Infusion of Reconstituted High-Density Lipoprotein, CSL112, in Patients With Atherosclerosis: Safety and Pharmacokinetic Results From a Phase 2a Randomized Clinical Trial

Pierluigi Tricoci, Denise M D'Andrea, Paul A Gurbel, Zhenling Yao, Marina Cuchel, Brion Winston, Robert Schott, Robert Weiss, Michael A Blazing, Louis Cannon, Alison Bailey, Dominick J Angiolillo, Andreas Gille, Charles L Shear, Samuel D Wright, John H Alexander, Pierluigi Tricoci, Denise M D'Andrea, Paul A Gurbel, Zhenling Yao, Marina Cuchel, Brion Winston, Robert Schott, Robert Weiss, Michael A Blazing, Louis Cannon, Alison Bailey, Dominick J Angiolillo, Andreas Gille, Charles L Shear, Samuel D Wright, John H Alexander

Abstract

Background: CSL112 is a new formulation of human apolipoprotein A-I (apoA-I) being developed to reduce cardiovascular events following acute coronary syndrome. This phase 2a, randomized, double-blind, multicenter, dose-ranging trial represents the first clinical investigation to assess the safety and pharmacokinetics/pharmacodynamics of a CSL112 infusion among patients with stable atherosclerotic disease.

Methods and results: Patients were randomized to single ascending doses of CSL112 (1.7, 3.4, or 6.8 g) or placebo, administered over a 2-hour period. Primary safety assessments consisted of alanine aminotransferase or aspartate aminotransferase elevations >3× upper limits of normal and study drug-related adverse events. Pharmacokinetic/pharmacodynamic assessments included apoA-I plasma concentration and measures of the ability of serum to promote cholesterol efflux from cells ex vivo. Of 45 patients randomized, 7, 12, and 14 received 1.7-, 3.4-, and 6.8-g CSL112, respectively, and 11 received placebo. There were no clinically significant elevations (>3× upper limit of normal) in alanine aminotransferase or aspartate aminotransferase. Adverse events were nonserious and mild and occurred in 5 (71%), 5 (41%), and 6 (43%) patients in the CSL112 1.7-, 3.4-, and 6.8-g groups, respectively, compared with 3 (27%) placebo patients. The imbalance in adverse events was attributable to vessel puncture/infusion-site bruising. CSL112 resulted in rapid (T(max)≈2 hours) and dose-dependent increases in apoA-I (145% increase in the 6.8-g group) and total cholesterol efflux (up to 3.1-fold higher than placebo) (P<0.001).

Conclusions: CSL112 infusion was well tolerated in patients with stable atherosclerotic disease. CSL112 immediately raised apoA-I levels and caused a rapid and marked increase in the capacity of serum to efflux cholesterol. This potential novel approach for the treatment of atherosclerosis warrants further investigation.

Clinical trial registration: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01499420.

Keywords: apolipoprotein; atherosclerosis; clinical trial; coronary disease; plaque.

© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1
Figure 1
Trial design. CAD indicates coronary artery disease; CrCl, creatinine clearance; PVD, peripheral vascular disease; Rx, prescription.
Figure 2
Figure 2
Study design.
Figure 3
Figure 3
Subject disposition. ITT indicates intention-to-treat.
Figure 4
Figure 4
Variation in serum creatinine before and after study drug administration.
Figure 5
Figure 5
Change in mean apolipoprotein A-I concentration after infusion of ascending doses of CSL112. Error bars represent the 95% CI for the mean.
Figure 6
Figure 6
Cholesterol concentrations in lipoprotein fractions following infusion of CSL112 by time and dose group. Shown are means and SD. (A) Baseline-corrected high-density lipoprotein (HDL)-cholesterol, (B) non-HDL cholesterol.
Figure 7
Figure 7
Change in serum total cholesterol efflux capacity after infusion of ascending doses of CSL112 or placebo. Error bars represent the 95% CI for the mean.

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