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 PCSK9 inhibition: Science, outcomes & guidance | 25 August 2018 | ESC 2018, Munich Benjamin Meaker Visiting Professor Institute for Advanced Studies University of Bristol

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

Abifadel M, et al. Nat Genet. 2003 Jun;34(2):154-6.

PCSK9 gain-of

• f-fu

function mutations and LD LDL-C

• 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

• f-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 lo loss-of

• f-function mutations, LD

LDL-C and CHD

PCSK9 mechanism of f action

Giugliano, R.P. and Sabatine M.S. J Am Coll Cardiol. 2015; 65(24):2638–51 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

PCSK9 mAbs and LDL-C reduction

Δ LDL-C = 1.86 mmol/L (72 mg/dL) Sabatine MS et al. N Engl J Med 2015;372:1500-9. Δ LDL-C = 1.83 mmol/L (71 mg/dL)

ODYSSEY LONG TERM OSLER-1 and OSLER-2

Robinson JG et al. N Engl J Med 2015;372:1489-99.

PCSK9 mAbs and CHD risk reduction: irrational exuberance?

Robinson JG et al. N Engl J Med 2015;372:1489-99. Sabatine MS et al. N Engl J Med 2015;372:1500-9.

50% risk reduction

Mendelian randomization: naturally randomized PCSK9 trial

Ference BA, et al. N Engl J Med. 2016; 375:2144-2153.

Primary, secondary, tertiary outcomes Dose response

Ference, BA et al. J Am Coll Cardiol 2012;60:2631-9. Ference, BA et al. J Am Coll Cardiol 2015;65:1552–61.

Can we directly anticipate the results of RCTs using MR?

Cumulative Effect of Lifelong LDL-C

LDL has BOTH a causal and a cumulative effect on CHD risk

Ference, BA et al. J Am Coll Cardiol 2012;60:2631-9. Ference, BA et al. J Am Coll Cardiol 2015;65:1552–61.

Mendelian randomization: naturally randomized statin trials

HMGCR variants statins

Cholesterol Treatment Trialists Collaboration. Lancet. 2010 376:1670-81 Ference, BA et al. J Am Coll Cardiol 2015;65:1552–61.

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

Sabatine MS, et al. N Engl J Med. 2017; 10.1056/NEJMoa1615664. Cholesterol Treatment Trialists Collaboration. Lancet. 2010 376:1670-81

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)