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Updated: Small trial, big deal for cystic fibrosis drugs

Markets moved yesterday on news that an experimental cystic fibrosis (CF) treatment improved lung function in a small trial of patients with one of the most severe and common forms of the disease. Vertex Pharmaceuticals’ shares climbed more than 50 percent on Monday 7 May, after the company released interim data on 37 CF patients who received its recently-approved drug (see Drug bests cystic-fibrosis mutation) ivacafactor (marketed as Kalydeco) in combination with an experimental drug (VX-809) for 8 weeks.

The patients all carried two copies of a mutation called F508del in the gene that underlies the inherited lung disease called CFTR, and 17 of them noticed an improvement in lung function of more 5 percentage points or more. Eleven patients reported a more than 10 percent improvement in lung function, while none of the 11 patients in the placebo arm of the trial noticed any improvement after 8 weeks.

Those improvements are potentially life changing for CF patients. An improvement from 40 percent to 50 percent could help a CF patient exercise more, while a leap from 50 percent lung function to 60 percent could mean the patient feels a difference when climbing stairs, according to the primary investigator of the trial, Michael Boyle, of Johns Hopkins University in Baltimore, Maryland. (Xconomy)

Boyle says it will also be important to see whether the drugs prevent decline in lung function, which is typically seen in CF patients.

The data are preliminary, and Vertex still has yet to report results from an additional 60 CF patients who are enrolled in the trial. They are due in coming months and will include patients who have just one copy of the F508del mutation. If all goes well, Vertex will launch a larger “pivotal” trial of the combination treatment, with regulatory approval in mind.

About 90 percent of CF patients have at least one F508del mutation. Ivacafactor, meanwhile, was approved by the FDA in February to treat patients with a CFTR mutation called G551D, which is present in about 5 percent of all CF patients.

Having a drug with the potential to improve symptoms in the majority of CF patients would be a game changer. “It’s exciting,” Boyle tells Nature. “There’s the potential to change the whole approach to the way we treat these patients.”

Chloride ions cross the cell membrane by travelling through a channel formed by the CFTR protein. This process is important in producing mucus, digestive enzymes and sweat. But the G551D mutation results in the channel failing to open properly, blocking chloride ions. The F508del mutation, in contrast, creates misshapen proteins that reduces the number of available channels. Both mutations cause an imbalance in ion concentration that makes the body’s mucus thick and sticky, blocking airways and making infection more likely.

For context on the quest to develop drugs to treat CF, check out my colleague Helen Pearson’s award-winning feature “One gene, twenty years”. The story chronicles the identification of CFTR gene by current National Institutes of Health director Francis Collins and colleagues, and the tortuous road to translating the finding into potential therapies like Vertex’s.

UPDATED 29 May 2012: Vertex today announced that it erred in reporting those interim trial results. The corrected data paint a slightly less rosy picture. Just 13 patients who received treatment experienced a greater than 5% improvement in lung function (Vertex reported 17), while 7 patients (not 11) noticed a greater than 10% boost in lung function after 8 weeks.

The snafu was discovered on Friday, according to The Street. The independent firm analysing the trial data confused relative improvement with absolute improvement in lung function when it sent the results back to Vertex. In what might be an attempt to cushion the blow, Vertex also revealed that, on average, all patients who received the drug combo saw their lung function improve by 8.6% (in absolute terms), compared to the placebo group. More than half this difference comes from the fact that the 11 patients in the placebo group experienced an absolute decrease in lung function of 4.6% over 8 weeks.

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