Clinical Pharmacokinetics and Pharmacodynamics of CSL112

Abstract

Cardiovascular diseases are the leading cause of death worldwide. Although there have been substantial advances over the last decades, recurrent adverse cardiovascular events after myocardial infarction are still frequent, particularly during the first year of the index event. For decades, high-density lipoprotein (HDL) has been among the therapeutic targets for long-term prevention after an ischemic event. However, early trials focusing on increasing HDL circulating levels showed no improvement in clinical outcomes. Recently, the paradigm has shifted to increasing the functionality of HDL rather than its circulating plasma levels. For this purpose, apolipoprotein-AI-based infusion therapies have been developed, including reconstituted HDL, such as CSL112. During the last decade, CSL112 has been extensively studied in Phase 1 and 2 trials and has shown promising results. In particular, CSL112 has been studied in the Phase 2b AEGIS trial exhibiting good safety and tolerability profiles, which has led to the ongoing large-scale Phase 3 AEGIS-II trial. This systematic overview will provide a comprehensive summary of the CSL112 drug development program focusing on its pharmacodynamic, pharmacokinetic, and safety profiles.

Fig. 1

High-density lipoprotein (HDL) structure and metabolism. Simplified HDL physiology and CSL112 mechanism of action. Reverse cholesterol transfer (RCT) is a process mediated by HDL through which cholesterol is picked up from lipid-laden macrophages in peripheral cells/tissues and is delivered to the liver or intestine for its removal. Cholesterol efflux is the first step of RCT and consists of free-cholesterol (F-Ch) transfer from cells to HDL. Cholesterol efflux pathway can occur in different ways. A Via the interaction between ATP binding cassette A1 receptor (ABCA1) and ApoA-I (i.e., main component of HDL). This interaction mostly involves smaller subsets of HDL such as pre-β1-HDL (i.e., poor lipidated poA-I and discoid HDL). B Pre-β1-HDL mature into bigger and spherical HDL (i.e., α-HDL) by the action of the lecithin–cholesterol acyltransferase (LCAT), that transform F-Ch into esterified cholesterol (E-Ch). E-CH then migrates to the particle’s core while F-Ch maintains on the membrane. C ATP binding cassette G1 receptor (ABCG1), scavenger receptor class B type 1 (SR-BI) receptor, and passive cholesterol transport pathways are other cholesterol efflux modalities mostly employed by mature HDL. D E-Ch can be transferred from mature HDL by cholesteryl ester transferase protein (CETP) to ApoB lipoproteins in exchange for triglycerides (TG). E E-Ch delivery by mature HDL to the hepatic cells can occur either directly, via SR-BI receptor-mediated or indirectly, through hepatocytes- LDL-receptor mediated-uptake of ApoB containing lipoproteins (i.e., very-low-density lipoprotein [VDL], lipoprotein(a) [Lp(a)], intermediate-density lipoprotein [IDL], and low-density lipoprotein [LDL]). (4b) The liver can excrete F-Ch into the bile as F-Ch or bile salt. F In a pathway known as transintestinal cholesterol efflux (TICE), F-cholesterol can be directly transferred to enterocytes and ultimately poured into the intestinal lumen. PL phospholipid, rHDL reconstituted high-density lipoprotein (rHDL)

Fig. 2

CSL112 plaque stabilization mechanism. *In humans, plaque volume assessments with intravascular ultrasound were evaluated with CSL111. Overall, CSL111/CSL112 has been associated with improvement in markers related to atherosclerotic plaque stabilization characteristics such as inflammatory parameters, reduces plaque lipid content and necrotic core, and increases the collagen content of the plaque fibrous cap, without a significant change in plaque volume

Fig. 3

Changes in apolipoprotein A-I and phosphatidylcholine following CSL112 infusion. Presented are mean ± standard deviation of baseline-corrected plasma concentration-time profiles for apolipoprotein A-I (apoA-I) (A) and phosphatidylcholine (PC) (B). Total study population: 63 (placebo [n = 18], 2 g CSL112 [n = 24], 6 g CSL112 [n = 21]). Normal renal function: 36 patients; Mild renal impairment: 26; Moderate renal impairment: Reproduced with permission from Gibson et al. [44]

Fig. 4

Correlation between apolipoprotein A-I and CEC exposure following infusion of CSL112. Presented are the linear relationships between pre-dose-corrected apolipoprotein. A-I (apoA-I) exposure, area under the curve in the first 24 h post-infusion (AUC_0–24), and pre-dose-corrected cholesterol efflux capacity (CEC), area under the effect curve in the first 24 h (AUEC_0–24): total (A), ABCA1-dependent (B), and ABCA1-independent CEC (C), following the first and last infusions of CSL112. Reproduced with permission from Gibson et al. [44]

Fig. 5

Elevations in cholesterol efflux capacity following CSL112 infusion. Presented are mean ± standard deviation baseline- (first infusion) and pre-dose-corrected (last infusion) total (A), ABCA1-dependent (B), and ABCA1-independent (C) cholesterol efflux capacity. Total study population: 63 (placebo [n = 18], 2 g CSL112 group [n = 24], 6 g CSL112 [n = 21]). Normal renal function: 36 patients; mild renal impairment: 26 patients; moderate renal impairment: 1 patient. Reproduced with permission from Gibson et al. [44]