Regulatory Decision Summary for Symdeko

Symdeko is a product intended to treat cystic fibrosis by combining the complementary approaches of tezacaftor (a cystic fibrosis transmembrane conductance regulator [CFTR] corrector) and ivacaftor (a CFTR potentiator) to theoretically increase the amount and function of CFTR at the cell surface.

The submission was seeking an indication for multiple CFTR mutations based on in vivo and/or in vitro data. In two pivotal efficacy clinical trials, clinically relevant lung function improvement compared to placebo was observed for Symdeko. The treatment differences between Symdeko and placebo for the primary endpoint of mean absolute change in percent predicted forced expiratory volume in 1 second (ppFEV1) from baseline ranged from 4.0 - 6.8 percentage points. Statistically significant advantages were demonstrated when comparing the combination to one of its individual monocomponents; 2.1 percentage points between Symdeko- and ivacaftor-treated patients. However the in vitro data was deemed unreliable, thus it was recommended Symdeko have an indication based primarily on clinical evidence.

At the recommended therapeutic dose, there is the potential for serious hepatic adverse reactions. To manage adverse reactions, dosage adjustments based on the severity of hepatic impairment are recommended. Dosing is also to be interrupted with elevated liver function tests and reduced when co-administering with a CYP3A inhibitor. Caution is recommended in patients with severe renal impairment and co-administration with a strong CYP3A inducer is not recommended. Patients should be monitored by a practitioner for liver function and for cases of non-congenital lens opacities (catatracts) when taking Symdeko. Symdeko displayed a safety profile generally similar in adverse reactions compared to previously approved CFTR modulators. Uncertainties with Symdeko surround the clinical relevance in lung function with regard to the contribution of tezacaftor towards the combination in patients with "residual function" mutations studied in Study 108. Furthermore, the long-term efficacy of tezacaftor / ivacaftor versus ivacaftor was not confirmed due to the short duration of Study 108.

However, considering the severity of the disease, the lack of a CFTR modulator treatment in Canada presently for a majority of the proposed mutations, the overall demonstrated efficacy in lung function and the reported safety of this product, the overall benefit-harm-uncertainty of the product was considered to be positive.