Regulatory Decision Summary for Trikafta

Trikafta treats cystic fibrosis (CF) by combining the complementary approaches of elexacaftor and tezacaftor (both cystic fibrosis transmembrane conductance regulator (CFTR) gene correctors) and ivacaftor (a CFTR potentiator) to increase the amount and function of CFTR at the cell surface.

The Sponsor was seeking to expand the indication age range for Trikafta from 12 years and older to 6 years and older for CF patients who have at least one F508del mutation in the CFTR gene.

The pharmacokinetic profile, safety and efficacy of Trikafta in patients aged 6 to less than 12 years was supported by evidence from studies in patients aged 12 years and older submitted previously, with additional data from patients aged 6 to less than 12 years assessed in the current submission. A 24-week open-label study in 66 patients aged 6 to less than 12 years who were homozygous for the F508del mutation or heterozygous for the F508del mutation and a minimal function mutation (that is [i.e.] a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor and tezacaftor/ivacaftor) was conducted to support this submission.

The primary endpoint of safety and tolerability was evaluated through 24 weeks. Secondary endpoints evaluated were pharmacokinetics, and efficacy including absolute change in percent predicted forced expiratory volume in one second (ppFEV1), sweat chloride, Cystic Fibrosis Questionnaire Revised (CFQ-R) respiratory domain score from baseline through week 24 and measure of growth parameters (including body mass index [BMI] and BMI-for-age z-scores) from baseline at week 24.

The mean absolute change in ppFEV1 from baseline through week 24 was 10.2 percentage points (95% confidence interval [CI]: 7.9, 12.6). The mean absolute change in sweat chloride from baseline through week 24 was 60.9 millimoles per litre (mmol/L) (95% CI: 63.7, 58.2). The mean absolute change in BMI at week 24 was 1.02 kilograms per metre squared (kg/m²) (95% CI: 0.76, 1.28) and BMI-for-age z-score at week 24 was 0.37 (95% CI: 0.26, 0.48). The mean absolute change in CFQ-R respiratory domain score from baseline through week 24 was 7.0 points (95% CI: 4.7, 9.2).

Consistent with the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guideline E11, the effectiveness of Trikafta in patients aged 6 to less than 12 years was extrapolated from patients aged 12 years and older with support from population pharmacokinetic analyses showing elexacaftor, tezacaftor and ivacaftor exposure levels in patients aged 6 to less than 12 years within the range of exposures observed in patients aged 12 years and older.

Furthermore, at the recommended therapeutic dose, the safety profile of patients in this trial was similar to those observed in the previous phase 3 trials conducted with Trikafta in CF patients 12 years and older. Trikafta treatment was generally safe and well tolerated for up to 24 weeks in CF subjects 6 through 11 years of age.

Uncertainties with Trikafta surround the clinical efficacy in lung function with regard to patients with “residual function” and “gating” mutations who were not enrolled in this study but due to the principles of ICH E11 were included in the approved patient population. The long-term efficacy of Trikafta in CF patients aged 6 to less than 12 years old was not confirmed due to study design as safety and tolerability were identified as primary endpoints instead of lung function measurements. An ongoing long-term study with patients rolled over from this study may help confirm the long-term efficacy in the near future.

Considering the severity of the disease, the lack of a CFTR modulator treatment in Canada presently for a proportion of the proposed mutations, the larger overall demonstrated efficacy in lung function compared to previously approved CFTR modulators and the reported safety of this product, an authorization was recommended for Trikafta.