Regulatory Decision Summary for ORKAMBI

Orkambi consists of a combination of lumacaftor and ivacaftor. Lumacaftor is part of a new class of drugs known as cystic fibrosis transmembrane conductance regulator (CFTR) correctors which improve the function of the CFTR protein. This is the second molecule that targets the underlying biochemical defect causing cystic fibrosis (CF). Ivacaftor, a CFTR potentiator, is currently approved in Canada for treatment of CF caused by eleven gating mutations.

The efficacy and safety of Orkambi in patients with CF who are homozygous for the F508del mutation in the CFTR gene was evaluated in two randomized, double-blind, placebo-controlled Phase 3 clinical trials in which 1108 clinically stable patients with CF were randomized and received at least 1 dose of study drug; 369 of these patients were randomized to the Orkambi (lumacaftor 400 mg q12h/ivacaftor 250 mg q12h) dose. The primary efficacy endpoint in both studies was improvement in lung function as determined by the absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) at Week 24, assessed as the average of the treatment effects at Week 16 and at Week 24. Analysis in these two pivotal clinical studies along with supporting data showed a moderate positive effect on lung function in patients ≥12 years of age that was relatively rapid (after two weeks) and sustained for at least 24 weeks (length of exposure). Since respiratory failure is the main cause of premature mortality in CF, administration of Orkambi has the potential to modify the natural history of the disease.

Lumacaftor/ivacaftor was generally well tolerated in the intended population, displaying a similar safety profile to previously studied CF target populations. However, at the recommended therapeutic dose, there is the potential for serious hepatic, respiratory and cardiovascular 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 temporarily reduced when co-administering with a cytochrome P450 (CYP)3A inhibitor.

Considering the severity of the disease and the current lack of treatment in the intended patient population, the benefit/risk ratio of Orkambi is favorable for the recommended indication and the intended population of CF patients age 12 years and older who are homozygous for the F508del mutation in the CFTR gene.