Infusion of Reconstituted High‐Density Lipoprotein, CSL112, in Patients With Atherosclerosis: Safety and Pharmacokinetic Results From a Phase 2a Randomized Clinical Trial. Issue 8 (25th August 2015)

• Record Type: Journal Article
• Authors: Tricoci, Pierluigi; D'Andrea, Denise M.; Gurbel, Paul A.; Yao, Zhenling; Cuchel, Marina; Winston, Brion; Schott, Robert; Weiss, Robert; Blazing, Michael A.; Cannon, Louis; Bailey, Alison; Angiolillo, Dominick J.; Gille, Andreas; Shear, Charles L.; Wright, Samuel D.; Alexander, John H.
• Is Part Of: Journal of the American Heart Association. Volume 4:Issue 8(2015)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2015-08-25
• Subjects: apolipoprotein -- atherosclerosis -- clinical trial -- coronary disease -- plaque; Heart -- Diseases -- Periodicals; Cardiovascular system -- Diseases -- Periodicals; Cerebrovascular disease -- Periodicals; Cardiology -- Periodicals; 616.1
• DOI: 10.1161/JAHA.115.002171
• Languages: English
• ISSNs: 2047-9980

Abstract

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.