Regulatory Decision Summary for Trikafta

The purpose of this Supplement to a New Drug Submission was to expand the indication for Trikafta to include the treatment of cystic fibrosis in patients aged 2 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, or a mutation in the CFTR gene that is responsive based on clinical and/or in vitro data. The submission was filed under the Priority Review Policy. The sponsor consented to information sharing between Health Canada and health technology assessment organizations as part of an aligned review pathway.

Trikafta (elexacaftor/tezacaftor/ivacaftor; ETI) is a fixed-dose combination drug that targets mutant variants of the cystic fibrosis transmembrane conductance regulator (CFTR) protein, whose dysfunction underlies cystic fibrosis (CF). The ivacaftor component serves to potentiate the anion transport activity of the CFTR protein, whereas elexacaftor and tezacaftor primarily serve to rescue the folding and processing defects of CFTR variants. While ETI has been demonstrated through randomized controlled trials to be safe and effective for the treatment of CF patients who harbour the most common CF-causing CFTR mutation, F508del, CF can be caused by over 700 different mutations in the CFTR gene. Each of these mutations is rare, which limits the opportunities to study the effectiveness of ETI in rescuing the defects caused by the various CFTR mutations. To assess the potential for efficacy in patients harbouring one of over 200 selected CFTR mutations, the sponsor has made use of in vitro functional assays conducted in cell lines engineered to express individual CFTR variants. This in vitro data, along with clinical trial data and real-world data demonstrating efficacy results for subsets of CFTR mutations, was provided to support the use of Trikafta in patients harbouring any one of 183 different CFTR mutations.

The single randomized controlled trial provided for the current submission enrolled CF patients who produced any one of 15 non-F508del CFTR variants found to be responsive to ETI in vitro, as well as patients who harboured one of 3 CFTR mutations that result in non-canonical splice mutations (that is [i.e.], that result in a reduced amount of CFTR transcript). The primary and secondary endpoints were similar to those used in Phase 3 clinical studies submitted for the initial drug approval. The primary analysis assessed change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV₁), an indicator of lung function. This demonstrated an average increase (9.2 percentage points through 24 weeks of treatment compared to placebo) that was comparable to prior studies conducted in patients with the F508del mutation (of at least 10 percentage points). Mean improvements in secondary endpoints were all statistically significant, supporting there being a clinically meaningful benefit, on average. The results of this study support the idea that patients harbouring CFTR mutations predicted to be responsive based on in vitro data may demonstrate clinical benefit with ETI treatment. When examined by-mutation, however, there was only sufficient data to provide substantive evidence of efficacy for a few of the individual CFTR mutations (noted in the accepted revised PM as being supported by clinical data).

A second submitted study relied on the analysis of United States CF patient registry data that was of an interim nature. This was judged to be of limited utility for assessing drug efficacy and was not relied on for the assessment of the proposed broadened indication.

Three investigator-led studies submitted by the sponsor examined the efficacy of ETI in the treatment of patients who harboured the N1303K mutation. This relatively more common mutation had been found to be unresponsive to ETI in the sponsor's in vitro functional assay. However, some published data had suggested that ETI may improve the functioning of the N1303K variant. Individual response data was consistent across the three studies in demonstrating substantially increased ppFEV₁ values with ETI treatment. Another key clinical endpoint reflective of increased CFTR functioning, decrease in sweat chloride, did not demonstrate consistent responses, however. Limited in vitro data produced for two of the studies using patient-derived cells supported the efficacy of ETI for the N1303K mutation. Though unique in the factors that determine its responsiveness, the clinical and in vitro data, overall, supported the efficacy of ETI in improving the lung function of patients harbouring the N1303K mutation.

The efficacy of ETI in treating the defects caused by all remaining CFTR mutations indicated in the Product Monograph as being responsive was based primarily on the sponsor's in vitro chloride transport assay. This assay demonstrated the potential for ETI to rescue the defects caused by 177 different CFTR mutations. In total, 152 CFTR mutations have been accepted for addition to the PM based largely on biological plausibility, in addition to the clinical data supportive of some of these. The CFTR mutations that were excluded consisted of mutations that: 1) have been found to not cause CF, 2) retain high residual function and have an unknown clinical consequence, 3) have data indicating that no full-length CFTR protein is likely to be produced as a result of the mutation, and 4), lacked any in vitro or clinical evidence supportive of efficacy.

Pharmacokinetic data from the pivotal clinical trial demonstrated that exposures to the active drug components were genotype-agnostic, with consistent exposure values for all analytes in adult CF patients across genotypes.

No unique safety issues were identified in patients with non-F508del CFTR genotypes from any clinical study data. Long-term safety, which was not demonstrated by the interim data from the sponsor's extension study in the current submission, can be extrapolated using data from previously received submissions for patients with the F508del mutation. Similarly, safety for children 2 - 5 years of age, which was not addressed in the current submission, has been demonstrated for children with the F508del mutation in a prior submission. No substantive revisions to the safety information for Trikafta have been made.

The clinical and in vitro data provided for this submission were generally supportive of Trikafta being an effective treatment for CF patients who harbour non-F508del mutations, in cases where in vitro functional data indicates the ability of this drug to increase chloride transport activity. This is only presumed to be true, however, when the targeted mutation is CF-causing, and when it allows for the production of a CFTR protein variant that is rescuable by the drug. In these cases, the potential for benefit outweighs the potential risks to the patient.

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