Regulatory Decision Summary for Ayvakyt

This New Drug Submission was filed to obtain market authorization for the following indication:

Ayvakyt (avapritinib) is indicated for the treatment of adult patients with Advanced Systemic Mastocytosis (AdvSM). AdvSM includes patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL).

The proposed indication was accepted.

The efficacy of Ayvakyt was evaluated in two multicentre, single-arm studies 2101 and 2202. The primary efficacy outcome was the overall response rate (ORR) based on the modified International Working Group - Myeloproliferative Neoplasms Research and Treatment - European Competence Network on Mastocytosis (mIWG-MRT-ECNM) response criteria determined by the central response assessment committee. In the 88 evaluable patients with advanced systemic mastocytosis (AdvSM, including aggressive systemic mastocytosis [ASM], systemic mastocytosis with an associated hematologic malignancy [SM-AHN] and mast cell leukemia [MCL]) who were pooled from Studies 2101 and 2202 and received the recommended 200 mg daily dose, the ORR was 68.2% (95% confidence interval: 57.4, 77.7), with 4.5% complete remission (CR), 13.6% complete remission with partial hematologic recovery (CRh), 44.3% partial remission (PR), and 5.7% Clinical Improvement. Responses were observed for all disease types. With a median follow-up of 15.4 months, the median duration of response was not estimable. The response is considered durable. Ayvakyt has not been directly compared with other available therapies for AdvSM. The survival and quality of life benefits of the therapy have not been established.

The safety of Ayvakyt was evaluated in 126 patients with AdvSM and treated with the recommended dose of 200 mg daily, pooled from Studies 2101 and 2202. The most common adverse reactions (reported in ≥ 20% of patients) were edema peripheral, anemia, periorbital edema, thrombocytopenia, diarrhea, and nausea. The most common serious adverse reactions (in ≥ 1% of patients) were subdural hematoma, anemia, ascites, pleural effusion, acute kidney injury, gastrointestinal hemorrhage, intra-abdominal hemorrhage, and hemorrhage. Fatal adverse reactions occurred in 2.4% of patients. Cognitive effects were reported in 19% of patients, including cognitive disorders, memory impairment and confusional state. Intracranial hemorrhage occurred in 3.2% of patients. Severe thrombocytopenia was identified as a primary risk factor for intracranial hemorrhage. Ayvakyt is not recommended for patients with severe thrombocytopenia. Based on the non-clinical study findings, avapritinib was teratogenic and embryotoxic and can cause fetal harm when administered to pregnant women. The adverse reactions were generally manageable in most patients with close monitoring, dosage modifications and supportive care. Key safety findings and risk mitigation recommendations are adequately described in the Product Monograph (PM). A Risk Management Plan (RMP) for Ayvakyt was submitted to Health Canada. Upon review, the RMP was considered to be acceptable.

The clinical pharmacological and non-clinical data support the intended use of Ayvakyt in the target population. Key clinical pharmacology and non-clinical findings, relevant risks and uncertainties were properly addressed in the final PM.

This submission was considered to comply with the Quality data requirements of Section C.08.002 of the Food and Drug Regulations.

The labelling documents conform to the necessary regulatory requirements and are consistent with the labelling guidance documents.

Advanced systemic mastocytosis represents a group of rare, debilitating, and potentially life-threatening mast cell malignancies that are not adequately managed with the current therapies. Few therapies are available for the treatment of AdvSM. Avapritinib, a small molecule inhibitor of KIT D816V mutant, offers patients a new treatment option. The high ORR demonstrated in Studies 2101 and 2202, supported by the durability of response, is considered evidence of clinical benefit. The final labelling and Product Monograph were considered acceptable. The overall benefit-harm-uncertainty profile of Ayvakyt is favourable for the treatment of adult patients with AdvSM.

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