ApoA-I Infusion Therapies Following Acute Coronary Syndrome: Past, Present, and Future

Abstract

Purpose of review: The elevated adverse cardiovascular event rate among patients with low high-density lipoprotein cholesterol (HDL-C) formed the basis for the hypothesis that elevating HDL-C would reduce those events. Attempts to raise endogenous HDL-C levels, however, have consistently failed to show improvements in cardiovascular outcomes. However, steady-state HDL-C concentration does not reflect the function of this complex family of particles. Indeed, HDL functions correlate only weakly with serum HDL-C concentration. Thus, the field has pivoted from simply raising the quantity of HDL-C to a focus on improving the putative anti-atherosclerotic functions of HDL particles. Such functions include the ability of HDL to promote the efflux of cholesterol from cholesterol-laden macrophages. Apolipoprotein A-I (apoA-I), the signature apoprotein of HDL, may facilitate the removal of cholesterol from atherosclerotic plaque, reduce the lesional lipid content and might thus stabilize vulnerable plaques, thereby reducing the risk of cardiac events. Infusion of preparations of apoA-I may improve cholesterol efflux capacity (CEC). This review summarizes the development of apoA-I therapies, compares their structural and functional properties and discusses the findings of previous studies including their limitations, and how CSL112, currently being tested in a phase III trial, may overcome these challenges.

Recent findings: Three major ApoA-I-based approaches (MDCO-216, CER-001, and CSL111/CSL112) have aimed to enhance reverse cholesterol transport. These three therapies differ considerably in both lipid and protein composition. MDCO-216 contains recombinant ApoA-I Milano, CER-001 contains recombinant wild-type human ApoA-I, and CSL111/CSL112 contains native ApoA-I isolated from human plasma. Two of the three agents studied to date (apoA-1 Milano and CER-001) have undergone evaluation by intravascular ultrasound imaging, a technique that gauges lesion volume well but does not assess other important variables that may relate to clinical outcomes. ApoA-1 Milano and CER-001 reduce lecithin-cholesterol acyltransferase (LCAT) activity, potentially impairing the function of HDL in reverse cholesterol transport. Furthermore, apoA-I Milano can compete with and alter the function of the recipient's endogenous apoA-I. In contrast to these agents, CSL112, a particle formulated using human plasma apoA-I and phosphatidylcholine, increases LCAT activity and does not lead to the malfunction of endogenous apoA-I. CSL112 robustly increases cholesterol efflux, promotes reverse cholesterol transport, and now is being tested in a phase III clinical trial. Phase II-b studies of MDCO-216 and CER-001 failed to produce a significant reduction in coronary plaque volume as assessed by IVUS. However, the investigation to determine whether the direct infusion of a reconstituted apoA-I reduces post-myocardial infarction coronary events is being tested using CSL112, which is dosed at a higher level than MDCO-216 and CER-001 and has more favorable pharmacodynamics.

Keywords: Acute coronary syndrome; ApoA-I infusion therapies; Cholesterol efflux capacity.

Fig. 1

Schematic overview of reverse cholesterol transport. ^†Free cholesterol in peripheral tissues is effluxed by ABCA1 and ABCG1 transporters to lipid-poor ApoA-I (Preβ-HDL) and larger spherical HDL particles, respectively. The enzyme LCAT, carried on HDL particles, esterifies the free cholesterol molecules to form cholesteryl esters, which migrate to the core of the HDL particle to form mature HDL particles. Subsequently, mature HDL particles deliver the lipid cargo back to the liver through uptake mediated by the scavenger receptor SR-BI. Finally, cholesterol is converted to bile salts in the liver and secreted into the small intestine. CSL112 is apolipoprotein A-I purified from human plasma and reconstituted with phosphatidylcholine to form lipoprotein particles suitable for infusion. CSL112 fuses with HDL in plasma with subsequent release of lipid-poor apoA-I (pre-beta HDL). Abbreviations: ABCA1, ATP-binding cassette protein A1; ABCG1, ATP-binding cassette protein G1; ApoA-1, apolipoprotein A-I; HDL, high-density lipoprotein; LCAT, lecithin cholesterol acyltransferase; SR-BI, scavenger receptor class-B, type I; FC, free cholesterol, CE, cholesteryl ester, ^†Created with BioRender.com

Fig. 2

Timeline of human studies on apolipoprotein A-I infusion therapies. ApoA1 Milano (Nissen et al.) [67]; ApoA1 Milano (Kempen et al.) [98]; MILANO PILOT study (ApoA1 Milano, Nicholls et al.) •; CER 001 (Keyserling et al.) [72]; CHI-SQUARE study (CER 001, Tardif et al.) [70]; CER 001 (Zheng et al.) [69]; CARAT study (CER 001, Nicholls et al.) •; ERASE study (CSL111, Tardif et al.) [60]; CSL112 (Easton et al.) [81]; CSL112 (Gille et al.) , ••; CSL112 (Tricoci et al.) [104]; AEGIS-I trial (CSL112, Gibson et al.) [••]; AEGIS-II trial design (Gibson et al.) [84]. Abbreviations: AEGIS-I, ApoA-I Event Reducing in Ischemic Syndromes I; AEGIS-II, ApoA-I Event Reducing in Ischemic Syndromes-II; ApoA-I, apolipoprotein A-I; CARAT, CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial; ERASE, Effect of HDL on Atherosclerosis-Safety and Efficacy study