CSL112 Infusion Rapidly Increases APOA1 Exchange Rate via Specific Serum Amyloid-Poor HDL Subpopulations When Administered to Patients Post-Myocardial Infarction.

Background: To characterize the effects of CSL112 (human APOA1 [apolipoprotein A1]) on the APOA1 exchange rate (AER) and the relationships with specific HDL (high-density lipoprotein) subpopulations when administered in the 90-day high-risk period post-acute myocardial infarction.

Methods: A subset of patients (n=50) from the AEGIS-I (ApoA-I Event Reducing in Ischemic Syndromes I) study received either placebo or CSL112 post-acute myocardial infarction. AER was measured in AEGIS-I plasma samples incubated with lipid-sensitive fluorescent APOA1 reporter.

Biological basis and proposed mechanism of action of CSL112 (apolipoprotein A-I [human]) for prevention of major adverse cardiovascular events in patients with myocardial infarction.

Despite current standard of care treatment, the period shortly after acute myocardial infarction (AMI) is associated with high residual cardiovascular (CV) risk, with high rates of recurrent AMI and CV death in the first 90 days following the index event. This represents an area of high unmet need that may be potentially addressed by novel therapeutic agents that optimize high-density lipoprotein cholesterol (HDL-C) function rather than increase HDL-C concentrations. Apolipoprotein A-I (apoA-I) is the major constituent of HDL and a key mediator of cholesterol efflux from macrophages within atherosclerotic plaque, a property especially relevant during the high-risk period immediately following an AMI when cholesterol efflux capacity is found to be reduced.

Inhibition of VEGF-B signaling prevents non-alcoholic fatty liver disease development by targeting lipolysis in the white adipose tissue.

Background & Aims: Hepatic steatosis is a hallmark of non-alcoholic fatty liver disease (NAFLD), a common comorbidity in type 2 diabetes mellitus (T2DM). The pathogenesis of NAFLD is complex and involves the crosstalk between the liver and the white adipose tissue (WAT). Vascular endothelial growth factor B (VEGF-B) has been shown to control tissue lipid accumulation by regulating the transport properties of the vasculature.

ApoA-I Infusion Therapies Following Acute Coronary Syndrome: Past, Present, and Future.

Purpose Of Review: The elevated adverse cardiovascular event rate among patients with low high-density lipoprotein cholesterol (HDL-C) formed the basis for the hypothesis that elevating HDL-C would reduce those events. Attempts to raise endogenous HDL-C levels, however, have consistently failed to show improvements in cardiovascular outcomes. However, steady-state HDL-C concentration does not reflect the function of this complex family of particles.

Co-administration of CSL112 (apolipoprotein A-I [human]) with atorvastatin and alirocumab is not associated with increased hepatotoxic or toxicokinetic effects in rats.

CSL112 (apolipoprotein A-I, apo AI [human]) is an investigational drug in Phase 3 development for risk reduction of early recurrent cardiovascular events following an acute myocardial infarction (AMI). Although CSL112 is known to be well tolerated with a regimen of four weekly 6 g intravenous infusions after AMI, high doses of reconstituted apo AI preparations can transiently elevate liver enzymes in rats, raising the possibility of additive liver toxicity and toxicokinetic (TK) effects upon co-administration with cholesterol-lowering drugs, i.e.

Pharmacometric analyses to characterize the effect of CSL112 on apolipoprotein A-I and cholesterol efflux capacity in acute myocardial infarction patients.

Aims: To characterize relationships between apolipoprotein A-I (apoA-I) exposure and cholesterol efflux capacity (CEC) and covariate effects following CSL112 (apoA-I [human]) administration in an integrated population including acute myocardial infarction (AMI) patients.

Methods: A pharmacometric analysis utilized data from seven clinical trials, including patients with AMI, subjects with renal impairment and healthy subjects. A population pharmacokinetic (PK) analysis was performed to relate CSL112 doses to changes in apoA-I plasma concentrations.

Nascent HDL (High-Density Lipoprotein) Discs Carry Cholesterol to HDL Spheres: Effects of HDL Particle Remodeling on Cholesterol Efflux.

Objective: To characterize the fate of protein and lipid in nascent HDL (high-density lipoprotein) in plasma and explore the role of interaction between nascent HDL and mature HDL in promoting ABCA1 (ATP-binding cassette transporter 1)-dependent cholesterol efflux. Approach and Results: Two discoidal species, nascent HDL produced by RAW264.7 cells expressing ABCA1 (LpA-I [apo AI containing particles formed by incubating ABCA1-expressing cells with apo AI]), and CSL112, human apo AI (apolipoprotein AI) reconstituted with phospholipids, were used for in vitro incubations with human plasma or purified spherical plasma HDL.

Moderate Renal Impairment Does Not Impact the Ability of CSL112 (Apolipoprotein A-I [Human]) to Enhance Cholesterol Efflux Capacity.

CSL112 (apolipoprotein A-I [human]) is a novel intravenous formulation of plasma-derived apolipoprotein A-I (apoA-I) that enhances cholesterol efflux capacity. Renal impairment is a common comorbidity in acute myocardial infarction patients and is associated with impaired lipid metabolism. The aim of this phase 1 study was to assess the impact of moderate renal impairment on the pharmacokinetic and pharmacodynamic profile of CSL112.

Pharmacokinetics and Safety of CSL112 (Apolipoprotein A-I [Human]) in Adults With Moderate Renal Impairment and Normal Renal Function.

CSL112 (Apolipoprotein A-I [human]) is an intravenous preparation of apolipoprotein A-I (apoA-I), formulated with phosphatidylcholine (PC) and stabilized with sucrose, in development to prevent early recurrent cardiovascular events following acute myocardial infarction (AMI). This phase 1 study was designed to determine if moderate renal impairment (RI) influenced the pharmacokinetics (PK) and safety of CSL112. Thirty-two subjects, 16 with moderate RI (estimated glomerular filtration rate [eGFR] ≥ 30 and < 60 mL/min/1.

Circulating HDL levels control hypothalamic astrogliosis via apoA-I.

Meta-inflammation of hypothalamic areas governing energy homeostasis has recently emerged as a process of potential pathophysiological relevance for the development of obesity and its metabolic sequelae. The current model suggests that diet-induced neuronal injury triggers microgliosis and astrocytosis, conditions which ultimately may induce functional impairment of hypothalamic circuits governing feeding behavior, systemic metabolism, and body weight. Epidemiological data indicate that low circulating HDL levels, besides conveying cardiovascular risk, also correlate strongly with obesity.

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

CSL112 (Apolipoprotein A-I [Human]), an infusible, plasma-derived apolipoprotein A-I, is being developed to reduce cardiovascular events following acute myocardial infarction (AMI). A predecessor compound (CSL111) demonstrated a potential antiplatelet effect. A phase 2a multicentre, randomised, single-ascending dose study in patients with stable atherosclerotic disease receiving dual antiplatelet therapy (DAPT) assessed the potential additive effects of CSL112 administration on platelet function and increase bleeding risk in the subacute period after AMI.

CSL112 (Apolipoprotein A-I [Human]) Enhances Cholesterol Efflux Similarly in Healthy Individuals and Stable Atherosclerotic Disease Patients.

Objective: CSL112 (apolipoprotein A-I [apoA-I; human]) is a novel formulation of apoA-I in development for reduction of early recurrent cardiovascular events after acute myocardial infarction. Cholesterol efflux capacity (CEC) is a marker of high-density lipoprotein (HDL) function that is strongly correlated with incident cardiovascular disease. Impaired CEC has been observed in patients with coronary heart disease.

Structure-function relationships in reconstituted HDL: Focus on antioxidative activity and cholesterol efflux capacity.

Aims: High-density lipoprotein (HDL) contains multiple components that endow it with biological activities. Apolipoprotein A-I (apoA-I) and surface phospholipids contribute to these activities; however, structure-function relationships in HDL particles remain incompletely characterised.

Methods: Reconstituted HDLs (rHDLs) were prepared from apoA-I and soy phosphatidylcholine (PC) at molar ratios of 1:50, 1:100 and 1:150.

A Consensus Definitive Classification of Scavenger Receptors and Their Roles in Health and Disease.

Scavenger receptors constitute a large family of proteins that are structurally diverse and participate in a wide range of biological functions. These receptors are expressed predominantly by myeloid cells and recognize a diverse variety of ligands including endogenous and modified host-derived molecules and microbial pathogens. There are currently eight classes of scavenger receptors, many of which have multiple names, leading to inconsistencies and confusion in the literature.

Enhanced HDL Functionality in Small HDL Species Produced Upon Remodeling of HDL by Reconstituted HDL, CSL112: Effects on Cholesterol Efflux, Anti-Inflammatory and Antioxidative Activity.

Rationale: CSL112, human apolipoprotein A-I (apoA-I) reconstituted with phosphatidylcholine, is known to cause a dramatic rise in small high-density lipoprotein (HDL).

Objective: To explore the mechanisms by which the formation of small HDL particles is induced by CSL112.

Methods And Results: Infusion of CSL112 into humans caused elevation of 2 small diameter HDL fractions and 1 large diameter fraction.

Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming.

Atherosclerosis is an inflammatory disease linked to elevated blood cholesterol concentrations. Despite ongoing advances in the prevention and treatment of atherosclerosis, cardiovascular disease remains the leading cause of death worldwide. Continuous retention of apolipoprotein B-containing lipoproteins in the subendothelial space causes a local overabundance of free cholesterol.

Reconstituted high-density lipoprotein can elevate plasma alanine aminotransferase by transient depletion of hepatic cholesterol: role of the phospholipid component.

Human apolipoprotein A-I preparations reconstituted with phospholipids (reconstituted high-density lipoprotein [HDL]) have been used in a large number of animal and human studies to investigate the physiological role of apolipoprotein A-I. Several of these studies observed that intravenous infusion of reconstituted HDL might cause transient elevations in plasma levels of hepatic enzymes. Here we describe the mechanism of this enzyme release.

Reconstituted high-density lipoproteins acutely reduce soluble brain Aβ levels in symptomatic APP/PS1 mice.

Many lines of evidence suggest a protective role for high-density lipoprotein (HDL) and its major apolipoprotein (apo)A-I in Alzheimer's Disease (AD). HDL/apoA-I particles are produced by the liver and intestine and, in addition to removing excess cholesterol from the body, are increasingly recognized to have vasoprotective functions. Here we tested the ability of reconstituted HDL (rHDL) consisting of human apoA-I reconstituted with soy phosphatidylcholine for its ability to lower amyloid beta (Aβ) levels in symptomatic APP/PS1 mice, a well-characterized preclinical model of amyloidosis.

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

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.

Reconstituted High-Density Lipoprotein Attenuates Cholesterol Crystal-Induced Inflammatory Responses by Reducing Complement Activation.

Chronic inflammation of the arterial wall is a key element in the development of atherosclerosis, and cholesterol crystals (CC) that accumulate in plaques are associated with initiation and progression of the disease. We recently revealed a link between the complement system and CC-induced inflammasome caspase-1 activation, showing that the complement system is a key trigger in CC-induced inflammation. HDL exhibits cardioprotective and anti-inflammatory properties thought to explain its inverse correlation to cardiovascular risk.

CSL112 enhances biomarkers of reverse cholesterol transport after single and multiple infusions in healthy subjects.

Objective: The ability of apolipoprotein A-I (apoA-I) to transport cholesterol from atherosclerotic plaque is thought to underlie its inverse correlation with cardiovascular risk. To gauge the potential of infused apoA-I to transport cholesterol, we quantified cholesterol transport markers in human subjects infused with a novel formulation of apoA-I (CSL112).

Approach And Results: CSL112 was infused into human subjects in single (57 subjects) and multiple (36 subjects) ascending dose trials.

High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3.

High-density lipoprotein (HDL) mediates reverse cholesterol transport and is known to be protective against atherosclerosis. In addition, HDL has potent anti-inflammatory properties that may be critical for protection against other inflammatory diseases. The molecular mechanisms of how HDL can modulate inflammation, particularly in immune cells such as macrophages, remain poorly understood.

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

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.

Novel formulation of a reconstituted high-density lipoprotein (CSL112) dramatically enhances ABCA1-dependent cholesterol efflux.

Objective: The ability of high-density lipoprotein (HDL) to remove cholesterol from atherosclerotic plaque is thought to underlie its inverse correlation with cardiovascular risk. Our objective was to produce and characterize a human apolipoprotein AI (apoA-I) product optimized to treat clinical atherosclerotic disease.

Approach And Results: A new formulation of full length, plasma-derived human apoA-I termed CSL112 was designed to maximize the cholesterol efflux from cells and exhibit favorable pharmacological properties.