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Lipoprotein(a)—antisense therapy

Lipoprotein(a)—antisense therapy Elevated levels of lipoprotein(a) (Lp(a)) contribute to the risk of early and severe cardiovascular disease (CVD) and Lp(a) is acknowledged as a risk factor to be included in risk assessment. The established lipid-modifying medical therapies do not lower Lp(a) except niacin but no data of endpoint trials are available. Of the new lipid-modifying drugs a few have some impact on Lp(a). Whether the Lp(a) lowering effect contributes to the reduction of CVD events would have to be shown in Lp(a) dedicated trials. None of the available agents is indicated to lower Lp(a). Lipoprotein apheresis lowers levels of Lp(a) significantly by >60% per treatment. Trial data and data of the German Lipoprotein Apheresis Registry show that regular apheresis reduces cardiovascular events. The Apo(a) antisense oligonucleotide is the only approach to specifically lower Lp(a). The IONIS-APO(a) phase 1 and 2 trials showed very substantial decreases of Lp(a) and good Rx tolerability. The hepatospecific variant IONIS-APO(a)-L is 30 times more potent. The results of the IONIS-APO(a)-L Rx Rx phase 2 trial were presented recently. The highest dosages reduced Lp(a) by 72 and 80%; in about 81 and 98% Lp(a) levels <50 mg/dl were achieved. Tolerability and safety were confirmed, whereby injection site reactions were the most common side effects. This raises hope that the planned phase 3 trial will reproduce these findings and show a reduction of cardiovascular events. Keywords LDL-Cholesterol · Lipid lowering therapy · Antisense oligonucleotides · Atherosclerosis · Cardiovascular disease Introduction rosis Society/European Society of Cardiology (EAS/ESC) Guidelines [13] and are considered to be a risk-enhancing In 1963 Berg described the lipoprotein(a) (Lp(a)) system factor by the 2018 American Heart Association/American in man, was the first to note that the individual level of College of Cardiology (AHA/ACC) Guideline [14]. The Lp(a) is inherited and that high levels are associated with consensus paper of the European Atherosclerosis Society early onset of atherosclerosis [1]. In the following decades gives a comprehensive overview of Lp(a) as a cardiovascu- epidemiological data supported the initial findings, genetic lar risk factor [15]. The authors suggest measuring Lp(a) trials confirmed that Lp(a) is a causal factor for develop- in individuals at intermediate or high risk of CVD, in case ing atherosclerosis, and the negative impact of high levels of premature CVD, familial hypercholesterolaemia, family of Lp(a) not only on coronary heart disease but also on history of premature CVD or high Lp(a), progressive CVD development of aortic stenosis, peripheral arterial disease, despite statin therapy, ≥3% 10-year risk of fatal CVD (Eu- and ischaemic stroke was shown [2–12]. On the other hand ropean SCORE), or ≥10% 10-year risk of fatal or non-fatal much is still almost unknown, e. g. the physiological role of coronary heart disease (US guidelines). Lowering LDL-c Lp(a), the catabolism, and the clinical relevance in throm- remains the first priority. Secondary a Lp(a) level <50 mg/dl botic and embolic events. High levels of Lp(a) are acknowl- (~ <80th percentile) is suggested as desirable. The some- edged as being associated with an increased risk of cardio- what arbitrary cut off level of 30 mg/dl is often used based vascular disease (CVD) by the 2016 European Atheroscle- on data showing the continuous increase of risk with in- creasing levels of Lp(a) and without an obvious threshold value [10]. Since no endpoint data are available no target This article is part of the special issue “Lp(a) – Update 2018” level can be specified. Anja Vogt Anja.Vogt@med.uni-muenchen.de Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstraße 1, 80336 Munich, Germany K 52 A. Vogt Treatment options the target or a primary endpoint. Since all agents primarily lower LDL-c it would be difficult to show if the Lp(a) lower- For statins, the backbone treatment for preventing and re- ing effect is clinically relevant, as with niacin. Of these, only ducing cardiovascular events by lowering LDL-c, small de- PCSK9 inhibitors are widely available. Both evolocumab creases or increases of Lp(a) have been shown [16]. But and alirocumab lower LDL-c about 50 to 60% and in some mostly Lp(a) is not affected by statins [15, 17, 18]. The trials the lowering of Lp(a) was assessed, too. The mecha- same is seen for ezetimibe [19]. nism by which Lp(a) is reduced is matter of debate. With Nicotinic acid (niacin) has a broad range of lipid-mod- evolocumab reductions of 25.5% [37] and with alirocumab ifying effects, lowering LDL-c and triglycerides and in- reductions of 30.2% [38] were reported. A pooled anal- creasing high density lipoprotein-cholesterol (HDL-c). In ysis [39] of three phase 2 trials using alirocumab for 8 or addition it was shown to lower Lp(a) for the first time in 12 weeks analysed the Lp(a) lowering effect. Levels ranged 1989 [20]. High doses of nicotinic acid (2000–4000 mg) from 2 to 181 mg/dl and the two groups consisted of par- are needed to reduce Lp(a) significantly [21]. However, ticipants with baseline levels of 50 mg/dl and ≥50 mg/dl. this effect has not yet been shown in patients with high The median absolute reduction was 3.5 and 27 mg/dl, re- baseline levels of Lp(a) with regard to the inclusion crite- spectively, the median percent reduction 36 and 27%, re- rion. A meta-analysis has summarised the beneficial effects spectively. Interestingly in patients with LDL-receptor neg- of nicotinic acid on cardiovascular events [22], but it was ative homozygous FH evolocumab reduced Lp(a) by 20% not evaluated if the benefit is attributable to reduced lev- while LDL-c did not decrease [40]. The upregulation of els of Lp(a). Additionally the positive effects are mainly other receptors, e. g. the very low density (VLDL) recep- from the pre-statin era. The EAS consensus paper states tor that mediates the uptake of Lp(a) into macrophages, that niacin should be used to reduce high levels of Lp(a) might be an explanation for this finding. There are further because of the evidence and despite the fact that it cannot contradictory results by what mechanism Lp(a) is reduced. be excluded that the benefits are not attributed to lower- Some data show an increased catabolic fraction rate, oth- ing Lp(a) but to the favorable effects on other lipoproteins ers a reduced synthesis [41]. In the FOURIER trial Lp(a) [15]. In 2013 the combination of extended release niacin was reduced significantly by evolocumab and participants and laropiprant, a flush inhibitor, was withdrawn from the with higher absolute reductions of Lp(a) tended towards a European market after the Heart Protection Study 2—Treat- greater benefit [42]. ment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) was stopped early because of a significant Antisense oligonucleotides increase in bleeding events, including intracranial haemor- rhage [23]. Although the reasons have not been elucidated the use of nicotinic acid continues to be debated. Antisense oligonucleotide (ASO) drugs are a relatively new Lipoprotein apheresis (LA) as an extracorporeal method way to very specifically target genes on the mRNA level and lowers LDL-c and Lp(a) acutely and significantly by are used in different medical fields. Mipomersen, the first 60–70% but has to be applied regularly (mostly weekly). ASO used in hypercholesterolaemia, interferes with the en- Few countries consider high levels of Lp(a) to be an indi- coding mRNA for ApoB100. The production of ApoB100 cation for lipoprotein apheresis in very high-risk patients is reduced via inhibition of translation to the protein. Con- if all other cardiovascular risk factors, mainly LDL-c, are sequently less very low density lipoprotein (VLDL) is as- treated optimally [24–27]. sembled in the liver resulting in lower levels of circulat- Beneficial effects of LA on the course of CVD are shown ing LDL-c. As a side effect, less triglycerides are excreted by retrospective evaluations, prospective (but not blinded, from the liver and accumulate often leading to fatty liver randomized controlled) trials, and analyses of the German disease and elevated transaminases [43, 44]. By what mech- Lipoprotein Apheresis Registry [28–35]. LA is generally anism levels of Lp(a) are lowered is not entirely clear. In well tolerated and safe [27, 36] but time consuming, ex- four phase 3 trials mipomersen given subcutaneously ver- pensive, only offered in specialised centres, and often not sus placebo levels of Lp(a) were significantly reduced by covered by health insurance. 21–39% [45]. Thus mipomersen might reduce the neces- sity for lipoprotein apheresis in high-risk patients [46, 47]. The most common side effects were severe injection site New drug developments reactions and liver steatosis is also of concern. Because of the side effects mipomersen was not widely approved and Several new lipid-modifying drugs to reduce LDL-c are is available in the USA only. currently under investigation. They lower LDL-c and Lp(a) to varying degrees though lowering of Lp(a) has never been K Lp(a)—antisense therapy 53 Apo(a) antisense oligonucleotide tion of 10, 40, 80, or 120 mg versus placebo. In the multi- ple-dose phase (n = 30) IONIS-APO(a)L 10 mg, 20 mg, or Rx IONIS-APO(a) , an antisense oligonucleotide molecule, 40 mg were administered at days 1, 3, 5, 8, 15, and 22 ver- Rx is the first measure developed to specifically address the sus placebo. The primary efficacy endpoint was reduction mRNA of Apo(a). Trials in transgenic mice [48] and phase 1 of Lp(a) at day 30 (single-dose phase) and day 36 (multi- results showed relevant decreases of Lp(a). In a phase 1 ple-dose phase). Baseline levels of Lp(a) were 147.8 nmol/l trial in healthy volunteers (Lp(a) levels ≥25 nmol/l) IO- (mean) and 128.6 nmol/l (median) in the single-dose phase NIS-APO(a) significantly lowered Lp(a) in a dose-depen- and 153.8 nmol/l (mean) and 145.6 nmol/l (median) in the Rx dent manner. The highest dose of 300 mg reduced Lp(a) by multiple-dose phase. 77.8%. In one individual the maximal reduction was 88.8% In the single ascending dose phase Lp(a) was reduced after 36 days. Impressively Lp(a) did not increase imme- significantly in a dose-dependent manner at day 30. The diately but was still low 84 days after the last application mean treatment differences versus placebo (+2.8%) were [49]. Theuse was safeand themostcommon sideeffects 24.8% (10 mg group), 35.1% (20 mg group), 48.2% (40 mg were injection site reactions. As a ligand-conjugated variant group), 82.5% (80 mg group), and 84.5% (120 mg group). of IONIS-APO(a) the hepatocyte specific IONIS-APO(a)- The reduction was still significant after 90 days (46% in Rx L was developed. The triantennary N-acetylgalactosamine the 80 mg group and 44% in the 120 mg group). Also Rx complex (GalNAc ) facilitates the fast and specific uptake in the multiple ascending dose phase Lp(a) was reduced by hepatocytes [50]. This modification enhanced the po- significantly. The treatment differences versus placebo tency of the Apo(a)-ASO by >30 times [51]. Since Apo(a) were 59.4% (10 mg group), 72.3 (20 mg group), and 82.4% is targeted VLDL is produced and there is no fat accumu- (40 mg group). At day 113 after the last application the low- lation in the liver. ering effect was still significant with 39% (10 mg group), The IONIS-APO(a) phase 2 trial confirmed the positive 53% (20 mg group), and 58% (40 mg group). Rx results regarding effectivity and safety [51]. In 64 partic- The results of the biggest conducted IONIS-APO(a)-L Rx ipants IONIS-APO(a) was applied subcutaneously in an (AKCEA-APO(a)-L ) phase 2 trial were presented at the Rx Rx escalating-dose manner for 12 weeks (100 mg, 200 mg, and AHA Scientific Sessions, Late-Breaking Clinical Trial Pre- 300 mg, each once a week for 4 weeks) versus placebo. sentation, on 10 November 2018 [52]. The trial was a ran- Two cohorts were formed according to Lp(a) baseline domized, double-blind, placebo-controlled, and dose-rang- levels: cohort A: Lp(a) 125–437 nmol/l (placebo group: ing trial in 286 patients with established CVD and high mean 251.6 nmol/l and median 216.3 nmol/l, verum group: levels of Lp(a) (baseline mean of approximately 100 mg/dl mean 254 nmol/l, median 261.4 nmol/l) and cohort B: Lp(a) [250 nmol/l]). Five cohorts were compared: 20 mg were ad- ≥438 nmol/l (placebo group: mean 488.3 nmol/l and me- ministered every 4 weeks, 40 mg every 4 weeks, 20 mg ev- dian 498.3 nmol/l, verum group: mean 444.9 nmol/l, median ery 2 weeks, 60 mg every 4 weeks, and 20 mg every week, 457.6 nmol/l). The primary efficacy endpoint was reduction each for 6–12 months. The primary efficacy endpoint was of Lp(a) at day 85 or 99. Secondary endpoints were effects percent change in Lp(a) from baseline at 6 months. on other lipoproteins and risk factors. AKCEA-APO(a)-LRx decreased Lp(a) in all groups In both cohorts Lp(a) was reduced significantly: co- (20 mg every 4 weeks: –35%, 40 mg every 4 weeks –56%, hort A—66.8%, cohort B—71.6% at day 85/99. Addition- 20 mg every 2 weeks: –58%). The effect was even greater ally, levels of LDL-c, ApoB, and oxidised phospholipids in the highest doses (60 mg every 4 weeks: –72%, 20 mg (OxPL) were reduced significantly in both cohorts. LDL- weekly: –80%) and in about 81% and 98%, respectively, c was lowered by 13.0% in cohort A and by 23.9% in co- Lp(a) levels <50 mg/dl were achieved. The completion rate hort B, ApoB by 11.3 and 18.5%, respectively, OxPL-ApoB was high (90%) and comparable in both groups (verum by 35.2 and 42.5%, respectively, and OxLP-Apo(a) 26.6 and 12.1%, placebo 14.9%). There were no severe safety con- 36.7%, respectively. Baseline statin therapy had no signif- cerns and few adverse events. Injection site reactions were icant effect on these results. The treatment was safe and the most common (26%) with one patient discontinuing. well tolerated. Two myocardial infarctions and one episode of angina pectoris in high-risk patients were not assessed as treatment related. Injection site reactions occurred in 10% Conclusion in cohort A and in 19% in cohort B (one participant stopped treatment). The new developments of lipid-modifying drugs will allow Another phase 1/2a first-in-man trial [51] was done with a more effective reduction of LDL-c and Lp(a) and a more the GalNAc modified IONIS-APO(a)-L in healthy vol- patient-individualised therapy. LDL-c treatment goals and 3 Rx unteers with levels of Lp(a) ≥75 nmol/l. In the single-dose even lower levels than recommended by guidelines today phase participants (n = 28) received one subcutaneous injec- can be reached. The first outcome trials show that car- K 54 A. Vogt Study. Circulation 117(2):176–184. https://doi.org/10.1161/ diovascular events are reduced as a consequence. If the CIRCULATIONAHA.107.715698 Lp(a) lowering capacity of PCSK9 inhibitors contributes to 4. Laschkolnig A, Kollerits B, Lamina C, Meisinger C, Rantner B, this favourable outcome is unclear. IONIS-APO(a) is the Rx Stadler M, Peters A, Koenig W, Stockl A, Dahnhardt D, Boger CA, first antisense oligonucleotide to reduce specifically Lp(a). Kramer BK, Fraedrich G, Strauch K, Kronenberg F (2014) Lipopro- tein (a) concentrations, apolipoprotein (a) phenotypes, and periph- Phase 1 and 2 trials showed the significant reduction of eral arterial disease in three independent cohorts. Cardiovasc Res Lp(a) and a very promising safety profile. The GalNAc 103(1):28–36. https://doi.org/10.1093/cvr/cvu107 modified molecule IONIS-APO(a)-L was developed for Rx 5. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG (2014) Ele- fast and specific uptake by hepatocytes which increased the vated lipoprotein(a) and risk of aortic valve stenosis in the general population. J Am Coll Cardiol 63(5):470–477. https://doi.org/10. potency more than 30 times. The highest dose of AKCEA- 1016/j.jacc.2013.09.038 APO(a)-L reduced Lp(a) in the phase 2a trial by 80% and Rx 6. Kronenberg F, Utermann G (2013) Lipoprotein(a): resurrected by in 98% of the participants Lp(a) was lowered to <50 mg/dl, genetics. J Intern Med 273(1):6–30. https://doi.org/10.1111/j.1365- the recommended threshold. 2796.2012.02592.x 7. Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, The high effectivity and the favourable tolerability and Parish S, Barlera S, Franzosi MG, Rust S, Bennett D, Silveira A, safety data of these trials raise the expectation that an out- Malarstig A, Green FR, Lathrop M, Gigante B, Leander K, de Faire come trial might reproduce these findings and that this U, Seedorf U, Hamsten A, Collins R, Watkins H, Farrall M, Con- significant reduction of Lp(a) might reduce cardiovascu- sortium P (2009) Genetic variants associated with Lp(a) lipopro- tein level and coronary disease. N Engl J Med 361(26):2518–2528. lar events. The data regarding reduction of cardiovascular https://doi.org/10.1056/NEJMoa0902604 events by lowering Lp(a) via lipoprotein apheresis sup- 8. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG port this expectation. AKCEA-APO(a)-L reduces other Rx (2009) Genetically elevated lipoprotein(a) and increased risk of my- lipoproteins and oxidised phospholipids which might con- ocardial infarction. JAMA 301(22):2331–2339. https://doi.org/10. 1001/jama.2009.801 tribute to the expected beneficial clinical effects. 9. Kraft HG, Lingenhel A, Kochl S, Hoppichler F, Kronenberg F, Abe The Apo(a)-ASO is the first drug to lower Lp(a) specifi- A, Muhlberger V, Schonitzer D, Utermann G (1996) Apolipopro- cally, to a great extent, and with a promising safety profile. tein(a) kringle IV repeat number predicts risk for coronary heart This, for the first time, will allow cardiovascular end point disease. Arterioscler Thromb Vasc Biol 16(6):713–719 10. Kronenberg F, Kronenberg MF, Kiechl S, Trenkwalder E, San- trials elucidating if lowering Lp(a) specifically reduces car- ter P, Oberhollenzer F, Egger G, Utermann G, Willeit J (1999) diovascular events. Role of lipoprotein(a) and apolipoprotein(a) phenotype in athero- genesis: prospective results from the Bruneck study. Circulation Compliance with ethical guidelines 100(11):1154–1160 11. Kronenberg F, Neyer U, Lhotta K, Trenkwalder E, Auinger M, Prib- Conflict of interest A. Vogt has received speakers’ honoraria for pre- asnig A, Meisl T, Konig P, Dieplinger H (1999) The low molecu- sentations and advisory board activities by Aegerion, Amgen, Berlin lar weight apo(a) phenotype is an independent predictor for coro- Chemie, Fresenius, Genzyme, a Sanofi company, Kaneka, OmniaMed, nary artery disease in hemodialysis patients: a prospective follow- Regeneron, Sanofi. AV has received research support by Merck Sharp up. J Am Soc Nephrol 10(5):1027–1036 & Dohme. 12. Sandholzer C, Saha N, Kark JD, Rees A, Jaross W, Dieplinger H, Hoppichler F, Boerwinkle E, Utermann G (1992) Apo(a) isoforms Ethical standards This article does not contain any studies with human predict risk for coronary heart disease. A study in six populations. participants or animals performed by any of the authors. Arterioscler Thromb 12(10):1214–1226 13. Authors/Task Force M, Piepoli MF, Hoes AW, Agewall S, Albus C, Open Access This article is distributed under the terms of the Brotons C, Catapano AL, Cooney MT, Corra U, Cosyns B, Deaton Creative Commons Attribution 4.0 International License (http:// C, Graham I, Hall MS, Hobbs FD, Lochen ML, Lollgen H, Mar- creativecommons.org/licenses/by/4.0/), which permits unrestricted ques-Vidal P, Perk J, Prescott E, Redon J, Richter DJ, Sattar N, use, distribution, and reproduction in any medium, provided you give Smulders Y, Tiberi M, van der Worp HB, van Dis I, Verschuren appropriate credit to the original author(s) and the source, provide a WM, Additional Contributor: Simone B, Document R, De Backer link to the Creative Commons license, and indicate if changes were G, Roffi M, Aboyans V, Bachl N, Bueno H, Carerj S, Cho L, Cox made. J, De Sutter J, Egidi G, Fisher M, Fitzsimons D, Franco OH, Gue- noun M, Jennings C, Jug B, Kirchhof P, Kotseva K, Lip GY, Mach F, Mancia G, Bermudo FM, Mezzani A, Niessner A, Ponikowski P, References Rauch B, Ryden L, Stauder A, Turc G, Wiklund O, Windecker S, Zamorano JL (2016) 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of 1. Berg K (1963) A new serum type system in man—the Lp system. the European Society of Cardiology and Other Societies on Cardio- Acta Pathol Microbiol Scand 59:369–382 vascular Disease Prevention in Clinical Practice (constituted by rep- 2. Erqou S, Thompson A, Di Angelantonio E, Saleheen D, Kaptoge S, resentatives of 10 societies and by invited experts): Developed with Marcovina S, Danesh J (2010) Apolipoprotein(a) isoforms and the the special contribution of the European Association for Cardiovas- risk of vascular disease: systematic review of 40 studies involving cular Prevention & Rehabilitation (EACPR). Eur J Prev Cardiol 23 58,000 participants. J Am Coll Cardiol 55(19):2160–2167. https:// (11):NP1–NP96. https://doi.org/10.1177/2047487316653709 doi.org/10.1016/j.jacc.2009.10.080 14. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blu- 3. Kamstrup PR, Benn M, Tybjaerg-Hansen A, Nordestgaard BG menthal RS, Braun LT, Braun LT, de Ferranti S, Faiella-Tom- (2008) Extreme lipoprotein(a) levels and risk of myocardial in- masino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, farction in the general population: the Copenhagen City Heart K Lp(a)—antisense therapy 55 Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Or- ness of lipid apheresis treatment to reduce high lipoprotein(a) levels ringer CE, Peralta CA, Saseen JJ, Smith SC Jr., Sperling L, Virani and prevent major adverse coronary events. Nat Clin Pract Cardio- SS, Yeboah J (2018) 2018 AHA/ACC/AACVPR/AAPA/ABC/ vasc Med 6(3):229–239. https://doi.org/10.1038/ncpcardio1456 ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the 29. Rosada A, Kassner U, Vogt A, Willhauck M, Parhofer K, Stein- Management of Blood Cholesterol: Executive Summary: A Report hagen-Thiessen E (2014) Does regular lipid apheresis in patients of the American College of Cardiology/American Heart Associa- with isolated elevated lipoprotein(a) levels reduce the incidence of tion Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. cardiovascular events? Artif Organs 38(2):135–141. https://doi.org/ https://doi.org/10.1016/j.jacc.2018.11.002 10.1111/aor.12135 15. Nordestgaard BG, Chapman MJ, Ray K, Boren J, Andreotti F, Watts 30. Schettler VJ, Neumann CL, Peter C, Zimmermann T, Julius U, Roe- GF, Ginsberg H, Amarenco P, Catapano A, Descamps OS, Fisher seler E, Heigl F, Ramlow W, Blume H, Scientific Board of Gft- E, Kovanen PT, Kuivenhoven JA, Lesnik P, Masana L, Reiner Z, GAWG (2015) First data from the German Lipoprotein Apheresis Taskinen MR, Tokgozoglu L, Tybjaerg-Hansen A (2010) Lipopro- Registry (GLAR). Atheroscler Suppl 18:41–44. https://doi.org/10. tein(a) as a cardiovascular risk factor: current status. Eur Heart J 1016/j.atherosclerosissup.2015.02.006 31(23):2844–2853. https://doi.org/10.1093/eurheartj/ehq386 31. Schettler VJJ, Neumann CL, Peter C, Zimmermann T, Julius U, 16. Khera AV, Everett BM, Caulfield MP, Hantash FM, Wohlgemuth Roeseler E, Heigl F, Grutzmacher P, Blume H, Scientific Board J, Ridker PM, Mora S (2014) Lipoprotein(a) concentrations, ro- of GftGAWG (2017) Current insights into the German Lipopro- suvastatin therapy, and residual vascular risk: an analysis from tein Apheresis Registry (GLAR)—Almost 5 years on. Atheroscler the JUPITER Trial (Justification for the Use of Statins in Preven- Suppl 30:50–55. https://doi.org/10.1016/j.atherosclerosissup.2017. tion: an Intervention Trial Evaluating Rosuvastatin). Circulation 05.006 129(6):635–642. https://doi.org/10.1161/CIRCULATIONAHA. 32. Leebmann J, Roeseler E, Julius U, Heigl F, Spitthoever R, Heut- 113.004406 ling D, Breitenberger P, Maerz W, Lehmacher W, Heibges A, 17. Kei A, Liberopoulos E, Tellis K, Rizzo M, Elisaf M, Tselepis A Klingel R, ProLiFe Study G (2013) Lipoprotein apheresis in pa- (2013) Effect of hypolipidemic treatment on emerging risk factors tients with maximally tolerated lipid-lowering therapy, lipopro- in mixed dyslipidemia: a randomized pilot trial. Eur J Clin Invest tein(a)-hyperlipoproteinemia, and progressive cardiovascular dis- 43(7):698–707. https://doi.org/10.1111/eci.12095 ease: prospective observational multicenter study. Circulation 18. Tziomalos K, Athyros VG, Wierzbicki AS, Mikhailidis DP (2009) 128(24):2567–2576. https://doi.org/10.1161/CIRCULATIONAHA. Lipoprotein a: where are we now? Curr Opin Cardiol 24(4):351– 113.002432 357. https://doi.org/10.1097/HCO.0b013e32832ac21a 33. Roeseler E, Julius U, Heigl F, Spitthoever R, Heutling D, Breiten- 19. Moutzouri E, Liberopoulos EN, Tellis CC, Milionis HJ, Tselepis berger P, Leebmann J, Lehmacher W, Kamstrup PR, Nordestgaard AD, Elisaf MS (2013) Comparison of the effect of simvastatin BG, Maerz W, Noureen A, Schmidt K, Kronenberg F, Heibges versus simvastatin/ezetimibe versus rosuvastatin on markers of A, Klingel R, ProLiFe-Study G (2016) Lipoprotein apheresis for inflammation and oxidative stress in subjects with hypercholes- lipoprotein(a)-associated cardiovascular disease: prospective 5 terolemia. Atherosclerosis 231(1):8–14. https://doi.org/10.1016/j. years of follow-up and apolipoprotein(a) characterization. Arte- atherosclerosis.2013.08.013 rioscler Thromb Vasc Biol 36(9):2019–2027. https://doi.org/10. 20. Carlson LA, Hamsten A, Asplund A (1989) Pronounced lowering 1161/ATVBAHA.116.307983 of serum levels of lipoprotein Lp(a) in hyperlipidaemic subjects 34. Safarova MS, Ezhov MV, Afanasieva OI, Matchin YG, Atanesyan treated with nicotinic acid. J Intern Med 226(4):271–276 RV, Adamova IY, Utkina EA, Konovalov GA, Pokrovsky SN 21. Goldberg A, Alagona P Jr., Capuzzi DM, Guyton J, Morgan JM, (2013) Effect of specific lipoprotein(a) apheresis on coronary Rodgers J, Sachson R, Samuel P (2000) Multiple-dose efficacy and atherosclerosis regression assessed by quantitative coronary an- safety of an extended-release form of niacin in the management of giography. Atheroscler Suppl 14(1):93–99. https://doi.org/10.1016/ hyperlipidemia. Am J Cardiol 85(9):1100–1105 j.atherosclerosissup.2012.10.015 22. Bruckert E, Labreuche J, Amarenco P (2010) Meta-analysis of 35. von Dryander M, Fischer S, Passauer J, Muller G, Bornstein the effect of nicotinic acid alone or in combination on cardiovas- SR, Julius U (2013) Differences in the atherogenic risk of pa- cular events and atherosclerosis. Atherosclerosis 210(2):353–361. tients treated by lipoprotein apheresis according to their lipid https://doi.org/10.1016/j.atherosclerosis.2009.12.023 pattern. Atheroscler Suppl 14(1):39–44. https://doi.org/10.1016/j. 23. Group HTC, Landray MJ, Haynes R, Hopewell JC, Parish S, Aung atherosclerosissup.2012.10.005 T, Tomson J, Wallendszus K, Craig M, Jiang L, Collins R, Ar- 36. Winters JL (2011) Lipid apheresis, indications, and principles. mitage J (2014) Effects of extended-release niacin with laropiprant J Clin Apher 26(5):269–275. https://doi.org/10.1002/jca .20299 in high-risk patients. N Engl J Med 371(3):203–212. https://doi.org/ 37. Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robin- 10.1056/NEJMoa1300955 son J, Ballantyne CM, Somaratne R, Legg J, Wasserman SM, Scott 24. Bundesausschuss G (2010) Richtlinie des Gemeinsamen Bunde- R, Koren MJ, Stein EA, Open-Label Study of Long-Term Evalu- sausschusses zu Untersuchungs- und Behandlungsmethoden der ation against LDLCI (2015) Efficacy and safety of evolocumab in vertragsärztlichen Versorgung. Bundesanzeiger 109:2561 reducing lipids and cardiovascular events. N Engl J Med. https:// 25. Derfler K, Steiner S, Sinzinger H (2015) Lipoprotein-apheresis: doi.org/10.1056/NEJMoa1500858 Austrian consensus on indication and performance of treatment. 38. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna Wien Klin Wochenschr 127(15–16):655–663. https://doi.org/10. M, Stroes ES, Langslet G, Raal FJ, Shahawy ME, Koren MJ, Lepor 1007/s00508-015-0833-4 NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein JJ, Investigators 26. Stefanutti C (2010) The 2009 2nd Italian Consensus Conference OLT (2015) Efficacy and safety of alirocumab in reducing lipids on LDL-apheresis. Nutr Metab Cardiovasc Dis 20(10):761–762. and cardiovascular events. N Engl J Med. https://doi.org/10.1056/ https://doi.org/10.1016/j.numecd.2010.04.007 NEJMoa1501031 27. Thompson GR (2008) Recommendations for the use of LDL 39. Gaudet D, Kereiakes DJ, McKenney JM, Roth EM, Hanotin C, apheresis. Atherosclerosis 198(2):247–255. https://doi.org/10. Gipe D, Du Y, Ferrand AC, Ginsberg HN, Stein EA (2014) Effect 1016/j.atherosclerosis.2008.02.009 of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 28. Jaeger BR, Richter Y, Nagel D, Heigl F, Vogt A, Roeseler E, 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of Parhofer K, Ramlow W, Koch M, Utermann G, Labarrere CA, Sei- 150 mg every two weeks dosing from phase 2 trials). Am J Cardiol del D, Group of (2009) Longitudinal cohort study on the effective- 114(5):711–715. https://doi.org/10.1016/j.amjcard.2014.05.060 K 56 A. Vogt 40. Raal FJ, Honarpour N, Blom DJ, Hovingh GK, Xu F, Scott R, 47. Waldmann E, Vogt A, Crispin A, Altenhofer J, Riks I, Parhofer Wasserman SM, Stein EA, Investigators T (2015) Inhibition of KG (2018) Corrigendum to: “Effect of mipomersen on LDL- PCSK9 with evolocumab in homozygous familial hypercholes- cholesterol in patients with severe LDL-hypercholesterolaemia terolaemia (TESLA Part B): a randomised, double-blind, placebo- and atherosclerosis treated by lipoprotein apheresis (The MICA- controlled trial. Lancet 385(9965):341–350. https://doi.org/10. Study). Atherosclerosis 275:461–462. https://doi.org/10.1016/j. 1016/S0140-6736(14)61374-X atherosclerosis.2018.05.020 41. Desai NR, Kohli P, Giugliano RP, O’Donoghue ML, Somaratne R, 48. Merki E, Graham M, Taleb A, Leibundgut G, Yang X, Miller ER, Zhou J, Hoffman EB, Huang F, Rogers WJ, Wasserman SM, Scott Fu W, Mullick AE, Lee R, Willeit P, Crooke RM, Witztum JL, R, Sabatine MS (2013) AMG145, a monoclonal antibody against Tsimikas S (2011) Antisense oligonucleotide lowers plasma lev- proprotein convertase subtilisin kexin type 9, significantly reduces els of apolipoprotein (a) and lipoprotein (a) in transgenic mice. lipoprotein(a) in hypercholesterolemic patients receiving statin J Am Coll Cardiol 57(15):1611–1621. https://doi.org/10.1016/j. therapy: an analysis from the LDL-C Assessment with Proprotein jacc.2010.10.052 Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibi- 49. Tsimikas S, Viney NJ, Hughes SG, Singleton W, Graham MJ, Baker tion Combined with Statin Therapy (LAPLACE)-Thrombolysis in BF, Burkey JL, Yang Q, Marcovina SM, Geary RS, Crooke RM, Myocardial Infarction (TIMI) 57 trial. Circulation 128(9):962–969. Witztum JL (2015) Antisense therapy targeting apolipoprotein(a): https://doi.org/10.1161/CIRCULATIONAHA.113.001969 a randomised, double-blind, placebo-controlled phase 1 study. 42. O’Donoghue ML, Fazio S, Giugliano RP, Stroes ESG, Kanevsky E, Lancet 386(10002):1472–1483. https://doi.org/10.1016/S0140- Gouni-Berthold I et al (2018) Lipoprotein(a), PCSK9 inhibition and 6736(15)61252-1 cardiovascular risk: insights from the FOURIER trial. Circulation. 50. Prakash TP, Graham MJ, Yu J, Carty R, Low A, Chappell A, https://doi.org/10.1161/CIRCULATIONAHA.118.037184 Schmidt K, Zhao C, Aghajan M, Murray HF, Riney S, Booten SL, 43. Parhofer KG (2012) Mipomersen: evidence-based review of its po- Murray SF, Gaus H, Crosby J, Lima WF, Guo S, Monia BP, Swayze tential in the treatment of homozygous and severe heterozygous fa- EE, Seth PP (2014) Targeted delivery of antisense oligonucleotides milial hypercholesterolemia. Core Evid 7:29–38. https://doi.org/10. to hepatocytes using triantennary N-acetyl galactosamine improves 2147/CE.S25239 potency 10-fold in mice. Nucleic Acids Res 42(13):8796–8807. 44. Rader DJ, Kastelein JJ (2014) Lomitapide and mipomersen: two https://doi.org/10.1093/nar/gku531 first-in-class drugs for reducing low-density lipoprotein choles- 51. Viney NJ, van Capelleveen JC, Geary RS, Xia S, Tami JA, Yu terol in patients with homozygous familial hypercholesterolemia. RZ, Marcovina SM, Hughes SG, Graham MJ, Crooke RM, Crooke Circulation 129(9):1022–1032. https://doi.org/10.1161/ ST, Witztum JL, Stroes ES, Tsimikas S (2016) Antisense oligonu- CIRCULATIONAHA.113.001292 cleotides targeting apolipoprotein(a) in people with raised lipopro- 45. Santos RD, Raal FJ, Catapano AL, Witztum JL, Steinhagen- tein(a): two randomised, double-blind, placebo-controlled, dose- Thiessen E, Tsimikas S (2015) Mipomersen, an antisense oligonu- ranging trials. Lancet 388(10057):2239–2253. https://doi.org/10. cleotide to apolipoprotein B-100, reduces lipoprotein(a) in various 1016/S0140-6736(16)31009-1 populations with hypercholesterolemia: results of 4 phase III trials. 52. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif Arterioscler Thromb Vasc Biol 35(3):689–699. https://doi.org/10. JC, Baum S, Steinhagen-Thiessen E, Shapiro M, Stroes E, Mori- 1161/ATVBAHA.114.304549 arty P, Nordestgaard B, Guerriero J, Viney N, O’Dea L, Witztum J, 46. Waldmann E, Vogt A, Crispin A, Altenhofer J, Riks I, Parhofer AKCEA-APO(a)-LRx Study Investigators (2018) Safety and effi- KG (2017) Effect of mipomersen on LDL-cholesterol in pa- cacy of AKCEA-APO(a)-LRx to lower lipoprotein(a) levels in pa- tients with severe LDL-hypercholesterolaemia and atherosclerosis tients with established cardiovascular disease: A phase 2 dose-rang- treated by lipoprotein apheresis (The MICA-Study). Atheroscle- ing trial. https://www.tctmd.com/slide/safety-and-efficacy-akcea- rosis 259:20–25. https://doi.org/10.1016/j.atherosclerosis.2017.02. apoa-lrx-lower-lipoproteina-levels-patients-established. Accessed 019 14 Jan 2019 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Research in Cardiology Supplements Springer Journals

Lipoprotein(a)—antisense therapy

Clinical Research in Cardiology Supplements , Volume 14 (1) – Mar 11, 2019

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Medicine & Public Health; Cardiology; Internal Medicine; Angiology; Cardiac Surgery; Diagnostic Radiology
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10.1007/s11789-019-00096-2
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Abstract

Elevated levels of lipoprotein(a) (Lp(a)) contribute to the risk of early and severe cardiovascular disease (CVD) and Lp(a) is acknowledged as a risk factor to be included in risk assessment. The established lipid-modifying medical therapies do not lower Lp(a) except niacin but no data of endpoint trials are available. Of the new lipid-modifying drugs a few have some impact on Lp(a). Whether the Lp(a) lowering effect contributes to the reduction of CVD events would have to be shown in Lp(a) dedicated trials. None of the available agents is indicated to lower Lp(a). Lipoprotein apheresis lowers levels of Lp(a) significantly by >60% per treatment. Trial data and data of the German Lipoprotein Apheresis Registry show that regular apheresis reduces cardiovascular events. The Apo(a) antisense oligonucleotide is the only approach to specifically lower Lp(a). The IONIS-APO(a) phase 1 and 2 trials showed very substantial decreases of Lp(a) and good Rx tolerability. The hepatospecific variant IONIS-APO(a)-L is 30 times more potent. The results of the IONIS-APO(a)-L Rx Rx phase 2 trial were presented recently. The highest dosages reduced Lp(a) by 72 and 80%; in about 81 and 98% Lp(a) levels <50 mg/dl were achieved. Tolerability and safety were confirmed, whereby injection site reactions were the most common side effects. This raises hope that the planned phase 3 trial will reproduce these findings and show a reduction of cardiovascular events. Keywords LDL-Cholesterol · Lipid lowering therapy · Antisense oligonucleotides · Atherosclerosis · Cardiovascular disease Introduction rosis Society/European Society of Cardiology (EAS/ESC) Guidelines [13] and are considered to be a risk-enhancing In 1963 Berg described the lipoprotein(a) (Lp(a)) system factor by the 2018 American Heart Association/American in man, was the first to note that the individual level of College of Cardiology (AHA/ACC) Guideline [14]. The Lp(a) is inherited and that high levels are associated with consensus paper of the European Atherosclerosis Society early onset of atherosclerosis [1]. In the following decades gives a comprehensive overview of Lp(a) as a cardiovascu- epidemiological data supported the initial findings, genetic lar risk factor [15]. The authors suggest measuring Lp(a) trials confirmed that Lp(a) is a causal factor for develop- in individuals at intermediate or high risk of CVD, in case ing atherosclerosis, and the negative impact of high levels of premature CVD, familial hypercholesterolaemia, family of Lp(a) not only on coronary heart disease but also on history of premature CVD or high Lp(a), progressive CVD development of aortic stenosis, peripheral arterial disease, despite statin therapy, ≥3% 10-year risk of fatal CVD (Eu- and ischaemic stroke was shown [2–12]. On the other hand ropean SCORE), or ≥10% 10-year risk of fatal or non-fatal much is still almost unknown, e. g. the physiological role of coronary heart disease (US guidelines). Lowering LDL-c Lp(a), the catabolism, and the clinical relevance in throm- remains the first priority. Secondary a Lp(a) level <50 mg/dl botic and embolic events. High levels of Lp(a) are acknowl- (~ <80th percentile) is suggested as desirable. The some- edged as being associated with an increased risk of cardio- what arbitrary cut off level of 30 mg/dl is often used based vascular disease (CVD) by the 2016 European Atheroscle- on data showing the continuous increase of risk with in- creasing levels of Lp(a) and without an obvious threshold value [10]. Since no endpoint data are available no target This article is part of the special issue “Lp(a) – Update 2018” level can be specified. Anja Vogt Anja.Vogt@med.uni-muenchen.de Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstraße 1, 80336 Munich, Germany K 52 A. Vogt Treatment options the target or a primary endpoint. Since all agents primarily lower LDL-c it would be difficult to show if the Lp(a) lower- For statins, the backbone treatment for preventing and re- ing effect is clinically relevant, as with niacin. Of these, only ducing cardiovascular events by lowering LDL-c, small de- PCSK9 inhibitors are widely available. Both evolocumab creases or increases of Lp(a) have been shown [16]. But and alirocumab lower LDL-c about 50 to 60% and in some mostly Lp(a) is not affected by statins [15, 17, 18]. The trials the lowering of Lp(a) was assessed, too. The mecha- same is seen for ezetimibe [19]. nism by which Lp(a) is reduced is matter of debate. With Nicotinic acid (niacin) has a broad range of lipid-mod- evolocumab reductions of 25.5% [37] and with alirocumab ifying effects, lowering LDL-c and triglycerides and in- reductions of 30.2% [38] were reported. A pooled anal- creasing high density lipoprotein-cholesterol (HDL-c). In ysis [39] of three phase 2 trials using alirocumab for 8 or addition it was shown to lower Lp(a) for the first time in 12 weeks analysed the Lp(a) lowering effect. Levels ranged 1989 [20]. High doses of nicotinic acid (2000–4000 mg) from 2 to 181 mg/dl and the two groups consisted of par- are needed to reduce Lp(a) significantly [21]. However, ticipants with baseline levels of 50 mg/dl and ≥50 mg/dl. this effect has not yet been shown in patients with high The median absolute reduction was 3.5 and 27 mg/dl, re- baseline levels of Lp(a) with regard to the inclusion crite- spectively, the median percent reduction 36 and 27%, re- rion. A meta-analysis has summarised the beneficial effects spectively. Interestingly in patients with LDL-receptor neg- of nicotinic acid on cardiovascular events [22], but it was ative homozygous FH evolocumab reduced Lp(a) by 20% not evaluated if the benefit is attributable to reduced lev- while LDL-c did not decrease [40]. The upregulation of els of Lp(a). Additionally the positive effects are mainly other receptors, e. g. the very low density (VLDL) recep- from the pre-statin era. The EAS consensus paper states tor that mediates the uptake of Lp(a) into macrophages, that niacin should be used to reduce high levels of Lp(a) might be an explanation for this finding. There are further because of the evidence and despite the fact that it cannot contradictory results by what mechanism Lp(a) is reduced. be excluded that the benefits are not attributed to lower- Some data show an increased catabolic fraction rate, oth- ing Lp(a) but to the favorable effects on other lipoproteins ers a reduced synthesis [41]. In the FOURIER trial Lp(a) [15]. In 2013 the combination of extended release niacin was reduced significantly by evolocumab and participants and laropiprant, a flush inhibitor, was withdrawn from the with higher absolute reductions of Lp(a) tended towards a European market after the Heart Protection Study 2—Treat- greater benefit [42]. ment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) was stopped early because of a significant Antisense oligonucleotides increase in bleeding events, including intracranial haemor- rhage [23]. Although the reasons have not been elucidated the use of nicotinic acid continues to be debated. Antisense oligonucleotide (ASO) drugs are a relatively new Lipoprotein apheresis (LA) as an extracorporeal method way to very specifically target genes on the mRNA level and lowers LDL-c and Lp(a) acutely and significantly by are used in different medical fields. Mipomersen, the first 60–70% but has to be applied regularly (mostly weekly). ASO used in hypercholesterolaemia, interferes with the en- Few countries consider high levels of Lp(a) to be an indi- coding mRNA for ApoB100. The production of ApoB100 cation for lipoprotein apheresis in very high-risk patients is reduced via inhibition of translation to the protein. Con- if all other cardiovascular risk factors, mainly LDL-c, are sequently less very low density lipoprotein (VLDL) is as- treated optimally [24–27]. sembled in the liver resulting in lower levels of circulat- Beneficial effects of LA on the course of CVD are shown ing LDL-c. As a side effect, less triglycerides are excreted by retrospective evaluations, prospective (but not blinded, from the liver and accumulate often leading to fatty liver randomized controlled) trials, and analyses of the German disease and elevated transaminases [43, 44]. By what mech- Lipoprotein Apheresis Registry [28–35]. LA is generally anism levels of Lp(a) are lowered is not entirely clear. In well tolerated and safe [27, 36] but time consuming, ex- four phase 3 trials mipomersen given subcutaneously ver- pensive, only offered in specialised centres, and often not sus placebo levels of Lp(a) were significantly reduced by covered by health insurance. 21–39% [45]. Thus mipomersen might reduce the neces- sity for lipoprotein apheresis in high-risk patients [46, 47]. The most common side effects were severe injection site New drug developments reactions and liver steatosis is also of concern. Because of the side effects mipomersen was not widely approved and Several new lipid-modifying drugs to reduce LDL-c are is available in the USA only. currently under investigation. They lower LDL-c and Lp(a) to varying degrees though lowering of Lp(a) has never been K Lp(a)—antisense therapy 53 Apo(a) antisense oligonucleotide tion of 10, 40, 80, or 120 mg versus placebo. In the multi- ple-dose phase (n = 30) IONIS-APO(a)L 10 mg, 20 mg, or Rx IONIS-APO(a) , an antisense oligonucleotide molecule, 40 mg were administered at days 1, 3, 5, 8, 15, and 22 ver- Rx is the first measure developed to specifically address the sus placebo. The primary efficacy endpoint was reduction mRNA of Apo(a). Trials in transgenic mice [48] and phase 1 of Lp(a) at day 30 (single-dose phase) and day 36 (multi- results showed relevant decreases of Lp(a). In a phase 1 ple-dose phase). Baseline levels of Lp(a) were 147.8 nmol/l trial in healthy volunteers (Lp(a) levels ≥25 nmol/l) IO- (mean) and 128.6 nmol/l (median) in the single-dose phase NIS-APO(a) significantly lowered Lp(a) in a dose-depen- and 153.8 nmol/l (mean) and 145.6 nmol/l (median) in the Rx dent manner. The highest dose of 300 mg reduced Lp(a) by multiple-dose phase. 77.8%. In one individual the maximal reduction was 88.8% In the single ascending dose phase Lp(a) was reduced after 36 days. Impressively Lp(a) did not increase imme- significantly in a dose-dependent manner at day 30. The diately but was still low 84 days after the last application mean treatment differences versus placebo (+2.8%) were [49]. Theuse was safeand themostcommon sideeffects 24.8% (10 mg group), 35.1% (20 mg group), 48.2% (40 mg were injection site reactions. As a ligand-conjugated variant group), 82.5% (80 mg group), and 84.5% (120 mg group). of IONIS-APO(a) the hepatocyte specific IONIS-APO(a)- The reduction was still significant after 90 days (46% in Rx L was developed. The triantennary N-acetylgalactosamine the 80 mg group and 44% in the 120 mg group). Also Rx complex (GalNAc ) facilitates the fast and specific uptake in the multiple ascending dose phase Lp(a) was reduced by hepatocytes [50]. This modification enhanced the po- significantly. The treatment differences versus placebo tency of the Apo(a)-ASO by >30 times [51]. Since Apo(a) were 59.4% (10 mg group), 72.3 (20 mg group), and 82.4% is targeted VLDL is produced and there is no fat accumu- (40 mg group). At day 113 after the last application the low- lation in the liver. ering effect was still significant with 39% (10 mg group), The IONIS-APO(a) phase 2 trial confirmed the positive 53% (20 mg group), and 58% (40 mg group). Rx results regarding effectivity and safety [51]. In 64 partic- The results of the biggest conducted IONIS-APO(a)-L Rx ipants IONIS-APO(a) was applied subcutaneously in an (AKCEA-APO(a)-L ) phase 2 trial were presented at the Rx Rx escalating-dose manner for 12 weeks (100 mg, 200 mg, and AHA Scientific Sessions, Late-Breaking Clinical Trial Pre- 300 mg, each once a week for 4 weeks) versus placebo. sentation, on 10 November 2018 [52]. The trial was a ran- Two cohorts were formed according to Lp(a) baseline domized, double-blind, placebo-controlled, and dose-rang- levels: cohort A: Lp(a) 125–437 nmol/l (placebo group: ing trial in 286 patients with established CVD and high mean 251.6 nmol/l and median 216.3 nmol/l, verum group: levels of Lp(a) (baseline mean of approximately 100 mg/dl mean 254 nmol/l, median 261.4 nmol/l) and cohort B: Lp(a) [250 nmol/l]). Five cohorts were compared: 20 mg were ad- ≥438 nmol/l (placebo group: mean 488.3 nmol/l and me- ministered every 4 weeks, 40 mg every 4 weeks, 20 mg ev- dian 498.3 nmol/l, verum group: mean 444.9 nmol/l, median ery 2 weeks, 60 mg every 4 weeks, and 20 mg every week, 457.6 nmol/l). The primary efficacy endpoint was reduction each for 6–12 months. The primary efficacy endpoint was of Lp(a) at day 85 or 99. Secondary endpoints were effects percent change in Lp(a) from baseline at 6 months. on other lipoproteins and risk factors. AKCEA-APO(a)-LRx decreased Lp(a) in all groups In both cohorts Lp(a) was reduced significantly: co- (20 mg every 4 weeks: –35%, 40 mg every 4 weeks –56%, hort A—66.8%, cohort B—71.6% at day 85/99. Addition- 20 mg every 2 weeks: –58%). The effect was even greater ally, levels of LDL-c, ApoB, and oxidised phospholipids in the highest doses (60 mg every 4 weeks: –72%, 20 mg (OxPL) were reduced significantly in both cohorts. LDL- weekly: –80%) and in about 81% and 98%, respectively, c was lowered by 13.0% in cohort A and by 23.9% in co- Lp(a) levels <50 mg/dl were achieved. The completion rate hort B, ApoB by 11.3 and 18.5%, respectively, OxPL-ApoB was high (90%) and comparable in both groups (verum by 35.2 and 42.5%, respectively, and OxLP-Apo(a) 26.6 and 12.1%, placebo 14.9%). There were no severe safety con- 36.7%, respectively. Baseline statin therapy had no signif- cerns and few adverse events. Injection site reactions were icant effect on these results. The treatment was safe and the most common (26%) with one patient discontinuing. well tolerated. Two myocardial infarctions and one episode of angina pectoris in high-risk patients were not assessed as treatment related. Injection site reactions occurred in 10% Conclusion in cohort A and in 19% in cohort B (one participant stopped treatment). The new developments of lipid-modifying drugs will allow Another phase 1/2a first-in-man trial [51] was done with a more effective reduction of LDL-c and Lp(a) and a more the GalNAc modified IONIS-APO(a)-L in healthy vol- patient-individualised therapy. LDL-c treatment goals and 3 Rx unteers with levels of Lp(a) ≥75 nmol/l. In the single-dose even lower levels than recommended by guidelines today phase participants (n = 28) received one subcutaneous injec- can be reached. The first outcome trials show that car- K 54 A. Vogt Study. Circulation 117(2):176–184. https://doi.org/10.1161/ diovascular events are reduced as a consequence. If the CIRCULATIONAHA.107.715698 Lp(a) lowering capacity of PCSK9 inhibitors contributes to 4. Laschkolnig A, Kollerits B, Lamina C, Meisinger C, Rantner B, this favourable outcome is unclear. IONIS-APO(a) is the Rx Stadler M, Peters A, Koenig W, Stockl A, Dahnhardt D, Boger CA, first antisense oligonucleotide to reduce specifically Lp(a). Kramer BK, Fraedrich G, Strauch K, Kronenberg F (2014) Lipopro- tein (a) concentrations, apolipoprotein (a) phenotypes, and periph- Phase 1 and 2 trials showed the significant reduction of eral arterial disease in three independent cohorts. Cardiovasc Res Lp(a) and a very promising safety profile. The GalNAc 103(1):28–36. https://doi.org/10.1093/cvr/cvu107 modified molecule IONIS-APO(a)-L was developed for Rx 5. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG (2014) Ele- fast and specific uptake by hepatocytes which increased the vated lipoprotein(a) and risk of aortic valve stenosis in the general population. J Am Coll Cardiol 63(5):470–477. https://doi.org/10. potency more than 30 times. The highest dose of AKCEA- 1016/j.jacc.2013.09.038 APO(a)-L reduced Lp(a) in the phase 2a trial by 80% and Rx 6. Kronenberg F, Utermann G (2013) Lipoprotein(a): resurrected by in 98% of the participants Lp(a) was lowered to <50 mg/dl, genetics. J Intern Med 273(1):6–30. https://doi.org/10.1111/j.1365- the recommended threshold. 2796.2012.02592.x 7. Clarke R, Peden JF, Hopewell JC, Kyriakou T, Goel A, Heath SC, The high effectivity and the favourable tolerability and Parish S, Barlera S, Franzosi MG, Rust S, Bennett D, Silveira A, safety data of these trials raise the expectation that an out- Malarstig A, Green FR, Lathrop M, Gigante B, Leander K, de Faire come trial might reproduce these findings and that this U, Seedorf U, Hamsten A, Collins R, Watkins H, Farrall M, Con- significant reduction of Lp(a) might reduce cardiovascu- sortium P (2009) Genetic variants associated with Lp(a) lipopro- tein level and coronary disease. N Engl J Med 361(26):2518–2528. lar events. The data regarding reduction of cardiovascular https://doi.org/10.1056/NEJMoa0902604 events by lowering Lp(a) via lipoprotein apheresis sup- 8. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG port this expectation. AKCEA-APO(a)-L reduces other Rx (2009) Genetically elevated lipoprotein(a) and increased risk of my- lipoproteins and oxidised phospholipids which might con- ocardial infarction. JAMA 301(22):2331–2339. https://doi.org/10. 1001/jama.2009.801 tribute to the expected beneficial clinical effects. 9. Kraft HG, Lingenhel A, Kochl S, Hoppichler F, Kronenberg F, Abe The Apo(a)-ASO is the first drug to lower Lp(a) specifi- A, Muhlberger V, Schonitzer D, Utermann G (1996) Apolipopro- cally, to a great extent, and with a promising safety profile. tein(a) kringle IV repeat number predicts risk for coronary heart This, for the first time, will allow cardiovascular end point disease. Arterioscler Thromb Vasc Biol 16(6):713–719 10. Kronenberg F, Kronenberg MF, Kiechl S, Trenkwalder E, San- trials elucidating if lowering Lp(a) specifically reduces car- ter P, Oberhollenzer F, Egger G, Utermann G, Willeit J (1999) diovascular events. Role of lipoprotein(a) and apolipoprotein(a) phenotype in athero- genesis: prospective results from the Bruneck study. Circulation Compliance with ethical guidelines 100(11):1154–1160 11. Kronenberg F, Neyer U, Lhotta K, Trenkwalder E, Auinger M, Prib- Conflict of interest A. Vogt has received speakers’ honoraria for pre- asnig A, Meisl T, Konig P, Dieplinger H (1999) The low molecu- sentations and advisory board activities by Aegerion, Amgen, Berlin lar weight apo(a) phenotype is an independent predictor for coro- Chemie, Fresenius, Genzyme, a Sanofi company, Kaneka, OmniaMed, nary artery disease in hemodialysis patients: a prospective follow- Regeneron, Sanofi. AV has received research support by Merck Sharp up. J Am Soc Nephrol 10(5):1027–1036 & Dohme. 12. Sandholzer C, Saha N, Kark JD, Rees A, Jaross W, Dieplinger H, Hoppichler F, Boerwinkle E, Utermann G (1992) Apo(a) isoforms Ethical standards This article does not contain any studies with human predict risk for coronary heart disease. A study in six populations. participants or animals performed by any of the authors. Arterioscler Thromb 12(10):1214–1226 13. Authors/Task Force M, Piepoli MF, Hoes AW, Agewall S, Albus C, Open Access This article is distributed under the terms of the Brotons C, Catapano AL, Cooney MT, Corra U, Cosyns B, Deaton Creative Commons Attribution 4.0 International License (http:// C, Graham I, Hall MS, Hobbs FD, Lochen ML, Lollgen H, Mar- creativecommons.org/licenses/by/4.0/), which permits unrestricted ques-Vidal P, Perk J, Prescott E, Redon J, Richter DJ, Sattar N, use, distribution, and reproduction in any medium, provided you give Smulders Y, Tiberi M, van der Worp HB, van Dis I, Verschuren appropriate credit to the original author(s) and the source, provide a WM, Additional Contributor: Simone B, Document R, De Backer link to the Creative Commons license, and indicate if changes were G, Roffi M, Aboyans V, Bachl N, Bueno H, Carerj S, Cho L, Cox made. J, De Sutter J, Egidi G, Fisher M, Fitzsimons D, Franco OH, Gue- noun M, Jennings C, Jug B, Kirchhof P, Kotseva K, Lip GY, Mach F, Mancia G, Bermudo FM, Mezzani A, Niessner A, Ponikowski P, References Rauch B, Ryden L, Stauder A, Turc G, Wiklund O, Windecker S, Zamorano JL (2016) 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of 1. Berg K (1963) A new serum type system in man—the Lp system. the European Society of Cardiology and Other Societies on Cardio- Acta Pathol Microbiol Scand 59:369–382 vascular Disease Prevention in Clinical Practice (constituted by rep- 2. Erqou S, Thompson A, Di Angelantonio E, Saleheen D, Kaptoge S, resentatives of 10 societies and by invited experts): Developed with Marcovina S, Danesh J (2010) Apolipoprotein(a) isoforms and the the special contribution of the European Association for Cardiovas- risk of vascular disease: systematic review of 40 studies involving cular Prevention & Rehabilitation (EACPR). Eur J Prev Cardiol 23 58,000 participants. J Am Coll Cardiol 55(19):2160–2167. https:// (11):NP1–NP96. https://doi.org/10.1177/2047487316653709 doi.org/10.1016/j.jacc.2009.10.080 14. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blu- 3. Kamstrup PR, Benn M, Tybjaerg-Hansen A, Nordestgaard BG menthal RS, Braun LT, Braun LT, de Ferranti S, Faiella-Tom- (2008) Extreme lipoprotein(a) levels and risk of myocardial in- masino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, farction in the general population: the Copenhagen City Heart K Lp(a)—antisense therapy 55 Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Or- ness of lipid apheresis treatment to reduce high lipoprotein(a) levels ringer CE, Peralta CA, Saseen JJ, Smith SC Jr., Sperling L, Virani and prevent major adverse coronary events. Nat Clin Pract Cardio- SS, Yeboah J (2018) 2018 AHA/ACC/AACVPR/AAPA/ABC/ vasc Med 6(3):229–239. https://doi.org/10.1038/ncpcardio1456 ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the 29. Rosada A, Kassner U, Vogt A, Willhauck M, Parhofer K, Stein- Management of Blood Cholesterol: Executive Summary: A Report hagen-Thiessen E (2014) Does regular lipid apheresis in patients of the American College of Cardiology/American Heart Associa- with isolated elevated lipoprotein(a) levels reduce the incidence of tion Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. cardiovascular events? Artif Organs 38(2):135–141. https://doi.org/ https://doi.org/10.1016/j.jacc.2018.11.002 10.1111/aor.12135 15. Nordestgaard BG, Chapman MJ, Ray K, Boren J, Andreotti F, Watts 30. Schettler VJ, Neumann CL, Peter C, Zimmermann T, Julius U, Roe- GF, Ginsberg H, Amarenco P, Catapano A, Descamps OS, Fisher seler E, Heigl F, Ramlow W, Blume H, Scientific Board of Gft- E, Kovanen PT, Kuivenhoven JA, Lesnik P, Masana L, Reiner Z, GAWG (2015) First data from the German Lipoprotein Apheresis Taskinen MR, Tokgozoglu L, Tybjaerg-Hansen A (2010) Lipopro- Registry (GLAR). Atheroscler Suppl 18:41–44. https://doi.org/10. tein(a) as a cardiovascular risk factor: current status. Eur Heart J 1016/j.atherosclerosissup.2015.02.006 31(23):2844–2853. https://doi.org/10.1093/eurheartj/ehq386 31. Schettler VJJ, Neumann CL, Peter C, Zimmermann T, Julius U, 16. Khera AV, Everett BM, Caulfield MP, Hantash FM, Wohlgemuth Roeseler E, Heigl F, Grutzmacher P, Blume H, Scientific Board J, Ridker PM, Mora S (2014) Lipoprotein(a) concentrations, ro- of GftGAWG (2017) Current insights into the German Lipopro- suvastatin therapy, and residual vascular risk: an analysis from tein Apheresis Registry (GLAR)—Almost 5 years on. Atheroscler the JUPITER Trial (Justification for the Use of Statins in Preven- Suppl 30:50–55. https://doi.org/10.1016/j.atherosclerosissup.2017. tion: an Intervention Trial Evaluating Rosuvastatin). Circulation 05.006 129(6):635–642. https://doi.org/10.1161/CIRCULATIONAHA. 32. Leebmann J, Roeseler E, Julius U, Heigl F, Spitthoever R, Heut- 113.004406 ling D, Breitenberger P, Maerz W, Lehmacher W, Heibges A, 17. Kei A, Liberopoulos E, Tellis K, Rizzo M, Elisaf M, Tselepis A Klingel R, ProLiFe Study G (2013) Lipoprotein apheresis in pa- (2013) Effect of hypolipidemic treatment on emerging risk factors tients with maximally tolerated lipid-lowering therapy, lipopro- in mixed dyslipidemia: a randomized pilot trial. Eur J Clin Invest tein(a)-hyperlipoproteinemia, and progressive cardiovascular dis- 43(7):698–707. https://doi.org/10.1111/eci.12095 ease: prospective observational multicenter study. Circulation 18. Tziomalos K, Athyros VG, Wierzbicki AS, Mikhailidis DP (2009) 128(24):2567–2576. https://doi.org/10.1161/CIRCULATIONAHA. Lipoprotein a: where are we now? Curr Opin Cardiol 24(4):351– 113.002432 357. https://doi.org/10.1097/HCO.0b013e32832ac21a 33. Roeseler E, Julius U, Heigl F, Spitthoever R, Heutling D, Breiten- 19. Moutzouri E, Liberopoulos EN, Tellis CC, Milionis HJ, Tselepis berger P, Leebmann J, Lehmacher W, Kamstrup PR, Nordestgaard AD, Elisaf MS (2013) Comparison of the effect of simvastatin BG, Maerz W, Noureen A, Schmidt K, Kronenberg F, Heibges versus simvastatin/ezetimibe versus rosuvastatin on markers of A, Klingel R, ProLiFe-Study G (2016) Lipoprotein apheresis for inflammation and oxidative stress in subjects with hypercholes- lipoprotein(a)-associated cardiovascular disease: prospective 5 terolemia. Atherosclerosis 231(1):8–14. https://doi.org/10.1016/j. years of follow-up and apolipoprotein(a) characterization. Arte- atherosclerosis.2013.08.013 rioscler Thromb Vasc Biol 36(9):2019–2027. https://doi.org/10. 20. Carlson LA, Hamsten A, Asplund A (1989) Pronounced lowering 1161/ATVBAHA.116.307983 of serum levels of lipoprotein Lp(a) in hyperlipidaemic subjects 34. Safarova MS, Ezhov MV, Afanasieva OI, Matchin YG, Atanesyan treated with nicotinic acid. J Intern Med 226(4):271–276 RV, Adamova IY, Utkina EA, Konovalov GA, Pokrovsky SN 21. Goldberg A, Alagona P Jr., Capuzzi DM, Guyton J, Morgan JM, (2013) Effect of specific lipoprotein(a) apheresis on coronary Rodgers J, Sachson R, Samuel P (2000) Multiple-dose efficacy and atherosclerosis regression assessed by quantitative coronary an- safety of an extended-release form of niacin in the management of giography. Atheroscler Suppl 14(1):93–99. https://doi.org/10.1016/ hyperlipidemia. Am J Cardiol 85(9):1100–1105 j.atherosclerosissup.2012.10.015 22. Bruckert E, Labreuche J, Amarenco P (2010) Meta-analysis of 35. von Dryander M, Fischer S, Passauer J, Muller G, Bornstein the effect of nicotinic acid alone or in combination on cardiovas- SR, Julius U (2013) Differences in the atherogenic risk of pa- cular events and atherosclerosis. Atherosclerosis 210(2):353–361. tients treated by lipoprotein apheresis according to their lipid https://doi.org/10.1016/j.atherosclerosis.2009.12.023 pattern. Atheroscler Suppl 14(1):39–44. https://doi.org/10.1016/j. 23. Group HTC, Landray MJ, Haynes R, Hopewell JC, Parish S, Aung atherosclerosissup.2012.10.005 T, Tomson J, Wallendszus K, Craig M, Jiang L, Collins R, Ar- 36. Winters JL (2011) Lipid apheresis, indications, and principles. mitage J (2014) Effects of extended-release niacin with laropiprant J Clin Apher 26(5):269–275. https://doi.org/10.1002/jca .20299 in high-risk patients. N Engl J Med 371(3):203–212. https://doi.org/ 37. Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robin- 10.1056/NEJMoa1300955 son J, Ballantyne CM, Somaratne R, Legg J, Wasserman SM, Scott 24. Bundesausschuss G (2010) Richtlinie des Gemeinsamen Bunde- R, Koren MJ, Stein EA, Open-Label Study of Long-Term Evalu- sausschusses zu Untersuchungs- und Behandlungsmethoden der ation against LDLCI (2015) Efficacy and safety of evolocumab in vertragsärztlichen Versorgung. Bundesanzeiger 109:2561 reducing lipids and cardiovascular events. N Engl J Med. https:// 25. Derfler K, Steiner S, Sinzinger H (2015) Lipoprotein-apheresis: doi.org/10.1056/NEJMoa1500858 Austrian consensus on indication and performance of treatment. 38. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna Wien Klin Wochenschr 127(15–16):655–663. https://doi.org/10. M, Stroes ES, Langslet G, Raal FJ, Shahawy ME, Koren MJ, Lepor 1007/s00508-015-0833-4 NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein JJ, Investigators 26. Stefanutti C (2010) The 2009 2nd Italian Consensus Conference OLT (2015) Efficacy and safety of alirocumab in reducing lipids on LDL-apheresis. Nutr Metab Cardiovasc Dis 20(10):761–762. and cardiovascular events. N Engl J Med. https://doi.org/10.1056/ https://doi.org/10.1016/j.numecd.2010.04.007 NEJMoa1501031 27. Thompson GR (2008) Recommendations for the use of LDL 39. Gaudet D, Kereiakes DJ, McKenney JM, Roth EM, Hanotin C, apheresis. Atherosclerosis 198(2):247–255. https://doi.org/10. Gipe D, Du Y, Ferrand AC, Ginsberg HN, Stein EA (2014) Effect 1016/j.atherosclerosis.2008.02.009 of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 28. Jaeger BR, Richter Y, Nagel D, Heigl F, Vogt A, Roeseler E, 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of Parhofer K, Ramlow W, Koch M, Utermann G, Labarrere CA, Sei- 150 mg every two weeks dosing from phase 2 trials). Am J Cardiol del D, Group of (2009) Longitudinal cohort study on the effective- 114(5):711–715. https://doi.org/10.1016/j.amjcard.2014.05.060 K 56 A. Vogt 40. Raal FJ, Honarpour N, Blom DJ, Hovingh GK, Xu F, Scott R, 47. Waldmann E, Vogt A, Crispin A, Altenhofer J, Riks I, Parhofer Wasserman SM, Stein EA, Investigators T (2015) Inhibition of KG (2018) Corrigendum to: “Effect of mipomersen on LDL- PCSK9 with evolocumab in homozygous familial hypercholes- cholesterol in patients with severe LDL-hypercholesterolaemia terolaemia (TESLA Part B): a randomised, double-blind, placebo- and atherosclerosis treated by lipoprotein apheresis (The MICA- controlled trial. Lancet 385(9965):341–350. https://doi.org/10. Study). Atherosclerosis 275:461–462. https://doi.org/10.1016/j. 1016/S0140-6736(14)61374-X atherosclerosis.2018.05.020 41. Desai NR, Kohli P, Giugliano RP, O’Donoghue ML, Somaratne R, 48. Merki E, Graham M, Taleb A, Leibundgut G, Yang X, Miller ER, Zhou J, Hoffman EB, Huang F, Rogers WJ, Wasserman SM, Scott Fu W, Mullick AE, Lee R, Willeit P, Crooke RM, Witztum JL, R, Sabatine MS (2013) AMG145, a monoclonal antibody against Tsimikas S (2011) Antisense oligonucleotide lowers plasma lev- proprotein convertase subtilisin kexin type 9, significantly reduces els of apolipoprotein (a) and lipoprotein (a) in transgenic mice. lipoprotein(a) in hypercholesterolemic patients receiving statin J Am Coll Cardiol 57(15):1611–1621. https://doi.org/10.1016/j. therapy: an analysis from the LDL-C Assessment with Proprotein jacc.2010.10.052 Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibi- 49. Tsimikas S, Viney NJ, Hughes SG, Singleton W, Graham MJ, Baker tion Combined with Statin Therapy (LAPLACE)-Thrombolysis in BF, Burkey JL, Yang Q, Marcovina SM, Geary RS, Crooke RM, Myocardial Infarction (TIMI) 57 trial. Circulation 128(9):962–969. Witztum JL (2015) Antisense therapy targeting apolipoprotein(a): https://doi.org/10.1161/CIRCULATIONAHA.113.001969 a randomised, double-blind, placebo-controlled phase 1 study. 42. O’Donoghue ML, Fazio S, Giugliano RP, Stroes ESG, Kanevsky E, Lancet 386(10002):1472–1483. https://doi.org/10.1016/S0140- Gouni-Berthold I et al (2018) Lipoprotein(a), PCSK9 inhibition and 6736(15)61252-1 cardiovascular risk: insights from the FOURIER trial. Circulation. 50. Prakash TP, Graham MJ, Yu J, Carty R, Low A, Chappell A, https://doi.org/10.1161/CIRCULATIONAHA.118.037184 Schmidt K, Zhao C, Aghajan M, Murray HF, Riney S, Booten SL, 43. Parhofer KG (2012) Mipomersen: evidence-based review of its po- Murray SF, Gaus H, Crosby J, Lima WF, Guo S, Monia BP, Swayze tential in the treatment of homozygous and severe heterozygous fa- EE, Seth PP (2014) Targeted delivery of antisense oligonucleotides milial hypercholesterolemia. Core Evid 7:29–38. https://doi.org/10. to hepatocytes using triantennary N-acetyl galactosamine improves 2147/CE.S25239 potency 10-fold in mice. Nucleic Acids Res 42(13):8796–8807. 44. Rader DJ, Kastelein JJ (2014) Lomitapide and mipomersen: two https://doi.org/10.1093/nar/gku531 first-in-class drugs for reducing low-density lipoprotein choles- 51. Viney NJ, van Capelleveen JC, Geary RS, Xia S, Tami JA, Yu terol in patients with homozygous familial hypercholesterolemia. RZ, Marcovina SM, Hughes SG, Graham MJ, Crooke RM, Crooke Circulation 129(9):1022–1032. https://doi.org/10.1161/ ST, Witztum JL, Stroes ES, Tsimikas S (2016) Antisense oligonu- CIRCULATIONAHA.113.001292 cleotides targeting apolipoprotein(a) in people with raised lipopro- 45. Santos RD, Raal FJ, Catapano AL, Witztum JL, Steinhagen- tein(a): two randomised, double-blind, placebo-controlled, dose- Thiessen E, Tsimikas S (2015) Mipomersen, an antisense oligonu- ranging trials. Lancet 388(10057):2239–2253. https://doi.org/10. cleotide to apolipoprotein B-100, reduces lipoprotein(a) in various 1016/S0140-6736(16)31009-1 populations with hypercholesterolemia: results of 4 phase III trials. 52. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif Arterioscler Thromb Vasc Biol 35(3):689–699. https://doi.org/10. JC, Baum S, Steinhagen-Thiessen E, Shapiro M, Stroes E, Mori- 1161/ATVBAHA.114.304549 arty P, Nordestgaard B, Guerriero J, Viney N, O’Dea L, Witztum J, 46. Waldmann E, Vogt A, Crispin A, Altenhofer J, Riks I, Parhofer AKCEA-APO(a)-LRx Study Investigators (2018) Safety and effi- KG (2017) Effect of mipomersen on LDL-cholesterol in pa- cacy of AKCEA-APO(a)-LRx to lower lipoprotein(a) levels in pa- tients with severe LDL-hypercholesterolaemia and atherosclerosis tients with established cardiovascular disease: A phase 2 dose-rang- treated by lipoprotein apheresis (The MICA-Study). Atheroscle- ing trial. https://www.tctmd.com/slide/safety-and-efficacy-akcea- rosis 259:20–25. https://doi.org/10.1016/j.atherosclerosis.2017.02. apoa-lrx-lower-lipoproteina-levels-patients-established. Accessed 019 14 Jan 2019

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