A multiple ascending dose study of CSL112, an infused formulation of ApoA‐I

Abstract

CSL112 is apoA-I purified from human plasma and reconstituted with phosphatidylcholine (PC) to form high-density lipoprotein (HDL)-particles suitable for infusion. CSL112 is in development for the potential treatment of acute coronary syndromes (ACS) by optimizing cholesterol efflux. This study assesses the pharmacokinetics (PK), safety and tolerability of CSL112. Repeat doses of CSL112 or placebo were administered intravenously once- (3.4 g or 6.8 g) or twice-weekly (3.4 g) to healthy subjects in a placebo-controlled, randomized (3 CSL112: 1 placebo), ascending-dose study (NCT01281774). Twenty-seven subjects received CSL112 and nine received placebo. Study endpoints included plasma apoA-I and PC concentrations and specific PK parameters. CSL112 infusions immediately produced robust increases in apoA-I concentration in a dose-proportional manner, reaching levels higher than observed with currently available or investigational HDL products. After infusion of CSL112, apoA-I levels remained above baseline for approximately 3 days. Multiple infusions of CSL112 were safe and well tolerated with no evidence of major organ toxicity or immunogenicity. CSL112 may provide a novel option to rapidly transport cholesterol from atherosclerotic plaque to the liver and reduce early recurrent events following ACS. The data presented here support continued clinical development of CSL112 in patient populations.

CSL112 Enhances Biomarkers of Reverse Cholesterol Transport After Single and Multiple Infusions in Healthy Subjects

“…15 Here, we report for the first time the effects of CSL112 on key biomarkers of RCT after single and multiple intravenous infusions in healthy adult subjects.…”

“…Here, we show that infusion of CSL112 causes an immediate rise in apoA-I (C max 2 hours) to levels that depending on the dose double or even triple endogenous levels of apoA-I (Figure 1). Like endogenously produced apoA-I, the infused apoA-I seems to have some but limited access to the extravascular space (volume of distribution range, 5.6-9.7 L) 15 and to have clearance properties similar to endogenous apoA-I.Infusion of CSL112 caused movement of tissue cholesterol into the plasma as documented by the rise in total plasma cholesterol (Figure 2A), and the pathway of this movement seems consistent with the normal steps documented in the literature: unesterified cholesterol but not cholesterol ester is known to move to HDL before further transport or metabolism. 20 In keeping with this pattern, the elevated plasma cholesterol caused by CSL112 infusion appeared as unesterified cholesterol (Figure 3) and appeared in the HDL fraction ( Figure 2B-2D).…”

“…Here, we show that infusion of CSL112 causes an immediate rise in apoA-I (C max 2 hours) to levels that depending on the dose double or even triple endogenous levels of apoA-I (Figure 1). Like endogenously produced apoA-I, the infused apoA-I seems to have some but limited access to the extravascular space (volume of distribution range, 5.6-9.7 L) 15 and to have clearance properties similar to endogenous apoA-I.…”

Anti-inflammatory and cholesterol-reducing properties of apolipoprotein mimetics: a review

“…Plaque volume, however, was reduced in the CSL-111 group compared with baseline ( 39 ). Recent studies show that CSL-112 administration in normal humans signifi cantly increases plasma apoA-I and HDL-C, suggesting an increase in cholesterol effl ux into the plasma compartment ( 40,41 ). apoA-I levels in CSL-112-treated patients remained elevated above baseline for 3 days after treatment ( 41 ).…”

“…Recent studies show that CSL-112 administration in normal humans signifi cantly increases plasma apoA-I and HDL-C, suggesting an increase in cholesterol effl ux into the plasma compartment ( 40,41 ). apoA-I levels in CSL-112-treated patients remained elevated above baseline for 3 days after treatment ( 41 ). At this time, effects of CSL-112 on atheroma regression have not been reported.…”