T hrombin R eceptor A ntagonist in Secondary P revention of - - PowerPoint PPT Presentation

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T hrombin R eceptor A ntagonist in Secondary P revention of - - PowerPoint PPT Presentation

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T hrombin R eceptor A ntagonist in Secondary P revention of Atherothrombosis NCT00526474; Trial funded by Merck On behalf of the TRA 2P-TIMI 50 Steering Committee and Investigators ** CONFIDENTIAL FINAL DRAFT ** EMBARGOED UNTIL SAT 3/24 10AM

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SLIDE 1

Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombosis

On behalf of the TRA 2°P-TIMI 50 Steering Committee and Investigators NCT00526474; Trial funded by Merck

** CONFIDENTIAL FINAL DRAFT ** EMBARGOED UNTIL SAT 3/24 10AM

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SLIDE 2

Protease-activated receptor (PAR)-1

Thr Thrombi bin

Signa gnal C C C C C C C C Vor

  • rap

apaxar ar

  • Vorapaxar is an oral, potent, and

selective antagonist of PAR-1

  • Metabolism by CYP3A4 enzymes
  • No meaningful renal clearance
  • Long half-life (T1/2 > 100 hrs)

Shape Change Activation Aggregation

X

** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

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SLIDE 3

TRA Program

(38,500 pts)

TRA (Vorapaxar) Program

NSTEACS

12,944

2º Prevention

~26,500 pts

Vorapaxar Placebo Vorapaxar Placebo

Median F/U 1.4 years

3

Median F/U 2.5 years

  • CV Death, MI, Stroke, Hosp for

ischemia, Urgent Coronary Revasc. HR 0.92 (0.85, 1.01), p=0.072

  • CV Death, MI, Stroke

HR 0.89 (0.81, 0.98), p=0.018

** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

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SLIDE 4

Primary Objectives

Primary Objective

To test the hypothesis that vorapaxar will ↓ athero- thrombotic events in stable pts w/ atherosclerosis treated for ≥1 yr in addition to standard therapy.

Parallel Scientific Objectives

To test the hypotheses that …

  • 1. antagonism of PAR1 is a valuable novel target
  • 2. adding a new antiplatelet agent to ASA is

effective for long-term 2° prevention in stable pts

** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

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SLIDE 5

Trial Organization

TIMI Study Group Eugene Braunwald (Chair) David A. Morrow (PI) BM Scirica, MP Bonaca Stephen D. Wiviott (CEC) Polly Fish Sabina A. Murphy (Statistics) Worldwide Monitoring Teams Covance – Jennifer Mead WCT – Lucy Bennett ICON – Jeroen Kleijne Merck Monitoring Sponsor: Merck John Strony Gail Berman/Leslie Lipka Ann Killian Xuan Liu, Weili He Data Safety Monitoring Board Robert Frye (Chair) Kent R. Bailey

  • J. Donald Easton

Judith Hochman

  • P. Gabriel Steg

Freek Verheught

** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

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SLIDE 6

Argentina S Ameriso/ E Paolasso Australia P Aylward/G Hankey Austria M Pichler Belgium F van de Werf Brazil J Nicolau Canada P Teal/P Theroux Chile R Corbolan Colombia D Isaza Czech Republic J Spinar

National Lead Investigators

Denmark P Grande Finland M Nieminen France JP Bassand Germany C Diehm/H Diener Hungary R Kiss Israel H Hod Italy D De Ferrari/P Merlini Japan S Goto Netherlands T Oude Ophius New Zealand H White Norway D Nilsen/L Thomassen Poland M Tendera Portugal J Morais South Africa A Dalby Spain A Betriu Sweden M Dellborg Switzerland H Bounameaux United Kingdom R Wilcox

** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

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SLIDE 7

Prior MI, CVA, or PAD Vorapaxar 2.5 mg/d Placebo

RANDOMIZE 1:1 DOUBLE BLIND

Follow up Visits Day 30, Mo 4, Mo 8, Mo 12 Q6 months

Standard care including oral antiplt rx

Final Visit Event Driven Design Minimum of 1 year of follow-up

Key Inclusion: 1) MI: 2 wks - 12 mo 2) Ischemic CVA: 2 wk-12 mo 3) PAD: claudication + abnl ABI or prior revasc

Trial Design

Stratified by: 1) Qualifying athero 2) Use of thienopyridine

** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

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SLIDE 8

Endpoints

Efficacy: hierarchical testing

  • 1. Cardiovascular (CV) death, MI, or stroke
  • 2. CV death, MI, stroke, or urgent coronary

revascularization

  • 3. CV death or MI

Bleeding endpoints of primary interest:

  • GUSTO moderate or severe bleeding
  • TIMI Clinically Significant Bleeding:

TIMI major, TIMI minor, or bleeding requiring medical attention (medical/surgical rx, lab eval)

** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

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SLIDE 9

DSMB Action

January, 2011, the DSMB announced that based on its ongoing review of safety: – ↑ ICH with vorapaxar in pts w/ a prior stroke  D/C all pts with a prior stroke – Trial should continue in pts without a hx of stroke Analyses

  • 1st line analysis in all patients, including stroke
  • 2nd line analysis (new): pts w/out prior stroke
  • Special interest in patients who qualified w/ MI

** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

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SLIDE 10

Enrollment

Enrolled 9/2007-11/2009: 32 countries, 1032 sites, 26449 patients

32 (0.1%) lost to F/U 2.0% withdrew consent for F/U

** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

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SLIDE 11

Baseline Characteristics

Age (yrs, median) ≥ 75 yrs (%) Female (%) MI (n = 17779, %) PAD (n = 3787, %) Stroke (n = 4883, %)

Qualifying Atherosclerosis

Placebo (N = 13224)

61 (53, 69) 11 24 67 14 19

Vorapaxar (N = 13225)

61 (53, 69) 11 24 67 14 18 Any CAD (%) Any prior stroke (%) Diabetes (%) Current smoker (%) eGFR <60 ml/min/1.73 m2 78 22 25 21 15 78 22 25 21 16

** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

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SLIDE 12

Background Therapy

Placebo (N = 13224) Vorapaxar (N = 13225)

Lipid-lowering agent (%) ACEI or ARB (%) Beta-blocker (qualifying MI) 92 75 84 91 74 84 Qualifying MI Aspirin Thienopyridine PAD Aspirin Thienopyridine Stroke Aspirin Thienopyridine Dipyridamole

Antiplatelet Therapy, %

98 78 88 37 81 24 19 98 78 88 37 81 24 20

Other Medications at Enrollment

** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

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SLIDE 13

Primary Efficacy Evaluation

CV Death, MI, or Stroke

0% 2% 4% 6% 8% 10% 12%

60 120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080

Event Rate (%) Days since randomization

9.3% 10.5%

Hazard Ratio 0.87; 95% CI 0.80 to 0.94 p < 0.001 N = 26449

Median f/u 2.5 years

Placebo Vorapaxar

** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

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SLIDE 14

Additional Major Efficacy Outcomes

CV death, MI, Stroke, or Urgent Coronary Revascularization

0% 2% 4% 6% 8% 10% 12% 14% 180 360 540 720 900 1080 Event Rate (%)

Days since randomization

Placebo Vorapaxar 11.2% 12.4% Hazard Ratio 0.88; 95% CI 0.82 to 0.95 p = 0.001

CV death or MI

0% 1% 2% 3% 4% 5% 6% 7% 8% 9% 180 360 540 720 900 1080 Event Rate (%)

Days since randomization

Placebo Vorapaxar 7.3% 8.2% Hazard Ratio 0.86; 95% CI 0.78 to 0.94 p = 0.002

** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

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SLIDE 15

Selected Efficacy Outcomes

CV death, MI, stroke CV death MI Any Stroke Ischemic stroke Urgent coronary revascularization CVD, MI, Stroke, UCR, vascular hosp. All-cause mortality

Placebo (N = 13224)

10.5 3.0 6.1 2.8 2.6 2.6 14.7 5.3

Vorapaxar (N = 13225)

9.3 2.7 5.2 2.8 2.2 2.5 13.1 5.0 HR

p-value

0.87 0.89 0.83 0.97 <0.001 0.15 0.001 0.73 0.85 0.88 0.87 0.95 0.059 0.11 <0.001 0.41 3-yr KM rate (%)

UCR = recurrent ischemia leading to urgent coronary revascularization ** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

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SLIDE 16

Efficacy Outcomes

No History of Stroke (N= 20,699)

CV death, MI, stroke CV death MI Any Stroke Ischemic stroke CVD, MI, Stroke, urg coronary revasc. CV death or MI CVD, MI, Stroke, UCR, vascular hosp.

Placebo (N = 10344)

9.6 2.8 6.4 1.7 1.5 11.8 8.4 14.0

Vorapaxar (N = 10335)

8.3 2.5 5.5 1.5 1.1 10.6 7.4 12.3 HR

p-value

0.84 0.87 0.84 0.82 <0.001 0.13 0.004 0.11 0.72 0.86 0.85 0.86 0.013 <0.001 0.002 <0.001 3-yr KM rate (%)

UCR = recurrent ischemia leading to urgent coronary revascularization ** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

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SLIDE 17

CV Death, MI, or Stroke in Major Subgroups

0.5 1 2 5 No 0.85 (0.74, 0.98) Yes 0.88 (0.79, 0.98) Thienopyridine at Rando 0.76 Stroke 1.03 (0.85, 1.25) PAD 0.94 (0.78, 1.14) MI 0.80 (0.72, 0.89) Qualifying Athero 0.058 <60kg 1.22 (0.88, 1.69) >=60kg 0.85 (0.78, 0.92) Body weight 0.033 >=75 0.91 (0.75, 1.10) <75 0.86 (0.78, 0.94) Age 0.54 Overall 0.87 (0.80, 0.94)

Vorapaxar Better Vorapaxar Worse

Hazard Ratio (95% CI) Subgroup total no. Yes 0.95 (0.80, 1.11) No 0.84 (0.76, 0.93) History of Stroke 0.22 26449 23429 3020 CV Death, MI, or Stroke 1852 24546 4883 3787 17779 5746 20699 10007 16442 Interaction p-value No interaction by sex, or region. ** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

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SLIDE 18

Bleeding Endpoints

Overall Population GUSTO Moderate or Severe TIMI Clinically Significant TIMI Non-CABG Major Intracranial Fatal

Placebo (N = 13166)

2.5 11.1 1.8 0.5 0.2

Vorapaxar (N = 13186)

4.2 15.8 2.8 1.0 0.3 HR

p-value

1.66 1.46 1.46 1.94 1.46 <0.001 <0.001 <0.001 <0.001 0.19 3-yr KM rate (%)

No significant heterogeneity in GUSTO Mod/Sev bleeding across any of major subgroups

** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

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SLIDE 19

Major Bleeding Endpoints

by History of Stroke

2.1 0.9 0.3 1.8 0.4 0.2 4.1 2.4 0.5 2.5 0.6 0.3 1 2 3 4 5 6 7 8 TIMI Non- CABG Major ICH Fatal TIMI Non- CABG Major ICH Fatal Placebo Vorapaxar

ARD 2.0% HR 1.87 P<0.001 ARD 1.5% HR 2.55 P<0.001 ARD 0.2% HR 1.48 P=0.46 ARD 0.2% HR 1.55 P=0.049 ARD 0.1% HR 1.44 P=0.30

3-yr KM rate (%)

ARD 0.7% HR 1.35 P=0.005

Prior Stroke n = 5746 No Hx of Stroke n = 20699

** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

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SLIDE 20

GUSTO Moderate or Severe Bleeding in Major Subgroups

5.5 2.2 3.7 2.4 2.4 4.5 2.1 8.4 3.7 7.7 4.0 4.2 7.4 3.4 1 2 3 4 5 6 7 8 9 10 Placebo Vorapaxar ARD HR 2.9% 1.69 3-yr KM rate (%) Age ≥75 y Age <75 y Wt <60kg Wt ≥60kg Stroke PAD MI Age Weight Qual Athero 1.5% 1.65 4.0% 1.95 1.6% 1.64 1.8% 1.93 2.9% 1.62 1.3% 1.61 P-interact 0.87 0.50 0.69

** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

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SLIDE 21

Net Clinical Outcome

1 1.25 0.9 0.8 Vorapaxar Better Vorapaxar Worse HR VORA PLAC RRR (%) 0.7 Death, MI, stroke, GUSTO severe bleed

11.9 12.8 8

P =0.020 CV death, MI, stroke, UCR, GUSTO mod/sev bleed

13.4 14.0 4

P =0.20

All pts

Death, MI, stroke, GUSTO severe bleed

10.0 11.7 16

P <0.001 CV death, MI, stroke, UCR, GUSTO mod/sev bleed

12.0 13.4 12

P =0.004 No Hx Stroke/TIA Wgt ≥60kg n = 18,966

** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

Death, MI, stroke, GUSTO severe bleed

10.8 11.8 11

P =0.010 CV death, MI, stroke, UCR, GUSTO mod/sev bleed

12.8 13.4 6

P =0.16

No Hx Stroke

n = 20,699

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SLIDE 22

Summary

When added to standard of care, including aspirin & thienopyridine, in stable pts w/ hx atherothrombosis, vorapaxar significantly …

  • ↓ CV death, MI, or stroke
  • ↑ mod & severe bleeding, including ICH

In addition, our findings indicate …

  • significant ↓ in thrombosis adding to standard

rx, including ASA, for long-term rx in pts with prior MI

  • unacceptable ICH risk in pts with prior stroke
  • uncertain benefit in pts with PAD

** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

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SLIDE 23

Conclusions

  • 1. PAR-1 antagonism is an effective

approach to reducing recurrent atherothrombosis

  • 2. More intensive antiplatelet therapy for

long-term 2° prevention reduces recurrent thrombosis in patients with prior MI

  • 3. Patient selection is necessary to balance

the antithrombotic benefit vs. risk of bleeding

** CONFIDENTIAL FINAL DRAFT / EMBARGOED **

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SLIDE 24

For Every 1000 Pts Treated with Vorapaxar

  • 19
  • 11
  • 6
  • 5

2 10

  • 25
  • 20
  • 15
  • 10
  • 5

5 10 15

Events / 1000 Pts

No History of Stroke/TIA; Wgt ≥60 kg (n = 18,966)

CVD, MI

  • r Stroke

P<0.001 MI P<0.001 CV Death P=0.033 Stroke P<0.001 Fatal Bleed P=NS ICH P=0.15 *GUSTO Mod/Sev P<0.001

*excluding ICH ** CONFIDENTIAL FINAL DRAFT / EMBARGOED **