Regulatory Decision Summary for Orkambi

The purpose of this Supplement to a New Drug Submission (SNDS) was to obtain market authorization, pursuant to section C.08.0004 of the Food and Drug Regulations for Orkambi (lumacaftor/ivacaftor). The SNDS was filed to add a new strength of lumacaftor/ivacaftor granules (75 milligram [mg]/94 mg) and expand the indication for the treatment of Cystic Fibrosis (CF) in patients 1 to less than 2 years of age who are homozygous for the F508del mutation in the Cystic Fibrosis transmembrane conductance regulator (CFTR) gene.

The submission was reviewed as part of the Access Consortium international work sharing initiative. Health Canada conducted the lead review of the quality module (module 3), the United Kingdom Medicines and Healthcare products Regulatory Agency (MHRA) conducted the lead review for the clinical module (module 5), and the Australian Therapeutic Goods Administration (TGA) was a peer reviewer. Health Canada was a peer reviewer for the clinical module (module 5).

To support the revised indication to include children 1 to less than 2 years of age with Cystic Fibrosis (CF) who are homozygous for the F508del CFTR mutation, the Sponsor submitted one clinical trial, Study 122, and conducted population pharmacokinetic (PK) modelling to identify the appropriate doses for this patient population. The recommended doses of Orkambi granules for children 1 to less than 2 years of age were based on patients’ weight and were determined to be 75 milligrams (mg) lumacaftor/94 mg ivacaftor (patients weighing 7 to less than 9 kilograms [kg]), 100/125 mg (patients 9 to less than14 kg) and 150/188 mg (patients greater than or equal to 14 kg), twice daily. The systemic exposures of lumacaftor and ivacaftor in this patient population was similar to that observed in older children and adults administered the recommended doses.

There is no direct evidence of efficacy in children aged 1 to less than 2 years of age. However, the demonstrated pharmacodynamic (PD) effects in Study 122 were consistent with those demonstrated in older children and adults. The underlying pathophysiology of the disease is similar, regardless of age, and therefore, it was acceptable to extrapolate efficacy to children 1 to less than 2 years of age from the conclusive evidence of efficacy demonstrated in older children and adults with the same mutation in previous pivotal studies and the similar exposure in this population. 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 122 was not designed to evaluate the efficacy of Orkambi in children 1 to less than 2 years of age, it included PD measurements. Improvements in sweat chloride and pancreatic function were observed over 24 weeks of treatment and were consistent with the effect of Orkambi treatment on the underlying pathophysiology of the disease. The levels returned to baseline at the end of the study after 2 weeks without treatment, indicating the improvements were due to treatment with Orkambi.

Due to the study design and limited patient population, there were uncertainties regarding the magnitude of benefit in this age group. There were uncertainties in the optimum age for treatment initiation, particularly due to the predicted long-term need for treatment. The collection of long-term data in the post-marketing setting is expected to provide information regarding efficacy in this patient population. Overall, the benefits of having Orkambi as a treatment option outweighed the uncertainties for use in these young children.

The safety profile of Orkambi treatment for children aged 1 to less than 2 years of age was consistent with the known safety profile observed in older children and adults. However, the limited size of the safety database of 46 patients in Study 122 may have precluded detection of rare or uncommon events. The most common adverse events were generally mild to moderate in severity and were cough, infective pulmonary exacerbations of CF, pyrexia, vomiting, upper respiratory tract infection, constipation, ear infection, rhinorrhea, and Pseudomonas, and are consistent with those already described in the Product Monograph. The incidence of transaminase elevations in the study were similar to that in older children. Overall, the study did not reveal any new safety concerns and the safety profile appeared to be acceptable in these young children. Additional safety data for this population will be collected from a 96-week, ongoing open-label extension study which enrolled 40 subjects who completed Study 122.

An updated Risk Management Plan (RMP) for Orkambi was reviewed by Health Canada and considered acceptable. Risks have been communicated in the Product Monograph and will continue to be monitored post-market as outlined in the RMP, with routine and non-routine pharmacovigilance activities.

A new strength of granules (75 mg lumacaftor/94 mg ivacaftor) was proposed for children 1 to less than 2 years of age weighing 7 to less than 9 kg. The chemistry and manufacturing information submitted for Orkambi 75 mg/94 mg granules has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications.

The final labelling and Product Monograph were considered acceptable.

Overall, the benefit-harm-uncertainty profile was favourable for Orkambi granules for patents 1 to less than 2 years of age and the recommended indication. Therefore, a Notice of Compliance (NOC) was recommended. The anticipated benefits of Orkambi are expected to outweigh the potential risks when used under the conditions of use recommended in the Product Monograph.

For further details about Orkambi, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.