Novel strategies targeting residual risk: the promise of PCSK-9 - PowerPoint PPT Presentation

Novel strategies targeting residual risk: the promise of PCSK-9 inhibiting therapies ESC August 29 th , Rome Erik Stroes, MD Academic Medical Center Amsterdam, The Netherlands

Faculty Disclosure Declaration of financial interests For the last 3 years and the subsequent 12 months: I I have received a research grant(s)/ in kind support A From current sponsor(s) YES B From any institution YES II I have been a speaker or participant in accredited CME/CPD A From current sponsor(s) YES B From any institution YES III I have been a consultant/strategic advisor etc A For current sponsor(s) YES B For any institution YES IV I am a holder of (a) patent/shares/stock ownerships A Related to presentation NO B Not related to presentation NO

Faculty Disclosure Declaration of non-financial interests: • Department of Vascular Medicine, AMC, Amsterdam, The Netherlands • Professor of Medicine • List of scientific or other organisations: • Chair Dutch Atherosclerosis Society • Member Lipid-evaluation committee of Dutch Internal medicine society • Member of ATVB council American Heart Association

Outline  Why LDL-c as target to reduce residual risk ?  The Promise of PCSK-9 inhibiting therapies  PCSK9-inhibiton and the Inflammation-Paradox

Genetic and Pharmacologic trials show causal role for LDLc in CVD 54.5% reduction in CHD risk for each 1mmol/L (38mg/dL) lower LDL-C 30% in CHD risk (log scale) Proportional reduction Genetically lower LDL-C 20% 18.2% reduction in CHD NPC1L1 LDL-C score risk for each 1mmol/L GISSI-P HMGCR LDL-C score A to Z (38mg/dL) lower LDL-C LDLR Pharmacologically rs2228671 LDLR lower LDL-C rs6511720 ABCG5/8 10% rs4299376 ALLHAT-LLT HMGCR rs12916 HMGCR LDL-C score PCSK9 rs2479409 IMPROVE-IT NPC1L1 LDL-C score NPC1L1 SEARCH rs217386 0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0 21.0 Lower LDL-C (mg/dL) Ference et al. J Am Coll Cardiol 2015;65:1552 – 1561.

Why further LDL-c lowering to reduce residual risk? I. Achieved very low LDL-C equals lower CV-risk Boekholdt SM, JACC 2015

Why further LDL-c lowering to reduce residual risk? II. No evidence for lower LDLc limit in CV-benefit JUPITER 2 PROVE-IT 3 TNT 1 Risk of primary endpoint † Risk of primary endpoint* Rate of major CV events Achieved LDL-C (mg/dL) >80 – 100 Placebo Referent P for trend across LDL-C <0.0001 0.76 Not <50 vs >60 – 80 0.80 (0.59, 1.07) ≥106 (0.57 – 1.00) placebo 90 – <106 0.35 >40 – 60 <50 vs 0.67 (0.50, 0.92) 77 – <90 (0.25 – 0.49) placebo 64 – <77 0.39 ≤40 0.61 (0.40, 0.91) <50 vs <64 (0.26 – 0.59) not <50 0 2 4 6 8 10 12 14 0 1 2 0.1 1 10 % of patients with Lower Higher Lower Higher major CV events LDL-C LDL-C LDL-C LDL-C Better Better Better Better 1. LaRosa et al. Am J Cardiol 2007;100:747 – 752. 2. Hsia et al. J Am Coll Cardiol 2011;57:1666 – 1675. 3. Wiviott et al. J Am Coll Cardiol 2005;46:1411 – 1416.

Why do we need further LDL-C lowering therapies ? I. Guidelines set LDL-C goals in high risk patients II. Special populations do not achieve LDL-C goals III. More patients with adverse effects on statins

I. post-ACS, 1:5 patients achieve LDL-C <70mg/dL despite statin prescription and good adherence EUROASPIRE IV 100 90 80 Prevalence (%) 70 60 50 87 40 30 58 20 21 10 0 Lipid-lowering drugs LDL-C <100mg/dL LDL-C <70mg/dL Kotseva et al. Eur J Prev Cardiol 2015;Feb 16. pii:2047487315569401. www.escardio.org/The-ESC/Press-Office/Press-releases/Last-5-years/EUROASPIRE-IV-reveals-success-and- challenges-in-secondary-prevention-of-CVD-acro. Accessed 22 Jan 16.

II. In patients with Familial Hypercholesterolemia only 1 : 5 achieves target LDLc 100 Attainment of target (%) • Of 1,249 HeFH patients, 21% achieved 80 LDL-C <2.6 mmol/L (100 mg/dL) 60 • Of those not achieving LDL-C 40 <2.6mmol/L, 73% were not receiving 20 maximal lipid lowering therapy 0 1 2 3 4 5 6 7 8 9 10 LDL-C target (mmol/L) Pijlman et al. Atherosclerosis 2010;209:189 – 194.

III. Statin-associated side effects often lead to discontinuation and reduced survival  Side effects are the most common reason patients discontinue statins 1  Survival is reduced in patients who discontinue, even compared to those on non-daily statin doses 2 Survival (%) Statin continued/daily dose Statin continued/non-daily dose Statin discontinued Years 1. Cohen et al. J Clin Lipidol 2012;6:208-15. 2. Mampuya et al. Am Heart J 2013;166:597 – 603.

Outline  Why LDL-c as target to reduce residual risk ?  The Promise of PCSK-9 inhibiting therapies  PCSK9-inhibiton and the Inflammation-Paradox

PCSK9 monoclonal antibodies binding PCSK9 PCSK9 bound to LDL mab particles PCSK9-mab LDLR Increased LDLR concentration LDL/LDLR complex LDLR recycling restored Presence of PCSK9-mab = absence of PCSK9  more LDLR  lower plasma LDL-C Chan et al. Proc Nat Acad Sci USA 2009;106:9820 – 9825.

Genetic variants of PCSK9 demonstrate its importance in regulating LDL levels PCSK9 gain of function (GOF) = Fewer LDLRs 1 (rare 2 ) GOF variant Population Characteristics Premature CHD, tendon xanthomas, severe D374Y British, Norwegian families, 1 Utah family hypercholesterolaemia S127R French, South African, Norwegian patients Tendon xanthomas; CHD, early MI, stroke Brother died at 31 from MI; D129G New Zealand family strong family history of CVD PCSK9 loss of function (LOF) = More LDLRs 3 (more common 2 ) LOF variant Population LDL-C CHD risk ↓ 15% ↓ 47% R46L ARIC, DHS ↓ 28%– 40% ↓ 88% Y142X or C679X ARIC, DHS ↓ 11% ↓ 46% R46L CGPS 1. Abifadel et al. Hum Mutat 2009;30:520 – 529. 2. Dadu et al. Nat Rev Cardiol 2014;11:563 – 575. 3. Benn et al. J Am Coll Cardiol 2010;55:2833 – 2842.

Genetics support cumulative effect of PCSK9-inhibition on top of statins Genetically Lower LDL-C 30% reduction in CHD risk (log scale) Proportional PCSK9 46L rs11591147 20% NPC1L1 LDL-C score ABCG5/8 HMGCR LDL-C score LDLR rs2228671 rs4299376 LDLR rs6511720 PCSK9 10% rs11206510 Combined NPC1L1 & HMGCR LDL-C score HMGCR rs12916 HMGCR LDL-C score PCSK9 rs2479409 NPC1L1 LDL-C score NPC1L1 rs217386 0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0 15.0 16.0 17.0 18.0 19.0 20.0 21.0 Absolute magnitude of lower LDL-C (mg/dL) Ference et al. J Am Coll Cardiol 2012;60:2631 – 2639. Ference et al. J Am Coll Cardiol 2015;65:1552 – 1561.

Evolocumab in phase III PROFICIO programme Combination therapy Phase 2 (n=631) Phase 3 (n=2,067) Monotherapy Phase 2 (n=411) Phase 3 (n=615) Phase 3 Phase 3 Statin intolerant Phase 2 (n=160) (n=307) (n=511)* HeFH Phase 2 (n=168) Phase 3 (n=331) HoFH/Severe FH Phase 2/3 (n=58) Phase 2/3 (n=300) Long-term safety and Phase 3 (n=905) efficacy Open-label extension Phase 2 (n=1,104) Phase 3 (n=3,671)* Atherosclerosis Phase 3 (n=970) Secondary Prevention Phase 3 (n=27,564) >35,000 patients Neurocognition Phase 3 (n=1,971)* *Data are planned numbers of randomised patients Completed trials

Evolocumab rapidly reduces LDL-C within 2 weeks HeFH patients on maximally- Patients unable to tolerate an tolerated statin dose 2 effective dose of statin 1 Mean LDL-C % change 0 0 -10 -10 n = 54 n = 51 -20 -20 from baseline -30 -30 -40 -40 -50 -50 -60 -60 n = 100 n = 110 -70 -70 -80 -80 -90 -90 -100 -100 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Time (weeks) Time (weeks) 2 weeks Evolocumab 140mg Q2W Ezetimibe 10mg QD + placebo Q2W Placebo Q2W 1. Stroes et al. J Am Coll Cardiol 2014;63:2541 – 2548. 2. Raal et al. Lancet 2015;385:331 – 340.

Evolocumab persistently reduces LDLc > 52 weeks Standard therapy LDL – C (mg/dL) Evolocumab Weeks 394 1,219 Standard therapy n = 864 2,508 Evolocumab Sabatine et al. N Engl J Med 2015;372:1500 – 1509.

Evolocumab reduces LDL-C irrespective of baseline characteristics Every 2 weeks dosing Overall Male patients Female patients Age ≥65 years Age <65 years BMI ≥30kg/m 2 BMI >25 to <30kg/m 2 BMI ≤25kg/m 2 Non-intensive statin therapy Intensive statin therapy No ezetimibe use Ezetimibe use LDL-C ≥ 4.1mmol/L (158mg/dL) LDL-C <4.1mmol/L (158mg/dL) -80 -60 -40 -20 0 Change from baseline in LDL-C (treatment differences of evolocumab vs placebo) Raal et al. Lancet 2015;385:331 – 340.

Evolocumab is well tolerated even in patients with statin intolerance 0 -10 Percent Change in LDL-C (%) -20 Mean reduction 16.7% (LDL-C = 181 mg/dL) -30 Ezetimibe Evolocumab -40 -50 Mean reduction 53.0% -60 (LDL-C = 104 mg/dL) -70 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Nissen S, Stroes E, et al. JAMA 2016 Weeks Following Randomization in Phase B

Evolocumab and safety in subjects with very low LDLc - OSLER Evolocumab subjects stratified by minimum achieved LDL-C All SOC Alone EvoMab (n=1489) 25 to <40 <40 ≥40 mg/ dL (n=2976) <25 mg/dL mg/dL mg/dL (n=773) (n=1426) (n=759) (n=1532) Adverse Events (%) Any 70.0 68.1 69.1 70.1 69.2 64.8 Serious 7.6 6.9 7.2 7.8 7.5 7.5 Muscle-related 4.9 7.1 6.0 6.9 6.4 6.0 Neurocognitive 0.5 1.2 0.8 1.0 0.9 0.3 Lab results (%) ALT/AST >3 × ULN 0.9 0.8 0.8 1.3 1.0 1.2 CK >5 × ULN 0.4 0.9 0.7 0.5 0.6 1.2 Sabatine MS et al. N Engl J Med 2015;372:1500-1509