Two apoA-I-based therapeutic strategies failed to show atherosclerotic plaque regression

Effect of Infusion of High-Density Lipoprotein Mimetic Containing Recombinant Apolipoprotein A-I Milano on Coronary Disease in Patients With an Acute Coronary Syndrome in the MILANO-PILOT Trial A Randomized Clinical Trial

Literature - Nicholls SJ et al., JAMA Cardiol 2018

Nicholls SJ, Puri R, Ballantyne CM et al., JAMA Cardiol. doi:10.1001/jamacardio.2018.2112

Effect of Serial Infusions of CER-001, a Pre-β High-Density Lipoprotein Mimetic, on Coronary Atherosclerosis in Patients Following Acute Coronary Syndromes in the CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial A Randomized Clinical Trial

Nicholls SJ, Andrews J, Kastelein JJP et al., JAMA Cardiol. doi:10.1001/jamacardio.2018.2121

Introduction and methods

In the search for novel therapeutic approaches to treat atherosclerotic CV disease, as well as the residual clinical risk that persists despite statin therapy, high-density lipoproteins (HDL) have received attention as therapeutic target. Epidemiology studies and animal studies have suggested a potential protective role for HDL. Several clinical trials evaluating HDL-raising therapies on top of statins did not demonstrate a favorable effect on CV events [1-6]. Recently, focus has shifted to approaches that may increase functional properties of HDL.

Infusion of lipid-poor HDL mimetics has been shown to favorably affect lipid transport [7,8] and endothelial function [9,10], and to raise HDL-c levels. A HDL mimetic containing a recombinant form of the naturally occurring variant apolipoprotein (apo)A-I-Milano (ETC-216) was tested in a proof-of-concept study and demonstrated that five weekly intravenous infusions resulted in potential rapid regression of coronary atherosclerosis on intravascular ultrasonography (IVUS) in patients with a recent acute coronary syndrome (ACS) [11]. A refined and purified form of the mimetic (MDCO-216) has been developed, with the ability to promote cholesterol efflux [12,13], without any adverse effect on immune function [14]. The randomized, multicenter, double-blind, placebo-controlled MILANO-PILOT trial was designed to investigate whether infusions of MDCO-216 can reduce the burden of coronary atherosclerosis as measured by IVUS (61 randomized to placebo and 52 to MDCO-216 had evaluable IVUS imaging results at baseline and follow-up).

CER-001 is a negatively charged, bioengineered pre-β HDL mimetic that contains recombinant wild-type apolipoprotein A-1 and sphingomyelin. Naturally circulating delipidated pre-β HDL also has a negative charge. The phospholipid composition is unique among HDL mimetics in clinical development, and is proposed to result in enhanced lipid transport activity and showed favorable effects in animal models of atherosclerosis [15,16]. Human studies have shown increases in cholesterol efflux capacity of plasma after CER-001 infusion [17] and preliminary imaging studies in patients with genetic dyslipidemia noted beneficial effects on plaque burden and inflammatory activity in the aorta and carotid arteries [18,19]. The CHI-SQUARE trial investigated the effect of infusing different doses of CER-001 on six occasions post ACS, and failed to demonstrate a benefit on the primary imaging endpoint [17]. Reanalysis in anatomically matched arterial segments revealed plaque regression at the lowest dose (3 mg/kg), especially in patients with larger plaque burden at baseline [20]. The CARAT trial was then designed to evaluate the effect of CER-001 infusions (3 mg/kg) in patients with ACS and a high coronary plaque burden [21]. 137 Patients in the placebo groups and 135 randomized to CER-001 had evaluable IVUS imaging at baseline and follow-up.

Main results


  • MDCO-216-treated patients showed a reduction in levels of HDL-c (-3.3 vs. +3.0 mg/dL in placebo-treated patients, P<0.001 for between-groups difference) and ApoA-I (-5.4 vs. +8.0 mg/dL, P<0.001).
  • In the two hours following MDCO-216 infusion, a progressive reduction of HDL-c was seen (-2.0 vs. 0.8 mg/dL, P=0.01) and an increase of ApoA-I (23.1 vs. 1.8 mg/dL, P<0.001).
  • Percent atheroma volume (PAV, primary efficacy measure) decreased by 0.21% in the MDCO-216 group (P=0.58 compared with baseline) and by 0.94% in the placebo group (P=0.02 vs baseline, P=0.07 for between-groups difference).
  • Total atheroma volume (TAV) was 6.4 mm3 lower in the MDCO-216 group (P=0.07 compared with baseline) and 7.9 mm3 lower in the placebo group (P=0.02, P=0.67 for between-groups difference).
  • ABCA1-mediated cholesterol efflux increased by 80.4% at 2 hours and by 41.6% at 4 hours after infusions on day 1, as compared with before infusion. At day 29, ABCA1 efflux increased by 90% at 2 hours and by 60.3% at 4 hours. There was no significant correlation between cholesterol efflux and plaque burden at baseline or their change.

CARAT trial

  • HDL-c did not change significantly after CER-001 infusions, nor in the placebo group, as compared with baseline, nor did apoA-I levels.
  • PAV (primary efficacy measure) decreased by 0.41% in the placebo group (P=0.005 compared with baseline), but no change was seen in CER-001-treated patients (-0.09%, P=0.67, P: 0.15 for between-groups difference).
  • TAV decreased by 6.6mm3 in the placebo group and by 5.6 m3 in the CER-001 group (both P<0.001 compared with baseline, P: 0.64 for between-groups difference).
  • In 52 patients, an exploratory analysis of plaque composition revealed no differences between treatment groups in absolute or percentage plaque volume of fibrous, fibrofatty, calcific or necrotic plaque at baseline, at follow-up, or in the change of any plaque component between baseline and follow-up.


The MILANO-PILOT trial showed that infusing MDCO-216 in patients with coronary disease who receive intensive treatment for management of ACS, did not yield an incremental benefit. Although MDCO-216 infusions increased cholesterol efflux, this did not translate into favorable effects on coronary atherosclerosis. This suggests that this HDL mimetic is unlikely to modify the residual CV risk.

The CARAT trial showed no benefit of ten weekly infusions of CER-001 compared with placebo, in statin-treated ACS patients; in these patients with high coronary plaque burden, no regression of atherosclerosis was noted.

Editorial comment

In an editorial comment, Rader [22] describes the evolution of research into therapeutic strategies targeting HDL and apoA-I. ApoA-I is the major protein in HDL. The rationale behind infusing apoA-I is to promote cellular cholesterol efflux and reverse cholesterol transport. The two studies evaluating MDCO-216 and CER-001 were well rigorously performed and powered appropriately, and thus Rader sees no reason to doubt the negative results. Nevertheless, he states that ‘these two negative imaging studies do not mean the end of the ballgame for apo-A-I-based therapeutics’. First, short-term plaque regression as assessed by IVUS may not be an appropriate surrogate for a reduction in CV events as a result of apoA-I infusion. It is also possible that apoA-I has stabilizing effects that do not decrease the size of plaque.

A third apoA-I product, CSL112, is still in clinical development, and has recently entered a phase III CV outcomes trial. These three apoA-I-based agents differ considerably in composition, dosing, pharmacokinetics and pharmacodynamics. Moreover, the products differ in the phospholipids used to reconstitute apoA-I, which may importantly affect their relative functionality.

Considering the differences, Rader thinks that ‘CSL112 at the dose being used in the outcomes trial (6g) has the most favorable surrogate measures, including promotion of ABCA1-specific cholesterol efflux capacity, and is perhaps best positioned to definitively test the hypothesis in a fully powered (n=17400) randomized clinical trial (NCT03473223).’

Interestingly, he points out that human genetics, translational science and basic investigation also suggest a potential role for apoA-I and promotion of cholesterol efflux in other complex disorders, such as age-related macular degeneration and Alzheimer’s disease and other neurodegenerative disorders. Research in these areas may benefit from efforts to develop apoA-I-based therapeutics for atherosclerotic CV disease.


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21. Andrews J, Janssan A, Nguyen T, et al. Effect of serial infusions of reconstituted high-density lipoprotein (CER-001) on coronary atherosclerosis: rationale and design of the CARAT study. Cardiovasc Diagn Ther. 2017;7(1):45-51.

22. Rader DJ. Apolipoprotein A-I Infusion Therapies for Coronary DiseaseTwo Outs in the Ninth Inning and Swinging for the Fences. JAMA Cardiol. Published online July 25, 2018. doi:10.1001/jamacardio.2018.2168

Vind het artikel over MDCO-216 online op JAMA CardiologyVind het artikel over CER-001 online op JAMA Cardiology

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