Contributions in Medicine: Will CETP Inhibition Contribute Toward Reduction of Cardiovascular Risk?

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1 Contributions in Medicine: Will TP Inhibition Contribute Toward Reduction of Cardiovascular Risk? Activity presentations are considered intellectual property. These slides may not be published or posted online without permission from Vindico Medical Education Please be respectful of this request so we may continue to provide you with presentation materials. Faculty R. Scott Wright, MD (Activity Chair) Philip Barter, MBBS, PhD, FRACP Professor of Medicine President, International Mayo Clinic College of Medicine Atherosclerosis Society Rochester, MN Centre for Vascular Research University of New South Wales Sydney Alan S. Brown, MD, FACC, FAHA, FNLA James A. Underberg, MD, MS, Director, Division of Cardiology FACPM, FACP, FASH, FNLA Advocate Lutheran General Hospital Lipidology & Cardiovascular Disease Director, Prevention Center/Lipid Clinic Prevention Midwest Heart Specialists Clinical Assistant Professor of Clinical Associate Professor of Medicine Medicine and Cardiology NYU Medical School & NYU Center for Loyola University of Chicago CV Prevention Stritch School of Medicine Director, Bellevue Hospital Lipid Clinic Chicago, IL Past President, Northeast Chapter National Lipid Association New York, NY

2 Event (%) Contributions in Medicine: Will TP Inhibition Contribute Toward Reduction of Cardiovascular Risk? Contributions in Medicine: Will TP Inhibition Contribute Toward Reduction of Cardiovascular Risk? This continuing medical education activity is provided by Vindico Medical Education. This activity is supported by an educational grant from Lilly, LLC. Agenda Reaching Consensus on CV Risk Reduction TP Inhibition Clinical Significance and Future Role in Dyslipidemias TP Inhibitors: Clinical Trial Updates Reaching Consensus on CV Risk Reduction Alan S. Brown, MD, FACC, FAHA, FNLA Director, Division of Cardiology Advocate Lutheran General Hospital Director, Prevention Center/Lipid Clinic Midwest Heart Specialists Clinical Associate Professor of Medicine and Cardiology Loyola University of Chicago Stritch School of Medicine Chicago, IL Statin-induced LDL Lowering and CVD Risk Reduction in Secondary Prevention Trials Statin Placebo LIPID CARE CARE HPS HPS TNT (A-10 mg) TNT (A-80 mg) LDL-C (mg/dl) LIPID CARE = Cholesterol and Recurrent Events Trial, 4S = Scandinavian Simvastatin Survival Study, HPS = Heart Protection Study, LIPID = Long-term Intervention with Pravastatin in Ischaemic Disease, TNT = Treating to New Targets LaRosa JC, et al. N Engl J Med. 2005;352: Reprinted with permission. 4S 4S

3 Contributions in Medicine: Will TP Inhibition Contribute Toward Reduction of Cardiovascular Risk? IMPROVE-IT versus CTT: Ezetimibe versus Statin Benefit Lowering LDL-C, Is it Enough? Major statin trials show from 25% to 40% CVD risk reduction regardless of baseline LDL-C Despite LDL-C lowering, two-thirds of expected CHD recurrences not avoided Many patients experience plaque progression under therapy, and those who do not have minimal regression Cannon CP, et al. N Engl J Med. 2004;350: de Lemos JA, et al. JAMA. 2004;292: Heart Protection Study Collaborative Group. Lancet. 2002;360:7-22. Assmann G, et al. Circulation. 2004;109(suppl III):8-14. LaRosa JC, et al. JAMA. 1999;282: Aggressive LDL-C Reduction Eliminates One-third of the Expected CVD Events 0% -10% -20% -30% -40% -50% -60% -70% -80% -90% -100% HPS WOSCOPS 4S ASCOT CARDS* ** Reduction in major coronary events vs. placebo (%) Unmodified Risk HPS: Heart Protection Study Collaborative Group, Lancet. 2002;360:7-22. WOSCOPS: West of Scotland Coronary Prevention Study. Shepherd J, et al. New Engl J Med. 1995;333: S: Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344: ASCOT: Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm. Sever P, et al. Lancet. 2003;361: CARDS: Collaborative Atorvastatin Diabetes Study. Colhoun HM, et al. Lancet. 2004;364: ** *Includes stroke P.0005 **P.001

4 Patients Suffering Events (%) Cumulative % with Primary Outcome % Efflux Contributions in Medicine: Will TP Inhibition Contribute Toward Reduction of Cardiovascular Risk? Does HDL Become Dysfunctional in CAD or Does Dysfunctional HDL Cause CAD? Lack of association between function and HDL-C levels suggests that atherosclerosis may modify HDL Dysfunctional HDL may be hiding in either the low or high HDL-C range Dysfunctional HDL may be present in unique patient types HDL of Patients on Renal Dialysis Have Impaired Cholesterol Efflux Capacity LXR agonist P<.05 P< CONTROL ESRD-HD HDL Zuo Y, et al. Arterioscler Thromb Vasc Biol. 2009;29(9): N.S. AIM-HIGH: Primary Outcome 50 Combination Therapy 40 Monotherapy 30 HR 1.02, 95% CI 0.87, 1, % 20 Log-rank P = % N at risk Time (years) Monotherapy Combination Therapy The AIM-HIGH Investigators. N Engl J Med. 2011;365: Reprinted with permission. HPS2-THRIVE: Effect of ERN/LRPT on MAJOR VASCULAR EVENTS Risk ratio 0.96 (95% CI ) Log rank P= % 14.5% Placebo ERN/LRPT Years of follow-up ERN/LRPT: The HPS2-THRIVE Collaborative Group. N Engl J Med. 2014;371: Extended-Release Niacin with Laropiprant Reprinted with permission.

5 Contributions in Medicine: Will TP Inhibition Contribute Toward Reduction of Cardiovascular Risk? Liver HDL Metabolism: Role of TP Bile LDLR SR-BI B A-I TP TG VLDL/LDL LCAT A-I ABCA1 Macrophage Kidney Liver HDL Metabolism: Role of Hepatic Lipase HL PL A-I TG HDL 2 A-I PL HDL 3 Kidney JF11 HDL in Reverse Cholesterol Transport

6 Contributions in Medicine: Will TP Inhibition Contribute Toward Reduction of Cardiovascular Risk? Conclusions HDL remains a significant predictor of risk at all levels of LDL-C LDL remains the primary target for lipid therapy based on the evidence HDL as a target of therapy remains of interest but HDL functionality resulting from such therapy is likely important TP is a major target of therapy and inhibition can raise HDL significantly and lower LDL levels Clinical outcome trials are pending and will assess the value of TP inhibitors in reducing cardiovascular events Discussion TP Inhibition: Clinical Significance and Future Role in Dyslipidemias James A. Underberg, MD, MS, FACPM, FACP, FASH, FNLA Lipidology & Cardiovascular Disease Prevention Clinical Assistant Professor of Medicine NYU Medical School & NYU Center for CV Prevention Director, Bellevue Hospital Lipid Clinic Past President, Northeast Chapter National Lipid Association New York, NY Outline Correlation between increased TP and low HDL MOA of TP Increased TP activity and incidence of atherosclerosis TP-mediated transfer of Clinical significance

7 Contributions in Medicine: Will TP Inhibition Contribute Toward Reduction of Cardiovascular Risk? Raal FJ, et al. Lancet. 2015;385(9983): TP Bound to HDL TP Polymorphisms and Cardiovascular Risk in Humans A meta-analysis has been conducted of studies investigating relationships between TP polymorphisms and cardiovascular disease in humans 46 studies had data on 27,196 coronary cases and 55,338 controls Those polymorphisms that were associated with lower TP mass and lower TP activity had higher levels of HDL-C and a significantly reduced coronary risk Thompson A, et al. JAMA. 2008;299(23): Tsai MY, et al. Atherosclerosis. 2008;200(2):

8 Contributions in Medicine: Will TP Inhibition Contribute Toward Reduction of Cardiovascular Risk? Relationship Between TP Polymorphism, TP Activity and HDL-C Levels Polymorphism Genotype HDL-C, mg/dl (SE) Adapted from Tsai MY, et al. Atherosclerosis. 2008;200(2): % change TP activity, nmol/ml/hr (SE) R451Q RR 49.7 (0.5)* 40.6 (0.5)* % change RQ 46.9 (1.7) (1.5) QQ 26.0 (-) (-) - A373P AA 49.7 (0.5)* 40.6 (0.5)* AP 46.7 (1.5) (1.4) +9.4 PP 26.0 (-) (-) C/A CC 47.5 (1.0)* 43.9 (0.9)* CA 49.0 (0.7) (0.7) -5.7 AA 52.1 (0.9) (0.9) TaqlB B1B (0.8)* 44.0 (0.7)* B1B (0.7) (0.7) -9.1 B2B (1.2) (1.1) C/A CC 48.2 (0.7)* 43.0 (0.6)* CA 50.5 (0.8) (0.7) -7.9 AA 53.2 (1.4) (1.3) Values are mean (standard error). No standard error was calculated (-) when one individual represented the group. The percentage change represents the increase (+) or decrease (-) over the baseline genotype; baseline genotypes were designated as: 451RR, 373AA, -629CC, Taq1 B1B1, and -2505CC. No percentage change was calculated (-) when one individual represented the group. *P-Value <.05 Mechanism of Action of TP Two hypotheses have been proposed for the mechanism by which TP transfers neutral lipids between plasma lipoproteins (i) a shuttle mechanism that involves TP collecting cholesteryl esters from 1 lipoprotein and delivering them through the aqueous phase to another lipoprotein. (ii) a tunnel mechanism in which TP bridges 2 lipoproteins to form a ternary complex, with lipids flowing from the donor to acceptor lipoprotein through the TP molecule Barter PJ, et al. Biochem J. 1982;208(1):1-7; Ihm J, et al. J Lipid Res. 1982;23(9): ; Swenson TL, et al. J Biol Chem. 1988;263(11): ; Tall AR. J Lipid Res. 1993;34(8): ; Zhang L, et al. Nature Chem Biol. 2012;8(4): Proposed Mechanism of TPi on Lipid Exchange Between Lipoprotein Particles TP mediated lipid exchange between lipoprotein particles In presence of TP, cholesterol and triglycerides can exchange between HDL particles and LDL or VLDL particles, in which case cholesterol that is essentially HDL-derived can return to the liver via VLDL and LDL via LDL receptor Often referred to as "indirect reverse cholesterol transport" Proposed effects of TP inhibition on lipid exchange Inhibition of TP inhibits movement of cholesterol from HDL to LDL and VLDL, and allows HDL to accumulate in HDL particles HDL-C goes up, but at same time movement of cholesterol from HDL to VLDL, and then back to the liver through the LDL receptor, may indeed become abnormal or impaired Nicholls SJ, et al. JAMA. 2011;306(19): Charles M, et al. Lipid Res. 2012;53: Reprinted with permission. TP s Molecular and Functional Mechanisms

9 Contributions in Medicine: Will TP Inhibition Contribute Toward Reduction of Cardiovascular Risk? Data Supporting the Tunnel Hypothesis for TPmediated Lipid Exchange 1. EM studies show HDL visually connected or bridged to LDL or VLDL by TP. 2. TP s ends penetrate the lipoproteins, forming a ternary complex. 3. X-ray crystallographic analyses show unconnected hydrophobic cavities located in the central axis of both the N- and C-terminal domains and lateral to the 60 Å long central cavity. 4. Molecular dynamics simulation data suggest that only minor twisting (15 ) along the long axis of TP creates 10 of tilt within the ß-barrel strands. 5. Torsional analysis suggests that 10 of tilting causes these cavities to become connected to each other and to the central cavity, forming a long, continuous, hydrophobic tunnel that extends the full length of the TP. 6. Tunnel has appropriate space and hydrophobicity capable of accommodating neutral lipids, eg, and triglyceride. 7. Functional EM studies indicate that after TP ternary complex formation between HDL and LDL, HDL particles decrease in size in the ternary complex, presumably due to transfer to LDL. 8. EM HDL size analyses of the ternary complexes permit an approximate transfer rate constant of /h (r 2 > 0.94) to be calculated. 9. TP C-terminal domain-specific antibody, which inhibits TP s association with LDL, inhibits functional transfer. 10. TP is deeply embedded into HDL and apparently has no off-rate after binding to HDL after several hours. Charles M, et al. Lipid Res. 2012;53: Genetic TP inhibition associates with reductions in risk of ischemic heart disease, myocardial infarction, ischemic cerebrovascular disease, and ischemic stroke, with a corresponding antiatherogenic lipid profile, and with increased longevity, without adverse effects. Johannsen TH, et al. J Am Coll Cardiol. 2012;60(20); HDL Metabolism: Role of TP Liver Bile LDLR SR-BI B A1 TG LCAT TP VLDL/LDL A1 ABCA1 Macrophage A1=apolipoprotein A1 ABCA1=ATP-binding cassette transporter A1 =cholesterol ester TP=cholesterol ester transfer protein =free cholesterol LCAT=lecithin cholesterol acyltransferase LDL=low-density lipoprotein LDLR=LDL receptor SR-BI=scavenger receptor class-b, type I TG=triglyceride VLDL=very low density lipoprotein

10 CD36 SR-A Contributions in Medicine: Will TP Inhibition Contribute Toward Reduction of Cardiovascular Risk? TP Deficiency is Associated with Markedly Increased HDL-C Levels Liver Bile LDLR SR-BI B A1 TG X TP VLDL/LDL HDL-C=high-density lipoprotein cholesterol LCAT A1 ABCA1 Macrophage A1=apolipoprotein A1 ABCA1=ATP-binding cassette transporter A1 =cholesterol ester TP=cholesterol ester transfer protein =free cholesterol LCAT=lecithin cholesterol acyltransferase LDL=low-density lipoprotein LDLR=LDL receptor SR-BI=scavenger receptor class-b, type I TG=triglyceride VLDL=very low density lipoprotein Impact of TPi on ApoB and LDL Millar JS, et al. J Clin Invest. 2015;125(6): Potential Mechanisms Responsible for the Increase in the LDL ApoB Millar JS, et al. J Clin Invest. 2015;125(6): Reprinted with permission. Intestine Effect of TP Inhibition on Plasma Lipoproteins Liver αhdl A-I A-I A-I αhdl LDL TP A-I αhdl ABCG1 A-I ABCA1 Preβ-HDL Lipid Filled Macrophage in the Heart

11 Contributions in Medicine: Will TP Inhibition Contribute Toward Reduction of Cardiovascular Risk? Discussion TP Inhibitors: Clinical Trial Updates Philip Barter, MBBS, PhD, FRACP University of New South Wales Sydney, Australia Effects of TP Inhibition on Cardiovascular Events Human clinical trials with TP inhibitors torcetrapib and dalcetrapib failed to show a reduction in cardiovascular (CV) events and, in case of torcetrapib, caused serious harm. However, there were problems with both of these trials that made it impossible to draw any conclusions about effects of TP inhibition on CV risk.

12 Contributions in Medicine: Will TP Inhibition Contribute Toward Reduction of Cardiovascular Risk? Effects of TP Inhibition on Cardiovascular Events Torcetrapib was found to have serious off-target effects unrelated to TP. Dalcetrapib was tested soon after an ACS event; it is now known that HDL function is impaired. Effects of TP Inhibition on Cardiovascular Events However, it has been suggested by some that these TP inhibitors failed to reduce CV events because the TP inhibition caused the HDL to be dysfunctional. So, What is Known About HDL Function When TP is Inhibited? Effects of Torcetrapib on HDL Function HDLs isolated from patients treated with torcetrapib had an enhanced ability to promote the efflux of cholesterol from macrophages. Yvan-Charvet L, et al. Arterioscler Thromb Vasc Biol. 2007;27(5):

13 CHD Death or Nonfatal MI (Hazard Ratio) LS Mean Change Percent Atheroma Volume Contributions in Medicine: Will TP Inhibition Contribute Toward Reduction of Cardiovascular Risk? Atheroma Regression at Highest HDL-C Levels with Torcetrapib in the ILLUSTRATE Trial Nicholls SJ, et al. Circulation. 2008;118(24): Q1 (<56) Q2 (56-69) P=.004 for trend Q3 ( ) Q4 (>86) Quartiles of Achieved HDL Cholesterol (mg/dl) Post-hoc Exploratory Analyses in the Torcetrapib/Atorvastatin Group Hazard ratios for CHD death or nonfatal MI by quintile of on-trial HDL-C (referent group is HDL-C <60 mg/dl stratum) * 0.57* Cox proportional hazard model adjusted for age, gender, and baseline HDL-C. 0.43* < >93 Quintiles of HDL-C (mg/dl) at Month 3 *P<.05 Barter P. Am J Cardiol. 2009;104(10 Suppl):10E-5E. Reprinted with permission. What About Anacetrapib?

14 Mean Percent Change Contributions in Medicine: Will TP Inhibition Contribute Toward Reduction of Cardiovascular Risk? Effects of Anacetrapib on HDL Function Inhibition of TP by treatment with anacetrapib led to a dramatic increase in ability of HDL to promote net cholesterol efflux. Yvan-Charvet L, et al. Arterioscler Thromb Vasc Biol. 2007;27(5): And, What About Evacetrapib? Effects of Evacetrapib on Cholesterol Efflux Evacetrapib (EVA) when given either as monotherapy or when added to a statin increased global cholesterol ** efflux by 28% and 21%, respectively ** Statin Alone 0 Placebo EVA Combination -5 Monotherapy * *P<.05 compared with placebo (for EVA monotherapy and statin monotherapy groups) or compared with statin alone for combination therapy group **P<.001 compared with placebo (for EVA monotherapy and statin monotherapy Rader DJ, et al. Circulation. 2014;130:A groups) or compared with statin alone for combination therapy group Error bars represent 90% CI. TA-8995 A New Inhibitor of TP

15 Contributions in Medicine: Will TP Inhibition Contribute Toward Reduction of Cardiovascular Risk? TA-8995: LDL-C: Percent Change at 12 Weeks 0% -20% -27%* -40% -34%* -47%* -47%* -60% Placebo TA-8995 (mg/day) Hovingh, et al. Lancet. On-line June *P<.001 compared with placebo Reprinted with permission. TA-8995: ApoB: Percent Change at 12 Weeks 0% -20% -19%* -24%* -40% -34%* -34%* -60% Placebo TA-8995 (mg/day) Hovingh, et al. Lancet. On-line June *P<.001 compared with placebo Reprinted with permission. TA-8995: HDL-C: Percent Change at 12 Weeks 200% 180%* 161%* 150% 122%* 100% 76%* 50% 2% 0% Placebo TA-8995 (mg/day) Hovingh, et al. Lancet. On-line June *P<.001 compared with placebo Reprinted with permission.

16 (% efflux/4h) Contributions in Medicine: Will TP Inhibition Contribute Toward Reduction of Cardiovascular Risk? TA-8995: ApoA-I: Percent Change at 12 Weeks 100% 75% 65%* 58%* 50% 48%* 32%* 25% 1% 0% Placebo TA-8995 (mg/day) Hovingh, et al. Lancet. On-line June *P<.001 compared with placebo Reprinted with permission. Effects of TA8995 on HDL Function TA-8995: HDL-mediated Cholesterol Efflux * * (+47%) (+27%) Placebo 1 10 *P<.001 compared with placebo TA-8995 (mg/day) Hovingh, et al. Lancet. On-line June Reprinted with permission. TP Inhibitors and HDL Function All of the available evidence indicates that TP inhibition increases HDL functionality. TP Inhibitors in Current Development Anacetrapib, evacetrapib, TA-8995 No safety issues yet detected for any of these 3 agents Long-term retention of anacetrapib in the body is an issue of potential concern even in the absence of safety issues todate Evacetrapib and TA-8995 are cleared from the body relatively rapidly

17 Contributions in Medicine: Will TP Inhibition Contribute Toward Reduction of Cardiovascular Risk? TP Inhibitors in Current Development Achieved HDL raising and LDL lowering is similar with all 3 inhibitors, although perhaps greater with TA Therapeutic dose of TA-8995 is much lower than for anacetrapib and evacetrapib. TP Inhibitors versus PCSK9 Inhibitors: Similarities and Differences TP Inhibitors versus PCSK9 Inhibitors: Similarities and Differences No safety issues with any of the PCSK9 and TP inhibitors in current development PCSK9 inhibitors are monoclonal antibodies administered by subcutaneous injection every 2 to 4 weeks TP inhibitors are oral agents administered daily

18 Contributions in Medicine: Will TP Inhibition Contribute Toward Reduction of Cardiovascular Risk? TP Inhibitors versus PCSK9 Inhibitors: Similarities and Differences PCSK9 inhibitors TP inhibitors LDL-C reduction >60% Up to 50% Lp(a) reduction Up to 40% Up to 40% HDL-C increase <5% Up to 180% Cholesterol efflux Not reported Up to 50% increase Updates on PCSK9 Inhibitors Alirocumab FDA approved July 2015 Indication: Adjunct to diet and maximally tolerated statin therapy for treatment of heterozygous familial hypercholesterolemia or clinical atherosclerotic CV disease who require additional LDL-C lowering Dosage: 75mg SQ once every 2 weeks Evolocumab Recommended by FDA advisory panel, June 10, 2015 Alirocumab Prescribing Information. July Regeneron Pharmaceuticals Inc./sanofi-aventis U.S. LLC. FDA Briefing Document. 10 June 2015 EMDAC meeting for evolocumab (Repatha). June 10, Discussion

19 Contributions in Medicine: Will TP Inhibition Contribute Toward Reduction of Cardiovascular Risk? Conclusions Thank you for participating Please complete the posttest and evaluation to receive your CME credit