Kengrexal

Pharmacotherapeutic group: Platelet aggregation inhibitors excluding heparin, ATC code: B01AC25. Mechanism of action Kengrexal contains cangrelor, a direct P2Y12 platelet receptor antagonist that blocks adenosine diphosphate (ADP)-induced platelet activation and aggregation in vitro and ex vivo .‍‍‍‍‍‍​​​‍​​​​​​ Cangrelor binds selectively and reversibly to the P2Y12 receptor to prevent further signalling and platelet activation. Pharmacodynamic effects Cangrelor exhibits inhibition of activation and aggregation of platelets as shown by aggregometry (light transmission and impedance), point-of care assays, such as the VerifyNow P2Y12test, VASP-P and flow cytometry. Onset of P2Y12 inhibition occurs rapidly upon cangrelor administration. Following the administration of a 30 microgram/kg bolus followed by a 4 microgram/kg/min infusion, platelet inhibition is observed within two minutes. The pharmacokinetic/pharmacodynamic (PK/PD) effect of cangrelor is maintained consistently for the duration of the infusion. Irrespective of dose, following cessation of the infusion, blood levels decrease rapidly and platelet function returns to normal within one hour. Clinical efficacy and safety The primary clinical evidence for the efficacy of cangrelor is derived from CHAMPION PHOENIX, a randomised, double-blind study comparing cangrelor (n=5,472) to clopidogrel (n=5,470), both given in combination with aspirin and other standard therapy, including unfractionated heparin (78%), bivalirudin (23%), LMWH (14%) or fondaparinux (2.7%). The median duration of cangrelor infusion was 129 minutes. GP IIb/IIIa inhibitors were permitted for bailout use only and were used in 2.9% of patients. Patients with coronary atherosclerosis were included who required PCI for stable angina (58%), non-ST-segment elevation acute coronary syndrome (NSTE-ACS) (26%), or ST-elevation myocardial infraction (STEMI) (16%). Data from the CHAMPION pooled population of over 25,000 PCI patients provide additional clinical support for safety. In CHAMPION PHOENIX, cangrelor significantly reduced (relative risk reduction 22%; absolute risk reduction 1.2%) the primary composite endpoint of all-cause mortality, MI, IDR, and ST compared to clopidogrel at 48 hours (Table 3). Table 3: Thrombotic events at 48 hours in CHAMPION PHOENIX (mITT population) Cangrelor vs. Clopidogrel n (%) Cangrelor N=5,470 Clopidogrel N=5,469 OR (95% CI) p-value Primary Endpoint Death/MI/IDR/ST a 257 (4.7) 322 (5.9) 0.78 (0.66,0.93) 0.005 Key Secondary Endpoint Stent thrombosis 46 (0.8) 74 (1.4) 0.62 (0.43, 0.90) 0.010 Death 18 (0.3) 18 (0.3) 1.00 (0.52, 1.92) >0.999 MI 207 (3.8) 255 (4.7) 0.80 (0.67, 0.97) 0.022 IDR 28 (0.5) 38 (0.7) 0.74 (0.45, 1.20) 0.217 a Primary endpoint from logistic regression adjusted for loading dose and patient status. p-values for secondary endpoints based on Chi-squared test. OR = odds ratio; CI = confidence interval; IDR = ischaemia-driven revascularisation; MI = myocardial infarction; mITT = modified intent-to-treat; ST = stent thrombosis. Significant reductions in death/MI/IDR/ST and ST observed in the cangrelor group at 48 hours were maintained at 30 days (Table 4). Table 4: Thrombotic events at 30 days in CHAMPION PHOENIX (mITT population) Cangrelor vs. Clopidogrel n (%) Cangrelor N=5,462 Clopidogrel N=5,457 OR (95% CI) p-value a Primary Endpoint Death/MI/IDR/ST 326 (6.0) 380 (7.0) 0.85 (0.73, 0.99) 0.035 Key Secondary Endpoint Stent thrombosis 71 (1.3) 104 (1.9) 0.68 (0.50, 0.92) 0.012 Death 60 (1.1) 55 (1.0) 1.09 (0.76, 1.58) 0.643 MI 225 (4.1) 272 (5.0) 0.82 (0.68, 0.98) 0.030 IDR 56 (1.0) 66 (1.2) 0.85 (0.59, 1.21) 0.360 a p-values based on Chi-squared test. OR = odds ratio; CI = confidence interval; IDR = ischaemia-driven revascularisation; MI = myocardial infarction; mITT = modified intent-to-treat; ST = stent thrombosis. Paediatric Population The European Medicines Agency has deferred the obligation to submit the results of studies with Kengrexal in one or more subsets of the paediatric population in the prevention of non-site specific embolism and thrombosis, for the treatment of thrombosis in paediatric patients undergoing diagnostic and / or therapeutic percutaneous vascular procedures. See section 4.2 for information on paediatric use. In a prospective, open-label, single-arm, multi-center, Phase I study, cangrelor was evaluated at 2 dose levels of 0.5 and 0.25 micrograms/kg/min in 15 neonates ≤28 days of life with congenital heart disease requiring palliation with a systemic-to-pulmonary artery shunt, a right ventricle-to-pulmonary artery shunt, or a ductus arteriosus stent (see section 4.2). Platelet aggregation inhibition was assessed by light transmission aggregometry (LTA) in response to stimulation with 20 and 5 µM ADP. The % inhibition of maximal aggregation 45 minutes into cangrelor infusion and the number of subjects who achieved >90% of maximal platelet aggregation inhibition are summarized in the table below. Cangrelor 0.5 mcg/kg/min N=8 Cangrelor 0.25 mcg/kg/min N=7 LTA method using ADP 20 µM using ADP 5 µM using ADP 20 µM using ADP 5 µM N 6 5 7 5 % inhibition of maximal aggregation 45 minutes into the infusion, mean (SD) median (min; max) 89.0 (11.42) 91.2 (69.0; 100.0) 93.7 (6.45) 92.9 (84.8; 100.0) 76.3 (16.89) 69.6 (53.2; 98.3) 88.2 (13.49) 96.0 (68.1; 100.0) Subjects who achieved >90% of maximal platelet aggregation inhibition, n (%) 3 (50) 4 (80) 2 (28.6) 3 (60)