PTC Therapeutics, Inc. (PTC) announced promising new data from two studies of PTC124 in cystic fibrosis (CF). Results from an Israeli Phase 2a extension study evaluating three months of oral PTC124 treatment in adult patients with nonsense-mutation-mediated CF demonstrated statistically significant improvements in the function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein and a statistically significant mean [28%] decrease in the frequency of cough, one of the most prominent and burdensome CF-related symptoms. Results from the Hadassah University Hospital in Israel were presented by Michael Wilschanski, M.D., Director, Pediatric Gastroenterology, and by Eitan Kerem, M.D., principal investigator and head of the Department of Pediatrics and Cystic Fibrosis Center. Separately, results from a European study evaluating 14-day courses of PTC124 in pediatric patients with nonsense-mutation-mediated CF confirmed the CFTR activity observed in previous short-term studies in adult patients. Data from the European study were presented today by Isabelle Sermet-Gaudelus, M.D., Ph.D., principal investigator at l'Hopital Necker-Enfants Malade.
Patients with CF lack adequate levels of the CFTR protein, a chloride channel that maintains proper hydration of epithelial surfaces in the lung, pancreas, and liver. Patients with nonsense-mutation-mediated CF generally have a severe form of CF because virtually no CFTR protein is produced. Previous studies of PTC124 adult patients with CF evaluated nasal transepithelial potential difference (TEPD) as a surrogate for the presence and activity of the CFTR protein. Across the short- and long-term clinical trials at high and low doses of PTC124, TEPD assessments showed statistically significant improvements of mean CFTR-dependent chloride secretion in the airways.
The Phase 2a extension study in Israel assessed 3 months of oral PTC124 therapy at two different dose levels in 19 adult men and women with nonsense- mutation-mediated CF who had participated in a prior short-term PTC124 Phase 2a study. More than 90% of the patients had chronic CF-related lung infection and also had CF-induced pancreatic insufficiency. Results from the study showed that treatment with PTC124 resulted in statistically significant (p< 0.001) improvements in CFTR function as measured by TEPD in both dose groups. The proportion of patients showing improvement in TEPD chloride secretion increased over time in the extension study. Trends towards improvements in mean FEV1 and FVC values were observed. Baseline data showed that CF patients cough a remarkable 643 times per day on average, with a range of 324 to 1,569 coughs per day. In comparison, healthy individuals generally cough fewer than 16 times per day, according to the European Respiratory Journal (Hsu 1994). Patients receiving PTC124 experienced a mean [28%] decrease in cough frequency by the end of three months of therapy (p< 0.01). PTC124 was generally well tolerated, resulting in excellent mean compliance with the treatment regimen ( >90%).
"Three months of treatment with PTC124 in nonsense-mutation-mediated CF patients was associated with time-dependent improvements in nasal TEPD chloride conductance, pulmonary function and cough -- important markers suggesting the potential for benefit in patients with CF," stated Dr. Wilschanski. "PTC124 increases CFTR-mediated chloride secretion in patients with a variety of nonsense mutation types, which suggests a broad spectrum of activity across one of the major subpopulations in CF."
Dr. Kerem added, "The impact on cough that we observed in this study by objective measurement is particularly notable given that cough is one of the major symptomatic manifestations of the underlying disease process in CF. The reduction in cough achieved with PTC124 in this three-month study suggests secondary clinical effects of drug activity. Based on these findings, we believe that objective measurement of cough may offer a meaningful new way to evaluate drug efficacy in future CF clinical trials."
In a separate Phase 2a study in Europe, data are currently available from 21 children who received two 14-day treatment courses of oral PTC124 therapy at two different dose levels. Patients ranged in age from six to 18 years. All had nonsense-mutation-mediated disease, pathological lung infection, and pancreatic insufficiency. Statistically significant (p< 0.05) increases in the proportion of epithelial cells showing surface staining with the CFTR protein were observed. In addition, statistically significant (p< 0.05) improvements in CFTR-mediated chloride conductance as measured by TEPD were evident. PTC124 was generally well tolerated in pediatric patients and mean compliance with treatment was excellent ( >95%).
"We are encouraged to see the activity of PTC124 observed in adults reproduced in a pediatric population in France and Belgium," commented Dr. Sermet-Gaudelus. "PTC124 causes the missing protein to be made, to be located in the right place in the cell, and to have functional effect. Combined with the generally well-tolerated profile of PTC124, we believe these data support inclusion of pediatric patients in future clinical trials."
"We are gratified by these results from our Israeli, French, and Belgian investigators, which demonstrated the activity of PTC124 in patients across a variety of age ranges, geographies, and nonsense mutation types," stated Langdon Miller, M.D., Chief Medical Officer of PTC. "These data offer the basis for initiating a randomized, controlled Phase 2b study later this year to evaluate the clinical benefit of PTC124 in adults and children with nonsense-mutation-mediated CF."
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