Regulatory Decision Summary for Cresemba

The purpose of this Supplement to a New Drug Submission (SNDS) was to expand the current indications for Cresemba in the treatment of invasive aspergillosis and invasive mucormycosis in adults to pediatric subjects aged 1 to < 18. In addition, a new 40 mg capsule strength was proposed.

The proposed pediatric indications in the treatment of invasive aspergillosis and invasive mucormycosis were supported primarily by two clinical studies in subjects aged 1 to < 18 (Study 9766-CL-0046 and 9766-CL-0107). Taken together, these studies demonstrated a comparable safety and pharmacokinetic (PK) profile of Cresemba to that observed in adult Phase 3 studies.

Study 9766-CL-0046 was an open-label, non-comparative Phase 1 clinical trial that evaluated the PK and safety of Cresemba following administration to 46 pediatric subjects aged 1 to < 18 deemed likely to benefit from prophylaxis intervention due to underlying disease that increased the risk of invasive fungal disease. Cresemba was administered every 8 hours for the first 48 hours (loading dose) and once daily for another 26 days thereafter (maintenance dose). Dosing was adjusted based on body weight: for intravenous (IV) infusion, subjects received 5.4 mg/kg isavuconazole when weighing < 40 kg and 200 mg isavuconazole when weighing ≥ 40 kg, and for oral dosing, subjects received 80 mg isavuconazole when weighing 16 to < 18 kg and this increased in increments of 40 mg isavuconazole for patients weighing 18 to < 25 kg and 25 to < 32 kg, with patients weighing ≥ 32 kg receiving 200 mg isavuconazole. Safety and PK data was acquired from 27 subjects that received IV isavuconazole (aged 1 to < 18) and 19 subjects that received oral isavuconazole (aged 6 to < 18).

Study 9766-CL-0107 was an open-label, non-comparative Phase 2 clinical trial that evaluated the PK, safety, acceptability, and efficacy of Cresemba following administration to 31 pediatric subjects aged 1 to < 18 with at least possible invasive fungal disease, including 27 subjects with possible, probably, or proven invasive aspergillosis or invasive mucormycosis. Cresemba was administered every 8 hours for the first 48 hours (loading dose) and once daily thereafter (maintenance dose). Dosing was adjusted based on body weight as in Study 9766-CL-0046, and oral or IV isavuconazole wereused interchangeably where clinically appropriate. Duration of treatment was up to 181 days, with a median treatment duration of 55 days. Safety and PK data was acquired from 31 subjects, including 5 subjects that received oral dose only, 15 subjects that received IV dose only, and 11 subjects that received either oral or IV dose interchangeably.

Cresemba was safe and well-tolerated in studies 9766-CL-0046 and 9766-CL-0107, and produced a comparable safety profile to adults. Treatment emergent adverse events that occurred at a greater frequency than observed in adults, i.e., abdominal pain, pyrexia, stomatitis and transaminase elevations, were not attributed to isavuconazole but a result of the chemotherapy agents being used by these patients, enhanced febrile responses in this population and/or the condition being present prior to Cresemba initiation. The Cresemba Product Monograph (PM) was updated to reflect this information.

Following body-weight based adjusted dosing of Cresemba in studies 9766-CL-0046 and 9766-CL-0107, isavuconazole exposures in pediatric subjects were comparable to exposures observed in pivotal Phase 3 adult studies. Therefore, it could be concluded that this dosing regimen in pediatric patients resulted in isavuconazole exposures that are expected to be safe and efficacious.

Both pediatric clinical studies were open-label and non-comparative and therefore not designed to adequately assess efficacy. However, efficacy conclusions were made based on extrapolation of isavuconazole exposures achieved in the pediatric population to exposures shown to be efficacious in the adult population.

Risks and data limitations related to pediatric subjects aged 1 to < 18 have been communicated in the approved PM and will continue to be monitored post market as outlined in the Risk Management Plan.

The proposed 40 mg capsule was acceptable from a quality review perspective and is recommended for use in subjects aged 6 to < 18 and weighing at least 16 kg.

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