PCSK9 as target for treatment: The genetic validation Brian A. - PowerPoint PPT Presentation

PCSK9 as target for treatment: The genetic validation Brian A. Ference, M.D., M.Phil., M.Sc., F.A.C.C. Director of Research / Professor in Translational Therapeutics Head, Centre for Naturally Randomized Trials University of Cambridge Benjamin Meaker Visiting Professor Institute for Advanced Studies University of Bristol PCSK9 inhibition: Science, outcomes & guidance | 25 August 2018 | ESC 2018, Munich

Financial Disclosures Research Grants: Merck, Novartis, Amgen, Esperion Therapeutics, Ionis Pharmaceuticals Consulting Fees, Advisory Boards, Honoraria: Merck, Amgen, Pfizer, Regeneron, Sanofi, Ionis Pharmaceuticals, Medicines Company, dalCOR, KrKa Phamaceuticals, Medtronic, Celera, Quest Diagnostics, American College of Cardiology, European Atherosclerosis Society PCSK9 inhibition: Science, outcomes & guidance | 25 August 2018 | ESC 2018, Munich

PCSK9 gain-of of-fu function mutations and LD LDL-C Abifadel M, et al. Nat Genet. 2003 Jun;34(2):154-6.

PCSK9 lo loss-of of-function mutations, LD LDL-C and CHD • 3363 black (2.6% carriers 142X or 9679X): 38 mg/dL lower LDL-C and HR: 0.11 (95%CI: 0.02-0.81; P=0.03); 1 event in total of 85 carriers • 88% lifetime risk reduction Cohen JC, et al. N Engl J Med 2006;354:1264-1272.

PCSK9 lo loss-of of-function mutations, LD LDL-C and CHD • 9524 white (3.2% carriers): 21 mg/dL lower LDL-C and HR: 0.50; (95%CI: 0.32-0.79; P=0.003) • 50% lifetime risk reduction Cohen JC, et al. N Engl J Med 2006;354:1264-1272.

PCSK9 mechanism of f action Maxwell KN, et al. Proc Natl Acad Sci U S A. 2004 May 4;101(18):7100-5. Park SW, et al. J Biol Chem. 2004 Nov 26;279(48):50630-8. Benjannet S, et al. J Biol Chem. 2004 Nov 19;279(47):48865-75 Giugliano, R.P. and Sabatine M.S. J Am Coll Cardiol. 2015; 65(24):2638 – 51

PCSK9 mAbs and LDL-C reduction OSLER-1 and OSLER-2 ODYSSEY LONG TERM Δ LDL-C = 1.86 mmol/L (72 mg/dL) Δ LDL-C = 1.83 mmol/L (71 mg/dL) Sabatine MS et al. N Engl J Med 2015;372:1500-9. Robinson JG et al. N Engl J Med 2015;372:1489-99.

PCSK9 mAbs and CHD risk reduction: irrational exuberance? 50% risk reduction Robinson JG et al. N Engl J Med 2015;372:1489-99. Sabatine MS et al. N Engl J Med 2015;372:1500-9.

Mendelian randomization: naturally randomized PCSK9 trial Primary, secondary, tertiary outcomes Dose response Ference BA, et al. N Engl J Med. 2016; 375:2144-2153.

Can we directly anticipate the results of RCTs using MR? Ference, BA et al. J Am Coll Cardiol 2015;65:1552 – 61. Ference, BA et al. J Am Coll Cardiol 2012;60:2631-9.

LDL has BOTH a causal and a cumulative effect on CHD risk Cumulative Effect of Lifelong LDL-C Ference, BA et al. J Am Coll Cardiol 2015;65:1552 – 61. Ference, BA et al. J Am Coll Cardiol 2012;60:2631-9.

Mendelian randomization: naturally randomized statin trials HMGCR variants statins Ference, BA et al. J Am Coll Cardiol 2015;65:1552 – 61. Cholesterol Treatment Trialists Collaboration. Lancet. 2010 376:1670-81

Comparison of effect of PCSK9 and HMGCR variants Ference BA, et al. N Engl J Med. 2016; 375:2144-2153.

Comparison of statin CTT and PCSK9 inhibitor trials Cholesterol Treatment Trialists Collaboration. Lancet. 2010 376:1670-81 Sabatine MS, et al. N Engl J Med. 2017; 10.1056/NEJMoa1615664.

CTT: Effect size by year of treatment Cholesterol Treatment Trialists Collaboration. Lancet. 2010 376:1670-81

Effect of statins by total duration of treatment Ference BA, et al. Eur Heart J. 2017; DOI: 10.1093/eurheartj/ehx450

Comparison of PCSK9 inhibitors and statins by duration of treatment Ference BA, et al. Eur Heart J. 2017; DOI: 10.1093/eurheartj/ehx450

Comparison of PCSK9 inhibitors and statins by duration of treatment Ference BA, et al. Eur Heart J. 2017; DOI: 10.1093/eurheartj/ehx450

Statins and PCSK9 inhibitors: Effect size by year of treatment

Conclusions • Gain of function mutations in the PCSK9 gene are associated with markedly elevated plasma LDL-C levels, while loss-of-function mutations are associated with modestly lower plasma LDL-C levels and a corresponding substantially lower lifetime risk of CHD • Common variants in the PCSK9 and HMGCR genes that mimic the effect of PCSK9 inhibitors and statins have biologically equivalent effects on the risk of cardiovascular events per unit change in LDL-C • PCSK9 inhibitors and statins appear to have therapeutically equivalent effects on the risk of cardiovascular events per unit change in LDL-C (for the same duration of therapy)