Regulatory Decision Summary for Kalydeco

Authorization of the extension of the Kalydeco (ivacaftor) indication for patients with cystic fibrosis (CF) with an R117H mutation in the cystic fibrosis transmembrane conductance receptor (CFTR) gene aged 4 months to less than 18 years of age was based on the efficacy, safety, and clinical pharmacokinetics (PK) in pediatric patients. The PK of ivacaftor in patients 4 months and older has been characterized and is consistent among patients with other mutations. Kalydeco was previously approved for patients 4 months and older with gating mutations as well as patients 18 years and older with the R117H mutation.

The efficacy of Kalydeco in pediatric patients with gating mutations was based on extrapolation of efficacy from placebo-controlled efficacy and safety studies in adult patients and patients 6 years and older with gating mutations as well as PK and safety studies that included secondary efficacy endpoints. Similarly, for patients with the R117H mutation, extrapolation of efficacy from adults to pediatric patients is based on the similar disease process in children and adults, similar systemic exposure as in adults and comparable response in sweat chloride for pediatric and adult patients with the R117H mutation.

The efficacy and safety of Kalydeco in pediatric patients with the R117H mutation are supported by the results of the 24-week placebo-controlled study 110 and the long-term (104-week) safety extension study 112 in patients 6 years and older, as well as the non-interventional CF patient registry-based 36 month study 122 in 369 patients 2 years and older with the R117H mutation.

In the 24-week placebo-controlled study 110, comparable rapid and sustained improvement (decrease) in sweat chloride levels was observed by week 2 for pediatric patients 6 to 11 years of age and patients 18 years and older demonstrating that ivacaftor has the same effect on the underlying cause of CF in both populations. However, an improvement in lung function (percent predicted forced expiratory volume in one second, ppFEV1) and the Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score was only observed for patients 18 years and older treated with ivacaftor compared to placebo but not for patients 6 to 11 years of age. The benefit of ivacaftor in patients 6 to 11 years of age was observed in the 104-week long-term safety study 112, which included patients rolled over from study 110, with improvements from baseline in both mean ppFEV1 and CFQ-R respiratory domain score throughout the treatment duration.

Results for the non-interventional CF registry-based 3 year study 122 in 369 patients 2 years and older with the R117H mutation provided supplemental evidence of the potential benefit of ivacaftor in pediatric patients. The benefit of treatment with Kalydeco was observed in pediatric patients in this study with improvements in lung function (ppFEV1), and decreases in pulmonary exacerbations, hospitalizations, pancreatitis, and lung infection with P. aeruginosa.

Overall, Kalydeco was well tolerated in pediatric patients with the R117H mutation in the studies 110, 112 and 122 and the safety profile for pediatric patients was consistent with the known safety profile in pediatric patients with gating mutations as well as adult patients. Although the safety database for patients 6 to 11 years of age (n = 17) and patients 12 to less than 18 years of age (n = 2) in controlled clinical trials is low, safety can be extrapolated from children in the same age range with gating mutations. The systemic exposure has been shown to not be affected by genotype, and therefore is similar for the different mutations.

Although, as observed in the clinical studies, pediatric patients with the R117H mutation have generally less severe clinical manifestations of CF than adult patients, early treatment may modify or limit the progression of the disease for patients with this mutation. The effect of ivacaftor on sweat chloride levels was consistent for pediatric patients and adult patients with the R117H mutation indicating the benefit on the underlying cause of the disease in these patients.

Overall, the benefit-harm-uncertainty profile of Kalydeco is favorable for the proposed expanded indication. The potential benefits outweigh the potential harms of treatment with Kalydeco in pediatric patients 4 months and older with an R117H mutation on the CFTR gene.