Regulatory Decision Summary for Orkambi

To support the revised indication to include patients 2 through 5 years of age homozygous for the F508del mutation, a 24-week open-label trial (Study 115) on the safety and the pharmacokinetics of the product was submitted. The efficacy of Orkambi in patients 2 through 5 years of age was based on extrapolation of exposure data from previous studies in patients 6 years of age and older with the same mutation in accordance with the International Council for Harmonisation (ICH) Guidance E11 (Clinical Investigation of Medicinal Products in the Pediatric Population).

A new formulation (granules) and strengths (100mg lumacaftor/125mg ivacaftor and 150mg /188mg) were evaluated in the Study 115 with 60 children 2 through 5 years of age with the lower dose for patients weighing < 14kg (19 subjects) and the higher dose for patients weighing ≥14kg (41 subjects).

The Orkambi pediatric program in CF relies on matching the PK exposures of both lumacaftor and ivacaftor in patients 2 through 5 years of age with the exposures in patients 6 through 11 years of age. Previously, the PK exposures of CF subjects 6 through 11 years were matched to exposures in patients 12 years and older. The final doses for lumacaftor and ivacaftor selected for the study were proportional to the dose for patients 6 - 11 years of age. Population PK modeling and simulations showed that lumacaftor and ivacaftor exposures in patients 2 through 5 years of age were comparable to those observed in patients 6 years and older at their respective doses of Orkambi. Therefore, these exposure data confirm the appropriateness of the doses evaluated in Study 115 and allow for the extrapolation of efficacy data from previous studies in patients 6 years of age and older.

Previous placebo-controlled studies (Studies 103 and 104), conducted in more than 1000 subjects have demonstrated the efficacy of Orkambi in the treatment of patients with CF 12 years of age and older who are homozygous for F508del. Although Study 115 was not designed to evaluate the efficacy of lumacaftor/ivacaftor in children 2 through 5 years of age, it included some PD measurements. Improvements in sweat chloride, nutritional status, and pancreatic function are consistent with clinical improvements with lumacaftor/ivacaftor treatment on the underlying pathophysiology of CF disease. Moreover, these improvements were reduced at the end of the study at the follow-up visit after 2 weeks without treatment, indicating that the improvements were due to treatment.

The safety profile of Orkambi treatment was characterized by adverse events (AEs) that were generally mild to moderate in severity, although the size of the safety database, 60 subjects in Part B of the study, may have precluded detection of rare or uncommon events. The most common AEs are similar to those already described in the Product Monograph (PM). In patients 2 through 5 years of age, the incidence of transaminase elevations appeared to be similar to children 6 through 11 years of age, and similarly 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. This study did not reveal any ophthalmologic concerns, a known safety concern for children treated with ivacaftor.

Study 115 is the first in which Orkambi was examined in subjects 2 through 5 years of age. The study enrolled a relatively small number of subjects (N = 60), treated for a comparatively short duration (24 weeks); therefore, the long-term safety of lumacaftor/ivacaftor treatment in this age group is unknown. Furthermore, this was an open-label study which did not include a placebo arm. The dose adjustment for patients with moderate hepatic impairment were determined by simulations using the PK model and is slightly lower than for patients 6 years and older. Therefore, there is uncertainty regarding efficacy and safety in patients with hepatic impairment. However, the predicted exposures were within the ranges for the patients without hepatic impairment.

The overall benefit-harm-uncertainty profile of Orkambi is favorable for the proposed revised indication.