Regulatory Decision Summary for Trikafta

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

In three pivotal efficacy clinical trials, clinically relevant lung function improvement, compared to placebo/active comparator, was observed for Trikafta. The treatment differences between Trikafta and placebo for the primary endpoint of absolute change in percent predicted forced expiratory volume in one second (ppFEV1) from baseline through 24 weeks reached 14.3 percentage points. Clinically significant advantages were also demonstrated when comparing the triple combination to a dual combination of its monocomponents; 10.0 percentage points between Trikafta- and tezacaftor/ivacaftor-treated patients. Lastly, statistically significant advantages of 3.7 percentage points were demonstrated when comparing the triple combination to a control group of either ivacaftor or tezacaftor/ivacaftor-treated patients.

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 were recommended. Dosing is also to be interrupted with elevated liver function tests and reduced when co-administering with a cytochrome P450 (CYP) 3A inhibitor. Caution was recommended in patients with severe renal impairment and co-administration with a strong CYP3A inducer was not recommended. Patients should be monitored by a practitioner for liver function and for cases of non-congenital lens opacities (cataracts) when taking Trikafta. Trikafta displayed a safety profile generally similar in adverse reactions compared to previously approved CFTR modulators (that is [i.e.] Kalydeco, Symdeko). However, post-market data did indicate the potential of drug induced liver failure in patients with pre-existing cirrhosis and portal hypertension. Thus, appropriate risk-mitigating labelling was added to several sections of the Product Monograph (PM) warning of the potential for liver injury.

Uncertainties with Trikafta surround the clinical relevance in lung function with regard to the contribution of elexacaftor in the fixed-dose combination, in patients with “residual function” and “gating” mutations studied in Study 103. Theoretically, the difference observed with Trikafta should be in addition to the treatment differences noted with Kalydeco (gating) and Symdeko (residual function) respectively. Furthermore, the long-term efficacy of Trikafta was not properly confirmed, due to the short duration of two pivotal studies (8 and 4 weeks for Studies 103 and 104, respectively). Ongoing long-term studies with patients rolled over from both studies should help confirm the long-term efficacy in the near future.

Considering the severity of the disease, the lack of treatment in Canada presently for a proportion of the proposed mutations (CF patients with minimal function (MF) 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.