Vertex Pharmaceuticals Incorporated has submitted a supplemental New Drug Application (sNDA) to the US Food and Drug Administration (US FDA) for the approval of Kalydeco in people with cystic fibrosis (CF) ages 18 and older who have the R117H mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.

In the United States, Kalydeco is currently approved for use in people with CF ages 6 and older who have one of the following nine mutations: G551D, G178R, S549N, S549R, G551S, G1244E, S1251N, S1255P or G1349D. CF is caused by a defective or missing CFTR protein that results from mutations in the CFTR gene. In the United States, approximately 300 people have the R117H mutation and are 18 years of age or older. R117H is the most common residual function mutation and also has a defect in the gating of the CFTR protein.

"This submission is another step forward in our goal to help more people with this devastating disease," said Jeffrey Chodakewitz, M.D., senior vice president and chief medical officer at Vertex. "While people with the R117H mutation exhibit a wide range in the severity of their disease, their lung function often declines as they get older, marking the need for new medicines."

In addition to the sNDA submission, Vertex intends to submit a Marketing Authorisation Application (MAA) variation in Europe in the third quarter of 2014 for people with CF ages 18 and older who have the R117H mutation in the CFTR gene.

The sNDA submission is based on previously announced data from a Phase 3 study of ivacaftor that enrolled 69 people with CF ages 6 and older who had at least one R117H mutation. The study did not meet its primary endpoint of the mean absolute change from baseline in ppFEV1 (per cent predicted forced expiratory volume in one second) for ivacaftor compared to placebo (treatment difference) across all patients, however a pre-specified subset analysis in people who were 18 years of age and older showed statistically significant improvements in lung function (ppFEV1) and other key secondary endpoints.

The subset analysis included 50 people with CF ages 18 and older who had a mean baseline absolute FEV1 of 65 per cent predicted. In these patients, a statistically significant mean absolute treatment difference of 5.0 percentage points (p=0.01) in ppFEV1 was observed through 24 weeks of treatment, which corresponded to a mean relative treatment difference of 9.1 per cent (p=0.008). Four weeks following the completion of treatment with ivacaftor, patients in this subset analysis showed a mean absolute within-group decrease of -3.1 percentage points (p=0.001) in ppFEV1. People who took part in this study were eligible to enroll in an open-label rollover study where all patients received ivacaftor after a washout period of at least three weeks. After the first 12 weeks of treatment in the rollover study, the mean absolute improvement from baseline in lung function for patients ages 18 and older (n=46) was 5.1 percentage points (p < 0.0001). Across the 24-week study and through 12 weeks of treatment in the rollover study, treatment with ivacaftor also resulted in decreases in sweat chloride and improvements in CFQ-R.

Across all the patients, the safety and tolerability results observed in the 24-week study and rollover study were consistent with those observed in prior Phase 3 studies of ivacaftor in people with CF. In the 24-week study, the most commonly observed adverse events in those who received ivacaftor were infective pulmonary exacerbation, cough and headache, which occurred with similar frequency compared to those who received placebo. Serious adverse events occurred in 17 per cent of patients who received placebo versus 12 per cent of patients who received ivacaftor. In the rollover study, the most common serious adverse event was infective pulmonary exacerbations.