Summary Basis of Decision for Kengrexal

As described above, the clinical review of the New Drug Submission for Kengrexal was conducted using various methods described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Clinical Pharmacology

Cangrelor (the medicinal ingredient in Kengrexal) is a structural analogue of adenosine triphosphate (ATP), which binds selectively and reversibly to the P2Y₁₂ platelet receptor to prevent further signaling and platelet activation. Cangrelor is a direct P2Y₁₂ platelet receptor inhibitor that blocks the binding of adenosine diphosphate (ADP) to the receptor and the consequent ADP-induced platelet activation and aggregation. The inhibition of ADP-induced platelet activation and aggregation during percutaneous coronary intervention (PCI) reduces the risk of thrombotic cardiovascular events.

The binding of cangrelor to the P2Y₁₂ receptor is suspected to prevent the binding of thienopyridine active metabolites. This mechanism is believed to be responsible for the loss of expected efficacy of thienopyridines when administered during intravenous infusion of cangrelor.

 

In plasma, cangrelor undergoes rapid inactivation by dephosphorylation to the major circulating metabolite, the nucleoside AR-C69712XX, which shows no pharmacological activity.

The pharmacokinetics and pharmacodynamics of cangrelor were evaluated in several Phase I and II studies. Cangrelor is readily available upon initiation of infusion, with a low volume of distribution (3.88 L). It reaches maximal plasma concentration within 3 minutes and steady-state concentrations within 10 minutes. Cangrelor is quickly de-activated by undergoing dephosphorylation in circulation, exhibiting a half-life of 3.6 minutes. Excretion occurs in the form of metabolites, either in urine (58%) or in feces (35%). In the dose range studied, cangrelor pharmacokinetic parameters exhibited linear behaviour.

An increase in exposure was observed in patients with mild to severe renal impairment (defined as a rate of creatinine clearance between 15 mL/min and 89 mL/min). However, no dose adjustment has been deemed necessary.

Since the metabolism of cangrelor is independent of hepatic function, studies on hepatic impairment were not preformed. Neither age nor sex influenced the pharmacokinetics and pharmacodynamics of cangrelor. Weight-based dosing is recommended for cangrelor, based on population pharmacokinetic modelling which identified weight as a significant covariate.

The only drug interaction detected in the clinical programme was at the level of the P2Y₁₂ receptor. The transition between intravenously administered cangrelor and oral P2Y₁₂ inhibitors was studied in three phase II studies in which oral P2Y₁₂ inhibitors were administered during, and immediately following, cangrelor infusion. Cangrelor prevented the expected antiplatelet effect of the irreversible P2Y₁₂ inhibitors clopidogrel and prasugrel when these agents were administered during cangrelor infusion, but not when administered immediately after cangrelor infusion. In contrast, cangrelor had a minimal effect on the antiplatelet effect of ticagrelor. For consistency and ease of transition, oral P2Y₁₂ inhibitors are to be administered immediately after cangrelor infusion has stopped. Co-administration of P2Y₁₂ inhibitors did not have an impact on the antiplatelet effect of cangrelor. The interaction between cangrelor and aspirin, heparin, and glyceryl trinitrate was evaluated in a Phase I study. Co-medication had no effect on the pharmacokinetics or pharmacodynamics of cangrelor. Similarly, cangrelor had no effect on the effects of aspirin, heparin or glyceryl trinitrate.

A cardiac safety study was conducted in 60 healthy subjects, which was designed and powered to test whether cangrelor has an effect on the corrected QT (QTc) interval exceeding 10 ms. All 60 subjects received cangrelor at therapeutic (30 mcg/kg intravenous bolus plus 4 mcg/kg/min of intravenous infusion for 3 hours) and supratherapeutic (60 mcg/kg intravenous bolus plus 8 mcg/kg/min intravenous infusion for 3 hours) doses. At the doses tested, cangrelor did not prolong the QTc interval to any clinically relevant extent. At the therapeutic dose, changes in mean heart rate from baseline were significantly different from placebo at 2, 30, 60, and 120 minutes after the administration of cangrelor. The maximum difference from placebo in mean change from baseline heart rate was 5.3 beats per minute (bpm) at the therapeutic dose and 6.5 bpm at the supratherapeutic dose, both at 120 minutes post dose. There was no risk detected of clinically relevant QTc prolongation.

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

Clinical Efficacy

The main evidence supporting the clinical efficacy of Kengrexal was obtained in the pivotal Phase III CHAMPION PHOENIX study (hereafter referred to as the PHOENIX study).

PHOENIX was a Phase III superiority study 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. Approximately half of the patients had SA, one fourth had NSTE-ACS, and the remaining patients had STEMI. The proportions of patient types were balanced between the Kengrexal and clopidogrel treatment groups. In the study population, the mean age of patients was 64 years (with 48% of patients 65 years of age or older), the mean body weight was 85.4 kg, 72% of patients were male, and 94% were white. Approximately 80% of patients had hypertension, 69% had hyperlipidemia, 28% had diabetes mellitus, and 40% had a family history of coronary artery disease. At baseline, the patients' demographic and medical histories were balanced between the Kengrexal and clopidogrel treatment groups.

Kengrexal was administered intravenously to 5,581 patients, as a 30 mcg/kg bolus followed immediately by a 4 mcg/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. Clopidogrel, the active control, was administered orally at a loading dose of either 600 mg or 300 mg (at the discretion of the treating physician), as soon as possible following randomization.

The primary endpoint in the PHOENIX study, assessed 48 hours after randomization, was the composite incidence of all-cause mortality, myocardial infarction (MI), ischemia-driven revascularization (IDR), and stent thrombosis (ST). Kengrexal was found to be superior to clopidogrel during PCI, as the risk of the primary composite endpoint was reduced by 22%. The adjusted analysis using logistic regression for potential confounding from patient baseline status and clopidogrel loading dose showed a statistically significant odds ratio of 0.78 (95% confidence interval [CI]: 0.66, 0.93; p = 0.005). The treatment effect for the primary outcome was determined to be driven mainly by the ST and MI components of the composite endpoint.

The risk of the key secondary efficacy endpoint, ST assessed at 48 hours, was also significantly reduced in patients treated with Kengrexal. The odds ratio was determined to be 0.62 (95% CI: 0.43, 0.90, p = 0.010).

In patients treated with Kengrexal, analyses at 30 days demonstrated statistically significant reductions in the incidence of all-cause mortality, MI, IDR, and stent thrombosis (primary composite endpoint, odds ratio 0.85, 95% CI: 0.73, 0.99, p = 0.035) and of ST (key secondary endpoint, odds ratio 0.68, 95% CI: 0.50, 0.92, p = 0.012), consistent with the findings at 48 hours.

The treatment effect on the primary and key secondary endpoints was generally consistent across multiple subgroups, including subgroups of patients receiving doses of 300 mg or 600 mg clopidogrel, patients receiving the loading dose of clopidogrel either before or after the start of PCI, and patient type (SA, NSTE-ACS, or STEMI).

The sponsor conducted a series of sensitivity analyses of the primary composite endpoint to investigate the effects of each of the components on the outcome and robustness of the conclusions from the primary analysis. Significant treatment effects were seen for Kengrexal compared to clopidogrel when the endpoints of intraprocedural stent thrombosis (IPST) and biomarker only MIs were removed from the primary composite endpoint. The removal of IPST from the composite endpoint did not substantially modify the point estimate odds ratio, which was determined to be 0.80 (95% CI: 0.67, 0.95), and statistical significance was maintained (p = 0.0115).

The result for the primary composite endpoint for the PHOENIX study had a low p-value (p = 0.005), and therefore qualifies as statistically persuasive. Additionally, all components of the primary efficacy composite endpoint trended in the same direction (except all-cause mortality, which was equal in the Kengrexal and clopidogrel groups [0.3%]). The treatment effect on the primary and key secondary composite endpoint was generally consistent across multiple subgroups.

Indication

Sponsor's proposed indication

Health Canada-approved indication

Kengrexal (cangrelor) is a P2Y12 platelet inhibitor indicated as an adjunct to percutaneous coronary intervention (PCI) for reducing the risk of periprocedural myocardial infarction (MI), repeat coronary revascularization, and stent thrombosis (ST) in patients who have not been treated with a P2Y12 platelet inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor.

Kengrexal (cangrelor) is indicated 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 who have not been treated with an oral P2Y12 platelet inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor.

For more information, refer to the Kengrexal Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety of Kengrexal was evaluated in the PHOENIX study described in the Clinical Efficacy section, in patients with SA, NSTE-ACS, or STEMI undergoing PCI.

The design of the PHOENIX study was based on results from two previous Phase III studies, CHAMPION PCI and CHAMPION PLATFORM, which were stopped early due to the low likelihood of meeting the primary endpoint. Although these two studies were not considered in the efficacy evaluation, pooled safety data from these studies (hereafter referred to as the CHAMPION Pool) were included in the safety analysis.

Kengrexal increases the risk of bleeding, which is attributed to its mechanism of action. The primary safety endpoint in the PHOENIX study was the incidence of non-coronary artery bypass graft (CABG)-related hemorrhage by clinically relevant scales, measured 48 hours after randomization. No significant increases were observed between treatment groups for the endpoint of non-CAGB-related bleeding for severe bleeding (odds ratio 1.50, 95% CI: 0.53, 4.22, p = 0.439) or moderate bleeding (odds ratio 1.69, 95% CI: 0.85, 3.37, p = 0.128), based on the Global Use of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) bleeding scale. In the PHOENIX study, higher numbers were reported in the Kengrexal treatment group than in the clopidogrel treatment group for intracranial hemorrhage (3 and 1, respectively) and cardiac tamponade (7 and 1, respectively).

In the CHAMPION Pool, major bleeding events occurred in more patients in the Kengrexal group than in the clopidogrel group, including intracranial hemorrhage (6 and 2, respectively) and cardiac tamponade (14 and 3, respectively). A statistically significant increase in mild bleeding was identified in the Kengrexal treatment group (odds ratio 1.72, 95% CI: 1.32, 2.25, p<0.001), and was driven primarily by ecchymosis, oozing, and hematomas less than 5 cm.

The overall incidence of serious adverse events in the PHOENIX study was similar between the Kengrexal and clopidogrel treatment groups (2.2% and 1.9%, respectively). Similar values were observed in the CHAMPION Pool, in which the overall incidence of serious adverse events was 2.3% in both the Kengrexal and clopidogrel treatment groups. In both the PHOENIX study and the CHAMPION Pool, permanent discontinuations due to adverse reactions were reported in 0.6% of patients receiving Kengrexal and in 0.4% of patients receiving clopidogrel.

The most frequently reported adverse events in the PHOENIX study and CHAMPION Pool were back pain, nausea, vessel puncture site pain, hypertension and headache, which were all reported with similar frequencies in both treatment groups. The adverse events of special interest were dyspnea, renal function adverse events, and hypersensitivity.

Dyspnea was reported more commonly in the Kengrexal treatment group than in the clopidogrel treatment group in both the PHOENIX study (1.2% and 0.3%, respectively) and the CHAMPION Pool (1.2% and 0.4%, respectively). In the CHAMPION Pool, serious adverse events of dyspnea were reported in 3 patients in the Kengrexal group and 1 patient in the clopidogrel group. Dyspnea was observed to start most commonly during the infusion of Kengrexal, and resolved after infusion was complete. Ten patients in the Kengrexal group and one patient in the clopidogrel group discontinued treatment due to dyspnea.

Higher incidences of renal failure (15 and 7 patients, respectively) and increased blood creatinine (30 and 14 patients, respectively) were observed in the Kengrexal group compared to the clopidogrel group in the all controlled studies pool. Higher incidences of renal failure (7 and 5 patients, respectively) and increased blood creatinine (7 and 5 patients, respectively) were also observed in the Kengrexal group compared to the clopidogrel group in the PHOENIX study. Additionally, the renal function adverse events appeared to increase with worsening baseline renal function, based on data from the CHAMPION PCI and CHAMPION PLATFORM studies, but not from the PHOENIX study.

Adverse events of hypersensitivity were reported in 0.4% of patients in the Kengrexal group and 0.6% of patients in the clopidogrel group in the PHOENIX study. In the CHAMPION Pool, at least one adverse event of hypersensitivity was reported in 0.6% of patients in the Kengrexal group and 0.5% of patients in the clopidogrel group. Serious events of hypersensitivity were reported in 5 patients in the Kengrexal group (2 cases of anaphylactic reaction, 2 cases of angioedema, and 1 case of anaphylactic shock) and 2 patients in the clopidogrel group.

Appropriate cautionary statements and descriptions of the findings and safety concerns are included in the Kengrexal Product Monograph. Additionally, contraindications are included for Kengrexal in patients with an increased risk of bleeding or in patients with a history of ischemic stroke or any previous hemorrhagic stroke.

Overall, the safety profile of Kengrexal was found to be acceptable for the target population.

For more information, refer to the Kengrexal Product Monograph, approved by Health Canada and available through the Drug Product Database.

Signs of time-dependent toxicity were observed following the continuous intravenous infusion of cangrelor (the medicinal ingredient in Kengrexal) in rats and dogs. Inflammatory cells in the urothelium epithelium, renal pelvis, ureter, and urinary bladder were present following the continuous intravenous infusion of cangrelor in male dogs at 60 mcg/kg/min for 7 days. Various histological changes affecting the kidneys and urinary system were observed in rats and dogs following the continuous administration of cangrelor for 28 days at doses corresponding to 12 and 15 times the recommended human dose, respectively. Gastrointestinal adverse effects were observed in male and female dogs at a 60 mcg/kg/min dose (15 times the maximum recommended human dose [MRHD]). No histological changes were observed at doses of 12 mcg/kg/min (3 times human exposure) and 15 mcg/kg/min (3.75 times human exposure), in rats and dogs respectively.

No changes were observed at any dose in electrocardiogram parameters or heart rate. However, an increase in the frequency of asynchronous premature ventricular contractions was observed in one animal receiving a 60 mcg/kg/min dose (15 times the MRHD).

Cangrelor is administered as a short infusion in the clinical setting (no more than 4 hours). Therefore, the translation of the adverse effects observed in the non-clinical studies to the patient population is not known. The risks observed with the infusion of cangrelor in the non-clinical studies are not expected at the therapeutic dose of cangrelor.

Due to the short duration for which cangrelor is administered, carcinogenicity studies were not required based on International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines. In various assays evaluating genotoxic potential, cangrelor and its base metabolites were found to be non-genotoxic.

In reproductive and developmental toxicity studies, no significant effects were observed on fertility in male and female rats following the continuous infusion of cangrelor for 28 days. Additionally, no significant effects were observed on early embryonic development at steady state plasma concentrations approximately equivalent to the concentration achieved in the percutaneous coronary intervention setting at the MRHD.

Various effects were observed on fertility in male rats at a dose corresponding to 12 times the MRHD, which were found to be reversible after administration had stopped for 8 weeks. In female rats, a risk of increased intrauterine deaths and post-implantation loss was observed at the same dose level.

Maternal mortality was observed in dams treated with 30 mcg/kg/min cangrelor (approximately 7.5 times the MRHD), administered continuously from Day 6 of gestation to Day 23 postpartum.

Embryo-fetal development was evaluated in rabbits, to which cangrelor was administered as a continuous intravenous infusion at 4, 12, or 36 mcg/kg/min from Day 6 to Day 19 post coitum. Increased incidences of abortion and intrauterine losses were observed at doses of 12 mcg/kg/min (3 times the MRHD) or higher. Fetal growth retardation was observed at 36 mcg/kg/min (9 times the MRHD) and was characterized by decreased fetal weights, slight reduction in ossification, and a slight increase in skeletal variants. Dose-related fetal growth retardation was observed in pregnant rats treated with 4, 12, or 36 mcg/kg/min cangrelor from Day 6 to Day 17 post coitum, which was characterized by increased incidences of incomplete ossification and unossified hind limb metatarsals at dose levels of 3 mcg/kg/min or higher. Dose-dependent and species-dependent differences in severity were also observed. Cangrelor did not produce malformations in either the rat or rabbit embryo-fetal development studies and is not considered to be a teratogen.

Active systemic anaphylaxis and passive cutaneous anaphylaxis studies were conducted in animals to examine the antigenicity of cangrelor. Cangrelor exhibited no indication of antigenicity in either test.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Kengrexal Product Monograph. Considering the intended use of Kengrexal, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Kengrexal Product Monograph, approved by Health Canada and available through the Drug Product Database.

As described above, the review of the quality component of the New Drug Submission for Kengrexal was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

The chemistry and manufacturing information submitted for Kengrexal has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations.

None of the excipients used in the formulation of Kengrexal is of human or animal origin.