1. A Pharmacodynamic Evaluation of Switching from Ticagrelor to Prasugrel in Subjects with Stable Coronary Artery Disease: Results of the SWAP-2 Study A Pharmacodynamic Evaluation of Switching from Ticagrelor to Prasugrel in Subjects with Stable Coronary Artery Disease: Results of the SWAP-2 Study Dominick J. Angiolillo, MD, PhD; Nicholas Curzen, BM (Hons), PhD; Paul Gurbel, MD; Paul Vaitkus, MD, MBA; Fred Lipkin, PharmD; Wei Li, PhD; Joseph A. Jakubowski, PhD; Marjorie Zettler, PhD, MPH; Mark B. Effron, MD; and Dietmar Trenk, PhD Journal of the American College of Cardiology (2014), doi: 10.1016/j.jacc.2013.11.032

2. Disclosures  Dominick J. Angiolillo: Received payment as an individual for: a) Consulting fee or honorarium from Bristol-Myers Squibb, Sanofi-Aventis, Eli Lilly, Daiichi Sankyo, Inc., The Medicines Company, AstraZeneca, Merck, Evolva, Abbott Vascular, and PLx Pharma; b) Participation in review activities from Johnson & Johnson, St. Jude, and Sunovion; c) he has received institutional payments for grants from Bristol-Myers Squibb, Sanofi-Aventis, GlaxoSmith Kline, Otsuka, Eli Lilly, Daiichi Sankyo, Inc., The Medicines Company, AstraZeneca, Evolva; Gilead; and has other financial relationships with Esther and King Biomedical Research Grant  Funding/Support: This study was sponsored by Daiichi Sankyo, Inc., and Eli Lilly and Company

3. Introduction  More potent platelet P2Y 12 receptor inhibitors (prasugrel and ticagrelor) have been developed with improved efficacy, albeit increased bleeding, compared with clopidogrel  In certain clinical situations, switching from ticagrelor to prasugrel may be considered e.g. patients who experience dyspnea or use of a once- daily dosing regimen due to adherence issues  However, the pharmacodynamic (PD) effects of switching from ticagrelor to prasugrel are unknown

4. Introduction  The dissociation rate of ticagrelor and its active metabolite from the P2Y 12 receptor would determine if, when switching to prasugrel, there is: no change in level of platelet inhibition additive platelet inhibition blunted/delayed platelet inhibition  The aim of the study was to compare the PD effects of switching from ticagrelor to prasugrel in subjects with stable CAD

5. Methods  Prospective, randomized, multicenter, international (12 sites), open-label study in subjects with stable CAD on ASA therapy Blinded platelet function assessment (VerifyNow ® P2Y12 assay and VASP)  Primary endpoint PRU by VerifyNow ® for prasugrel 10 mg QD MD and ticagrelor 90 mg BID MD after 7 days of randomized treatment  Secondary endpoints PRI by VASP assay 2, 4, 24, and 48 hours and 7 days PRU by VerifyNow ® P2Y12 assay 2, 4, 24, and 48 hours Percentage of subjects with HPR, defined as  ≥230 PRU and ≥208 PRU by the VerifyNow ® P2Y12 assay, and  >50% PRI by the VASP assay ASA= aspirin; BID=twice-daily; CAD= Coronary Artery Disease; HPR=high on-treatment platelet reactivity, MD=maintenance dose; PRI=platelet reactivity index, PRU=P2Y 12 reaction units, VASP-P=vasodilator stimulated phosphoprotein phosphorylation assay; QD= once-daily

6. Study Hypothesis  Hypothesis Platelet reactivity (PRU) after 7 days of randomized treatment would be non-inferior in subjects who switched from ticagrelor to prasugrel compared with subjects treated continuously with ticagrelor using 45 PRU as the non-inferiority margin for the upper 95% CI limit of the difference  Sample size Based on the objective of establishing non-inferiority of prasugrel 10 mg QD MD (based on combined prasugrel-treated subjects) compared with ticagrelor 90 mg BID MD Assuming a zero difference in mean PRU between treatment groups, a common standard deviation of 60 PRU, and a drop-out rate not exceeding 15%, a sample size of 105 allows for the 95% CI of the treatment difference to stay within 45 PRU with a probability of 0.90 BID=twice-daily; MD=maintenance dose; PRU=P2Y 12 reaction units; QD=once-daily

7. SWAP-2: Study design ASA=aspirin, CAD=Coronary Artery Disease; BID=twice-daily, h=hours, LD=loading dose, MD=maintenance dose, QD=once-daily Patients with stable CAD on low-dose ASA not indicated for P2Y 12 receptor antagonist Baseline platelet function studies followed by ticagrelor 180 mg LD/90 mg MD every 12 h post LD Platelet function studies 12 h post last ticagrelor MD and prior to randomized study drug (pre-randomization baseline) Prasugrel 60 mg LD + 10 mg MD QD Prasugrel 10 mg MD QD Ticagrelor 90 mg MD BID Platelet function studies at 2, 4, 24 and 48 hours and 7 days post first dose of randomized study drug 3 – 5 daysRun-in phase

8. SWAP-2: Subjects Inclusion criteria  Male and female subjects aged 18-75 y, ≥60 kg, stable CAD, low dose daily ASA (75-150 mg) for ≥7 days prior to screening  Stable CAD defined as History of positive stress test Previous coronary revascularization Angiographic demonstration of CAD At least moderate plaque by CT angiography Electron beam CT coronary artery calcification score ≥100 Agatston units Exclusion criteria  Need for P2Y 12 receptor antagonist therapy within 12 months of an ACS or PCI  Use of antiplatelet agents except ASA (warfarin, NSAIDs, or COX-2 inhibitors)  Strong inducers/inhibitors of CYP3A4  High doses of simvastatin or lovastatin (>40 mg/d)  Active peptic ulcer  History of TIA/stroke ACS=Acute Coronary Syndrome, ASA=aspirin, CAD=Coronary Artery Disease; COX-2=cyclooxygenase-2, CYP=cytochrome P450, CT=computed tomography, NSAIDs=nonsteroidal anti-inflammatory drugs, TIA=Transient ischemic attack

9. SWAP-2: Subject Disposition Subjects screened (N=167) Subjects enrolled in run-in period (N=120) Subjects randomized (N=110)* Prasugrel 60 mg LD + 10 mg MD QD (Safety population) (n=34) Prasugrel 10 mg MD QD (Safety population) (n=41)* Ticagrelor 90 mg MD BID (Safety population) (n=35) *4 subjects randomized to Prasugrel 60 mg LD/10 mg MD group inadvertently only received MD and were included in the Prasugrel 10 MD group for analyses. BID=twice-daily, LD=loading dose, MD=maintenance dose, QD=once-daily. Primary analysis population (n=31) Primary analysis population (n=34) Primary analysis population (n=33)

10. SWAP-2: Baseline Demographics* Treatment Group Characteristic Prasugrel 60 mg LD + 10 mg MD (n=31) Prasugrel 10 mg MD (n=34) Total Prasugrel (n=65) Ticagrelor (n=33) P value † Age, mean (SD), y57.5 (10.1)58.9 (8.5)58.2 (9.3)61.8 (7.0)0.057 Male, n (%)22 (71.0)24 (70.6)46 (70.8)25 (75.8)0.641 Weight, mean (SD), kg96.9 (18.0)95.1 (19.0)96.0 (18.4)88.3 (18.0)0.054 BMI, mean (SD), kg/m 2 32.9 (6.0)32.5 (6.1)32.7 (6.0)29.2 (4.7)0.004 Medical History, n (%) Diabetes14 (45.2)11 (32.4)26 (38.5)5 (15.2)0.021 HTN24 (77.4)25 (73.5)49 (75.4)22 (66.7)0.473 Hyperlipidemia30 (96.8)29 (85.3)59 (90.8)29 (87.9)0.729 Peripheral arterial disease 2 (6.5)1 (2.9)3 (4.6)2 (6.1)1.00 *primary population, † total prasugrel group vs ticagrelor

11. SWAP-2: Primary Endpoint The upper 95% CI limit exceeded 45 PRU and did not reach the primary non- inferiority endpoint Sensitivity analysis correcting for imbalances in baseline characteristics did not alter the resultsSensitivity analysis correcting for imbalances in baseline characteristics did not alter the results

12. SWAP-2: PRU Over Time PRU increased at 24 and 48 hours in the prasugrel MD only group relative to pre-randomization values 0 50 100 150 200 250 300 350 Prasugrel 60 mg LD/ 10 mg MD Prasugrel 10 mg MD Prasugrel Total Ticagrelor Pre-Run-In Baseline Pre- Rand. Baseline 2 hrs Post First Rand. Dose 4 hrs Post First Rand. Dose 24 hrs Post First Rand. Dose 48 hrs Post First Rand. Dose 7 Days Post First Rand. Dose 230 208 PRU (mean  SD) Smaller increase in the prasugrel LD group compared with the prasugrel MD only groupSmaller increase in the prasugrel LD group compared with the prasugrel MD only group PRU was higher in the prasugrel total group compared with the ticagrelor group at 7 days post- randomization

13. SWAP-2: PRI Over Time Results for PRI over time paralleled those of PRU PRI was higher in the prasugrel total group compared with the ticagrelor group at 7 days post-randomization

14. SWAP-2: HPR Status Rates of HPR were higher at 24 and 48 hours in both prasugrel groups. No differences in PRU were observed at 7 days Similar findings were observed for PRU ≥208

15. SWAP-2: HPR Status Rates of HPR were higher at 24 and 48 hours and at 7 days in both prasugrel groups

16. SWAP-2: Adverse Events  Both prasugrel and ticagrelor were well tolerated  Serious adverse events: only in 1 patient (ticagrelor group) and were considered unrelated to study drug  Incidence of dyspnea: Prasugrel: 0% Ticagrelor: 3.3% (n=4) during run-in phase; 2.9% (n=1) randomized  Minor bleeding (mostly mild ecchymosis): Prasugrel: 10.7% (n= 8) Ticagrelor: 20.0% (n=7)  No deaths or ischemic events observed during the course of the study

17. SWAP-2 Conclusions  SWAP-2 did not achieve the primary objective of demonstrating non-inferiority of PD response after switching from ticagrelor to prasugrel after 7 days of treatment  Results suggest a PD interaction when switching from ticagrelor to prasugrel that is partially mitigated with administration of a LD of prasugrel  This is associated with higher rates of HPR in the first 24-48 hours after switching, which diminishes by 7 days of treatment  The optimal timing between the discontinuation of ticagrelor and the administration of a LD of prasugrel remains to be determined

18. Thank you to all the SWAP-2 investigators and study coordinators

19. Investigators Dr. Richard Anderson University Hospital of Wales Health Park, UK Dominick J. Angiolillo, MD, PhD University of Florida College of Medicine, US Dr. James Cotton New Cross Hospital, UK James Feldman, MD West Houston Area Clinical Trial Consultants, LLC, US Professor Nicholas P. Curzen Southampton General Hospital, UK Professor Anthony H. Gershlick Department of Cardiovascular Science University of Leicester, UK Paul Gurbel, MD Sinai Center for Thrombosis Research Sinai Hospital of Baltimore, US Dr. Thomas Johnson Bristol Heart Institute, UK Douglas K. Logan, MD Medpace Clinical Pharmacology Unit, US Samuel Oberstein, MD Clinical Pharmacology of Miami, Inc., US Randeep Suneja, MD Cardiology Center of Houston, US James Walder, MD Black Hills Cardiovascular Research, US Alexander White, MD Progressive Medical Research, US