Regulatory Decision Summary for Idhifa

Acute myeloid leukemia (AML) is a rare, aggressive and rapidly progressive disease that is generally incurable. For AML patients in the relapsed/refractory (R/R) setting, effective and tolerable treatment options are limited and prognosis is generally very poor. Isocitrate dehydrogenase 2 (IDH2) mutations define a specific subset of patients with AML. The mutation confers a gain of function whereby the aberrant enzyme catalyzes the production of the oncogenic metabolite 2 hydroxyglutarate (2-HG). 2-HG induces a block of cell differentiation. Idhifa is a small molecule inhibitor of the IDH2 mutant enzyme. Inhibition of the mutant IDH2 enzyme by Idhifa leads to decreased 2-HG levels, which is believed to induce myeloid differentiation.

Efficacy and safety for Idhifa in the treatment of IDH2 mutated patients with R/R AML was demonstrated in Study AG221-C-001, a phase 1/2, single arm clinical trial. At baseline, patients in the study were not considered candidates for potentially curative therapies. The primary endpoint was Overall Response Rate (ORR) based on investigator assessment and was defined as the rate of responses, including complete response (CR), CR with incomplete neutrophil recovery (CRi), CR with incomplete platelet recovery (CRp), partial response, and morphologic leukemia-free state. An ORR of 37.1% was observed, with CRs in 20.0% of patients and CR plus CRi/CRp in 31.4% of patients. Responses were durable at 5.6 months, 6.7 months and 5.6 months respectively for ORR, CR, and CR plus CRi/CRp. Clinical benefit was demonstrated by achievement of red blood cell and platelet transfusion independence and a decrease in AML complications, including febrile neutropenia, infections and bleeding events during periods of response. A median overall survival of 7.0 months was observed, which appears promising compared with historical controls; however, overall survival must be interpreted with caution in a single arm trial. Additionally, the prognostic significance of the IDH2 mutation in AML has yet to be clearly defined. Overall, the efficacy evaluation of Idhifa is considered promising evidence of benefit for IDH2 mutated relapsed/refractory AML patients for whom effective and tolerable therapies are limited. There are currently no therapies in Canada targeting AML patients selected for IDH2 mutations. Given the single arm design of the study, the clinical effectiveness and specifically the overall survival benefit of Idhifa require confirmation with Phase 3 data. Market authorization under the Notice of Compliance with Conditions policy was recommended. In a Letter of Undertaking dated January 10, 2019, Celgene Inc. committed to submitting to Health Canada the final results of the Phase III pivotal study AG221-AML-004 in order to confirm the clinical benefit of Idhifa treatment in comparison with conventional care regimens.

The safety population was comprised of 214 R/R IDH2 mutated AML patients from Study AG221-C-001 treated with 100 mg/day of Idhifa. Idhifa was generally well tolerated with relatively few dose modifications or discontinuations required for adverse reactions. The key safety concerns identified in the study included IDH differentiation syndrome, tumour lysis syndrome, non-infectious leukocytosis, elevation of blood bilirubin and gastrointestinal disturbances. IDH differentiation syndrome is the most serious of these events and was labeled in a Serious Warnings and Precautions box in the Product Monograph due to a potential for fatal outcome. Patients must be informed of the need to seek immediate medical attention should symptoms of the condition occur to ensure prompt treatment initiation. Celgene Inc. has committed to distributing a Wallet Card for patients and caregivers in each Idhifa carton to help mitigate this risk. Although there are significant toxicities associated with Idhifa, they are generally tolerated with recommended dose modifications and are appropriately labeled in the Product Monograph. The safety profile of Idhifa is considered acceptable in this treatment setting.

Idhifa was administered under fasting conditions in Study AG221-C001. A food effect study in healthy volunteers demonstrated that the consumption of a high fat, high calorie meal resulted in an increase in the extent and rate of absorption of Idhifa. Based on review of pharmacokinetic and clinical safety data, this increase is not anticipated to be of clinical relevance. As such, Idhifa is recommended to be taken with or without food.

A Risk Management Plan (RMP) for enasidenib mesylate was submitted by Celgene Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and, when needed, to describe measures that will be put in place to minimize risks associated with the product. Celgene has committed to submit to Health Canada annual Periodic Safety Update Reports or Periodic Benefit Risk Evaluation Reports to analyse significant safety findings and to ensure a continued positive benefit/risk profile of Idhifa in the post-market setting.

Health Canada considers the documentation provided in this Response to Qualifying Notice to be sufficient to recommend approval for Idhifa for the treatment of adult patients with relapsed or refractory AML with an IDH2 mutation.

Overall, Idhifa demonstrated clinically relevant efficacy effects in the subset of relapsed refractory AML patients with an IDH2 mutation. In the context of this life-threatening, generally incurable disease that is not adequately managed by available therapies in Canada, the promising clinical benefit of Idhifa is considered to outweigh the associated risks.