Regulatory Decision Summary for Kalydeco

Kalydeco (ivacaftor) is approved for the treatment of CF in patients 2 years and older with a gating mutation in the CFTR gene. The purpose of this submission was to revise the indication to include children that are 12 to <24 months of age with the same gating mutations for which Kalydeco is already approved. The same formulation (granules) and dosages (50 mg and 75 mg) as for patients 2 through 5 years of age was proposed for children 12 to <24 months of age based on weight (50 mg for subjects 7 to <14 kg and 75 mg for subjects 14 to <25 kg).

To support the treatment of patients 12 to <24 months of age with Kalydeco, an interim report for Study 124, an open-label 24-week clinical trial with 19 subjects was submitted. 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 in accordance with the International Council for Harmonisation (ICH) Guidance E11 (Clinical Investigation of Medicinal Products in the Pediatric Population). The exposure of ivacaftor in subjects 12 to <24 months in Study 124 was similar to that in patients 12 years and older for which efficacy has previously been established. The exposure was also consistent with that in patients 2 through 5 years of age administered the same doses.

Previous placebo-controlled studies (Studies 102, 103, 110 and 111), conducted in more than 300 subjects have demonstrated the efficacy of ivacaftor in the treatment of patients with CF 6 years of age and older with a gating mutation on the CFTR gene. These studies showed sustained improvements in CFTR channel function (reduction in sweat chloride concentration), improvements in lung function (forced expiratory volume in 1 second; FEV1), pulmonary exacerbations, respiratory symptoms, and nutritional status.

Although Study 124 was a safety study, secondary and tertiary pharmacodynamic (PD) measurements were included. Improvements in sweat chloride, nutritional status, and pancreatic function were observed over 24 weeks of treatment and are consistent with clinical improvements seen with ivacaftor. This was not a placebo controlled trial and thus the interpretation of results has limitations. In addition, over 24 weeks, all subjects were administered the 50 mg dose based on their weight at baseline and throughout the study.

Overall Kalydeco was well tolerated in this age group. 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, 19 subjects in Part B of the study, may have precluded detection of rare or uncommon events. The most common adverse events were cough, aspartate transaminase increased, pyrexia, alanine transaminase increased and rhinorrhea. In patients 12 to <24 months, the incidence of transaminase elevations appeared to be more common than in older patient populations however, the clinical features and outcomes were comparable. This study did not reveal any safety concerns during the ophthalmological examinations. Appropriate Warnings and Precautions including recommendations for monitoring for potential transaminase elevations as well as the potential for developing cataracts in children treated with ivacaftor are already in the Product Monograph.

There remain uncertainties regarding the benefits and harms of Kalydeco in patients 12 to <24 months of age. Study 124 enrolled a relatively small number of subjects (N=19), 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 which did not include a placebo arm due to ethical reasons; therefore, the level of the evidence regarding the benefits and harms is limited. However, seventeen subjects who completed Study 124 rolled over into the ongoing 96-week extension Study 126 for which no data is currently available. This will provide additional safety and efficacy data for this patient population.

The overall benefit-harm-uncertainty profile of Kalydeco is favourable: the potential benefits outweigh the potential harms in patients 12 to <24 months of age with an approved gating mutation on the CFTR gene. The review of the Risk Management Plan (RMP) was completed by the Marketed Health Products Directorate (MHPD). The MHPD will request that the Sponsor submit the results of Study 126, the on-going extension study, upon completion. Study 126 was also added to the pharmacovigilance plan for Kalydeco to evaluate safety and PD of long-term ivacaftor treatment in patients less than 24 months.