1. Prospects for Risk Reduction with CETP and PCSK9 Inhibitor Therapies
CRT 2015, Washington, DC.
Prospects for Risk Reduction with CETP and PCSK9 Inhibitor Therapies
A. Michael Lincoff, M.D.
Director, C5Research
(Cleveland Clinic Coordinating Center for Clinical Research)
Vice Chairman for Clinical Research,
Lerner Research Institute
Vice Chairman of Cardiovascular Medicine
Professor of Medicine
Heart and Vascular Institute

2. Speaker Disclosure – A. Michael Lincoff, MD
Relationships with Industry Research Sponsors
Amgen
AstraZeneca
Atricure
Bristol-Myers Squibb (BMS)
Cardiovascular Systems
Centocor
CSL Behring
Edwards Lifesciences
Early Sense
Eli Lilly
Ethicon
Janssen
Juventas
Medicines Company
Medtronic
Novartis
Omthera
Orexigen
Pfizer
Regado
Resverlogix
Stemedica Cell Tech
Roche / Genentech
Takeda
VIVUS 2

3. Residual Risk in Statin Trials
JUPITER
WOS
AF/Tex
LIPID
CARE
HPS
2o PREVENTION
1o PREVENTION
HIGH RISK
Percent of Events
Residual Events
Prevented Events

4. Dyslipidemia Rx Beyond Statins
CETP Inhibitors
PCSK9 Inhibitors

5. Extrahepatic Tissues (including the artery wall
CETP Inhibition
Liver
LDL-R
VLDL/LDL CE CE
SR-B1
SR-B1 FC
CETP CE
Extrahepatic Tissues (including the artery wall
Free Cholesterol
LCAT
HDL FC
Bile
Courtesy of Dr. Philip Barter, The Heart Research Institute, Sydney, Australia

6. Investigational Potent CETP Inhibitors
Anacetrapib and Evacetrapib
Changes in HDL-C and LDL-C
Cannon CP, et al. NEJM 2010;363:2406.
Nicholls et al. JAMA. 2011;306:2099

7. PCSK9 Physiology – Regulation of LDL Receptors
Modified from Lose et al. Pharmacotherapy 2013;33:447.

8. Evolocumab – PCSK9 monoclonal Ab
DESCARTES Trial – Evolocumab for 52 Weeks
905 Patients (LDL-C < 75 mg/dL) – 2:1 Randomization
Evolocumab
Placebo
Overall
Diet
Alone
Atorvastatin
10 mg
80 mg
80 mg +
Ezetimibe 10 mg
Blom. NEJM 2014;370:1809

9. LDL-C Lowering and Clinical Benefit
CTT Collaboration. Lancet 2005; 366: ; Lancet 2010;376:

10. CETP and PCSK9 Inhibition
The Science Behind Clinical Development
Animal models
Human genetic variations – GOF (“gain of function”) or LOF (“loss of function”)
Associations with plasma mass or activity

11. Attenuates Atherosclerosis in Rabbits
CETP Inhibition
Attenuates Atherosclerosis in Rabbits
Cholesterol-fed Japanese white rabbits
JTT-705 produced 90% increase in HDL-C and 40-50% decrease in non-HDL-C
Simvastatin produced 28% increase HDL-C and 70% decreased in non-HDL-C
Progression of aortic atherosclerosis reduced by 70% with JTT-705 and by 80% with simvastatin
Okamoto et al. Nature 2000;406:203

12. CETP Genotypes – Meta-Analysis
Association with CETP Phenotype and Lipid Levels
Thompson A, et al. JAMA 2008;299:2777.

13. CETP Genotypes – Meta-Analysis
Odds Ratios for Coronary Disease vs
Odds Ratios for HDL-C
0.95
( )
0.94
( )
0.95
( )
Thompson A, et al. JAMA 2008;299:2777.

14. CETP Gene Polymorphisms
Genomewide Analysis – 18,245 Healthy Women
Women’s Genome Health Study
CETP SNP
Per Allele HDL Shift (mg/dL)
Incident MI HR Per Allele
(Age Adjusted)
Incident MI HR Per Allele (Fully Adjusted)
rs708272
3.08
0.76 (0.62–0.94)
0.01
0.83 (0.66–1.04)
0.099 rs
-1.03
1.34 (1.08–1.66)
0.008
1.29 (1.02–1.63)
0.031 rs
3.14
0.78 (0.64–0.96)
0.018
0.83 (0.66–1.05)
0.12 rs
3.09
0.82 (0.67–1.00)
0.048
0.88 (0.70–1.09)
0.24 rs
1.10
0.79 (0.62–0.99)
0.045
0.76 (0.59–0.99)
0.042 rs
1.09
0.79 (0.62–1.00)
0.047
0.043
Fully adjusted model controlled for age, body mass index, smoking status, hormone replacement therapy, blood pressure, diabetes, parental history of myocardial infarction before age 60 yr, LDL-C, HDL-C, and log transformed triglycerides.
Ridker et al. Circ Cardiovasc Genet. 2009;2:26.

15. CETP Mass or Concentration
Studies NOT supportive of inhibition, showing reduced risk of CV events with higher CETP levels
Khera et al pts in PROVE-IT
MI/death in highest vs lowest quartile:
HR 0.81 ( ), p = 0.027
Ritsch et al pts in LURIC study
CV death in highest vs lowest quartile:
HR 0.72 ( ), p = 0.021
Borggreve et al cases/116 controls in PREVEND Study
CV events above vs below median
(only pts with TGs below median)
HR 0.46 ( ), p = 0.03
1AJC 2010;106:451
2Circ 2010;121:366
3EHJ 2007;28:1012

16. PCSK9 Functional Mutations of the Protein
Davignon, Dubec, Seidah. Curr Atheroscler Rep 2010;12:308.

17. PCSK9 PCSK9 Expression Produces LDL-Receptor Knockout Phenotype
Injection of adenovirus constitutively expressing murine PCSK9
Wild Type Mice
LDLR Knockout Mice
Maxwell and Breslow. PNAS 2004;18:7100.

18. ARIC Study – 3552 Black Subjects (Y142X or C679X in ~2%)
PCSK9 LOF Mutations
ARIC Study – 3552 Black Subjects (Y142X or C679X in ~2%)
Patients with no CHD at baseline
developing CHD over 15 yr f/u
88% reduction in CHD
~40% reduction
Cohen J et al. NEJM 2006;354:1264

19. ARIC Study – 9890 White Subjects (R46L in ~3.2%)
PCSK9 LOF Mutations
ARIC Study – 9890 White Subjects (R46L in ~3.2%)
Patients with no CHD at baseline
developing CHD over 15 yr f/u
47% reduction in CHD
~20% reduction
Cohen J et al. NEJM 2006;354:1264

20. PCSK9 R46L LOF Mutation
Meta-Analysis of 59,198 Subjects: LDL Reduction and
Expected vs Observed Reduction in IHD
Benn M et al. JACC 2010;55:2833

21. CETP and PCSK9 Inhibition
Summary
CETP inhibition may enhance reverse cholesterol transport to liver. Most genotypes causing reductions in CETP mass or activity (5-10%) are associated with modest increases in HDL-C (3-5%) and small decreases in CV risk (3-5%).
CETP inhibitors in current trials increase HDL-C by ~100% and reduce LDL-C by ~40%: CVOTs will determine if these marked changes translate to improved CV outcomes
PCSK9 is a key modulator of LDL-C levels via degradation of the LDL receptor. Loss-of-function genetic variants consistently associated with reduced levels of LDL-C and reduced risk of CV disease.
PCSK9 antibodies in current CVOTs reduce LDL-C by ~60% beyond by statins: very promising potential to further improve CV outcomes.

22. Heart and Vascular Institute