Influence of Pelacarsen on Patients After Myocardial Infarction With High Lp(a) Values (PEMILA)
Summary
The aim of study is to examine the relationship between lipid subfractions, inflammation and structural-functional properties of the arterial wall in patients after myocardial infarction with high lipoprotein (a) (Lp (a)) levels, to study genetic polymorphisms that determine lipid subfractions concentration on the functional and morphological properties of the arterial vascular wall in patients after myocardial infarction with high Lp (a) levels, to study the effect of pelacarsen on lipid subfractions, inflammation and structural-functional properties of arterial wall in patients after myocardial infarction with high Lp (a) levels and to study the influence of NOS-3 gene expression on the functional and morphological properties of the arterial vascular wall in the same patients. Impaired blood fat metabolism and chronic inflammation represent possible causes of atherosclerosis. Lp (a) is an independent risk factor for cardiovascular disease and a prognostic predictor in patients after myocardial infarction. Despite recommended screening for elevated Lp (a), there is no specific drug treatment approved to reduce cardiovascular risk through lowering Lp (a). Besides subtilisin-kexin convertase type 9 (PCSK9) inhibitors, antisense oligonucleotides (ASOs) are currently only therapeutic agents that significantly reduce serum Lp (a) concentration. Pelacarsen by using an ASO directed against the messenger ribonucleic acid (mRNA) of apolipoprotein (a), reduces the production of apolipoprotein (a) in the liver and thus, the level of Lp (a). However, there are no data on the relationship between Lp (a) values and polymorphisms for Lp (a), indicators of inflammation and impaired arterial function, and response to treatment with pelacarsen in patients after myocardial infarction with extremely high Lp (a) levels.
Timeline
- Start
- 2021-10-01
- Primary completion
- 2022-06-30
- Completion
- 2022-10-01
Publications
- Background Pagidipati NJ, Gaziano TA. Estimating deaths from cardiovascular disease: a review of global methodologies of mortality measurement. Circulation. 2013 Feb 12;127(6):749-56. doi: 10.1161/CIRCULATIONAHA.112.128413. No abstract available.
- Background McGill HC Jr, McMahan CA, Herderick EE, Malcom GT, Tracy RE, Strong JP. Origin of atherosclerosis in childhood and adolescence. Am J Clin Nutr. 2000 Nov;72(5 Suppl):1307S-1315S. doi: 10.1093/ajcn/72.5.1307s.
- Background Wang JC, Bennett M. Aging and atherosclerosis: mechanisms, functional consequences, and potential therapeutics for cellular senescence. Circ Res. 2012 Jul 6;111(2):245-59. doi: 10.1161/CIRCRESAHA.111.261388.
- Background Egashira K. Clinical importance of endothelial function in arteriosclerosis and ischemic heart disease. Circ J. 2002 Jun;66(6):529-33. doi: 10.1253/circj.66.529.
- Background Bisoendial RJ, Kastelein JJ, Stroes ES. C-reactive protein and atherogenesis: from fatty streak to clinical event. Atherosclerosis. 2007 Dec;195(2):e10-8. doi: 10.1016/j.atherosclerosis.2007.04.053. Epub 2007 Jul 31.
- Background Giles TD, Sander GE, Nossaman BD, Kadowitz PJ. Impaired vasodilation in the pathogenesis of hypertension: focus on nitric oxide, endothelial-derived hyperpolarizing factors, and prostaglandins. J Clin Hypertens (Greenwich). 2012 Apr;14(4):198-205. doi: 10.1111/j.1751-7176.2012.00606.x.
- Background Tada H, Takamura M, Kawashiri MA. Lipoprotein(a) as an Old and New Causal Risk Factor of Atherosclerotic Cardiovascular Disease. J Atheroscler Thromb. 2019 Jul 1;26(7):583-591. doi: 10.5551/jat.RV17034. Epub 2019 Apr 30.
- Background Machado-Silva W, Alfinito-Kreis R, Carvalho LS, Quinaglia-E-Silva JC, Almeida OL, Brito CJ, Ferreira AP, Cordova C, Sposito AC, Nobrega OT; Brasilia Heart Study Group. Endothelial nitric oxide synthase genotypes modulate peripheral vasodilatory properties after myocardial infarction. Gene. 2015 Sep 1;568(2):165-9. doi: 10.1016/j.gene.2015.05.042. Epub 2015 May 20.
- Background Marsden PA, Heng HH, Scherer SW, Stewart RJ, Hall AV, Shi XM, Tsui LC, Schappert KT. Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene. J Biol Chem. 1993 Aug 15;268(23):17478-88.
- Background Oliveira-Paula GH, Lacchini R, Tanus-Santos JE. Endothelial nitric oxide synthase: From biochemistry and gene structure to clinical implications of NOS3 polymorphisms. Gene. 2016 Jan 10;575(2 Pt 3):584-99. doi: 10.1016/j.gene.2015.09.061. Epub 2015 Sep 28.
- Background Hingorani AD, Liang CF, Fatibene J, Lyon A, Monteith S, Parsons A, Haydock S, Hopper RV, Stephens NG, O'Shaughnessy KM, Brown MJ. A common variant of the endothelial nitric oxide synthase (Glu298-->Asp) is a major risk factor for coronary artery disease in the UK. Circulation. 1999 Oct 5;100(14):1515-20. doi: 10.1161/01.cir.100.14.1515.
- Background Bostom AG, Cupples LA, Jenner JL, Ordovas JM, Seman LJ, Wilson PW, Schaefer EJ, Castelli WP. Elevated plasma lipoprotein(a) and coronary heart disease in men aged 55 years and younger. A prospective study. JAMA. 1996 Aug 21;276(7):544-8. doi: 10.1001/jama.1996.03540070040028.
- Background Schaefer EJ, Lamon-Fava S, Jenner JL, McNamara JR, Ordovas JM, Davis CE, Abolafia JM, Lippel K, Levy RI. Lipoprotein(a) levels and risk of coronary heart disease in men. The lipid Research Clinics Coronary Primary Prevention Trial. JAMA. 1994 Apr 6;271(13):999-1003. doi: 10.1001/jama.1994.03510370051031.
- Background Willeit P, Ridker PM, Nestel PJ, Simes J, Tonkin AM, Pedersen TR, Schwartz GG, Olsson AG, Colhoun HM, Kronenberg F, Drechsler C, Wanner C, Mora S, Lesogor A, Tsimikas S. Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials. Lancet. 2018 Oct 13;392(10155):1311-1320. doi: 10.1016/S0140-6736(18)31652-0. Epub 2018 Oct 4.
- Background Berthold HK, Gouni-Berthold I. Hyperlipoproteinemia(a): clinical significance and treatment options. Atheroscler Suppl. 2013 Jan;14(1):1-5. doi: 10.1016/j.atherosclerosissup.2012.10.037.
- Background Hoover-Plow J, Huang M. Lipoprotein(a) metabolism: potential sites for therapeutic targets. Metabolism. 2013 Apr;62(4):479-91. doi: 10.1016/j.metabol.2012.07.024. Epub 2012 Oct 4.
- Background Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009 Jun 10;301(22):2331-9. doi: 10.1001/jama.2009.801.
- Background Nordestgaard BG, Chapman MJ, Ray K, Boren J, Andreotti F, Watts GF, Ginsberg H, Amarenco P, Catapano A, Descamps OS, Fisher E, Kovanen PT, Kuivenhoven JA, Lesnik P, Masana L, Reiner Z, Taskinen MR, Tokgozoglu L, Tybjaerg-Hansen A; European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010 Dec;31(23):2844-53. doi: 10.1093/eurheartj/ehq386. Epub 2010 Oct 21.
- Background Lawn RM. How often has Lp(a) evolved? Clin Genet. 1996 Apr;49(4):167-74. doi: 10.1111/j.1399-0004.1996.tb03281.x.
- Background Emerging Risk Factors Collaboration; Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, White IR, Marcovina SM, Collins R, Thompson SG, Danesh J. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009 Jul 22;302(4):412-23. doi: 10.1001/jama.2009.1063.
- Background Maranhao RC, Carvalho PO, Strunz CC, Pileggi F. Lipoprotein (a): structure, pathophysiology and clinical implications. Arq Bras Cardiol. 2014 Jul;103(1):76-84. doi: 10.5935/abc.20140101.
- Background Ma L, Chan DC, Ooi EMM, Barrett PHR, Watts GF. Fractional turnover of apolipoprotein(a) and apolipoprotein B-100 within plasma lipoprotein(a) particles in statin-treated patients with elevated and normal Lp(a) concentration. Metabolism. 2019 Jul;96:8-11. doi: 10.1016/j.metabol.2019.04.010. Epub 2019 Apr 14.
- Background Marcovina SM, Albers JJ. Lipoprotein (a) measurements for clinical application. J Lipid Res. 2016 Apr;57(4):526-37. doi: 10.1194/jlr.R061648. Epub 2015 Dec 4.
- Background Tsimikas S. A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies. J Am Coll Cardiol. 2017 Feb 14;69(6):692-711. doi: 10.1016/j.jacc.2016.11.042.
- Background Rehberger Likozar A, Zavrtanik M, Sebestjen M. Lipoprotein(a) in atherosclerosis: from pathophysiology to clinical relevance and treatment options. Ann Med. 2020 Aug;52(5):162-177. doi: 10.1080/07853890.2020.1775287. Epub 2020 Jun 8.
- Background Helgadottir A, Gretarsdottir S, Thorleifsson G, Holm H, Patel RS, Gudnason T, Jones GT, van Rij AM, Eapen DJ, Baas AF, Tregouet DA, Morange PE, Emmerich J, Lindblad B, Gottsater A, Kiemeny LA, Lindholt JS, Sakalihasan N, Ferrell RE, Carey DJ, Elmore JR, Tsao PS, Grarup N, Jorgensen T, Witte DR, Hansen T, Pedersen O, Pola R, Gaetani E, Magnadottir HB, Wijmenga C, Tromp G, Ronkainen A, Ruigrok YM, Blankensteijn JD, Mueller T, Wells PS, Corral J, Soria JM, Souto JC, Peden JF, Jalilzadeh S, Mayosi BM, Keavney B, Strawbridge RJ, Sabater-Lleal M, Gertow K, Baldassarre D, Nyyssonen K, Rauramaa R, Smit AJ, Mannarino E, Giral P, Tremoli E, de Faire U, Humphries SE, Hamsten A, Haraldsdottir V, Olafsson I, Magnusson MK, Samani NJ, Levey AI, Markus HS, Kostulas K, Dichgans M, Berger K, Kuhlenbaumer G, Ringelstein EB, Stoll M, Seedorf U, Rothwell PM, Powell JT, Kuivaniemi H, Onundarson PT, Valdimarsson E, Matthiasson SE, Gudbjartsson DF, Thorgeirsson G, Quyyumi AA, Watkins H, Farrall M, Thorsteinsdottir U, Stefansson K. Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism. J Am Coll Cardiol. 2012 Aug 21;60(8):722-9. doi: 10.1016/j.jacc.2012.01.078.
- Background Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, Parish S, Barlera S, Franzosi MG, Rust S, Bennett D, Silveira A, Malarstig A, Green FR, Lathrop M, Gigante B, Leander K, de Faire U, Seedorf U, Hamsten A, Collins R, Watkins H, Farrall M; PROCARDIS Consortium. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009 Dec 24;361(26):2518-28. doi: 10.1056/NEJMoa0902604.
- Background Chasman DI, Shiffman D, Zee RY, Louie JZ, Luke MM, Rowland CM, Catanese JJ, Buring JE, Devlin JJ, Ridker PM. Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy. Atherosclerosis. 2009 Apr;203(2):371-6. doi: 10.1016/j.atherosclerosis.2008.07.019. Epub 2008 Jul 26.
- Background Ober C, Nord AS, Thompson EE, Pan L, Tan Z, Cusanovich D, Sun Y, Nicolae R, Edelstein C, Schneider DH, Billstrand C, Pfaffinger D, Phillips N, Anderson RL, Philips B, Rajagopalan R, Hatsukami TS, Rieder MJ, Heagerty PJ, Nickerson DA, Abney M, Marcovina S, Jarvik GP, Scanu AM, Nicolae DL. Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q. J Lipid Res. 2009 May;50(5):798-806. doi: 10.1194/jlr.M800515-JLR200. Epub 2009 Jan 5.
- Background Hobbs HH, White AL. Lipoprotein(a): intrigues and insights. Curr Opin Lipidol. 1999 Jun;10(3):225-36. doi: 10.1097/00041433-199906000-00005.
- Background Hajjar KA, Gavish D, Breslow JL, Nachman RL. Lipoprotein(a) modulation of endothelial cell surface fibrinolysis and its potential role in atherosclerosis. Nature. 1989 May 25;339(6222):303-5. doi: 10.1038/339303a0.
- Background Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine MS, Taskinen MR, Tokgozoglu L, Wiklund O; ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020 Jan 1;41(1):111-188. doi: 10.1093/eurheartj/ehz455. No abstract available.
- Background Anderson TJ, Gregoire J, Pearson GJ, Barry AR, Couture P, Dawes M, Francis GA, Genest J Jr, Grover S, Gupta M, Hegele RA, Lau DC, Leiter LA, Lonn E, Mancini GB, McPherson R, Ngui D, Poirier P, Sievenpiper JL, Stone JA, Thanassoulis G, Ward R. 2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult. Can J Cardiol. 2016 Nov;32(11):1263-1282. doi: 10.1016/j.cjca.2016.07.510. Epub 2016 Jul 25.
- Background O'Donoghue ML, Fazio S, Giugliano RP, Stroes ESG, Kanevsky E, Gouni-Berthold I, Im K, Lira Pineda A, Wasserman SM, Ceska R, Ezhov MV, Jukema JW, Jensen HK, Tokgozoglu SL, Mach F, Huber K, Sever PS, Keech AC, Pedersen TR, Sabatine MS. Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk. Circulation. 2019 Mar 19;139(12):1483-1492. doi: 10.1161/CIRCULATIONAHA.118.037184.
- Background Tsimikas S, Moriarty PM, Stroes ES. Emerging RNA Therapeutics to Lower Blood Levels of Lp(a): JACC Focus Seminar 2/4. J Am Coll Cardiol. 2021 Mar 30;77(12):1576-1589. doi: 10.1016/j.jacc.2021.01.051.
- Background Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif JC, Baum SJ, Steinhagen-Thiessen E, Shapiro MD, Stroes ES, Moriarty PM, Nordestgaard BG, Xia S, Guerriero J, Viney NJ, O'Dea L, Witztum JL; AKCEA-APO(a)-LRx Study Investigators. Lipoprotein(a) Reduction in Persons with Cardiovascular Disease. N Engl J Med. 2020 Jan 16;382(3):244-255. doi: 10.1056/NEJMoa1905239. Epub 2020 Jan 1.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Subject | Pelacarsen | Antisense oligonucleotide | 80 mg | Subcutaneous |