Lp(a) Ready for prime time? E Stroes AMC Case Male, 45 years old - - PowerPoint PPT Presentation

Lp(a) Ready for prime time?

E Stroes AMC

Male, 45 years old Hypertension: – DM: – Smoking: – Dyslipidemia: – Fam history: brother MI (55yr) Case

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

Leibundgut et al JACC 2012 and JLR 2013, Rao ATVB 2015

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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

Torzewski, M. et al. J Am Coll Cardiol Basic Trans Science (2017). 2(3):229-41

Lp(a) is associated with atherosclerosis ánd calcified aortic valve stenosis

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

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]

Lp(a) patients have increased vessel wall inflammation measured with 18F-FDG PET/CT-scan

Van Der Valk et al. Circ 2016. 134(8):611-24

18F-FDG PET/CT-scan Yellow = metabolic activity

* * Lp(a) patients have increased influx of monocytes in atherosclerotic plaques In vivo

Van Der Valk et al. Circ 2016. 134(8):611-24

SPECT/CT-scans met 99mTc-labeled autologous PBMCs Green = accumulated monocytes

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)

Time Lp(a) (mg/dL)

Time Averaged (35%) Diet Therapy (No effect) Apheresis Treatment

Pre Post 150 45 102

175 mg/dL

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45 mg/dL 102 mg/dL 150 mg/dL Statin Therapy

15% increase)

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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

Leebman et al. Circulation 2013;128:2567–2576

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.

Antisense Oligonucleotides Targeting Lp(a)

Tsimikas JACC 2017;69:692-711

Antisense Oligonucleotide

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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) Viney et al, Lancet 2016

A B

Transendothelial migration Assay

Lowering Lp(a) Reduces Plasma Monocyte Activation

Changes in Monocyte Transendothelial Migration (TEM)

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)-LRx Produced Dose-dependent Significant Reductions in Lp(a)

Up to 97% Reduction in Lp(a), with Mean Reduction of 85% Up to 99% Reduction in Lp(a), with Mean Reduction of 92%

Single Ascending Dose Multiple Ascending Dose

▪ Well tolerated with no safety

concerns

Lp(a) (nmol/L) Mean % Change from Baseline (+/- SEM) Study Day

20 mg Placebo 80 mg 10 mg 40 mg 120 mg

Lp(a) (nmol/L) Mean % Change From Baseline (+/- SEM) Study Day

20 mg Placebo 10 mg 40 mg

Viney et al. Lancet 2016

Mean Lp(a) reductions: 10 mg= ↓ 68% 20 mg= ↓ 80% 40 mg= ↓ 93%

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• 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

Clinical Safety and Tolerability for Hepatic Targeted Antisense

Prevalence of Lp(a) Levels Globally

• -CVD Outcome Trials will be Needed--

Varvel et al. Arterioscler Thromb Vasc Biol 2016

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

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Significant Advances in Medicinal Chemistry of Antisense Improve Potency and Tolerability

LICA

LIC A

Gen 2.5

LIC A

Gen 2/2+

cEt Gapmer Design GalNac Design

MOE Gapmer Design

LIC A

1st Gen

P-S

1X ↑10X ↑10X ↑10X =1000X

Side effect profile Potency

(600-1200/wk) 100-300/wk 10-40/wk 10-40/wk 1-3/wk

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“Urgent need for Awareness, Measuring and ACTION!”

Take home message 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