Increased cholesterol efflux with a single infusion of ApoA-1 Milano/POPC

D.G. Kallend, J.A.A. Reijers, S.E. Bellibas, et al.
European Heart Journal – Cardiovascular Pharmacotherapy (2016) 2, 23–29

Background

Epidemiological evidence and experimental data support targeting HDL-c and apolipoprotein A-1 (ApoA-1) levels to reduce the residual cardiovascular (CV) risk that remains despite LDL-c lowering with statins [1]. Two inhibitors of the protein CETP, which promotes transfer of cholesteryl esters from HDL to LDL particles, were found to improve atherogenic lipid profiles, but failed to improve CV outcomes [2,3]. Niacin also favourably affects HDL and ApoA-1 levels without giving CV benefit (4,5). It is postulated that HDL function, rather than its concentration, is more relevant for atherosclerosis and CV disease [6].
ApoA-1 Milano (ApoA-1M) is a variant of ApoA-1 identified in individuals in Northern Italy [8], who seem to be protected from the development of atherosclerosis despite HDL-c concentrations in the lowest 5^th percentile (10-30 mg/dL), low ApoA-1 concentrations and elevated triglycerides [9]. Moreover, ApoA-1M carriers show increased cholesterol efflux potential as compared with normal ApoA-1 [10].
MDCO-216 consists of a purified ApoA-1M and POPC, and regression of atherosclerotic plaque burden was seen with a predecessor compound in a phase II intravascular ultrasound (IVUS) study [11]. Following improvements in the manufacturing process, MDCO-2016 as a 2-hour infusion was evaluated in a single ascending dose phase I study in healthy volunteers (receiving a single dose of 5-40 mg/kg or placebo), and subsequently in stable coronary artery disease (CAD) patients (receiving 10-40 mg/kg or placebo).

Main results

• Following infusion, ApoA-1 rapidly increased in a dose-dependent manner both in healthy volunteers and CAD patients. At the two highest doses, ApoA-1 levels in CAD patients that dropped below baseline levels after 24 h, to return to baseline between day 6 and 28.
• Pre-beta 1 HDL increased to a similar extent in volunteers and CAD patients, despite the higher baseline levels seen in CAD patients. Maximum levels were reached at the end of infusion, and levels returned to baseline at 24 h.
• LDL-c decreased from 4 to 8 h in stable CAD patients who received the two highest doses, with return to baseline between 8 h and 7 days post-infusion. No LDL-c decrease was seen at lower doses, nor in the volunteers.
• ApoB levels increased at 48 h in both groups, returning to baseline by day 30 in all but the highest dose groups. Triglycerides also increased, with a maximum at 8 h post-administration, and remained elevated until day 7 in the 30 and 40 mg/kg groups.
• ABCA1-mediated cholesterol efflux was increased up to four-fold with the highest doses MDCO-2016 treatment, with a maximal effect at the end of infusion, and reaching baseline levels at day 7. In healthy volunteers 20 mg/kg was needed to obtain a significantly increase efflux, and in CAD patients 10 mg/kg sufficed.  
• SR-BI-mediated and ABCG1-mediated cholesterol efflux were also increased.
• A single dose of MDCO-216 was safe and generally well tolerated. No serious adverse events or deaths were reported in either treatment group. Mild adverse events such as headache, catheter site pain and fatigue were observed in both groups and did not increase with drug dose.
• No clinically relevant changes in safety laboratory parameters were seen after MDCO-216 infusion. No pro-inflammatory effect was seen (IL-6 and TNF-alpha).

Conclusion

Cholesterol efflux was assessed as a potential surrogate for HDL function. In this study, MDCO-216 markedly increased ABCA1 efflux, both in healthy volunteers and in patients with stable CAD, despite little change in HDL-c. Healthy volunteers and CAD patients showed similar baseline efflux levels, potentially reflecting the stable clinical status of the CAD patients. Future, larger studies will need to establish whether these effects impact CV outcomes.

Editorial comment [11]

Cholesterol efflux of sera from ApoA-IM carriers has been shown to be as efficient as sera of control subjects, despite lower apoA-I and HDL levels in ApoA-IM carriers, which suggests a higher relative apoA-I efflux potential in ApoA-IM carriers. Other studies have confirmed increases in cholesterol efflux capacity of HDL particles or mice expressing this variant.
The results published by Kallend etal “support (i) the enhancement of cholesterol efflux and cholesterol reverse transport as the mechanisms by which apoA-IM may exert its protective effect, (ii) the importance of HDL function rather than HDL-C levels, and (iii) the potential role of apoA-IM as a therapeutic strategy to reduce cardiovascular risk.” It remains to be established whether increases in cholesterol efflux medicated mostly by ABCA1, as seen in this study, yield different effects than the increased cholesterol efflux obtained with CETP inhibition (mostly non-ABCA1-mediated). The results are “preliminary but promising and should encourage further confirmation”. (…) “Its intravenous administration and the duration of the effects suggest that it might be more suitable for patients with acute or unstable CVD”.

Find this article online at Eur Heart J – Cardiovasc Pharmacother

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