Cangrelor C angrelor versus standard t H erapy to A chieve optimal M anagement of P latelet I nhibiti ON Trials A chieve optimal M anagement of P latelet I nhibiti ON Trials Rationale and Background

THE MEDICINES COMPANY ® ® Cangrelor Optimal acute care anti-platelet strategyOptimal acute care anti-platelet strategy Profile: IV platelet inhibitor via P2Y 12 receptorProfile: IV platelet inhibitor via P2Y 12 receptor Potent effectTitrate up to 100% platelet inhibition Rapid onsetImmediate (seconds) Rapid offset 6 minutes T/2 ReversibleReturn to platelet function within 60 minutes Status: Phase III underwayStatus: Phase III underway License: AstraZeneca, 2003License: AstraZeneca, 2003

THE MEDICINES COMPANY ® ® Rationale for Cangrelor Platelet inhibition accepted practicePlatelet inhibition accepted practice Aspirin Plavix mg for rapid onset ACC/AHA & ESC Guidelines GP IIb/IIIa inhibitors ActivationAggregation

THE MEDICINES COMPANY ® ® Rationale for Cangrelor Inadequate platelet inhibition in acute settingInadequate platelet inhibition in acute setting Oral P2Y 12 IV GP IIb/IIIa Delayed onset Prolonged effect Unpredictable effect (low responders) Long infusion (12-18 hrs) Return to platelet fn (6 hrs to days) Aggregation inhibition only

THE MEDICINES COMPANY ® ® CHAMPION Program Phase III program underwayPhase III program underway 1 O Ischemic superiority Vs. Plavix 600 mg at the start of PCI Vs. Plavix 600 mg at the end of PCI N = 9,000 ptsN = 6,300 pts

Cangrelor Pharmacology Pharmacology

THE MEDICINES COMPANY ® ® _ O _ P O _ O P O O O P O _ O O O OH N N N N H2NH2N 4Na + Chemical structure of ATP O

THE MEDICINES COMPANY ® ® Cangrelor metabolism N N N N NH S CF 3 OHO H O O P O O P P O O O Cl O O O S 4Na + N N N N NH S CF 3 OHO H O OH S N N N N NH S CF 3 OHO H O S N N N N NH S CF 3 S N N N N NH S CF 3 S cangrelor O O main plasma metabolite main biliary metabolite SC and SC

THE MEDICINES COMPANY ® ® _ O _ P O _ O Cl P O O O P O _ O O O OH N N NSF F F N HN S 4Na + Chemical structure of cangrelor Stabilised analogue of ATP

THE MEDICINES COMPANY ® ® Human Metabolism Independent of renal or hepatic function Mechanism of inactivation – – sequential dephosphorylation to the nucleoside – – major circulating metabolite 10,000-fold less active than parent SC and SC N N N N NH S CF 3 OHO H O O P O O P P O O O Cl O O O S 4Na + N N N N NH S CF 3 OHO H O OH S cangrelor dephosporylated major metabolite

THE MEDICINES COMPANY ® ®

® Pharmacologic effect in vitro Potent, dose-dependent & selective inhibition of ADP-induced aggregation Studies 30144, 30145, 30316, IC 50 vs ADP: 0.45 nM (human washed platelets) P1, other P2: 3000-fold selectivity No effect at unrelated mM

THE MEDICINES COMPANY ® ® ADP-induced platelet aggregation ex vivo Cyclic flow reduction - thrombosis bleeding time cangrelor ng/kg/min i.v % inhibition aggn & thrombosis BT (fold increase) Antithrombotic effect: canine model Dose-related antithrombotic (reduction in CFR) and antiplatelet effects with little impact on bleeding time Study PR Ingall et al. J Med Chem 1999; 42: 213

THE MEDICINES COMPANY ® ® Adjunct to reperfusion: canine model Cangrelor administered after t-PA prolongs reperfusion and restores myocardial tissue perfusion Wang et al ATVB 2003;23: BaseOcclusion20 min2 h dB/sec. Time Placebo cangrelor * * Myocardial blood flow assessed by contrast echocardiography *p=0.05

THE MEDICINES COMPANY ® ® Effect of cangrelor on ADP-induced platelet aggregation in patients with NSTE ACS Whole blood impedance aggregometry Time after onset of infusion (h)Time after termination of infusion 0.05  g/kg/min 0.2  g/kg/min 0.5  g/kg/min 2  g/kg/min Infusion dose From Storey RF et al. Thromb Haemost. 2001; 85:401-7.

THE MEDICINES COMPANY ® ® Effect of cangrelor infusion on ex vivo ADP-induced P-selectin expression in patients with ACS Storey RF et al. Thromb Haemost. 2002; 88:

THE MEDICINES COMPANY ® ® Effect of cangrelor infusion on ex vivo ADP-induced platelet-monocyte conjugate formation in patients with ACS Storey RF et al. Thromb Haemost. 2002; 88:

THE MEDICINES COMPANY ® ® Effects of in vitro cangrelor and aspirin on Annexin V binding induced by TRAP 20 mol/L Storey et al. Br. J. Haematol Cangrelor (nmol/L)

THE MEDICINES COMPANY ® ® Effects of in vitro cangrelor and aspirin on microparticle formation induced by TRAP 20 mol/L Storey et al. Br. J. Haematol Cangrelor (nmol/L)

THE MEDICINES COMPANY ® ® Storey RF et al. Platelets 2002; 13: Variable response to clopidogrel with incomplete P2Y 12 receptor blockade ADP-induced platelet aggregation before and after clopidogrel 300 mg followed by 75 mg daily for 4-7 days in patients undergoing PCI Cangrelor added in vitro blocks the unblocked receptors BaselinePost Clopidogrel Post Clopidogrel + cangrelor Mean % Platelet Aggregation * * * P<0.05 Wide inter- individual variation in response

Cangrelor Clinical Program Clinical Program

THE MEDICINES COMPANY ® ® Clinical Program Twelve Studies Completed to Date #5014 N=40 [28] Men #5014 N=40 [28] Men #5036 N=23 [15] Women #5036 N=23 [15] Women #5109 N=24 [24] Renal #5109 N=24 [24] Renal #5037 N=12 [12] Interact’ #5037 N=12 [12] Interact’ #5058 N=43 [39] ACS NSTEMI #5058 N=43 [39] ACS NSTEMI #5060 N=94 [45] ACS NSTEMI #5060 N=94 [45] ACS NSTEMI #5092 N=25 [0] ACS NSTEMI #5092 N=25 [0] ACS NSTEMI # N=209 [149] PCI # N=209 [149] PCI # N=216 [105] PCI # N=216 [105] PCI #5135 N=101 [85] ACS STEMI #5135 N=101 [85] ACS STEMI PK-PD Volunteers N=143 [123 drug] Phase I-II Patients N=688 [423 drug] #9017 N=4 [4] Inf #9017 N=4 [4] Inf #0402 N=40 [40] Bolus+Inf #0402 N=40 [40] Bolus+Inf

THE MEDICINES COMPANY ® ® Human Pharmacokinetics Linear relationship SC

THE MEDICINES COMPANY ® ® Human Pharmacokinetics Half-life – 3.3 minutes – rapidly metabolized by dephosphorylation SC

THE MEDICINES COMPANY ® ® Human Pharmacokinetics Rapid attainment of steady state following bolus Bolus Infusion Time (min) Cangrelor (ng/mL) Group A: 15 mcg/kg bolus + 2 mcg/kg/min (n=9) Group B: 30 mcg/kg bolus + 4 mcg/kg/min (n=9) #0402 N=40 [40] Bolus+Inf #0402 N=40 [40] Bolus+Inf

THE MEDICINES COMPANY ® ® Whole blood impedance aggregometry Human Pharmacokinetics

THE MEDICINES COMPANY ® ® Cangrelor in Renal Impairment* No effect of renal impairment on cangrelor PK Time (h) Plasma Conc (ng/ml) SC *Mild to severe, median CL cr = 55 mL/min

THE MEDICINES COMPANY ® ® Renal Impairment No measurable change in PK Time (h) Plasma Conc (ng/ml) 1 Mild to severe, median CL cr = 55 mL/min SC

THE MEDICINES COMPANY ® ® Objectives: Primary:Primary: – Test infusion for up to 72 hours Secondary:Secondary: – Find dose that gives 100% inhibition of ADP-induced platelet aggregation in >90% of patients Phase II study in ACS #5058 N=43 [39] ACS NSTEMI #5058 N=43 [39] ACS NSTEMI

THE MEDICINES COMPANY ® ® Phase II study in ACS Three part study Part 1 (n=12) Part 2 (n=13) Part 3 (n=14) Total (n=39) Dose (  g/kg/min) Duration (hr)2472 Male (%)8 (67%)10 (77%)12 (86%)30 (77%) Age (mean) Age (range) #5058 N=43 [39] ACS NSTEMI #5058 N=43 [39] ACS NSTEMI

THE MEDICINES COMPANY ® ® Platelet aggregation results Phase II study in ACS Part 1 (n=12) Part 2 (n=13) Part 3 (n=14) Mean Inhibition of Aggregation at 24h 96.0%94.9%98.7% Patients with 100% Inhibition of Aggregation During Infusion 64%77%86% #5058 N=43 [39] ACS NSTEMI #5058 N=43 [39] ACS NSTEMI

THE MEDICINES COMPANY ® ® Phase II Study in PCI Objective: Assess safety of 3 doses vs. placebo,Assess safety of 3 doses vs. placebo, – 18-to 24-hour infusions Methods – Double-blind, multicenter – Aspirin, heparin and nitrate co-meds – Clopidogrel or ticlopidine not used – Part 1 dose finding vs. placebo – Part 2 vs. abciximab # N=209 [149] PCI # N=209 [149] PCI # N=216 [105] PCI # N=216 [105] PCI

THE MEDICINES COMPANY ® ® Phase II Study in PCI Part I: Dose finding Cangrelor dose (µg/kg / min) PlaceboTotal No. randomized No. Treated Males/Females37/1235/1229/1941/10142/58 Mean age yrs (range) 61 (37-83)63 (44-79)65 (43-79)62 (38-78)63 (37-83) Median inhib. platelet aggr. at h 93%98%100%13% # N=209 [149] PCI # N=209 [149] PCI

THE MEDICINES COMPANY ® ® Phase II Study in PCI Part I: Dose finding Bleed category Cangrelor dose (µg/kg / min) Placebo (n=51) Total (n=200) 1.0 (n=49)2.0 (n=52)4.0 (n=48) Any bleeding39 (80%)38 (73%)38 (79%)30 (59%)145 (73%) Major bleed0 (0%) 4 (8%)0 (0%)4 (2%) Minor bleed4 (8%)6 (12%)5 (10%)4 (8%)19 (10%) # N=209 [149] PCI # N=209 [149] PCI

THE MEDICINES COMPANY ® ® Phase II Study in PCI Dose-dependent effect Study SC Table Inhibition of 20  mol ADP-induced platelet aggregation 7, 9, 6 and 5 patients in groups 0, 1, 2 and 4 respectively 13% 93% 98% 100% 0% 20% 40% 60% 80% 100% Cangrelor dose (ug/kg) Median (range) inhibition # N=209 [149] PCI # N=209 [149] PCI

THE MEDICINES COMPANY ® ® 5.7% 1.0% 5.7% 5.4% 2.1% 7.4% 0% 2% 4% 6% 8% Death/MI/revascTIMI major bleedTIMI minor bleed Cangrelor (N=105) Abciximab (N=93) Phase II Study in PCI Comparable results to abciximab in PCI Phase II randomized double-blind trial Events at 7-days # N=216 [105] PCI # N=216 [105] PCI

THE MEDICINES COMPANY ® ® Summary Cangrelor Potent direct platelet P2Y12 antagonist Onset of effect in seconds to 100% effect Predictable steady-state dose-concentration-effect relationship Plasma t0.5 (3.3 min) - clearance independent of renal or hepatic function Platelet recovery ~1 hour Clinical effects similar to abciximab in PCI