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

Abstract

BackgroundCSL112 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 ResultsPatients 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 (Tmax≈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).ConclusionsCSL112 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 RegistrationURL: http://www.ClinicalTrials.gov. Unique identifier: NCT01499420.

ApoA-I-Directed Therapies for the Management of Atherosclerosis

“…Multiple dosing of CSL112 in healthy volunteers was well tolerated with no evidence of major organ toxicity [53]. Similar results were also observed in a phase 2a, dose-ranging trial in patients with stable atherosclerotic disease [54]. A phase 2b trial in ACS patients is currently underway.…”

Evaluation of potential antiplatelet effects of CSL112 (Apolipoprotein A-I [Human]) in patients with atherosclerosis: results from a phase 2a study

“…The baseline characteristics were described previously [14]. The majority of randomised patients were male (73%), and Caucasian (79%).…”

“…CSL112 (Apolipoprotein A-I [Human]) is a novel formulation of apoA-I purified from human plasma and formulated with phosphatidylcholine to yield reconstituted HDL particles [10–12]. CSL112 infusion has shown dramatic elevation of cholesterol efflux capacity (CEC) in healthy subjects [13] and in patients with stable atherosclerotic disease [14] or a recent AMI [15]. CEC measured ex vivo at baseline in a population-based cohort free from CVD was shown to be independently associated with incident atherosclerotic CVD [16, 17].…”

“…The safety, pharmacokinetic (PK) and pharmacodynamic (PD) profiles of CSL112 were assessed in a phase 2a multicentre, randomised, placebo-controlled, single ascending dose (SAD) study (NCT01499420) in patients with stable atherosclerotic disease on DAPT [14]. Prior work on an early formulation of apoA-I, CSL111, revealed an effect on platelet aggregation [18, 19].…”

Therapeutic strategies for atherosclerosis and atherothrombosis: Past, present and future

“…Two HDLmimetics, CER-001 and CSL-112, were recently studied in phase II clinical trials. Although their impact on HDL levels was substantial, the beneficial effects on cardiovascular outcome remain unclear (73,74). ADP-P2Y 12 , adenosine diphosphate P2Y 12 ; ASO, antisense oligonucleotide; CETP, cholesterol ester transfer protein; IL-1β, interleukin-1-β; IL-6, interleukin-6; TNF, tumour necrosis factor; HDL, high density lipoprotein; HMGCoAR, β-hydroxy-β-methyl glutaryl-CoA reductase; LDL, low-density lipoprotein; Lp-PLA2, lipoproteinassociated phospholipaseA2; MTP, microsomal transfer protein; NLRP3, nucleotide-binding leucine-rich repeat-containing pyrin receptor; NPC1L1, N-terminal Niemann-Pick C1-like protein 1; PAR-1, protease activated receptor-1; PCSK9, proprotein convertase subtilisin/kexin type 9; sPLA2, soluble phospholipaseA2; VLDL, very low density lipoprotein.…”