Regulatory Decision Summary for Orkambi

Orkambi is a prescription product approved under Division 8 of the Food and Drug Regulations for the treatment of CF in patients aged 12 years and older who are homozygous for the F508del mutation in the CF transmembrane conductance regulator (CFTR) gene. This submission was filed to extend the approved indication to children that are 6 years and older and who are homozygous for the F508del CFTR mutation. A new strength of 100 mg lumacaftor and 125 mg ivacaftor is also being proposed for children from 6 to 11 years old.

To support the indication, the Sponsor has submitted one trial, Study 011, which is considered "pivotal" for safety and pharmacokinetics (PK). The efficacy of Orkambi was based on extrapolation of data from studies in patients 12 years of age and older with the same mutation in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidance E11: "Clinical Investigation of Medicinal Products in the Pediatric Population".

In order to be able to extrapolate the efficacy data to patients age 6 through 11, the pediatric program in CF relies on matching PK exposure with CF subjects, age 12 years and older. The final dose for lumacaftor selected for the study was half of the adult dose (200 mg vs 400 mg q.12h), whereas the ivacaftor dose was the same (250 mg q.12 h). The systemic exposure in children administered 200 mg lumacaftor and 250 mg ivacafor q12h was similar to that observed in adults and adolescents administered 400 mg lumacaftor and 250 mg ivacafor q12h. These exposure data confirm the appropriateness of the doses evaluated in Study 011 for subjects with CF 6 through 11 years of age, and allow for the extrapolation of efficacy data from previous studies in adolescents and adults ≥12 years old.

Previous placebo-controlled studies (Studies 103 and 104) conducted in more than 1,000 subjects have demonstrated the efficacy of lumavaftor/ivacaftor in the treatment of patients with CF, 12 years of age and older, who are homozygous for F508del. These studies showed sustained improvements in CFTR channel function (measured by reduction in sweat chloride concentration), improvements in lung function, pulmonary exacerbations, respiratory symptoms, and nutritional status. Although Study 011 was not designed to evaluate the efficacy of lumacaftor/ivacaftor in children 6 through 11 years of age, it included some Pharmacodynamic (PD) measurements. There were improvements in sweat chloride, nutritional status, and lung function, confirming the clinical improvements with lumacaftor/ivacaftor treatment on the underlying pathophysiology of CF disease in subjects 6 through 11 years of age.

The intended population for lumacaftor/ivacaftor treatment is anticipated to be easy to identify because genotyping for mutations in the CFTR gene is now routine practice in Canada.

The safety profile of lumacaftor/ivacaftor treatment was characterized by adverse events that were generally mild to moderate in severity and did not lead to treatment discontinuation, although the size of the safety database, 58 subjects in Part B of the study, may have precluded detection of rare or uncommon events. The most common adverse events are similar to those already described in the Product Monograph (PM). In patients 6 through 11 years of age, marked transaminase elevations appeared to be more common than in older patients, although the clinical features and outcome appeared to be comparable. There are appropriate Warnings and Precautions already included in the PM. Ivacaftor is a substrate of cytochrome P450 (CYP), whereas lumacaftor is an inducer of the same enzymes. The drug interaction profile for lumacaftor 200 mg/ivacaftor 250 mg q12h is considered to be the same as that for lumacaftor 400 mg q12h/ivacaftor 250 mg q12h, based on exposure at the indicated dose. This study did not reveal any concern during the ophthalmological examinations. However, the potential for developing cataracts, suggested by pre-clinical studies in juvenile rats has also been included in the PM.

Study 011 is the first in which Orkambi was examined in subjects 6 through 11 years of age. The study enrolled a relatively small number of subjects (N = 58), treated for a comparatively short duration (24 weeks); therefore, the safety of long-term lumacaftor/ivacaftor treatment in this age group is unknown. Furthermore, this was an open-label study which did not include a placebo arm. However, the Sponsor has conducted a randomized, placebo controlled study in 204 CF subjects age 6 through 11 with the same mutation, which confirms the safety findings from Study 011. In addition, a 96-week rollover study, Study 110, is currently being conducted in these patients. At this time, data is available from patients cumulative treatment duration of at least 60 weeks. No safety concerns have been identified.

In conclusion, 200 mg lumacaftor/250 mg ivacaftor, q12hr was well tolerated in the 6 through 11 years old group, as evidenced by the results of safety assessments. The safety outcomes were similar relative to other CF patients and the established safety profile of lumacaftor/ivacaftor treatment. No new safety concerns were identified with continued treatment and when compared with subjects aged 12 years and older.