Regulatory Decision Summary for Alyftrek

The purpose of this New Drug Submission was to obtain market authorization, pursuant to section C.08.004 of the Food and Drugs Regulations, for Alyftrek, filed by Vertex Pharmaceuticals (Canada) Incorporated.

This submission was filed for Alyftrek (vanzacaftor calcium/tezacaftor/deutivacaftor), 4 milligram (mg) /20 mg /50 mg and 10 mg /50 mg /125 mg tablets, for oral use, for the treatment of cystic fibrosis in patients aged 6 years and older with at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or another responsive mutation in the CFTR gene. The sponsor proposed a total of 302 other mutations in the Product Monograph. Upon review of the submitted data package, Health Canada authorized Alyftrek for the proposed indication; however, limited the list to 265 CFTR mutations other than F508del.

The sponsor consented to information sharing between Health Canada and health technology assessment organizations as part of an aligned review pathway.

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, resulting in reduced amount or function of CFTR protein at the cell surface. CFTR is an chloride transport channel.

Alyftrek is a fixed-dose combination product containing vanzacaftor (VNZ), tezacaftor (TEZ) and deutivacaftor (D-IVA) indicated for the treatment of cystic fibrosis in patients 6 years and older with certain CFTR mutations. VNZ and TEZ, CFTR correctors, improve the processing and trafficking of CFTR to the cell surface and D-IVA is a CFTR potentiator that increase anion transport activity of the CFTR protein at the cell surface.

The efficacy and safety of Alyftrek was evaluated in two randomized, elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA)-controlled, multicenter, 52 week studies (Study 102 and Study 103) in CF patients aged 12 years and older. All subjects were treated with ELX/TEZ/IVA, the current standard of care, in a 4 week run-in period and then randomized (1:1) to Alyftrek (20/100/250 milligram [mg]) once daily or ELX/TEZ/IVA (approved dose). Patients with different mutations were included in the different studies, with the majority of patients having one copy of the F508del mutation. A total of 42 patients in Study 103 had at least 1 copy of a triple combination responsive mutations and no F508del mutation. Patients who did not tolerate ELX/TEZ/IVA were excluded from the study. The majority of subjects were treated with other CFTR modulators prior to the start of the study.

Alyftrek demonstrated non-inferiority to ELX/TEZ/IVA in both clinical trials for the absolute change from baseline through 24 weeks in percent predicted forced expiratory volume in 1 second (ppFEV1), a measure of lung function. The key secondary endpoint of absolute change from baseline through week 24 for sweat chloride showed a decrease (improvement) with Alyftrek compared to ELX/TEZ/IVA in both studies (-8.4 millimole per litre [mmol/L] and -2.9 mmol/L in Studies 102 and 103, respectively). Sweat chloride is a measure of the effect of treatment on the function of CFTR and does not always correlate with clinical outcomes. The results for other secondary efficacy endpoints, including the rate of CF pulmonary exacerbations and the change in the cystic fibrosis questionnaire-revised respiratory domain score, support the efficacy of Alyftrek in the study. Interpretation of these endpoints was limited due to the lack of multiplicity control.

The safety, pharmacodynamics and tolerability were evaluated in children 6 through 11 years of age in an open-label, 24-week study. Efficacy in these pediatric patients was extrapolated from the demonstrated efficacy in adolescents and adults in the randomized controlled trials, since the disease process is the same and the exposure levels were similar between populations.

The efficacy of Alyftrek for the treatment of CF patients with the other CFTR mutations not evaluated in the clinical trials were primarily based on demonstrated in vitro responsiveness of the individual mutations in a chloride transport assay using Fisher rat thyroid (FRT) cells expressing the individual CFTR proteins. The assay demonstrated the potential for Alyftrek to improve the function of 135 CFTR mutations including F508del. Additionally, the responsiveness of another 118 mutations were based on previous in vitro studies that showed they were responsive to the components ivacaftor and/or tezacaftor/ivacaftor. In total, 266 CFTR mutations were accepted for addition to the Product Monograph based largely on biological plausibility, in addition to the clinical data supportive for some. The 37 CFTR mutations that were excluded consisted of mutations that have been found to not cause CF, retained high function in the in vitro chloride assay and would probably not result in benefit with treatment, and have data indicating that no full-length CFTR protein is likely to be produced as a result of the mutation. For the mutation N1303K, in vitro responsiveness was only demonstrated with patient derived bronchial epithelial cells and not with the FRT system.

The clinical and in vitro data for this submission were generally supportive of the efficacy of Alyftrek treatment of CF patients who have the F508del mutations and the evaluated non-F508del mutations. Efficacy of Alyftrek for patients with CFTR mutations only evaluated in vitro, or with IVA and TEZ/IVA, expected as long as the mutation results in the production of CFTR protein. Mutations that are known to not cause CF were excluded from the Product Monograph based on the indication for the treatment of CF.

The safety database for Alyftrek was adequate and demonstrated comparable safety to ELX/TEZ/IVA in the clinical development for children 6 years and older, adolescents, and adults. However, due to the design of the pivotal clinical trials in which patients were treated with ELX/TEZ/IVA during the run-in period, exclusion of patients who did not tolerate ELX/TEZ/IVA, and lack of a placebo arm, there are limitations to the safety data. Additionally, the majority of subjects had previously been taking ELZ/TEZ/IVA or other CFTR modulators. However, overall the data supported the safety of Alyftrek. The reported adverse events (AEs) were comparable between the two treatment arms, regarding reports of AEs, serious AEs and severe AEs. The most common adverse reactions reported in the clinical Studies 102 and 103 were headache, diarrhea, rash, and increased blood creatinine phosphokinase, alanine aminotransferase and aspartate aminotransferase. The elevated liver function tests were also observed with the other CFTR modulators. Overall, safety issues were identified in the Product Monograph. The safety in patients 6 through 11 years were consistent with that observed in adolescents and adults.

Pre-clinical pharmacology and toxicology studies were conducted according to the regulatory requirements and demonstrated no safety concerns for VNZ, or D-IVA. TEZ pre-clinical data was reviewed during a previous submission.

A Risk Management Plan (RMP) for Alyftrek was reviewed by Health Canada and considered acceptable. Risks have been communicated in the approved Product Monograph and will continue to be monitored post market as outlined in the RMP, with routine.

The chemistry and manufacturing information submitted for Alyftrek has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

Comparative bioavailability data was reviewed and demonstrated that a high-fat, high-calorie meal had a significant impact on the rate and extent of exposure of VNZ, TEZ, and D-IVA in the commercial formulation of Alyftrek.

The final labelling and Product Monograph were considered acceptable.

Overall, the benefit-harm-uncertainty profile was favourable for Alyftrek 4/20/50 mg and 10/50/125 mg tablets for the approved indication when used under the conditions of use recommended in the approved Product Monograph. A Notice of Compliance was recommended.

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