Regulatory Decision Summary for Trikafta

The purpose of this priority Supplemental New Drug Submission was to expand the indicated patient age from 6 years of age and older to include children 2 to 5 years of age. A new dosage form and new strength were proposed to support appropriate dosing in children under the age of 6.

Trikafta (oral elexacaftor/tezacaftor/ivacaftor fixed dose combination) has previously been demonstrated to be safe and effective for use in treating cystic fibrosis patients who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The current submission addressed the safety and efficacy of Trikafta in children with cystic fibrosis who were 2 to 5 years of age.

A single-arm Phase 3 study that enrolled 75 children 2 to 5 years of age for safety and efficacy assessments, and 18 children for pharmacokinetic (PK) assessments, was submitted to support the use of Trikafta in this age group. As safety and tolerability were primary endpoints of this study, the determination of adequate efficacy was dependent on extrapolation of efficacy from placebo-controlled studies conducted with older patients. Previously assessed data had indicted similar effects of Trikafta on lung function and sweat chloride (an objective measure of CFTR function) across age groups, including in children 6 to 11 years of age, adolescents, and adults. Extrapolation of efficacy to younger children is appropriate for cystic fibrosis.

Assessments of lung function in children 2 to 5 years of age following Trikafta administration that were supportive of efficacy relied on the use of Lung Clearance Index (LCI) calculations. LCI provides a sensitive measure of lung function in pre-school aged children. While baseline LCI measurements indicated generally less severe deficits compared to those in previously assessed children 6 to 11 years of age, substantial improvement in the average LCI score in the 2 to 5 year-old children was still observed. The average time course of this improvement coincided with decreases (improvements) in sweat chloride levels that were similar to those seen in older patients. Evidence from additional efficacy endpoints (including surrogate markers of pancreatic function and inflammation) was further supportive of significant efficacy in children 2 to 5 years of age.

The sponsor has conducted extensive PK modeling during the development program of Trikafta. Data provided in the current submission incorporated sparse PK sampling data from children 2 to 5 years of age. PK modeling and empirical data indicated acceptable exposure values for each of the active pharmaceutical ingredients and their major active metabolites, based on comparisons to exposure values in older patients.

Safety was assessed in children 2 to 5 years of age primarily by adverse event reporting in the Phase 3 study. No adverse events unique to this age group were observed that were attributable to Trikafta. Overall, safety was similar to that observed for older children, adolescents, and adults. Appropriate labelling in the Product Monograph and on packaging includes updated dosage and administration information, and dosage adjustment information, for children. While additional pediatric data regarding risk of increases in liver enzymes and bilirubin (i.e. risk of liver injury) has been added to the Product Monograph, this data did not indicate any greater risk for children aged 2 to 5 years of age. No new warnings have been added to the labelling for this age group.

A new dosage form and strengths were developed for administration of Trikafta to children 2 to 5 years of age. Rather than tablets, young children were administered granule formulations mixed with food, and used at higher or lower strengths dependent on patient weight. No significant quality issues were identified with the new formulations.

Overall, the risks and benefits of the new Trikafta granules in children aged 2 to 5 years of age were consistent with what has been observed with tablets used for older cystic fibrosis patients and was considered favourable. A Notice of Compliance (NOC) was issued.

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