Potent reduction of plasma lipoprotein (a) with an antisense oligonucleotide in human subjects does not affect ex vivo fibrinolysis

It is postulated that lipoprotein (a) [Lp(a)] inhibits fibrinolysis, but this hypothesis has not been tested in humans due to the lack of specific Lp(a) lowering agents. Patients with elevated Lp(a) were randomized to antisense oligonucleotide [IONIS-APO(a)Rx] directed to apo(a) (n = 7) or placebo (n = 10). Ex vivo plasma lysis times and antigen concentrations of plasminogen, factor XI, plasminogen activator inhibitor 1, thrombin activatable fibrinolysis inhibitor, and fibrinogen at baseline, day 85/92/99 (peak drug effect), and day 190 (3 months off drug) were measured. The mean ± SD baseline Lp(a) levels were 477.3 ± 55.9 nmol/l in IONIS-APO(a)Rx and 362.1 ± 89.9 nmol/l in placebo. The mean± SD percentage change in Lp(a) for IONIS-APO(a)Rx was −69.3 ± 12.2% versus −5.4 ± 6.9% placebo (P < 0.0010) at day 85/92/99 and −15.6 ± 8.9% versus 3.2 ± 12.2% (P = 0.003) at day 190. Clot lysis times and coagulation/fibrinolysis-related biomarkers showed no significant differences between IONIS-APO(a)Rx and placebo at all time points. Clot lysis times were not affected by exogenously added Lp(a) at concentrations up to 200 nmol/l to plasma with very low (12.5 nmol/l) Lp(a) levels, whereas recombinant apo(a) had a potent antifibrinolytic effect. In conclusion, potent reductions of Lp(a) in patients with highly elevated Lp(a) levels do not affect ex vivo measures of fibrinolysis; the relevance of any putative antifibrinolytic effects of Lp(a) in vivo needs further study. It is postulated that lipoprotein (a) [Lp(a)] inhibits fibrinolysis, but this hypothesis has not been tested in humans due to the lack of specific Lp(a) lowering agents. Patients with elevated Lp(a) were randomized to antisense oligonucleotide [IONIS-APO(a)Rx] directed to apo(a) (n = 7) or placebo (n = 10). Ex vivo plasma lysis times and antigen concentrations of plasminogen, factor XI, plasminogen activator inhibitor 1, thrombin activatable fibrinolysis inhibitor, and fibrinogen at baseline, day 85/92/99 (peak drug effect), and day 190 (3 months off drug) were measured. The mean ± SD baseline Lp(a) levels were 477.3 ± 55.9 nmol/l in IONIS-APO(a)Rx and 362.1 ± 89.9 nmol/l in placebo. The mean± SD percentage change in Lp(a) for IONIS-APO(a)Rx was −69.3 ± 12.2% versus −5.4 ± 6.9% placebo (P < 0.0010) at day 85/92/99 and −15.6 ± 8.9% versus 3.2 ± 12.2% (P = 0.003) at day 190. Clot lysis times and coagulation/fibrinolysis-related biomarkers showed no significant differences between IONIS-APO(a)Rx and placebo at all time points. Clot lysis times were not affected by exogenously added Lp(a) at concentrations up to 200 nmol/l to plasma with very low (12.5 nmol/l) Lp(a) levels, whereas recombinant apo(a) had a potent antifibrinolytic effect. In conclusion, potent reductions of Lp(a) in patients with highly elevated Lp(a) levels do not affect ex vivo measures of fibrinolysis; the relevance of any putative antifibrinolytic effects of Lp(a) in vivo needs further study. Lipoprotein(a) [Lp(a)] is a genetic risk factor for CVD and calcific aortic valve stenosis. Lp(a) is thought to mediate clinical events by three main mechanisms: proatherogenic effects via its LDL cholesterol (LDL-C) moiety (1.Tsimikas S. A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies.J. Am. Coll. Cardiol. 2017; 69: 692-711Crossref PubMed Scopus (497) Google Scholar, 2.Tsimikas S. Fazio S. Ferdinand K.C. Ginsberg H.N. Koschinsky M.L. Marcovina S.M. Moriarty P.M. Rader D.J. Remaley A.T. Reyes-Soffer G. et al.NHLBI Working Group recommendations to reduce lipoprotein(a)-mediated risk of cardiovascular disease and aortic stenosis.J. Am. Coll. Cardiol. 2018; 71: 177-192Crossref PubMed Scopus (238) Google Scholar), proinflammatory effects via its content of oxidized phospholipids (3.Leibundgut G. Scipione C. Yin H. Schneider M. Boffa M.B. Green S. Yang X. Dennis E.A. Witztum J.L. Koschinsky M.L. et al.Determinants of binding of oxidized phospholipids on apolipoprotein(a) and lipoprotein(a).J. Lipid Res. 2013; 54: 2815-2830Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 4.Scipione C.A. Sayegh S.E. Romagnuolo R. Tsimikas S. Marcovina S.M. Boffa M.B. Koschinsky M.L. Mechanistic insights into Lp(a)-induced IL-8 expression: a role for oxidized phospholipid modification of apo(a).J. Lipid Res. 2015; 56: 2273-2285Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 5.van der Valk F.M. Bekkering S. Kroon J. Yeang C. Van den Bossche J. van Buul J.D. Ravandi A. Nederveen A.J. Verberne H.J. Scipione C. et al.Oxidized phospholipids on lipoprotein(a) elicit arterial wall inflammation and an inflammatory monocyte response in humans.Circulation. 2016; 134: 611-624Crossref PubMed Scopus (281) Google Scholar), and antifibrinolytic effects via its apolipoprotein(a) [apo(a)] component (6.Boffa M.B. Koschinsky M.L. Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease?.J. Lipid Res. 2016; 57: 745-757Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar). Lp(a) has high homology (75–99%) to plasminogen but lacks protease activity and therefore has been hypothesized to inhibit fibrinolysis and mediate prothrombotic potential. This hypothesis has been supported by in vitro/ex vivo studies primarily using free apo(a), of which little if any is present in plasma in vivo, rather than purified Lp(a) (7.Loscalzo J. Weinfeld M. Fless G.M. Scanu A.M. Lipoprotein(a), fibrin binding, and plasminogen activation.Arteriosclerosis. 1990; 10: 240-245Crossref PubMed Google Scholar, 8.Rouy D. Grailhe P. Nigon F. Chapman J. Angles-Cano E. Lipoprotein(a) impairs generation of plasmin by fibrin-bound tissue-type plasminogen activator. In vitro studies in a plasma milieu.Arterioscler. Thromb. 1991; 11: 629-638Crossref PubMed Google Scholar, 9.Hervio L. Chapman M.J. Thillet J. Loyau S. Angles-Cano E. Does apolipoprotein(a) heterogeneity influence lipoprotein(a) effects on fibrinolysis?.Blood. 1993; 82: 392-397Crossref PubMed Google Scholar, 10.Palabrica T.M. Liu A.C. Aronovitz M.J. Furie B. Lawn R.M. Furie B.C. Antifibrinolytic activity of apolipoprotein(a) in vivo: human apolipoprotein(a) transgenic mice are resistant to tissue plasminogen activator-mediated thrombolysis.Nat. Med. 1995; 1: 256-259Crossref PubMed Scopus (132) Google Scholar, 12.Biemond B.J. Friederich P.W. Koschinsky M.L. Levi M. Sangrar W. Xia J. Buller H.R. ten Cate J.W. Apolipoprotein(a) attenuates endogenous fibrinolysis in the rabbit jugular vein thrombosis model in vivo.Circulation. 1997; 96: 1612-1615Crossref PubMed Scopus (48) Google Scholar). More recently, several association studies using genetic instruments related to LPA, the gene encoding apo(a), have suggested elevated Lp(a) levels are not associated with deep venous thrombosis (13.Helgadottir A. Gretarsdottir S. Thorleifsson G. Holm H. Patel R.S. Gudnason T. Jones G.T. van Rij A.M. Eapen D.J. Baas A.F. et al.Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism.J. Am. Coll. Cardiol. 2012; 60: 722-729Crossref PubMed Scopus (141) Google Scholar, 14.Kamstrup P.R. Tybjaerg-Hansen A. Nordestgaard B.G. Genetic evidence that lipoprotein(a) associates with atherosclerotic stenosis rather than venous thrombosis.Arterioscler. Thromb. Vasc. Biol. 2012; 32: 1732-1741Crossref PubMed Scopus (123) Google Scholar). These studies argue against a direct role of Lp(a) in thrombosis, except perhaps when there is a second concomitant prothrombotic etiology such as Factor V Leiden in pediatric stroke (15.Goldenberg N.A. Bernard T.J. Hillhouse J. Armstrong-Wells J. Galinkin J. Knapp-Clevenger R. Jacobson L. Marcovina S.M. Manco-Johnson M.J. Elevated lipoprotein (a), small apolipoprotein (a), and the risk of arterial ischemic stroke in North American children.Haematologica. 2013; 98: 802-807Crossref PubMed Scopus (44) Google Scholar) or elevated homocysteine levels (16.Foody J.M. Milberg J.A. Robinson K. Pearce G.L. Jacobsen D.W. Sprecher D.L. Homocysteine and lipoprotein(a) interact to increase CAD risk in young men and women.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 493-499Crossref PubMed Scopus (93) Google Scholar). Furthermore, elevated Lp(a) levels are causally associated with calcific aortic valve stenosis, where thrombosis is not a part of the clinical phenotype (17.Tsimikas S. Potential causality and emerging medical therapies for lipoprotein(a) and its associated oxidized phospholipids in calcific aortic valve stenosis.Circ. Res. 2019; 124: 405-415Crossref PubMed Scopus (45) Google Scholar). On the other hand, whether Lp(a) might directly contribute to the thrombotic sequelae of arterial plaque rupture has been difficult to assess because of the inability to disentangle such effects from underlying atherosclerotic disease. The role of Lp(a) lowering on its effects on fibrinolysis in humans has not been previously investigated due to the lack of specific Lp(a) lowering agents. IONIS-APO(a)Rx and IONIS-APO(a)-LRx, having the same sequence as IONIS-APO(a)Rx but additionally containing the hepatocyte targeting moiety n-acetylgalactosamine, are second-generation antisense oligonucleotides directed to apo(a). In phase I and II clinical trials they have been demonstrated to lower mean Lp(a) levels by 70% to 92% (18.Tsimikas S. Viney N.J. Hughes S.G. Singleton W. Graham M.J. Baker B.F. Burkey J.L. Yang Q. Marcovina S.M. Geary R.S. et al.Antisense therapy targeting apolipoprotein(a): a phase 2015; Full Text Full Text PDF PubMed Scopus Google Scholar, N.J. van Geary R.S. Xia S. J.A. Marcovina S.M. Hughes S.G. Graham M.J. R.M. et al.Antisense oligonucleotides targeting apolipoprotein(a) in with lipoprotein(a): 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). This of in Lp(a) is than has been by that are not specific for Lp(a) lowering such as H.R. H.N. and disease its is a 2017; 11: Full Text Full Text PDF PubMed Scopus Google Scholar) and of H. L. S.M. arterial wall inflammation in patients with elevated lipoprotein(a) lipoprotein cholesterol by J. 2018; Scopus Google Scholar). In this whether lowering of elevated Lp(a) in an in using ex vivo lysis and were from three trials antisense oligonucleotides directed to apo(a). The was a phase that in (18.Tsimikas S. Viney N.J. Hughes S.G. Singleton W. Graham M.J. Baker B.F. Burkey J.L. Yang Q. Marcovina S.M. Geary R.S. et al.Antisense therapy targeting apolipoprotein(a): a phase 2015; Full Text Full Text PDF PubMed Scopus Google Scholar), the second was a phase in with elevated Lp(a) with the same drug as N.J. van Geary R.S. Xia S. J.A. Marcovina S.M. Hughes S.G. Graham M.J. R.M. et al.Antisense oligonucleotides targeting apolipoprotein(a) in with lipoprotein(a): 2016; Full Text Full Text PDF PubMed Scopus Google Scholar), and the was a phase in with elevated Lp(a) that an antisense oligonucleotide to apo(a) N.J. van Geary R.S. Xia S. J.A. Marcovina S.M. Hughes S.G. Graham M.J. R.M. et al.Antisense oligonucleotides targeting apolipoprotein(a) in with lipoprotein(a): 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). Ex vivo lysis time was in baseline from (n = in a phase of to the of lysis were with a and Lp(a) levels In the phase patients (n = with Lp(a) nmol/l were randomized to placebo or at for 200 for the second and for the (18.Tsimikas S. Viney N.J. Hughes S.G. Singleton W. Graham M.J. Baker B.F. Burkey J.L. Yang Q. Marcovina S.M. Geary R.S. et al.Antisense therapy targeting apolipoprotein(a): a phase 2015; Full Text Full Text PDF PubMed Scopus Google Scholar). In a of patients with the Lp(a) levels ex vivo plasma lysis time and antigen concentrations of plasminogen, factor XI, plasminogen activator inhibitor thrombin activatable fibrinolysis inhibitor fibrinogen and oxidized phospholipid content on apo(a), and plasminogen G. K. A. Yin H. Scipione C. Koschinsky M.L. Chapman M.J. Witztum J.L. Tsimikas S. phospholipids are present on plasminogen, affect fibrinolysis, and increase Am. Coll. Cardiol. 2012; PubMed Scopus Google Scholar) were at baseline, day 85/92/99 drug effect), and day 190 (3 months off at day 85/92/99 was as not all patients had on all assess whether the were ex vivo lysis in three human with highly elevated Lp(a) levels in the N.J. van Geary R.S. Xia S. J.A. Marcovina S.M. Hughes S.G. Graham M.J. R.M. et al.Antisense oligonucleotides targeting apolipoprotein(a) in with lipoprotein(a): 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). for the was at and to Ex vivo and lysis were in plasma in added to containing concentrations of and nmol/l tissue-type plasminogen activator Clot and lysis times were at in a In plasma from a with low Lp(a) was and were with of purified as R. A. M.J. A. F. C. S. et from lipoprotein(a) and valve inflammation and of the aortic 2015; PubMed Scopus Google Scholar), or the recombinant variants of apo(a) were and Boffa M.B. S.M. Koschinsky M.L. Apolipoprotein(a) inhibits the of to a for lipoprotein(a)-mediated of plasminogen Thromb. PubMed Scopus Google Scholar). Lp(a) concentrations were in and apo(a) were at the Lipid and at the of as previously N.J. van Geary R.S. Xia S. J.A. Marcovina S.M. Hughes S.G. Graham M.J. R.M. et al.Antisense oligonucleotides targeting apolipoprotein(a) in with lipoprotein(a): 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). concentrations of cholesterol and were with N.J. van Geary R.S. Xia S. J.A. Marcovina S.M. Hughes S.G. Graham M.J. R.M. et al.Antisense oligonucleotides targeting apolipoprotein(a) in with lipoprotein(a): 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). Lp(a) cholesterol was by the Lp(a) in nmol/l to Lp(a) in and by this was by N.J. van Geary R.S. Xia S. J.A. Marcovina S.M. Hughes S.G. Graham M.J. R.M. et al.Antisense oligonucleotides targeting apolipoprotein(a) in with lipoprotein(a): 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). concentrations of Factor fibrinogen and were with and were with at of as previously G. K. A. Yin H. Scipione C. Koschinsky M.L. Chapman M.J. Witztum J.L. Tsimikas S. phospholipids are present on plasminogen, affect fibrinolysis, and increase Am. Coll. Cardiol. 2012; PubMed Scopus Google Scholar). are as ± the between the and in the IONIS-APO(a)Rx were using the from the test was are as of patients in and the between the in the IONIS-APO(a)Rx were using between lysis time and baseline plasma Lp(a) were by and differences in lysis time between Lp(a) and recombinant apo(a) variants were by with or apo(a) variants and concentrations as the and using or The were with of the and biomarkers of fibrinolysis and are in The mean ± SD baseline Lp(a) levels in the placebo and IONIS-APO(a)Rx were 362.1 ± 89.9 nmol/l and 477.3 ± 55.9 The mean of apo(a) was and or which are associated with elevated were present in of The mean ± SD change in Lp(a) was −69.3 ± 12.2% versus −5.4 ± 6.9% (P < 0.0010) at day 85/92/99 and −15.6 ± 8.9% versus 3.2 ± 12.2% (P = 0.003) at day 190 in the IONIS-APO(a)Rx versus The had baseline Lp(a) levels of ± and (n = (n = (n = ± ± ± ± ± ± coronary or or ischemic or ± ± ± of ± ± ± of ± ± of ± ± ± and or ± ± ± ± ± ± ± ± ± ± ± ± cholesterol ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± antigen ± ± ± ± antigen ± ± antigen ± ± placebo to of day 85/92/99 for IONIS-APO(a)Rx and day for of day 190 for IONIS-APO(a)Rx and day for the the between the and in the IONIS-APO(a)Rx were using the or the the between the in the IONIS-APO(a)Rx were using in a placebo to of day 85/92/99 for IONIS-APO(a)Rx and day for of day 190 for IONIS-APO(a)Rx and day for the the between the and in the IONIS-APO(a)Rx were using the or the the between the in the IONIS-APO(a)Rx were using the highly elevated baseline Lp(a) levels and the significant in the mean percentage change or change in lysis times in the or placebo showed no significant differences or any significant were no significant in the biomarkers of fibrinolysis and and no significant between biomarkers and lysis time at any time of antisense therapy on biomarkers in patients with placebo or of of ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 3.2 ± ± ± antigen ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± antigen ± ± ± ± ± ± ± ± ± ± antigen ± ± ± ± ± ± ± ± ± ± placebo to of day of day 190. The between IONIS-APO(a)Rx and placebo were using the or in a placebo to of day of day 190. The between IONIS-APO(a)Rx and placebo were using the or differences in lysis times were in the lysis times in a of with a mean ± SD of ± and of Lp(a) concentrations A and of lysis times were in this and no between Lp(a) and lysis time was In a of ex vivo lysis were using plasma from a with low Lp(a) levels (12.5 nmol/l) with concentrations of purified Lp(a) apo(a) or a of recombinant apo(a). The of Lp(a) up to 200 nmol/l had no on lysis were using purified Lp(a) from with a or not In the of the recombinant apo(a) lysis time the of of apo(a) in the of fibrinolysis, a of recombinant variants of the binding in the in the of the had no on its antifibrinolytic effect. variants than antifibrinolytic effects as they the which lacks and is not had no antifibrinolytic This that potent reductions in Lp(a) in patients with elevated Lp(a) not in significant in ex vivo lysis or in biomarkers of and Lp(a) levels at the of levels, which are or nmol/l N.J. van Geary R.S. Xia S. J.A. Marcovina S.M. Hughes S.G. Graham M.J. R.M. et al.Antisense oligonucleotides targeting apolipoprotein(a) in with lipoprotein(a): 2016; Full Text Full Text PDF PubMed Scopus Google Scholar, S. Tsimikas S. of elevated Lp(a) levels and in patients in the Thromb. Vasc. Biol. 2016; PubMed Scopus Google Scholar). they had very small and had associated with elevated the patients in this the of patients with elevated Lp(a) to have baseline antifibrinolytic These are with studies no association of elevated Lp(a) with deep venous thrombosis (13.Helgadottir A. Gretarsdottir S. Thorleifsson G. Holm H. Patel R.S. Gudnason T. Jones G.T. van Rij A.M. Eapen D.J. Baas A.F. et al.Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism.J. Am. Coll. Cardiol. 2012; 60: 722-729Crossref PubMed Scopus (141) Google Scholar, 14.Kamstrup P.R. Tybjaerg-Hansen A. Nordestgaard B.G. Genetic evidence that lipoprotein(a) associates with atherosclerotic stenosis rather than venous thrombosis.Arterioscler. Thromb. Vasc. Biol. 2012; 32: 1732-1741Crossref PubMed Scopus (123) Google Scholar), which a of thrombosis than or ischemic stroke where atherosclerosis is Lp(a) not a on thrombosis in vivo, and its association with to effects on and atherosclerosis as S. Fazio S. Ferdinand K.C. Ginsberg H.N. Koschinsky M.L. Marcovina S.M. Moriarty P.M. Rader D.J. Remaley A.T. Reyes-Soffer G. et al.NHLBI Working Group recommendations to reduce lipoprotein(a)-mediated risk of cardiovascular disease and aortic stenosis.J. Am. Coll. Cardiol. 2018; 71: 177-192Crossref PubMed Scopus (238) Google Scholar). It is that a is in lysis in with very high Lp(a) levels as as a of a of baseline Lp(a) In with the lack of of Lp(a) lowering on lysis there was no between baseline Lp(a) levels and lysis for the that the ex vivo not in vivo is that prothrombotic effects of Lp(a) in vivo are present the of fibrinolysis and that are not by this previously the of M.L. Sangrar W. Marcovina S.M. Koschinsky M.L. Apolipoprotein(a) to the thrombin Thromb. Vasc. Biol. PubMed Scopus Google Scholar) and of C. G.M. Lipoprotein (a) and tissue factor a between and 98: PubMed Scopus Google Scholar). In have been on the between and lysis times ex vivo D. Green L. M.J. A. Lipoprotein (a), and fibrin Res. Full Text Full Text PDF PubMed Scopus Google Scholar, J. S. S. C. et biomarkers and risk of in the J. 2016; PubMed Scopus Google Scholar). In the not in vivo of plasminogen activity by Lp(a) because the plasma levels of plasminogen or nmol/l) are in to Lp(a) with the levels of Lp(a) at the of levels antifibrinolytic effects of Lp(a) in in which of Lp(a) plasminogen to plasmin to fibrinolysis in Furthermore, Lp(a) with other prothrombotic risk and not have a significant on its (16.Foody J.M. Milberg J.A. Robinson K. Pearce G.L. Jacobsen D.W. Sprecher D.L. Homocysteine and lipoprotein(a) interact to increase CAD risk in young men and women.Arterioscler. Thromb. Vasc. 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These that of apo(a) by of Lp(a) in vivo not of of this the small and to in Furthermore, ex vivo lysis not in vivo of Lp(a) on the in the lysis times for a at the time have any of Lp(a) In conclusion, in patients with highly elevated no evidence that a very potent in Lp(a) ex vivo These the main of Lp(a) to CVD and aortic stenosis its proatherogenic and proinflammatory such as oxidized phospholipids M.B. Koschinsky M.L. phospholipids as a for lipoprotein(a) and cardiovascular Cardiol. 2019; PubMed Scopus Google Scholar). is using and to The Marcovina for purified Lp(a) of with cholesterol LDL cholesterol lipoprotein (a) plasminogen activator inhibitor thrombin activatable fibrinolysis inhibitor tissue-type plasminogen activator

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