protein function is essential for progress, Mueller said. Linking the genetics involved with the observed phenotypes pointed to two distinct functional consequences that would need to be corrected to reverse or halt the effects of cystic fibrosis: a lack of surface expression and a lack of transport activity by the CFTR channel. Accordingly, Vertex investigated both potentiators that increase channel activity and correctors that increase the delivery, or trafficking, of CFTR protein to the cell surface. A search of about 10,000 molecules turned up a particular molecule, ivacaftor, that restored function and removed mucus in patient cells with a particular mutation known as G551D. This result was strong enough to take the drug into the clinic.
After negotiations with regulatory agencies in different countries, four studies were conducted: a study in patients 12 and older with the G551D mutation, a similar study in children 6 to 11 years old, a safety study in subjects homozygous for a common cystic fibrosis mutation, and a rollover extension trial of patients who completed two previous trials.
The outcome was “stellar,” according to Mueller (Figure 3-3). After just 2 weeks, patients demonstrated a 10 to 12 percent improvement on average in their lung function which persisted throughout the trial (Ramsey et al., 2011). “That never has been seen with any other drug in the respiratory field,” Mueller said. “Normally you get about 3 or 4 percent, and then you are really happy.” At the same time, sweat chloride concentrations dropped to almost normal levels, indicating an increased function of
SOURCE: Ramsey et al., 2011.