Regulatory Decision Summary for Kalydeco

The proposed formulation for the treatment of 2 to 5-year-olds includes 50-mg and 75-mg strength ivacaftor granules. The proposed doses of ivacaftor for 2 to 5-year-olds are 50 mg every 12 hours (q12h) for patients weighing <14 kilograms (kg) and 75 mg q12h for patients weighing ≥14 kg. To support the indication, the sponsor has submitted one pivotal trial, Study 108 which is considered "pivotal" for safety and pharmacokinetics, whereas the efficacy of Kalydeco was based on extrapolation of data from studies in patients 6 years of age and older with similar mutations as per the International Conference on Harmonisation (ICH) Guidance E11, "Clinical Investigation of Medicinal Products in the Pediatric Population".

The sponsor provided evidence that the selected doses of 50 mg two-times daily (BID) for patients weighing <14 kg, and 75 mg BID for patients weighing >14 kg produced blood levels similar to those observed in adults and children 6 years of age and older treated with 150 mg of ivacaftor [who have the G551D- CFTR mutation (Study 102 and Study 103) and a non-G551D mutation that causes CFTR gating defects (Study 111)] BID for whom efficacy has been shown. The efficacy of ivacaftor treatment can therefore be extended to 2 to 5-year-old patients with CF with all approved mutations (except for R117H).

The intended population for ivacaftor treatment is anticipated to be easy to identify as genotyping for mutations in the CFTR gene is now routine practice in the countries where CF is more highly prevalent.

The safety profile of ivacaftor treatment was characterized by adverse events that were generally mild to moderate in severity and did not lead to treatment discontinuation; however, the size of the safety database, 34 subjects in Part B of the study, may have precluded detection of rare or uncommon events. The most common adverse events are similar to those already described in the Kalydeco Product Monograph. In patients 2 through 5 years of age, marked transaminase elevations appeared to be more common than in older patients, although the clinical features and outcome appeared to be comparable. These elevations were seen in the subset of patients with transaminase levels >2 times the upper limit of normal at the start of treatment. To mitigate this safety issue, this information is included in the Warnings and Precautions section of the Product Monograph. Ivacaftor is a substrate of cytochrome P450 (CYP) 3A4 and 3A5 isoenzymes. As a consequence, any medicinal product that modifies CYP3A activity may impact the pharmacokinetics of ivacaftor. A reduction of the ivacaftor dose from twice a day to twice a week is recommended for coadministration with strong CYP3A inhibitors. A reduction in the ivacaftor dose from twice daily to once daily is recommended for coadministration with moderate CYP3A inhibitors. This information is also reflected in the Kalydeco Product Monograph.

This clinical data submitted did not reveal any concern during the ophthalmological examinations; however, the potential for developing cataracts, suggested by pre-clinical studies in juvenile rats has also been included in the Product Monograph.

The sponsor is currently conducting a longer term study, Study 109, in CF patients in the age group between 5 and less than 6 years of age.

Ivacaftor was well tolerated by the patients in the 2 through 5 years old group, as evidenced by the rates and reasons for premature discontinuation and results of safety assessments. No new safety concerns emerged from the review of the safety data.

The benefit/risk ratio of Kalydeco is favorable for the amended indication.