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

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

QRISK2 assessment 10-year risk ≥10% No established CVD Discuss and support lifestyle changes Manage other risk factors 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

Atorvastatin 80 mg Established CVD Potential drug interactions High risk of AEs Patient preference Consider lower dose ACS Angina, MI, TIA, Stroke PAD Do not delay statin Do not use a risk assessment tool

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?”

Reduction MACE statin vs placebo (%)

• 30
• 100

Potential for further risk reduction

• 60
• 100
• 30

additional therapy

From today’s reality -> tomorrow’s perspective ?

Residual CVD risk: at least partially modifiable

Packard et al. Vascul Pharmacol 2015;71:37– 39. Plaque rupture Asymptomatic phase Clinical event horizon Non-modifiable risk age, sex, genetics Age

40 80 50 60 70

Total modifiable risk Residual modifiable risk Gain in event free years Statin Combination Rx Postponement of coronary event

• 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

Novel Lipid targeted agents

Bottom line: CVD risk reduction =

• LDL-cholesterol
• Remnant cholesterol
• Lp(a)
• Lipids or inflammation / lipid and inflammation?

LDL-C; the lower, the better.

1 0.36 >175 <50 LDL-C (mg/dL) HR adj

LDL-C does matter, also in statin treated patients

Reasons why ‘Lipid’ targets are not achieved

• Lack of potency.
• Lower LDL-C targets over time1
• Low tolerance to available therapy3

– 7-15% of statin users experience muscle complaints

• Absence of effective therapy1,2

– Triglyceride-rich remnants, Lipoprotein(a)

• 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.

LDL-C

And what about the doctors??

Intensity of Statin Therapies Used in Primary and Secondary Prevention Populations

Low Medium High

Secondary Prevention Primary Prevention

Statin Intensity

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

• 1. Robinson et al. JAMA 2014;311:1870–1882. 2. Raal et al. Lancet 2015;385:331–340

% change in LDL-C from baseline at mean of Weeks 10 and 12

Evolocumab 140mg Q2W Placebo Q2W Primary hypercholesterolaemia or mixed dyslipidaemia HeFH High-intensity statin1 (atorvastatin 80mg) Statin + ezetimibe2 Moderate-intensity statin1 (simvastatin 40mg)

Evolocumab reduces LDL-C by ≥ 60% by 1 injection per 2-4 weeks

• 1. Robinson et al. JAMA 2014;311:1870–1882. 2. Raal et al. Lancet 2015;385:331–340

% change in LDL-C from baseline at mean of Weeks 10 and 12

Evolocumab 140mg Q2W Placebo Q2W Primary hypercholesterolaemia or mixed dyslipidaemia HeFH High-intensity statin1 (atorvastatin 80mg) Statin + ezetimibe2 Moderate-intensity statin1 (simvastatin 40mg)

Similar figures for alirocumab

No increases in adverse events at very low LDL-C

• Evolocumab-treated subjects in OSLER programme

stratified by minimum achieved LDL-C

Adverse events (AEs), % LDL-C <25 mg/dL (N=773) LDL-C 25 to <40 mg/dL (N=759) LDL-C <40 mg/dL (N=1532) LDL-C ≥40 mg/dL (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.

1 2 3 4 3.3 1.7 2.3 0.9

Placebo Alirocumab SOC Evolocumab ODYSSEY LONG-TERM OSLER 1 & 2

CVD Event rate (%)

HR 0.52 (95% CI 0.31-0.91) HR 0.47 (95% CI 0.28-0.78)

CVD events from ODYSSEY LONG TERM and OSLER Trials

Robinson JG et al. NEJM 2015; 372:1489-99 Sabatine MS et al. N Engl J Med 2015;372:1500-1509

Evolocumab Alirocumab Bococizumab

Sponsor Amgen Sanofi / Regeneron Pfizer Trial FOURIER ODYSSEY Outcomes SPIRE I SPIRE II 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 Statin Atorva ≥20 mg or equiv Evid-based med Rx Lipid-lowering Rx LDL-C mg/dL(mmol/L) ≥70 (≥1.8) ≥70 (≥1.8) 70-99 (1.8- 2.6) ≥100 (≥2.6) PCSK9i Dosing Q2W or Q4W Q2W Q2W Endpoint 1°: CV death, MI, stroke, revasc/hosp for UA, 2°: CV death, MI, stroke CHD death, MI, ischemic stroke, or hosp for UA CV death, MI, stroke,

• r urgent revasc

Recruitment Status done done almost done

PCSK9 Inhibitor CVD Outcomes Trials

Evolution and Humanization of Therapeutic Monoclonal Antibodies

Adapted from Foltz IN, Karow M, Wasserman SM. Circulation 2013;127:2222-

Mouse (0% human) Fully Human (100% human) Humanized (> 90% human) Chimeric (65% human)

• umab
• zumab
• ximab
• omab

Generic suffix Low High

Potential for immunogenicity

Tositumomab (Bexxar) Abciximab (ReoPro) Infliximab (Remicade) Rituximab (Rituxan) Bococizumab Tocilizumab (Actemra) Evolocumab (Repatha) Alirocumab (Praluent) Canakinumab (Ilaris)

The SPIRE Bococizumab Clinical Development Program

SPIRE (Studies of PCSK9 Inhibition and the Reduction of Vascular Events) N=31,887 SPIRE Lipid Lowering Trials (N=4,449) SPIRE CV Outcome Trials (N=27,438)

SPIRE HR (n=711) On maximally tolerated statin High risk of CV event LDL-C ≥70 mg/dL SPIRE FH (n=370) HeFH (genetic diagnosis or Simon Broome Criteria LDL-C ≥70 mg/dL SPIRE SI (n=184) Statin intolerant LDL-C ≥70 mg/dL SPIRE LDL (n=2,139) On maximally tolerated statin High risk of CV event LDL-C ≥70 mg/dL SPIRE LL (n=746) On statin High/very high risk of CV event LDL-C ≥100 mg/dL SPIRE AI (n=299) Autoinjector Hyperlipidemia SPIRE-1 (n=16,817) High risk primary and secondary prevention LDL-C ≥70 mg/dL On highly effective statin (or partially statin intolerant) SPIRE-2 (n=10,621) High risk primary and secondary prevention LDL-C ≥100 mg/dL On highly effective statin (or statin intolerant)

Ridker et al, Am Heart J 2016;178:135–44

Ridker P. Late breaker ACC. 2017

Screen 4 weeks 12 week and 52 week change in lipid levels R Placebo SC Q2 Weeks + maximally tolerated statin Bococizumab 150 mg SC Q2 Weeks + maximally tolerated statin

Treatment period (52 weeks) Safety follow-up (6 weeks)

The Six SPIRE Lipid Lowering Trials (N=4,449) Screen ≤14 days CV events* R Placebo SC Q2 Weeks + maximally tolerated statin Bococizumab 150 mg SC Q2 Weeks + maximally tolerated statin

Treatment period (>2 years) Safety follow-up (6 weeks)

The Six SPIRE 1 and SPIRE 2 Cardiovascular Outcome Trials (N=27,438) Pre-screen ≤30 days Run-in 3 visits

*Nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death SPIRE-1 (N=16,817) SPIRE-2 (N=10,621)

Patients with or at high risk for cardiovascular events SPIRE-1: LDLC ≥70 mg/dL or non-HDLC ≥100 mg/dL SPIRE-2: LDLC ≥100 mg/dL or non-HDLC ≥130 mg/dL

The SPIRE Bococizumab Lipid Lowering Trials: Large Reductions in LDLC with PCSK9 Inhibition at 12 weeks

Ridker P. Late breaker ACC. 2017

The SPIRE Bococizumab Lipid Lowering Trials: Unanticipated Attenuation of LDLC Reductions at 52 Weeks

Ridker P. Late breaker ACC. 2017

Development of Antidrug Antibodies (ADAs) and Attenuation of LDL regression over time

Ridker PM, et al. N Engl J Med 2017. Published online ahead of print doi: 10.1056/NEJMoa1614062

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Caveat: cost

Fourier study

delta: n= 219 primary endpoints during follow up 26 mo. treat 13,780 patients. Assumption: Rx 6000E yearly. cost to prevent 1 primary endpoint: > 800.000. Similar figure for key secondary…

Cost of a statin vs PCSK9ab on a yearly basis

400 x

6000 E PCSK9i

Cost of a statin vs PCSK9ab on a yearly basis

400 x

6000 E PCSK9i

NNT X EUR +NNH = net expenditure Vs Overall reduction cost CVD

45

March 17, 2017 : online

• 1. Fitzgerald et al. Lancet 2014; 383: 60-8

ORION

• 2. Fitzgerald et al. N Engl J Med 2017; 376: 41-51

 Objective of ORION-1: evaluate optimal dosing regimens in patients with elevated LDL-C and high CV risk  In phase I, 300 mg Inclisiran lowered LDL-C 50

• 60% for 84 days (n=69) 2

 Inclisiran, a synthetic si RNA molecule, inhibits PCSK9 synthesis in the liver 1

• 1. Fitzgerald et al. Lancet 2014; 383: 60-8
• 2. Fitzgerald et al. N Engl J Med 2017; 376: 41-51

ORION

Ray et al. N Engl J Med 2017; March 17: online

48

Safety population One dose starting regimen Two dose starting regimen Placebo N=65 n (%) Inclisiran N=186 n (%) Placebo N=62 n (%) Inclisiran N=184 n (%) Any TEAE 46 (70.8) 140 (75.3) 50 (80.6) 142 (77.2) Serious Severe Related 3 (4.6) 2 (3.1) 12 (18.5) 17 (9.1) 11 (5.9) 39 (21.0) 6 (9.7) 7 (11.3) 18 (29.0) 24 (13.0) 19 (10.3) 51 (27.7) Injection site reaction 7 (3.8) 12 (6.5)

No LFT elevations related to drug No difference in incidence of myalgias /CPK elevation No death related to drug administration No thrombocytopenia No neuropathy No immunogenicity (no anti-drug antibodies) No pro-inflammatory symptoms or elevated markers

Conclusions

1) Statins and Ezetimibe first choice; go for high dose 2) Novel, additional therapies needed; residual risk 3) PCSK9... a one way ticket to success….but with a huge burden on healthcare expenditure 4) anything else, or is this the end??

No way… outcome trials in the pipeline

• REVEAL: CETPi: anacetrap
• BETONMACE: BETi, RVX208 (apabetalone)
• CLEAR outcomes: ETC1002
• ORION: PCSK9, Inclisiran
• CANTOS: IL1beta, Canakinumab

…..