Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study

The Lancet

Volumn 386, Issue 10002, 2015, Pages 1472-1483

  Tsimikas, Sotirios ^a,b   Viney, Nicholas J ^b   Hughes, Steven G ^b   Singleton, Walter ^b   Graham, Mark J ^b   Baker, Brenda F ^b   Burkey, Jennifer L ^b   Yang, Qingqing ^b   Marcovina, Santica M ^c   Geary, Richard S ^b   Crooke, Rosanne M ^b   Witztum, Joseph L ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b ISIS PHARMACEUTICALS   (United States)

^c UNIVERSITY OF WASHINGTON   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTISENSE OLIGONUCLEOTIDE; APOLIPOPROTEIN A; APOLIPOPROTEIN B100; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; LOW DENSITY LIPOPROTEIN CHOLESTEROL; PHOSPHOLIPASE A2; PHOSPHOLIPID; PLACEBO; TRIACYLGLYCEROL; ISIS-APO(A)RX; MESSENGER RNA; OLIGONUCLEOTIDE; PROTEIN BINDING;

ADULT; AGED; ANTISENSE THERAPY; ARTICLE; BLOOD CHEMISTRY; BODY MASS; CHOLESTEROL BLOOD LEVEL; CONTROLLED STUDY; DOSE RESPONSE; DOUBLE BLIND PROCEDURE; DRUG DOSE COMPARISON; DRUG DOSE REGIMEN; DRUG WITHDRAWAL; ELECTROCARDIOGRAPHY; ELIMINATION HALF-LIFE; FATIGUE; FLU LIKE SYNDROME; HEADACHE; HUMAN; INJECTION SITE REACTION; LABORATORY TEST; LIPOPROTEIN BLOOD LEVEL; MAXIMUM PLASMA CONCENTRATION; MEAN RESIDENCE TIME; NORMAL HUMAN; OUTCOME ASSESSMENT; PHASE 2 CLINICAL TRIAL; PHOSPHOLIPID BLOOD LEVEL; PHYSICAL EXAMINATION; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; SCREENING; VITAL SIGN; ADOLESCENT; ANTAGONISTS AND INHIBITORS; CLINICAL TRIAL; GENETICS; METABOLISM; MIDDLE AGED; PHASE 1 CLINICAL TRIAL; TREATMENT OUTCOME; YOUNG ADULT;

ADOLESCENT; ADULT; AGED; APOLIPOPROTEINS A; APOPROTEIN(A); DOUBLE-BLIND METHOD; HEALTHY VOLUNTEERS; HUMANS; MIDDLE AGED; OLIGONUCLEOTIDES; OLIGONUCLEOTIDES, ANTISENSE; PROTEIN BINDING; RNA, MESSENGER; TREATMENT OUTCOME; YOUNG ADULT;

EID: 84944152398     PISSN: 01406736     EISSN: 1474547X     Source Type: Journal    
DOI: 10.1016/S0140-6736(15)61252-1     Document Type: Article

References (35)

1. F Kronenberg, G Utermann Lipoprotein(a): resurrected by genetics J Intern Med 273 2013 6 30
2. S Tsimikas, JH Hall Lipoprotein(a) as a potential causal genetic risk factor of cardiovascular disease: a rationale for increased efforts to understand its pathophysiology and develop targeted therapies J Am Coll Cardiol 60 2012 716 721
3. JD Spence, ML Koschinsky Mechanisms of lipoprotein(a) pathogenicity Arterioscler Thromb Vasc Biol 32 2012 1550 1551
4. MM Luke, JP Kane, DM Liu et al. A polymorphism in the protease-like domain of apolipoprotein(a) is associated with severe coronary artery disease Arterioscler Thromb Vasc Biol 27 2007 2030 2036
5. R Clarke, JF Peden, JC Hopewell et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease N Engl J Med 361 2009 2518 2528
6. S Erqou, S Kaptoge, PL Perry et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality JAMA 302 2009 412 42
7. PR Kamstrup, A Tybjaerg-Hansen, R Steffensen, BG Nordestgaard Genetically elevated lipoprotein(a) and increased risk of myocardial infarction JAMA 301 2009 2331 2339
8. G Thanassoulis, CY Campbell, DS Owens et al. Genetic associations with valvular calcification and aortic stenosis N Engl J Med 368 2013 503 512
9. ST Crooke, RS Geary Clinical pharmacological properties of mipomersen (Kynamro), a second generation antisense inhibitor of apolipoprotein B Br J Clin Pharmacol 76 2013 269 276
10. JJ Albers, ML Koschinsky, SM Marcovina Evidence mounts for a role of the kidney in lipoprotein(a) catabolism Kidney Int 71 2007 961 962
11. SM Marcovina, JJ Albers, B Gabel, ML Koschinsky, VP Gaur Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a) Clin Chem 41 1995 246 255
12. SM Marcovina, HH Hobbs, JJ Albers Relation between number of apolipoprotein(a) kringle 4 repeats and mobility of isoforms in agarose gel: basis for a standardized isoform nomenclature Clin Chem 42 1996 436 439
13. LJ Seman, WC Breckenridge Isolation and partial characterization of apolipoprotein (a) from human lipoprotein (a) Biochem Cell Biol 64 1986 999 109
14. G Leibundgut, K Arai, A Orsoni et al. Oxidized phospholipids are present on plasminogen, affect fibrinolysis, and increase following acute myocardial infarction J Am Coll Cardiol 59 2012 1426 1437
15. P Willeit, S Kiechl, F Kronenberg et al. Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck Study J Am Coll Cardiol 64 2014 851 860
16. S Tsimikas, GW Duff, PB Berger et al. Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a) J Am Coll Cardiol 63 2014 1724 1734
17. S Tsimikas, P Willeit, J Willeit et al. Oxidation-specific biomarkers, prospective 15-year cardiovascular and stroke outcomes, and net reclassification of cardiovascular events J Am Coll Cardiol 60 2012 2218 2229
18. S Tsimikas, ES Brilakis, ER Miller et al. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease N Engl J Med 353 2005 46 57
19. K Arai, A Orsoni, Z Mallat et al. Acute impact of apheresis on oxidized phospholipids in patients with familial hypercholesterolemia J Lipid Res 53 2012 1670 1678
20. S Tsimikas, P Clopton, ES Brilakis et al. Relationship of oxidized phospholipids on apolipoprotein B-100 particles to race/ethnicity, apolipoprotein(a) isoform size, and cardiovascular risk factors: results from the Dallas Heart Study Circulation 119 2009 1711 1719
21. G Leibundgut, C Scipione, H Yin et al. Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a) J Lipid Res 54 2013 2815 2830
22. AV Khera, BM Everett, MP Caulfield et al. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER Trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) Circulation 129 2014 635 642
23. ML O'Donoghue, DA Morrow, S Tsimikas et al. Lipoprotein(a) for risk assessment in patients with established coronary artery disease J Am Coll Cardiol 63 2014 520 527
24. PJ Nestel, EH Barnes, AM Tonkin et al. Plasma lipoprotein(a) concentration predicts future coronary and cardiovascular events in patients with stable coronary heart disease Arterioscler Thromb Vasc Biol 33 2013 2902 2908
25. RD Santos, FJ Raal, AL Catapano, JL Witztum, E Steinhagen-Thiessen, S Tsimikas Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia: results of 4 Phase III Trials Arterioscler Thromb Vasc Biol 35 2015 689 699
26. JR Guyton Niacin in cardiovascular prevention: mechanisms, efficacy, and safety Curr Opin Lipidol 18 2007 415 420
27. JJ Albers, A Slee, KD O'Brien et al. Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes) J Am Coll Cardiol 62 2013 1575 1579
28. MJ Landray, R Haynes, JC Hopewell et al. Effects of extended-release niacin with laropiprant in high-risk patients N Engl J Med 371 2014 203 212
29. BR Jaeger, Y Richter, D Nagel et al. Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein(a) levels and prevent major adverse coronary events Nat Clin Pract Cardiovasc Med 6 2009 229 239
30. J Leebmann, E Roeseler, U Julius et al. Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease: Prospective observational multicenter study Circulation 128 2013 2567 2576
31. A Rosada, U Kassner, A Vogt, M Willhauck, K Parhofer, E Steinhagen-Thiessen Does regular lipid apheresis in patients with isolated elevated lipoprotein(a) levels reduce the incidence of cardiovascular events? Artif Organs 38 2014 135 141
32. S Lamon-Fava, SM Marcovina, JJ Albers et al. Lipoprotein(a) levels, apo(a) isoform size, and coronary heart disease risk in the Framingham Offspring Study J Lipid Res 52 2011 1181 1187
33. E Merki, M Graham, A Taleb et al. Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) and lipoprotein (a) in transgenic mice J Am Coll Cardiol 57 2011 1611 1621
34. HR Buller, C Bethune, S Bhanot et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis N Engl J Med 372 2015 232 240
35. TP Prakash, MJ Graham, J Yu et al. Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice Nucleic Acids Res 42 2014 8796 8807