The FOURIER Trial. On behalf of the FOURIER Investigators. American Heart Association Scientific Sessions November 13, 2017

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1 The FOURIER Trial Sabina A. Murphy, Terje R. Pedersen, Zbigniew A. Gaciong, Richard Ceska, Marat V. Ezhov, Derek Connolly, Oleg Kraydashenko, J. Wouter Jukema, Kalman Toth, Matti J. Tikkanen, Kyungah Im, Stephen D. Wiviott, Christopher Kurtz, Narimon Honarpour, Robert P. Giugliano, Anthony C. Keech, Peter S. Sever, Marc S. Sabatine On behalf of the FOURIER Investigators American Heart Association Scientific Sessions November 13, 2017

2 PCSK9 blocks LDLR-Recycling More LDL-Receptor Less LDL-C AB More Less LDL-Receptor Higher Less LDL-C modifiziert nach Cohen JC, Hobbs HH. Science 2013 (6133):689-90

3 Statin vs. Statin + PCSK9 antibody

4 Statin vs. Statin + PCSK9 antibody Sabatine et al N Engl J Med. 2017;376:

5 Hypothesis PCSK9 inhibition with evolocumab reduces total vascular events, both first and recurrent!

6 Type of Primary Endpoint Events Total PEP = 4906 First Events Additional Events CV Death MI Stroke Hosp for UA Coronary Revasc

7 # Events Total Primary Endpoint Events st Event HR 0.85 ( )

8 # Events Total Primary Endpoint Events Additional Events RR 0.74 ( ) st Event HR 0.85 ( )

9 # Events Total Primary Endpoint Events Total Events RR 0.82 (95%CI ) P< Additional Events RR 0.74 ( ) st Event HR 0.85 ( )

10 Primary Endpoint Events: Wei, Lin, Weissfeld Model HR (95% CI) 1 Event (n=2907) 2 Events (n=1333) 3 Events (n=373) 4+ Events (n=152) HR Better HR 0.76 HR 0.74 HR 0.85 Better

11 Events per 1,000 Patients Total Primary Endpoint Events Number of Events Prevented for 1,000 Patients Treated with for 3 Years First Event Only

12 Events per 1,000 Patients Total Primary Endpoint Events Number of Events Prevented for 1,000 Patients Treated with for 3 Years First Event Only -52 Total Events

13 CV Death, MI or Stroke CV Death, MI or Stroke FOURIER subanalysis PAD CV Death, MI or stroke in patients with and without PAD CV Death, MI or stroke in patients with PAD and no MI or stroke 14% 12% 10% PAD N=3,642 27% RRR HR 0.73 (0.59; 0.91) P= ,0% PAD 3,5% ARR NNT 2.5y 29 14% 12% 10% PAD (no MI/stroke, N=1505) 43% RRR HR 0.57 (0.38; 0.88) P= ,3% 8% 6% 4% 2% 0% No PAD N=23,922 HR %CI (0.73; 0.90) P<0.001 P-interaction = Days from randomization 9,5% 7,6% 6,2% No PAD 1,4% ARR NNT 2.5y 72 8% 6% 4% 2% 0% Days from randomization 5,5% PAD 4,8% ARR NNT 2.5y 21 Outcome HR 95%CI MACE 0.57 (0.38; 0.88) CV death 0.78 (0.39; 1.57) MI 0.66 (0.38; 1.14) Stroke 0.30 (0.11; 0.82) Bonaca M LBS-02 Bonaca M et al, Circulation 2017;137. DOI: /CIRCULATIONAHA Congress Update Cardiovascular AHA 2017

14 Major, adverse limb events FOURIER subanalysis PAD Major adverse limb events 0,5% 0,4% All patients N=27,564 42% RRR HR 0.58 (0.38; 0.88) P= ,45% 0,3% 0,2% 0,27% 0,1% 0,0% Days from randomization Outcome HR 95%CI MALE 0.58 (0.38; 0.88) ALI or major amputation ; 0.89 ALI ; 0.97 Major amputation ; 1.95 Urgent revascularization ; 1.26 Bonaca M LBS-02 Bonaca M et al, Circulation 2017;137. DOI: /CIRCULATIONAHA Congress Update Cardiovascular AHA 2017

15 CV death, MI, or stroke FOURIER subanalysis history of MI results Benefit of EvoMab based on time from qualifying MI Benefit of EvoMab based on multivessel disease Qualifying MI <2 years ago Qualifying MI 2 years ago Multivessel disease No multivessel disease 12% 10% 8% 6% 24% RRR HR 0.76 (95%CI 0.64; 0.89) P< ,8% 2.9% NNT 35 7,9% 12% 10% 8% 6% 13% RRR HR 0.87 (95%CI 0.76; 0.99) P< % 8.3% 14% 12% 10% 8% 6% 30% RRR HR 0.70 (95%CI 0.58; 0.84) P< % 3.4% NNT % 14% 12% 10% 8% 6% 11% RRR HR 0.89 (95%CI 0.79; 1.00) P< % 4% 2% 4% 2% 1.0% NNT 101 4% 2% 4% 2% 7.6% 0% 0% 0% 0% 1.3% NNT 78 P interaction =0.18 P interaction = Months after randomization Months after randomization Sabatine MS LBS-02 Congress Update Cardiovascular AHA 2017

16 Summary Addition of the PCSK9 inhibitor evolocumab to statin therapy improved clinical outcomes with reductions in total primary endpoint events Driven by reductions in MI, stroke, and coronary revascularization Taking into account total events more than doubled the number of events prevented with evolocumab compared with first events only Patients with PAD experienced the greatest benefit from evolocumab treatment