the phase 2 program, a number of patients described decreased sputum volume and thickness, decreased frequency and severity of coughing and a better sense of well-being during PTC124 therapy. PTC124 was well tolerated, resulting in excellent compliance with the treatment regimen (>95%).

Eitan Kerem, M.D., Head of Pediatrics and CF Center at the Hadassah University Hospital in Mount Scopus, Jerusalem commented, "More than 60% of CF patients in Israel have CF due to a nonsense mutation. Thus, we were very gratified to see such remarkable improvements in CFTR function and other parameters in just a two-week treatment period. Based on this clear demonstration of PTC124 activity we will be initiating a three-month study of PTC124 in patients with nonsense-mutation-mediated CF to further evaluate its potential for providing clinical benefit."

Based on the results of the PTC124 CF studies, PTC will be conducting a longer term study in Israel at the Hadassah Medical Center in Jerusalem, and will initiate a paediatric clinical trial in France with a lead investigator who has extensive experience in nonsense- mutation-mediated CF. Collective results from the Phase 2 studies will be reviewed with regulatory authorities with the intent of initiating an international Phase 3 trial program within 2007.

"The results of these trials clearly establish clinical support for the potential of PTC124 in genetic disorders due to a nonsense mutation," said Stuart W. Peltz, Ph.D., President and Chief Executive Officer, PTC Therapeutics. "When considered together with the encouraging results recently announced in patients with Duchenne muscular dystrophy, we have established a strong basis for advancing the clinical development of PTC124 and we are currently conducting preclinical studies with the intent to extend this concept into other disorders."

The patients included in the analyses were enrolled at a single center in Israel, at the Hadassah Medical Center, Jerusalem and at five clinical sites in the United States: University of Alabama at Birmingham, Birmingham, AL; the Johns Hopkins Hospital, Baltimore, MD; Rainbow Babies' and Children's Hospital, Cleveland, OH; Denver Children's Hospital, Denver, CO; and Stanford University Medical Center, Stanford, CA. All of these sites are member institutions of the Cystic Fibrosis Foundation Therapeutics Development Network (CFF-TDN), which is supported by the Cystic Fibrosis Foundation (CFF), and is collaborating with PTC in the development of PTC124. PTC will also conduct a longer-term Phase 2b cystic fibrosis program in Israel at the Hadassah Medical Center, Jerusalem and will initiate a study in France in children with CF.