Data from two studies evaluating PTC Therapeutics' cystic fibrosis candidate PTC124 confirmed the drug's disease modifying potential, prompting the company to move forward with a Phase IIb registration trial, CEO Stewart Peltz said in an interview.

The South Plainfield, N.J., biopharma, which presented data on PTC124 during the European Cystic Fibrosis Conference in Prague, Czech Republic, June 12, is pursing development of the drug in patients with nonsense-mutation-mediated CF.

The nonsense mutation completely blocks production of the cystic fibrosis transmembrane conductance regulator protein (CFTR), thought to regulate the balance of fluid and salt in the airways. Because production of the protein is entirely blocked, patients with the mutation generally have a severe form of disease.

There are no current treatments approved by FDA to address the underlying cause of CF, but several disease modifying drugs are nearing later stages of development. Among them is a candidate from Vertex Pharmaceuticals, VX-770, which similarly addresses the malfunctioning CFTR protein.

However, PTC124 and VX-770 target patients with different gene mutations. VX-770 addresses the G551D mutation, in which patients have CFTR protein on the cell surface, but the protein's "gating effect" is defective, blocking normal chloride ion flow. The G551D mutation accounts for about 4 percent of the CF patient population, whereas the nonsense mutation accounts for 10 percent, or about 3,000 patients in the U.S.

VX-770 "won't do any good for nonsense mutation patients, [and] if the patients don't have a nonsense mutation, 124 won't do any good," Peltz explained. For its part, Vertex has said it expects VX-770 to offer benefit to a broader patient population beyond those with the G551D mutation.

PTC presented data from a Phase IIa extension study conducted in Israel evaluating treatment with oral PTC124 for three months in 19 adults with nonsense-mutation-mediated CF. The trial met its primary endpoint, showing a statistically significant improvement in the function of the CFTR protein, as measured by nasal transepithelial potential difference.

Improvements in mean FEV1 (Forced Expiratory Volume) -a standard test measuring the amount of air that can be exhaled in one second - values also were seen.

The study also measured the impact of PTC124 on cough, a burdensome symptom of the disease, showing that treatment led to a statistically significant mean decrease (28 percent) in the frequency of coughing. CF patients cough an average of 643 times per day and up to 1,500 times per day, compared to healthy individuals who generally cough fewer than 16 times per day.

"Everyone knows that CF patients cough a lot, but people haven't quantitatively assessed it previously," Peltz said.

Nonetheless, the use of cough as an endpoint for approval would require validation from FDA. Generally, FEV1 is the standard used by the agency to assess the impact of drugs on lung function. PTC plans to measure pulmonary function, cough and other endpoints in the Phase IIb registration trial, expected to initiate in the second half of the year.

In addition to the adult trial, PTC released data from a separate Phase IIa trial in pediatric patients in Europe. In the 21 children for whom data was available, all of whom have nonsense-mutation-mediated CF, statistically significant increases in the proportion of epithelial cells showing surface staining with the CFTR protein were observed following treatment. Patients were treated for two 14-day courses at two different dose levels. Improvements in CFTR-mediated chloride conductance as measured by TEPD also were evident.

PTC is also evaluating PTC124 in patients with nonsense-mutation-mediated Duchenne muscular dystrophy in Phase IIb.

Vertex released interim Phase IIa results on VX-770 in March, showing an improvement in lung function and CFTR protein function following treatment (¹ Also see "Vertex Advance In Cystic Fibrosis May Treat The Underlying Disease" - Pink Sheet, 27 March, 2008.).

Inspire Pharmaceuticals also is developing a disease modifying CF candidate, denufosol, albeit through a different mechanism of action. Inspire's approach involves hydrating the airways by stimulating chloride and liquid secretions on the epithelial cell surface and inhibiting epithelial sodium absorption. One of two planned Phase III trials met its primary endpoint, change in FEV1 from baseline (² Also see "Inspiring Results For Phase III Disease-Modifying Cystic Fibrosis Drug" - Pink Sheet, 6 June, 2008.).

-Jessica Merrill (j.merrill@elsevier.com)

PTC Advances Cystic Fibrosis Candidate On Encouraging Data

More from Archive

More from Pink Sheet