Regulatory Decision Summary for Kalydeco

The purpose of this Supplement to a New Drug Submission (SNDS) for Kalydeco (ivacaftor) was to expand the indication for the treatment of cystic fibrosis (CF) in patients aged 1 month to less than 4 months and weighing 3 kilograms (kg) and more, who have one of the following mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R or R117H.

A new strength, 13.4 milligram (mg) granules, was also proposed to support the expansion of the indication. The proposed dosing regimen was 13.4 mg twice daily for patients 1 to less than 3 months old and weighing 3 kg or more, and 25 mg twice daily for patients 3 to less than 4 months old weighing 3 kg or more.

Following review of the submission, the dosing regimen was revised to 13.4 mg twice daily for patients 2 months to less than 4 months of age and the authorized indication was revised to: “Kalydeco (ivacaftor) granules (13.4 mg, 25 mg, 50 mg and 75 mg) are indicated for the treatment of children with cystic fibrosis (CF) aged 2 months and older and weighing 3 kg to less than 25 kg who have one of the following mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, or R117H.”

The submission was filed and reviewed under the Priority Review policy.

The efficacy of Kalydeco (ivacaftor) in pediatric patients with CF aged 1 to less than 4 months was based on extrapolation of efficacy from placebo-controlled efficacy studies in patients 6 years and older and similar systemic ivacaftor exposure in this patient population. CF is a rare, progressive, autosomal genetic disease. Extrapolation of efficacy is acceptable since the underlying cause of CF is the same in children and adults. Safety was based on pharmacokinetics (PK) analysis of ivacaftor systemic exposure and safety data in this patient population.

An interim analysis for a safety and pharmacokinetic (PK) study was submitted to support the proposed expanded indication for patients 1 to less than 4 months of age. Study 124 was a Phase 3, open-label, 24 week, multicenter, multiple-age cohort study. Cohort 8 of Study 124 enrolled seven patients aged 1 to less than 4 months of age weighing 3 kg or more. Patients were initially treated with low dose Kalydeco granules, 5.7 mg or 11.4 mg, administered twice daily, based on age and weight. The doses were adjusted at Day 15 based on the PK results for ivacaftor exposure at Day 4 with the aim to have systemic exposure more similarly match adult exposure at the approved dose, 150 mg twice daily. During the 24 weeks of treatment, patients were treated with approved doses when they turned 4 months of age (25 mg twice daily) and 6 months of age (25 mg or 50 mg twice daily based on weight).

Study 124 included pharmacodynamic (PD) assessments, and improvements in sweat chloride levels, nutritional status, and pancreatic function were observed over 24 weeks of treatment. Improvement (decreases) in sweat chloride was observed as early as 2 weeks after the start of treatment and were maintained through to week 24 (-40.3 millimole per litre (mmol/L); n = 5). This improvement was consistent with clinical improvements on the underlying pathophysiology of CF disease and the observed improvements in patients 4 months of age and older. Due to the open-label study design and small patient population, the results were interpreted with caution.

Kalydeco was well tolerated in the cohort of patients treated for 24 weeks. The safety profile of Kalydeco treatment was characterized by adverse events that were mild in severity, and no new safety signals were identified. There were no deaths, CF-related hospitalizations, or pulmonary exacerbations during the trial. However, the small size of Cohort 8, seven subjects treated for 24 weeks, may have precluded detection of rare or uncommon events. One patient discontinued study treatment due to elevated alanine transaminase; however, this is a known risk of treatment with Kalydeco, and should be monitored before and during treatment. The Product Monograph (PM) includes warnings and precautions for this safety risk. Overall, no new safety concerns were identified at the doses evaluated in Study 124.

A population PK model with data from patients 3 months and older was updated with the PK data from patients 1 month to less than 4 months of age from Cohort 8. The population PK model was considered to reasonably describe ivacaftor concentrations in pediatric patients aged 1 month to less than 4 months. The proposed doses of 13.4 mg twice daily for 1 month olds, and 25 mg twice daily for 3 month olds are expected to produce considerably higher exposure levels in these patients compared to older pediatric patients, raising a safety concern. Therefore, the recommended dose of 13.4 mg twice daily for patients aged 2 months to less than 4 months is expected to produce sufficient exposure for efficacy and consistent exposure levels to those of patients 4 months and older. In addition, the 13.4 mg dose is expected to produce similar exposure levels compared to the studied dose of 11.4 mg twice daily for which safety and PD effects were demonstrated in Study 124.

An updated Risk Management Plan was reviewed by Health Canada and considered acceptable. Risks have been communicated in the approved PM and the current pharmacovigilance and risk minimization measures were deemed sufficient. The chemistry and manufacturing information submitted for the 13.4 mg granule strength was reviewed and considered acceptable. The final labelling and PM were considered acceptable.

Overall, the benefit-harm-uncertainty profile was favourable for Kalydeco, 13.4 mg granule dosage strength, for the approved indication for patients with CF aged 2 months to less than 4 months. The anticipated benefits of Kalydeco are expected to outweigh the potential risks when used under the conditions of use recommended in the approved PM. Therefore, a Notice of Compliance (NOC) was recommended.

For further details about Kalydeco, please refer to the PM, approved by Health Canada and available through the Drug Product Database.