Regulatory Decision Summary for Kalydeco

Authorization of Kalydeco in patients with CF, 4 months to less than 12 months of age, was based on interim analyses of an ongoing international, multicentre, 2 part, open-label safety, pharmacokinetic (PK) and pharmacodynamic study (Study 124). The benefits of Kalydeco in this patient population were based on extrapolation of data from placebo-controlled efficacy studies in patients 6 years of age and older with the same mutations, in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidance E11 and the addendum, Clinical Investigation of Medicinal Products in the Pediatric Population. The previous placebo-controlled studies conducted in more than 300 subjects have demonstrated the efficacy of Kalydeco in the treatment of patients with CF 6 years of age and older with a gating mutation on the CFTR gene.

Study 124 was the first in which Kalydeco was evaluated in subjects 4 months to less than 12 months of age. The study enrolled a relatively small number of subjects (N = 6 for subjects 4 to less than 6 months of age and N = 11 for subjects 6 to less than 12 months of age) treated for a comparatively short duration (24 weeks), therefore the long-term safety of ivacaftor treatment in this age group is unknown. Furthermore, this was an open-label study that did not include a placebo arm due to ethical reasons, therefore the level of the evidence regarding the benefits and harms was limited and interpreted with caution.

In Part A of the study, cohorts of patients 3 months to less than 6 months of age and patients 6 months to less than 12 months of age were treated for 4 days with Kalydeco granules (25 mg or 50 mg, twice daily) to evaluate safety and PK parameters. The dose of Kalydeco was based on weight; 25 mg granules were administered to patients weighing 5 kg to less than 7 kg and 50 mg granules were administered to patients weighing 7 kg to less than 14 kg.

The systemic exposure of ivacaftor in the cohort of subjects 4 months to less than 6 months of age and the cohort of subjects 6 months to less than 12 months of age in Study 124 was similar to that observed in adult patients administered Kalydeco 150 mg tablets twice daily for which efficacy has previously been demonstrated. The exposure was also consistent with that in patients 12 months through 5 years of age administered Kalydeco.

Due to higher exposure in one patient 3 months of age, in Part B of the study where patients were treated for 24 weeks, the patient population was limited to patients 4 months to less than 6 months of age and all patients were treated with 25 mg granules regardless of weight. When patients turned 6 months of age, their treatment was increased to 50 mg when their weight was 7 kg or greater. 

Study 124 was not designed to evaluate efficacy; however, pharmacodynamic measurements were included during the 24 week treatment period. Improvements in sweat chloride, nutritional status, and pancreatic function were observed over 24 weeks of treatment and are consistent with clinical improvements on the underlying pathophysiology of CF disease. The mean absolute change from baseline (improvement) in sweat chloride was -50.0 millimoles/litre (mmol/L) (n = 3) at week 24 for patients 4 months to less than 6 months of age and was -58.6 mmol/L (n = 6) for patients 6 months to less than 12 months of age. These changes were consistent with those for pediatric patients 12 months of age and older as well as adult patients.

In conclusion, based on pediatric extrapolation, the benefits of ivacaftor treatment can be extended to patients with CF 4 months to less than 12 months of age who have a gating mutation for which Kalydeco is already approved in Canada. The extrapolation is supported by observed improvements in sweat chloride, nutritional parameters and pancreatic function in Study 124.

Kalydeco was well tolerated in the cohorts of patients treated for 24 weeks. The safety profile of ivacaftor treatment was characterized by adverse events that were generally mild to moderate in severity, although the size of the safety database, six subjects 4 months to less than 6 months of age and eleven subjects 6 months to less than 12 months treated for 24 weeks, may have precluded detection of rare or uncommon events. The most common adverse events in patients 4 months to less than 6 months of age were cough, pyrexia and upper respiratory tract infection. For patients 6 months to less than 12 months of age, the most common adverse events were cough, nasal congestion, rhinorrhea, pyrexia and vomiting. No clinically relevant increases in transaminase levels were observed. No new safety concerns were identified. 

Overall, the safety outcomes were similar relative to CF patients 12 months and older and no new safety concerns were identified with treatment. Pharmacodynamic assessments also suggested the benefits of treatment with ivacaftor in this population. Therefore, the overall benefit-harm-uncertainty profile of Kalydeco is favorable for the proposed expanded indication.

The recommended dose of Kalydeco for the patient population evaluated in this submission is 25 mg granules twice daily for patients 4 months to less than 6 months of age weighing 5 kg or more, and for patients 6 months and older weighing 5 kg to less than 7 kg. The recommended dose for patients 6 months and older weighing 7 kg to less than 14 kg is 50 mg granules twice daily.

A Notice of Compliance (NOC) was granted for Kalydeco for patients 4 months to less than 12 months of age based on the clinical, quality and labelling review.