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J Am Heart Assoc. 2015 Aug 25;4(8):e002171. doi: 10.1161/JAHA.115.002171.

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

Author information

1
Duke Clinical Research Institute, Durham, NC (P.T., M.A.B., J.H.A.).
2
CSL Behring, King of Prussia, PA (D.M.A., Z.Y., C.L.S., S.D.W.).
3
Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore and Johns Hopkins University School of Medicine, Baltimore, MD (P.A.G.).
4
University of Pennsylvania, Philadelphia, PA (M.C.).
5
Black Hills Cardiovascular Research, Rapid City, SD (B.W.).
6
diaDexus, Inc., San Francisco, CA (R.S.).
7
Maine Research Associates, Auburn, ME (R.W.).
8
Cardiac and Vascular Research Center of Northern Michigan, Petoskey, MI (L.C.).
9
Gill Heart Institute, University of Kentucky, Lexington, KY (A.B.).
10
University of Florida College of Medicine-Jacksonville, Jacksonville, FL (D.J.A.).
11
CSL Limited, Parkville, Victoria, Australia (A.G.).

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

PMID:
26307570
PMCID:
PMC4599471
DOI:
10.1161/JAHA.115.002171
[Indexed for MEDLINE]
Free PMC Article

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