integrating novel insights with gold standard therapies G.Kees - PowerPoint PPT Presentation

Managing lipids: integrating novel insights with gold standard therapies G.Kees Hovingh MD PhD MBA Department of Vascular Medicine AMC Amsterdam, the Netherlands g.k.hovingh@amc.uva.nl

Gold standard: “guidelines” The history of guidelines: a moving target

Guideline Evidence rating Daily Clinic Evidence from clinical trials Gaps identified (and observational) studies in clinic

Current Guidelines

CVD: cost of prevention Prevention of CVD, either by implementation of lifestyle changes or use of medication, is cost effective in many scenarios, including population-based approaches and actions directed at high-risk individuals. Cost-effectiveness depends on several factors, including baseline CV risk, cost of drugs or other interventions, reimbursement procedures and implementation of preventive strategies. WHO, policy and environmental changes could reduce CVD in all countries for less than US$1/person/year. (1) CAD mortality rates could be halved by only modest risk factor reductions and it has been suggested that eight dietary priorities alone could halve CVD death. (2) 1) World Health Organization. Scaling up action agains noncommunicable diseases: how much will it cost? Geneva: World Health Organization, 2011 2) CollinsM,MasonH,O’FlahertyM,Guzman -CastilloM,CritchleyJ,CapewellS.An economic evaluation of salt reduction policies to reduce coronary heart disease in England: a policy modeling study. Value Health 2014;17:517 – 524. .

Do some benefit more? CTT 2012 Cholesterol Treatment Trialists, Lancet 2012

NICE guidelines: primary prevention No established CVD Discuss and support lifestyle changes Manage other risk factors QRISK2 assessment 10- year risk ≥10% Atorvastatin 20 mg National Institute for Health and Care Excellence Lipid modification July 2014 http://www.nice.org.uk/Guidance/CG181

NICE guidelines: established CVD Established CVD Do not use a risk assessment tool Potential drug interactions ACS High risk of Angina, MI, Atorvastatin 80 mg AEs TIA, Stroke Patient PAD preference Do not Consider lower dose delay statin National Institute for Health and Care Excellence Lipid modification July 2014 http://www.nice.org.uk/Guidance/CG181

2017 Context “Why should we search for novel drugs to combat dyslipidemia?”

From today’s reality -> tomorrow’s perspective ? 0 Reduction 0 MACE statin vs placebo (%) -30 -30 additional therapy - 60 Potential for further risk reduction -100 -100

Residual CVD risk: at least partially modifiable Postponement of coronary event Plaque rupture Gain in event free years Combination Rx Statin Clinical event horizon Residual Asymptomatic phase modifiable risk Total modifiable risk Non-modifiable risk age, sex, genetics 40 50 60 70 80 Age Packard et al. Vascul Pharmacol 2015;71:37 – 39.

Novel Lipid targeted agents • Squalene synthase inhibitors (SSI) • Microsomal triglyceride transfer protein (MTP) inhibitor (Lomitapid) • Acyl coenzyme A acyltransferase (ACAT) inhibitors • Diacylglycerol acyltransferase (DGAT) inhibitors • Thyroxin receptor agonists (MGL-3196) • ApoB mRNA antisense (Mipomersen) • ApoA1-based strategies (iv; CER001) • Cholesterol ester transfer protein (CETP) inhibitors (Anacetrapib, TA8995) • ATP-citrate Lysase inhibitors (ETC-1002) • PCSK9 based (i.e. Ali, Evolocumab) Inclisiran • apoC3 antisense (ISIS304801) • Lp(a) antisense

Bottom line: CVD risk reduction = - LDL-cholesterol - Remnant cholesterol - Lp(a) - Lipids or inflammation / lipid and inflammation?

LDL-C; the lower, the better.

HR adj 1 0.36 <50 LDL-C (mg/dL) >175 LDL-C does matter, also in statin treated patients

Reasons why ‘Lipid’ targets are not achieved • Lack of potency. • Lower LDL-C targets over time 1 • Low tolerance to available therapy 3 LDL-C – 7-15% of statin users experience muscle complaints • Absence of effective therapy 1,2 – Triglyceride-rich remnants, Lipoprotein(a) And what about the doctors?? 1. Béliard et al. Atherosclerosis 2014;234:136 – 141. 2. NCEP Expert Panel. Circulation 2002;106:3143 – 3421. 3. Cohen et al. J Clin Lipidol 2012;6:208 – 215. 4. Kuklina et al. MMWR Morb Mortal Wkly Rep 2011;60:109 – 114.

Intensity of Statin Therapies Used in Primary and Secondary Prevention Populations Primary Secondary Statin Intensity Prevention Prevention Low Medium High Unni SK et al. J Clin Lipidol. 2016;10:63-71.

“Game - changers” ? Candidate game-changers: Compound Target PCSK9- antibodies (ab) LDLc reduction ApoCIII-antisense (as) TG/TRL reduction Apo(a)-antisense Lp(a) reduction ANGPTL3 ab or as overall lipids Canakinumab Il-1beta Apabetalone “inflammation - complement”

PCSK9 - decade

PCSK9 - decade

Evolocumab reduces LDL- C by ≥ 60% by 1 injection per 2-4 weeks Moderate-intensity High-intensity statin 1 Statin + statin 1 (atorvastatin 80mg) ezetimibe 2 % change in LDL-C from baseline at (simvastatin 40mg) mean of Weeks 10 and 12 Primary hypercholesterolaemia or HeFH mixed dyslipidaemia Evolocumab 140mg Q2W Placebo Q2W 1. Robinson et al. JAMA 2014;311:1870 – 1882. 2. Raal et al. Lancet 2015;385:331 – 340

Evolocumab reduces LDL- C by ≥ 60% by 1 injection per 2-4 weeks Moderate-intensity High-intensity statin 1 Statin + statin 1 (atorvastatin 80mg) ezetimibe 2 % change in LDL-C from baseline at (simvastatin 40mg) mean of Weeks 10 and 12 Similar figures for alirocumab Primary hypercholesterolaemia or HeFH mixed dyslipidaemia Evolocumab 140mg Q2W Placebo Q2W 1. Robinson et al. JAMA 2014;311:1870 – 1882. 2. Raal et al. Lancet 2015;385:331 – 340

No increases in adverse events at very low LDL-C • Evolocumab-treated subjects in OSLER programme stratified by minimum achieved LDL-C LDL-C ≥40 LDL-C LDL-C 25 to <40 LDL-C <40 <25 mg/dL mg/dL mg/dL mg/dL Adverse events (AEs), % (N=773) (N=759) (N=1532) (N=1426) Any AE 70.0 68.1 69.1 70.1 Serious AEs 7.6 6.9 7.2 7.8 Muscle-related AE 4.9 7.1 6.0 6.9 CK >5 x ULN 0.4 0.9 0.7 0.5 ALT or AST >3 x ULN 0.9 0.8 0.8 1.3 Neurocognitive AE 0.5 1.2 0.8 1.0 Sabatine et al. N Engl J Med 2015;372:1500 – 1509 Supplementary Appendix.

CVD events from ODYSSEY LONG TERM and OSLER Trials HR 0.52 4 (95% CI 0.31-0.91) 3.3 HR 0.47 CVD Event rate (%) 3 (95% CI 0.28-0.78) 2.3 1.7 2 0.9 1 Placebo Alirocumab SOC Evolocumab ODYSSEY LONG-TERM OSLER 1 & 2 Robinson JG et al. NEJM 2015; 372:1489-99 Sabatine MS et al. N Engl J Med 2015;372:1500-1509

PCSK9 Inhibitor CVD Outcomes Trials Evolocumab Alirocumab Bococizumab Sponsor Amgen Sanofi / Regeneron Pfizer ODYSSEY Trial FOURIER SPIRE I SPIRE II Outcomes Sample size 27,500 18,000 17,000 9,000 Patients MI, stroke or PAD 4-52 wks post-ACS High risk of CV event Atorva ≥20 mg or equiv Evid-based med Rx Statin Lipid-lowering Rx LDL-C 70-99 (1.8- ≥70 (≥1.8) ≥70 (≥1.8) ≥100 (≥2.6) mg/dL(mmol/L) 2.6) PCSK9i Dosing Q2W or Q4W Q2W Q2W Endpoint 1°: CV death, MI, CHD death, MI, CV death, MI, stroke, stroke, revasc/hosp ischemic stroke, or or urgent revasc for UA, hosp for UA 2°: CV death, MI, stroke Recruitment done done almost done Status

Evolution and Humanization of Therapeutic Monoclonal Antibodies Mouse Chimeric Humanized Fully Human (0% human) (65% human) (> 90% human) (100% human) Generic suffix -omab -ximab -zumab -umab Tositumomab Abciximab Bococizumab Evolocumab (Bexxar) (ReoPro) Tocilizumab (Repatha) Infliximab (Actemra) Alirocumab (Remicade) (Praluent) Rituximab Canakinumab (Rituxan) (Ilaris) Potential for immunogenicity High Low Adapted from Foltz IN, Karow M, Wasserman SM. Circulation 2013;127:2222-

The SPIRE Bococizumab Clinical Development Program SPIRE (Studies of PCSK9 Inhibition and the Reduction of Vascular Events) N=31,887 SPIRE Lipid Lowering Trials SPIRE CV Outcome Trials (N=4,449) (N=27,438) SPIRE HR (n=711) SPIRE LDL (n=2,139) SPIRE-1 SPIRE-2 On maximally On maximally (n=16,817) (n=10,621) tolerated statin tolerated statin High risk primary High risk primary High risk of CV event High risk of CV event and secondary and secondary LDL- C ≥70 mg/dL LDL- C ≥70 mg/dL prevention prevention SPIRE FH SPIRE LL LDL- C ≥70 LDL- C ≥100 (n=370) (n=746) mg/dL mg/dL HeFH (genetic On statin On highly On highly diagnosis or High/very high effective statin effective statin Simon Broome risk of CV event (or partially statin (or statin SPIRE SI SPIRE AI LDL- C ≥100 Criteria intolerant) intolerant) (n=184) (n=299) LDL- C ≥70 mg/dL Statin intolerant Autoinjector mg/dL LDL- C ≥70 Hyperlipidemia mg/dL Ridker et al, Am Heart J 2016;178:135 – 44