Regulatory Decision Summary for Kengrexal

This New Drug Submission (NDS) was filed to obtain market authorization pursuant to section C.08.004 of the Food and Drug Regulations for Kengrexal (cangrelor) for reducing the risk of thrombotic cardiovascular events (periprocedural myocardial infarction [MI], repeat coronary revascularization, and stent thrombosis [ST]) in patients with coronary artery disease undergoing percutaneous coronary intervention (PCI) who have not been treated with an oral P2Y₁₂ platelet inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor.

The effect of Kengrexal was evaluated in one randomized, double-blind, standard of care clopidogrel-controlled, multicenter Phase III superiority study (PHOENIX). PHOENIX was conducted in patients with stable angina (SA), non-ST-segment elevation acute coronary syndrome (NSTE-ACS), or ST-segment elevation myocardial infarction (STEMI) undergoing PCI.

In the PHOENIX trial, a total of 5,581 patients were treated with intravenous (IV) Kengrexal, administered as a 30 microgram per kilogram (µg/kg) bolus followed immediately by a 4 microgram per kilogram per minute (µg/kg/min) infusion. The infusion was continued for at least 2 hours or until the conclusion of the index PCI procedure, whichever was longer, until the maximum duration of 4 hours at the discretion of the treating physician. In the clopidogrel treatment arm (n = 5,564), oral clopidogrel was given at a loading dose of either 600 milligram (mg) or 300 mg (dose was determined by the investigator) and administered as soon as possible following randomization. The primary efficacy endpoint in the PHOENIX trial was the composite incidence of all-cause mortality, myocardial infarction, ischemia-driven revascularization (IDR), or stent thrombosis, assessed 48 hours after randomization.

The efficacy results demonstrated that Kengrexal was superior to clopidogrel standard of care during PCI by reducing the risk of the primary efficacy endpoint at 48 hours by 22%. The logistic regression adjusted for potential confounding from patient baseline status and clopidogrel loading dose showed a statistically significant odds ratio (OR) for the primary efficacy endpoint: 0.78; 95% CI: 0.66-0.93; p = 0.005. The treatment effect for the primary outcome was mainly driven by the stent thrombosis and IDR components. The treatment effect on the primary and key secondary composite endpoints was generally consistent across multiple subgroups, including the subgroups of patients receiving a clopidogrel dose of 300 mg or 600 mg, those receiving a clopidogrel loading dose either before or after the start of PCI, and type of diagnosis at presentation (SA, NSTE-ACS and STEMI).

Kengrexal increased the risk of bleeding due to its mechanism of action. The primary safety endpoint was the incidence of non-coronary artery bypass graft (non-CABG) related hemorrhage by clinically relevant criteria (Global Utilization of Streptokinase and Tpa for Occluded Arteries [GUSTO]) at 48 hours after randomization. The increase in the GUSTO bleeding endpoint for severe (OR: 1.50; 95% CI: 0.53-4.22; p = 0.439) or moderate bleeding (OR: 1.69; 95% CI: 0.85-3.37; p = 0.128) showed no statistically significant difference between the Kengrexal and clopidogrel groups. Statistically significant increase in GUSTO mild bleeding was identified in the Kengrexal arm (OR: 1.72; 95% CI: 1.32-2.25; p<0.001), and was driven primarily by ecchymosis, oozing, and hematomas less than 5 centimetres (cm). Higher number of intracranial hemorrhage (3 versus 1) and cardiac tamponade (7 versus 1) events were reported in the Kengrexal than clopidogrel arm in the PHOENIX trial. Adverse events of special interest were dyspnea, renal function adverse events, and hypersensitivity. Dyspnea was reported more commonly in the Kengrexal (1.2%) than clopidogrel (0.3%) group. Most events were non-serious, and most commonly dyspnea started during Kengrexal infusion and resolved after the completion of infusion. Numerical increase of renal failure (7 versus 5) and increased blood creatinine (7 versus 5) adverse events were noted in Kengrexal group compared to the clopidogrel group. Additionally, the frequency of renal function adverse events appeared to increase with worsening baseline renal function. Serious events of hypersensitivity were reported for 5 participants in the Kengrexal group and 2 participants in the clopidogrel group.

Cautionary statements and risk minimization measures have been included in the Product Monograph to address these safety issues and uncertainties.

A Risk Management Plan (RMP) for Kengrexal was submitted. Upon review, the RMP was considered to be acceptable in order to ensure that the benefit of Kengrexal continues to outweigh any risk after authorization.

The overall benefit-harm-uncertainty profile is favourable for Kengrexal for the recommended indication, therefore a Notice of Compliance (NOC) pursuant to section C.08.004 of the Food and Drug Regulations was recommended.

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