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PTC Announces Data Showing That PTC124 Causes Statistically Significant Improvements in Chloride Channel Function in Cystic Fibrosis Patients

- PTC124 Highlighted in Multiple Presentations at North American Cystic Fibrosis Conference -

SOUTH PLAINFIELD, N.J. and ORLANDO, Fla., Oct. 24 /PRNewswire/ -- PTC Therapeutics, Inc. (PTC) today announced that results from a randomized Phase 2a European study demonstrated that treatment with the investigational drug PTC124 caused statistically significant improvements in the chloride channel function of children with cystic fibrosis (CF) caused by a particular genetic mutation, called a nonsense mutation. Results from the study were presented today by Isabelle SermetGaudelus, M.D., Ph.D., principal investigator at l'Hopital Necker-Enfants Malade. In addition, results from an Israeli Phase 2a study demonstrated statistically significant improvements in the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein and a statistically significant decrease in the frequency of cough, one of the most prominent and burdensome CF-related symptoms. Data from the Israeli study were presented by Eitan Kerem, M.D., principal investigator and head of the department of pediatrics and Cystic Fibrosis Center at Hadassah University Hospital.

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PTC124 is also being featured in a plenary presentation given by Preston Campbell, III, M.D., Executive Vice President of Medical Affairs at the Cystic Fibrosis Foundation, on promising developments in CF research.

"We are very pleased by the data continuing to emerge from the Phase 2 clinical development program for PTC124 in CF," noted Dr. Campbell. "Our alliance with PTC and the development of PTC124 are key elements of our strategic work supporting novel therapeutic approaches with the potential to modify the course of CF. We look forward to continuing our work with PTC to move PTC124 to the next stage of development, including pivotal clinical trials that evaluate long-term clinical benefit for CF patients."

Patients with CF lack adequate levels of the CFTR protein, a chloride channel which is required for normal function of the lung, pancreas, liver and other organs. Nonsense mutations are single-point alterations in the genetic code that when transcribed into mRNA prematurely stop the mRNA translation process, preventing production of a full-length, functional protein. Patients with nonsense-mutation CF make virtually no CFTR protein and thus often have a more severe form of CF. Nonsense mutations are responsible for approximately 10 percent of the cases of CF worldwide.

By inducing the production of functional CFTR, PTC124 addresses one of the underlying genetic defects responsible for CF. Earlier studies of PTC124 in adults with CF evaluated nasal transepithelial potential difference (TEPD) as a surrogate for the presence and activity of the CFTR protein. Across a variety of studies, TEPD assessments showed statistically significant improvements of mean CFTR-dependent chloride secretion in the airways.

European Phase 2a Study Results

The multicenter, randomized, open-label Phase 2a study demonstrated that treatment with PTC124 caused improvements in CFTR-mediated chloride conductance and in apical expression of CFTR protein in nasal epithelium. The study enrolled 30 children ages 6 to 18 years to evaluate the activity, safety and pharmacokinetic activity of PTC124 in pediatric patients. All of the patients had nonsense-mutation CF, pathological lung infection, and CF-induced pancreatic insufficiency. In a cross-over design testing 14 days of PTC124 at two dose levels, patients were randomized to receive either the lower or higher dose first. PTC124 treatment across both dose levels was associated with a statistically significant (p=0.03) increase in the proportion of epithelial cells showing cell surface CFTR protein. PTC124 also induced significantly improved CFTR-mediated chloride channel activity as measured by nasal potential difference, with 40 percent of patients achieving values in the normal range during PTC124 administration. The study demonstrated improvements in patients with multiple nonsense mutation types and indicated a similar PTC124 pharmacokinetic profile as that seen in previous studies in adults. PTC124 was generally well tolerated in this study and compliance was greater than or equal to 93 percent.

"We are encouraged by the results of this study showing PTC124 to be as pharmacologically active and well tolerated in children with CF as it is in adults," said Dr. Sermet-Gaudelus. "There is a serious need for new methods to treat the underlying cause of CF, particularly in younger patients who have not yet experienced irreversible disease-related lung injury. These data in pediatric patients support inclusion of children with CF in long-term studies of PTC124."

Israeli Phase 2a 12-Week Study Results

The Phase 2a extension study evaluated 12 weeks of oral PTC124 at two different dose levels in 19 adults with nonsense-mutation CF who participated in a prior short-term PTC124 Phase 2a study. Greater than 85 percent of the patients had chronic CF-related lung infection and pancreatic insufficiency. Study results showed that treatment with PTC124 resulted in statistically significant improvements in CFTR function as measured by nasal potential difference in both dose groups. Improvements in lung function, including forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), were also observed. Baseline data showed that the patients coughed a remarkable 630 times per day on average, with a range of 320 to 1,330 coughs per day, compared to healthy individuals who typically cough fewer than 16 times per day, according to the European Respiratory Journal (Hsu 1994). Patients in this study experienced a mean decrease in cough frequency of almost 200 coughs per day by the end of the study (p<0.01). PTC124 was generally well tolerated in this study, resulting in excellent compliance (>95%).

In a separate presentation, Dr. Kerem provided a review of all PTC124 studies to date, including studies in patients with Duchenne muscular dystrophy, a genetic disorder that can also be caused by a nonsense mutation.

"We are enthusiastic about the growing body of data on PTC124, and this study specifically, which suggests the benefits of PTC124 treatment may increase over time," said Dr. Kerem. "The safety profile of the 12-week administration of PTC124 in patients with CF supports further investigations in long-term clinical trials."

"We are pleased to see PTC124 highlighted in so many presentations at NACFC," said Langdon Miller, M.D., Chief Medical Officer of PTC. "These data demonstrate the activity of PTC124 across a broad range of patients and suggest that it could be a valuable option for many patients living with CF. 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. We hope that PTC124 will be among the first treatments that addresses the underlying cause of the disease."

About Cystic Fibrosis

Cystic fibrosis (CF) is a life-threatening genetic disease that causes serious lung infections and digestive complications. According to the Cystic Fibrosis Foundation, CF affects approximately 30,000 adults and children in the United States and nearly 70,000 people worldwide. 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 percent of patients in the United States and Europe and over 50 percent of patients in Israel. 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 treatments that address the underlying cause of CF. More information regarding CF is available through the Cystic Fibrosis Foundation (

About PTC124

PTC124 is an orally delivered, investigational new drug discovered by PTC Therapeutics. The drug is being developed for the treatment of nonsense mutation genetic disorders. Nonsense mutations are single-point alterations in the genetic code that prematurely stop the mRNA translation process, leading to production of truncated, non-functional proteins. PTC124 induces the cellular translation machinery to read through nonsense mutations in mRNA, inducing production of full-length, functional proteins. PTC124 has demonstrated proof of concept in Phase 2a clinical trials. Across all clinical studies to date, PTC124 has been generally well tolerated. PTC124 is currently in Phase 2b development with the goal of demonstrating that increasing functional protein levels in patients with nonsense mutation genetic disorders will safely provide clinical benefits.

PTC124 has been granted orphan drug status by the FDA and the European Commission for the treatment of cystic fibrosis and Duchenne muscular dystrophy due to nonsense mutations. The FDA has also granted PTC124 Subpart E designation for expedited development, evaluation, and marketing.

PTC has an exclusive collaboration with Genzyme Corporation to develop and commercialize PTC124 outside the United States and Canada. The development of PTC124 has also been supported by grants from the Muscular Dystrophy Association, Parent Project Muscular Dystrophy, FDA's Office of Orphan Products Development, the National Center for Research Resources and notably, the Cystic Fibrosis Foundation Therapeutics, Inc. (the nonprofit affiliate of the Cystic Fibrosis Foundation), which recently expanded support of PTC124 to include funding up to $25 million.

About PTC Therapeutics, Inc.

PTC is a biopharmaceutical company focused on the discovery, development and commercialization of orally administered, proprietary, small-molecule drugs that target post-transcriptional control processes. Post-transcriptional control processes regulate the rate and timing of protein production and are of central importance to proper cellular function. PTC's internally-discovered pipeline addresses multiple therapeutic areas, including genetic disorders, oncology and infectious diseases. PTC has extensive knowledge of post-transcriptional control processes and has developed proprietary technologies that it applies in its drug discovery activities, including the Gene Expression Modulation by Small-molecules (GEMS) technology, which has been the basis for collaborations with leading biopharmaceutical companies such as Genzyme, Pfizer, Celgene, CV Therapeutics and Schering-Plough. For more information, visit the company's website

SOURCE PTC Therapeutics, Inc.
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