1 The Safety and Efficacy Of Cangrelor, a Short Acting, IV, Reversible, Platelet P2Y 12 Inhibitor In Patients Awaiting Cardiac Surgery: Results Of the.

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The Safety and Efficacy Of Cangrelor, a Short Acting, IV, Reversible, Platelet

P2Y12 Inhibitor In Patients Awaiting Cardiac Surgery:

Results Of the BRIDGE Trial

Dominick J. Angiolillo MD, PhD, Michael S. Firstenberg MD, Matthew J. Price MD, Pradyumna E. Tummala MD, Martin Hutyra MD, Ian J. Welsby MD,

Michele D. Voeltz MD, Harish Chandna MD, Chandrashekhar Ramaiah MD, Miroslav Brtko MD, PhD, Louis Cannon MD, Cornelius Dyke MD Tiepu Liu MD, PhD, Gilles

Montalescot MD, Steven V. Manoukian MD, Jayne Prats PhD, Eric J. Topol MD for the BRIDGE Investigators

Disclosures

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The BRIDGE trial was funded by The Medicines Company. Statistical analyses were performed by The Medicines Company and independently validated by Penn State University.

Dr. Angiolillo has received honoraria for lectures (speaker’s bureau) from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc., honoraria for consulting/advisory board from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly Co, Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals, Novartis, Arena Pharmaceuticals, Accumetrics, Medicure, Evolva, Abbott Vascular, and research grants (paid to Institution) from GlaxoSmithKline, Otsuka, Accumetrics, Eli Lilly Co, Daiichi Sankyo, Inc., The Medicines Company, Portola Pharmaceuticals, Schering-Plough, AstraZeneca, Johnson & Johnson, Bristol-Myers Squibb, Sanofi-Aventis

This presentation includes off label and/or investigational uses of drugs.

Unmet need & rationale

● Surgery is frequent in patients presenting with an ACS or treated with stents (1-2)

– 10–15% of patients presenting with ACS have to undergo CABG

– 5% to 25% of patients have to undergo non-cardiac surgery

● Oral P2Y12 therapy following ACS and coronary stenting is Guideline-recommended for up to 12 months (3-4)

● Continue or stop P2Y12 therapy? (5-10)

– Continuation puts patients at 35% incidence of bleeding. Bleeding and transfusion ∼are associated with increased risk of mortality

– Preoperative discontinuation of anti-platelet therapy is associated with 20% ∼incidence of ischemic events

● No proven and efficacious alternative solution for bridging to surgery is currently available (11-12)

1. Vicenzi MN, et al. Br J Anaesth 2006; 96: 686–693; 2. Ebrahimi R., et al. J ACC 2009; 53: 1965–19724;3. King, S.B., 3rd, et al. JACC 2008; 51: 172–209; 4. Patrono C, et al. Chest 2008; 133: 199S-233S; 5. Berger JS, et al. JACC 2008; 52: 1693–1701; 6. Kaluza GL, et al. JACC 2000; 35: 1288–1294; 7. Berger PB, et al. JACC Cardiovasc Interv 2010; 3:.920-7; 8. Rao SV, et al. Eur Heart J 2007; 28: 1193–1204; 9. Hajjar LA, et al. J Am Med Assoc 2010; 304: 1559–1567; 10. Murphy GJ, et al. Circulation 2007; 116: 2544–255; 11.Hamm C et al Eur Heart J 2011 Sep 21. [Epub ahead of print]; 12. Anderson J et al. Circulation. 2011;123:e426-e579.

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Cangrelor

● Intravenous ADP–P2Y12 receptor antagonist – Rapid acting: quick onset, quick offset– Plasma half-life of 3 – 6 minutes– 60 minutes for return to normal platelet function

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Study objective / hypothesis

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● Objective: To evaluate the use of cangrelor, an IV, reversible P2Y12 platelet inhibitor, for bridging

thienopyridine-treated patients to CABG

● Hypothesis: Cangrelor infusion provides a level of platelet inhibition equivalent to that expected to be maintained if oral thienopyridine was not discontinued

Trial design: Stage IDose Identification

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Treat per Standard of Care

(CABG rule-in)

0

25

50

75

100

-1 0 1 2 3 4 5-7Elapsed Days

Pla

tele

t In

hibi

tion

(%)

Bridge Stage I: Identification of Effective Cangrelor Infusion Dose

CABGCABG

Thru Hospital Discharge

Identify infusion dose that achieves/maintains>60% platelet inhibition in >80% samples.

Cangrelor Step-Up Infusion 0.50 to 2.0 µg/kg/min IV

Cangrelor IV infusion was to be administered to cohorts of 5 patients at a time in a step-wise fashion at pre-determined doses (0.5 g/kg/min, 0.75 g/kg/min, 1.0 g/kg/min and 1.5 g/kg/min) until platelet inhibition measured by VerifyNow™ P2Y12 was > 60% in 80% of daily samples or a dose of 2.0 g/kg/min was reached.

Clopidogrel or prasugrel

Cangrelor infusion of 0.75 g/kg/min met the efficacy endpoint (94.4%, 95% confidence interval [CI]: 83.9% – 100%), and was implemented for the randomized, double-blind, placebo-controlled stage II of the trial

Trial design: Stage IIRandomized, Double-Blind, Placebo-Controlled

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Treat per Standard of Care

(CABG rule-in)

0

100

200

300

400

-1 0 1 2 3 4 5-7Elapsed Days

PR

U

Bridge Stage II: Demonstration of Effective Cangrelor Infusion Dose

CABGCABG

Thru Hospital Discharge

Demonstrate that cangrelor infusion of maintains PRU< 240

Cangrelor/Placebo Infusion Dose Determined in Stage I :

0.75 µg/kg/min

• Patients with an ACS or treated with a coronary stent (BMS or DES) on a thienopyridine (ticlopidine, clopidogrel or prasugrel) awaiting CABG.

• After thienopyridine discontinuation (<72 hours), patients were administered cangrelor/placebo for at least 48 hours and up to 7 days, which was discontinued 1-6 hours prior to CABG.

• Objective: demonstrate that cangrelor would maintain levels of platelet reactivity <240 P2Y12 Reaction Units (PRU) throughout the pre-operative period as measured by the VerifyNow™ P2Y12 test.

Clopidogrel or prasugrel

Global implementation

● First patient enrolled on October 14th, 2009

● Last patient enrolled on April 30th, 2011

Number of patients enrolled in each country:

US – 125

Czech Republic – 55

UK – 12

Netherlands – 11

Austria – 7

Maintenance of platelet inhiBition with cangreloR after dIscontinuation

of thienopyriDines in patients undergoing surGEry

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Trial organization

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Enrolled patients requiring bridging from oral thienopyridine prior to CABG (N=210)

1:1 RANDOMIZATION

Withdrew Consent (N=1) —

Physician Decision (N=1) —

Lost to Follow-up (N=0) —

Death (N=3) —

Other (N=0) —

— Withdrew Consent (N=2)

— Physician Decision (N=0)

— Lost to Follow-up (N=1)

— Death (N=5)

— Other (N=2)

Safety CANGRELOR

(N=106)

Primary Efficacy/ITT CANGRELOR

(N=93)

Safety PLACEBO

(N=101)

Primary Efficacy/ITT PLACEBO

(N=90)

30 day complete(N=101)

30 day complete

(N=94)

— No Study Drug Received(N=2)

— No Study Drug Received(N=1)

— Incorrect Study Drug Received (N=1)

— Unblinded in Dose Confirmation Analysis (N=12)

Unblinded in Dose —Confirmation

Analysis(N=12)

Incorrect Study —Drug Received

(N=1)

Patient distribution

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Baseline characteristics

Cangrelor(N= 106)

Placebo(N= 101)

Age, yrs 65.0 (42, 84) 62.0 (39, 89)

Female 24.5% 26.7%

Diabetes mellitus 46.2% 46.5%

Current smoker 29.2% 37.6%

Hypertension 82.1% 82.2%

Hyperlipidemia 71.7% 76.2%

Stroke/TIA 8.5% 4.0%

Prior MI 43.4% 35.6%

Prior PCI 50.0% 45.5%

Congestive HF 15.1% 5.9%

STEMI 15.1% 11.9%

NSTEMI 32.1% 44.5%

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Primary endpoint● Percent of patients with PRU<240 for all on-treatment samples:

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p<0.0001

OR (95% CI)353 (45.6-2728)

0

50

100

150

200

250

300

350

400

Baseline Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Last on-infusion

sample

Pre-CABGsample

Time Point

n=80n=70

n=55 n=33n=7

n=1

n=6

n=85

n=84

n=78

Cangrelor Placebo

Ver

ifyN

ow P

RU

N indicates number of patients with valid samples in the intention to treat population; PRU= P2Y12 reaction units; Data expressed as mean±SD

Platelet reactivity by day

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Bleeding endpoint● Excessive CABG-related bleeding (primary safety endpoint)*

*Excessive CABG-related bleeding is defined as the occurrence of one or more of the following 3 components during the CABG procedure or post-operative hospitalization: Surgical re-exploration, 24 hour CT output > 1.5 liters, Incidence of PRBC transfusion > 4 units.

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P=0.76

CABG-related bleeding events● CABG-related bleeding during the procedure through

hospital discharge, safety population

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Cangrelor(N= 106)

Placebo(N= 101)

Odds Ratio (95% CI)

p-value

Protocol-defined excessive bleeding* 11.8% 10.4% 1.15 (0.47, 2.79) 0.763

Surgical re-exploration 2.0% 2.1% 0.94 (0.13, 6.81) 0.951

24h chest tube output of >1.5 liters 7.8% 5.2% 1.55 (0.49, 4.91) 0.457

Incidence of PRBC transfusions > 4 U 5.9% 8.3% 0.69 (0.23, 2.06) 0.503

Bleeding         Transfusions 32.1% 34.7% 0.89 (0.50, 1.59) 0.694 4 hour chest tube output (mL), median 254 250 NA 0.985BARC definition 9.8% 10.4% 0.93 (0.37, 2.36) 0.886

Fatal bleeding ( BARC Type 5) 0% 0% NA NAPerioperative intracranial bleed <48 h† 0% 0% NA NA

Reoperation for bleeding† 2.0% 2.1% 0.94 (0.13, 6.81) 0.951Transfusion of ≥ 5Uof whole blood or PRBC < 48h† 6.9% 8.3% 0.81 (0.28, 2.33) 0.696

Chest tube output ≥ 2 L <24 h† 2.9% 4.2% 0.70 (0.15, 3.20) 0.642

*Excessive CABG-related bleeding is defined as the occurrence of one or more of the following 3 components during the CABG procedure or post-operative hospitalization: Surgical re-exploration, 24 hour CT output > 1.5 liters, Incidence of PRBC transfusion > 4 unitsPBRC= packed red blood cells; BARC= Bleeding Academic Research Consortium; †BARC CABG-related,Type 4

Pre-operative* bleeding

*From randomization until surgical incision

ACUITY: Acute Catheterization and Urgent Intervention Triage Strategy; GUSTO: Global Use of Strategies To Open coronary arteries; TIMI: Thrombolysis in Myocardial Infarction 16

 Cangrelor(N= 106)

Placebo(N= 101)

Odds Ratio (95% CI)

p-value

ACUITY        

Major 2.8% 1.0% 2.91 (0.30, 28.5) 0.358

Minor 17.9% 9.9% 1.99 (0.88, 4.51) 0.101

GUSTO        

Severe/Life threatening

0% 0% NA NA

Moderate 1.9% 1.0% 1.92 (0.17, 21.5) 0.596

Mild 17.9% 9.9% 1.99 (0.88, 4.51) 0.101

TIMI        

Major 0.9% 0% NA NA

Minor 0.9% 0% NA NA

Ischemic events*

*Ischemic events not adjudicated; site reportedMI= myocardial infarction; IDR= ischemia-driven revascularization

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 Parameter Cangrelor(N= 106)

Placebo(N= 101)

Incidence of Pre-Procedure Ischemic endpoints (randomization to surgery)

Death/MI/IDR/Stroke 2.8% 4.0%

Death 0.9% 3.0%

MI 1.9% 0%

IDR 0.9% 0%

Stroke 0% 1.0%

Incidence of Post Surgery ischemic endpoints (through 30 days)

Death/MI/IDR/Stroke 3.9% 4.2%

Death 1.0% 2.1%

MI 2.0% 1.0%

IDR 2.5% 0%

Stroke 1.0% 1.0%

Summary results

● When used as a bridging strategy to CABG after thienopyridine discontinuation, cangrelor (at 0.75 µg/kg/min) achieves levels of platelet inhibition known to be associated with a low risk of thrombotic events:

– Without increased risk of bleeding before or during CABG, although with a numerical increase in minor pre-CABG bleeding

– Independent of prior thienopyridine dose & time of discontinuation

– Consistent pharmaocdynamic effect during IV infusion

– Rapid offset after IV discontinuation prior to surgery

● No increased incidence of adverse events (e.g. dyspnea) or laboratory abnormalities despite extended dosing.

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Conclusions

● The results of the BRIDGE trial support the hypothesis that IV cangrelor is a feasible and safe management strategy in patients who require prolonged platelet P2Y12 inhibition after thienopyridine discontinuation prior to cardiac surgery.

● Larger patient samples are warranted to more definitively assert the safety and efficacy of cangrelor as a bridging therapy in patients with ACS or treated with coronary stents who require surgery.

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● Back-up slides

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Pharmacodynamic (con’t)

Intenion to treat population; Chi-square test was performed for proportions. Logistic regression was performed adjusted for the expected days to surgery (either ≤3 days or >3 days). Analysis of variance was used for PRU value. NA =Not Applicable.

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 Cangrelor

(N= 93)Placebo(N= 90)

Odds Ratio (95% CI)

p-value

Prior to Study Drug Infusion  

Patients with platelet reactivity PRU <240

62.4% 52.3% 1.5 (0.8 – 2.8) 0.185

PRU values, Mean ± SD 210.9 ± 94.0 214.1 ± 85.9 NA 0.817

During Study Drug Infusion  

Samples with platelet reactivity PRU <240

99.6% 33.3% 516 (71.3 - 3732) <0.001

Total samples with > 60% platelet inhibition

83.8% 3.7% 133 (66.9 - 264) <0.001

Patients with last-on infusion sample with PRU <240

98.8% 31.0% 185 (24.4 - 1403) <0.001

PRU values last sample during infusion, Mean ± SD

68.9 ± 67.8 263.7 ± 68.3 NA <0.001

After End of Study Drug Infusion 

Patients with PRU <240 26.9% 20.0% 1.5 (0.7 – 3.1) 0.313

PRU values, Mean ± SD 279.7 ± 106.5 297.8 ± 67.3 NA 0.212