Lp(a) Ready for prime time? E Stroes AMC

Lp(a) Ready for prime time? E Stroes AMC

Case Male, 45 years old Hypertension: DM: Smoking: Dyslipidemia: Fam history: brother MI (55yr) Lipoprotein(a): 1240 mg/l!!!

Lipoprotein(a) = LDL + apo(a) tail + OxPls

Tail = kringle repeats Tsimikas S. JACC (2017). 69(6):692-711

Structure of Lp(a) and Sites of OxPL Accumulation 5 Leibundgut et al JACC 2012 and JLR 2013, Rao ATVB 2015

Distribution lipoprotein(a) levels in the normal population Nordestgaard et al. (2010). Eur Heart J. 31(23): 2844-2853 Copenhagen General Population Study

Impact of Lp(a) elevation Prevalence of Lp(a) elevation 75th percentile 470 mg/l 90th percentile 900 mg/l 99th percentile 1800 mg/l Lp(a) 1800mg/L risk equivalent of heterozygous FH More prevalent than heterozygous FH (1:100 vs 1:250)

Impact of Lp(a) on LDL -cholesterol

Lp(a) is an indepedent, genetic risk factor for cardiovascular disease Erquo et al. (2009) JAMA. 302:412-423 Kamstrup et al. (2009) JAMA. 301:2331-2339 Clarke et al. (2009) NEJM: 361:2518-2528

Lp(a) is associated with atherosclerosis ánd calcified aortic valve stenosis Torzewski, M. et al. J Am Coll Cardiol Basic Trans Science (2017). 2(3):229-41

Pathogenic mechanisms of Lp(a) Tsimikas S. JACC (2017). 69(6):692-711

Pathogenic mechanisms of Lp(a) Tsimikas S. JACC (2017). 69(6):692-711

1. Lp(a) atherogenic trough it s LDL moiety accumulation in atherosclerotic plaques Libby. Nature (2002). 420, 868-874 / Van Dijk et al. JLR (2012). 53, 2773-2790.

Contribution of lp(a) to residual risk after statin treatment

Pathogenic mechanisms Lp(a) Tsimikas S. JACC (2017). 69(6):692-711

2. Lp(a) also atherogenic via apo(a) tail / OxPL Tsimikas S. JACC (2012).

OxPls on Lp(a) induce a systemic pro-inflammatory response Bernelot Moens et al, Eur hrt J, 2017 & vd Valk et al, Circulation 2016

Lp(a) patients have increased vessel wall inflammation measured with 18F-FDG PET/CT-scan 18F-FDG PET/CT-scan Characteristic Healthy controls (n=30) Subjects with elevated lp(a) (n=30) Age, y 53±12 52±11 Gender, %male 45 (9) 43 (15) BMI 24±4 24±3 Lp(a), mg/dl 7[2-28] 108[50-195] Total cholesterol 5.21±0.83 5.79±1.44 LDL-c 2.91±0.8 2.80±1.16 HDL-c 1.68±0.42 1.60±0.40 Triglycerides 0.8[0.24-2.18] 0.82[0.39-2.16] Yellow = metabolic activity Van Der Valk et al. Circ 2016. 134(8):611-24

Lp(a) patients have increased influx of monocytes in atherosclerotic plaques In vivo * * SPECT/CT-scans met 99mTc-labeled autologous PBMCs Green = accumulated monocytes Van Der Valk et al. Circ 2016. 134(8):611-24

Therapeutic agents affecting Lp(a) levels Increase: Statins Low fat diets Garlic supplements small decrease: Niacin LDL-apheresis CETP-inhibition apob-antisense MTP inhibitors Anabolic steroids aspirin

Effect of diet, statin therapy and apheresis on Lp(a) Statin Apheresis Treatment Therapy 15% increase) 175 mg/dl 150 Pre 150 mg/dl Lp(a) (mg/dl) 102 Diet Therapy (No effect) Time Averaged (35%) 102 mg/dl 45 Post 45 mg/dl Time 21

Mean Annual Rates for MACE, ACVE, MI, PCI, and CABG for 2 Years Before (y-2, y-1) and After (y+1, y+2) Commencing Chronic lipid Apheresis and Percentage Changes (Δ) Between Periods Before and During Apheresis ACVE indicates adverse cardiac or vascular events; CABG, coronary artery bypass graft; LA, lipoprotein apheresis; MACE, major adverse coronary events; MI, myocardial infarction; and PCI, percutaneous coronary intervention. Leebman et al. Circulation 2013;128:2567 2576 22

Antisense Oligonucleotides Targeting Lp(a) Antisense Oligonucleotide Tsimikas JACC 2017;69:692-711 23

Phase 2 IONIS-APO(a) Rx Study- mean % Change in Lp(a) in Placebo and Patients with Lp(a) (50-175 mg/dl) and >175 mg/dl Placebo Cohort A (50-175 mg/dl) Cohort B (>175 mg/dl) A B Viney et al, Lancet 2016

Lowering Lp(a) Reduces Plasma Monocyte Activation Changes in Monocyte Transendothelial Migration (TEM) Transendothelial migration Assay Changes & correlations of TEM vs. changes in Lp(a) and OxPL-apoB in response to IONIS-APO(a) Rx vs. Placebo Viney et al, Lancet 2016

Hepatocyte Targeting Antisense via Asialoglycoprotein Receptor (ASGPR) Enhances Drug Delivery to the Liver 10-15x LICA - ligand conjugated antisense T. P. Prakash et al. Nucleic Acids Res. 2014 Jul;42(13):8796-807

Lp(a) (nmol/l) Mean % Change from Baseline (+/- SEM) IONIS-APO(a)-L Rx Produced Dose-dependent Significant Reductions in Lp(a) Lp(a) (nmol/l) Mean % Change From Baseline (+/- SEM) Up to 97% Reduction in Lp(a), with Mean Reduction of 85% Single Ascending Dose Up to 99% Reduction in Lp(a), with Mean Reduction of 92% Multiple Ascending Dose Placebo Study Day 10 mg 20 mg 40 mg 80 mg 120 mg Study Day Placebo 10 mg 20 mg 40 mg Well tolerated with no safety concerns Viney et al. Lancet 2016 Mean Lp(a) reductions: 10 mg= 68% 20 mg= 80% 40 mg= 93% 27

Clinical Safety and Tolerability for Hepatic Targeted Antisense No serious AEs No AEs leading to treatment discontinuation No hepatic or renal signals No injection site or flu-like reactions No clinically significant findings in routine hematology or biochemistry No platelet reductions

Prevalence of Lp(a) Levels Globally --CVD Outcome Trials will be Needed-- Lp(a) distribution in general population extrapolated from the graph Lp(a) levels >30 mg/dl >60 mg/dl >90 mg/dl >116 mg/dl >180 mg/dl Prevalence 35% 20% 10% 5% 1% Number (US) 112,000,000 64,000,000 32,000,000 16,000,000 3,200,000 Number (EU) 262,500,000 150,000,000 750,000,000 37,500,000 7,500,000 Globally 2,450,000,000 1,400,000,000 700,000,000 350,000,000 70,000,000 N=~531,000 Estimated prevalence assumes: 320M in US, 750M in EU and 7B globally Varvel et al. Arterioscler Thromb Vasc Biol 2016 29

Significant Advances in Medicinal Chemistry of Antisense Improve Potency and Tolerability LIC 1 A st Gen Gen LIC A 2/2+ Gen LIC2.5 A LICA P-S MOE Gapmer Design cet Gapmer Design GalNac Design 1X 10X 10X 10X =1000X (600-1200/wk) 100-300/wk 10-40/wk 10-40/wk 1-3/wk Potency Side effect profile 30

Take home message Urgent need for Awareness, Measuring and ACTION! Lp(a) measurement in: - Patients above 50yr (both primary as secondary prevention) - Premature atherosclerosis patients - Unexplained CVD - Progressive disease dispite CVRM For questions: lpa@amc.nl

Acknowledgments AMC - Jeffrey Kroon, PhD - Lotte Stiekema, PhD - Simone Verweij, MD - Renate Hoogeveen, MD - Jan Schnitzler - Rutger Verbeek, MD - Fleur van der Valk, MD PhD UCSD - Sam Tsimikas - Joe Witztum REPROGRAM consortium - Alberico Catapano - Borge Nordestgaard - Mihai Netea - Menno de Winter