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 Characteristic Healthy Subjects with controls elevated lp(a) (n=30) (n=30) 53 ± 12 52 ± 11 Age, y Gender, 45 (9) 43 (15) %male 24 ± 4 24 ± 3 BMI Lp(a), mg/dl 7[2-28] 108[50-195] 5.21 ± 0.83 5.79 ± 1.44 Total cholesterol 2.91 ± 0.8 2.80 ± 1.16 LDL-c 1.68 ± 0.42 1.60 ± 0.40 HDL-c Triglycerides 0.8[0.24-2.18] 0.82[0.39-2.16] 18F-FDG PET/CT-scan 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: • ‘small’ decrease: – Statins – Niacin – Low fat diets – LDL-apheresis – Garlic supplements – 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 150 150 mg/dL Pre Lp(a) (mg/dL) Diet Therapy 102 (No effect) Time Averaged (35%) 102 mg/dL Post 45 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 Cohort A (50-175 mg/dL) Cohort B (>175 mg/dL) Placebo 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
IONIS-APO(a)-L Rx Produced Dose-dependent Significant Reductions in Lp(a) Up to 97% Reduction in Lp(a), Up to 99% Reduction in Lp(a), with Mean Reduction of 85% with Mean Reduction of 92% Single Ascending Dose Multiple Ascending Dose Mean % Change From Baseline (+/- SEM) Mean % Change from Baseline (+/- SEM) Lp(a) (nmol/L) Lp(a) (nmol/L) Study Day Study Day Placebo 10 mg 20 mg 40 mg 80 mg 120 mg Placebo 10 mg 20 mg 40 mg ▪ Well tolerated with no safety Mean Lp(a) reductions: 10 mg= ↓ 68% concerns 20 mg= ↓ 80% 40 mg= ↓ 93% 27 Viney et al. Lancet 2016
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 Estimated prevalence assumes: 320M in US, 750M in EU and 7B globally N=~531,000 29 Varvel et al. Arterioscler Thromb Vasc Biol 2016
Significant Advances in Medicinal Chemistry of Antisense Improve Potency and Tolerability LIC LIC LIC Gen 2.5 LICA Gen 2/2+ 1 st Gen A A A GalNac Design MOE Gapmer Design cEt Gapmer Design P-S 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
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