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Ivacaftor (Kalydeco) Monotherapy Improves Lung Function in CF Patients With Residual Function Mutation

Clinical effect observed within 2 weeks

Positive results have been reported from a two-part proof-of-concept study of ivacaftor (Kalydeco, Vertex Pharmaceuticals) in 24 patients aged 12 years and older with cystic fibrosis (CF) who had a residual function mutation.

All CF patients with a residual function mutation have some functioning CF transmembrane conductance regulator (CFTR) proteins. Depending on the specific mutation, residual function mutations can result in defective CFTR proteins on the cell surface and/or a reduced number of these cell-surface proteins.

The first part of the study compared ivacaftor with placebo in a 2-week crossover design during two treatment cycles, and the second part evaluated ivacaftor in an 8-week open-label design.

In part one, a statistically significant improvement in mean absolute lung function (the percent predicted forced expiratory volume in one second [PPFEV1]) — the primary endpoint — was observed after treatment with ivacaftor for 2 weeks compared with placebo. The results showed a mean absolute improvement in PPFEV1 of 2.3 percentage points compared with placebo.

In part two, after 8 weeks of open-label treatment, ivacaftor showed a mean absolute improvement in PPFEV1 of 4.7 percentage points compared with placebo (P < 0.0001), for a mean relative change in PPFEV1 of 7.8% (P = 0.0001).

A mean decrease in sweat chloride of 15.7 mmol/L from study baseline (before the administration of the first dose of study drug in part one) was observed at the end of the 8-week open-label period. The mean baseline sweat chloride level for patients entering the study was 64.7 mmol/L. Sweat chloride was not measured in part one of the study.

Ivacaftor was generally well-tolerated. The most common adverse events in the treatment group were cough and respiratory tract infection.

This proof-of-concept study was the first to evaluate the use of ivacaftor in CF patients with multiple residual function mutations. The study was supported by in vitro data, which showed that ivacaftor enhanced the function of the CFTR protein in cells with residual function mutations. Based on these findings, a larger phase III study is planned to evaluate longer-duration treatment with ivacaftor in people with residual function mutations, pending discussions with regulatory authorities.

More than 3,000 people 6 years of age and older in North America, Europe, and Australia have a non-R117H residual function mutation.

Source: Vertex Pharmaceuticals; June 4, 2014.

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