Healthcare Industry News:  Duchenne Muscular Dystrophy 


 News Release - November 3, 2006

PTC Therapeutics Announces Positive Phase 2 Results For PTC124 in Cystic Fibrosis

Data Indicate that PTC124 Addresses Underlying Cause of Cystic Fibrosis Through Improvements in CFTR Function

SOUTH PLAINFIELD, N.J., Nov. 3 (HSMN NewsFeed) -- PTC Therapeutics, Inc. (PTC), a biopharmaceutical company focused on the discovery and development of small-molecule drugs targeting post-transcriptional control processes, today 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 today 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 Pediatric Pulmonary Division, University of Alabama at Birmingham, and the lead investigator of the U.S. 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 program 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% 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% (18/42) had responded with a change of at least -5 mV in chloride secretion TEPD and 36% (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 U.S. 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 U.S. 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 pediatric 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.

About 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. More information regarding CF is available through the Cystic Fibrosis Foundation (

About PTC124

PTC124 is an orally delivered product candidate 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 demonstrated activity in preclinical genetic disease models harboring nonsense mutations allowing the restoration of the production of full-length, functional proteins. 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 readthrough 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 Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMEA). 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).

About the University of Alabama at Birmingham

The University of Alabama at Birmingham (UAB) is a research university and academic health center that discovers, teaches and applies knowledge for the intellectual, cultural, social and economic benefit of Birmingham, the state and beyond. UAB encompasses 82 city blocks and has a student enrollment of more than 17,000. UAB also is home to a large graduate school, a world- renowned health care complex and more than 70 research centers, focusing on such diverse issues as AIDS vaccines and aging to the environment, urban affairs, and telecommunications.

About The Hadassah University Medical Center, Jerusalem
* A state-of-the-art medical center incorporating all medical and surgical
sub-specialties, with two hospitals at Ein Kerem and on Mt. Scopus;
conducts more than half the hospital research in Israel.

* The largest employer in Jerusalem excluding the government: 850
physicians 1,940 nurses, 1,020 paramedical and support staff; two
campuses with 1,000 beds, 31 operating theaters, 9 intensive care units
and over 120 outpatient clinics. Committed to excellence in health
care, medical research and medical education.

* Welcomes every individual who requires medical attention without regard
for race, religion, gender, ethnicity or political persuasion -- and has
done so since its inception. Provides hospital services for nearly one
million people annually; treated more than 2500 victims of the recent

* Partners with the Hebrew University in five medical academic
institutions: the Schools of Medicine; Nursing; Dental Medicine;
Occupational Therapy; Public Health and Community Medicine.

* A Bridge to Peace - programs for medical personnel from the Palestinian
Authority and students from 90 countries around the world. Was
nominated for the 2005 Nobel Peace Prize.

* A member of the American Hospital Association; recipient of
Congressionally funded American Schools and Hospital Abroad (ASHA)

Founded, owned and supported by Hadassah, the Women's Zionist Organization of America, the largest women's, largest Jewish and largest volunteer organization in America, with over 300,000 members in more than 1,000 chapters.

About PTC Therapeutics, Inc.

PTC is a biopharmaceutical company focused on the discovery and development 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 has assembled proprietary technologies and extensive knowledge of post-transcriptional control processes that it applies in its drug discovery and development activities. PTC's current pipeline of clinical and preclinical product candidates addresses multiple indications, including genetic disorders, oncology, and infectious diseases.

Source: PTC Therapeutics

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