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. CSL112 is a novel formulation of human plasma-derived apolipoprotein A-I (apoA-I), currently being evaluated in a Phase 3 clinical trial (AEGIS-II) for the reduction of major adverse CV events in the 90-day high-risk period post-AMI. In this review, we provide an overview of the biological properties of CSL112 that contribute to its proposed mechanism of action for potential therapeutic benefit. These properties include rapid and robust promotion of cholesterol efflux from cells abundant in atherosclerotic plaque, in addition to anti-inflammatory effects, which together, may have a stabilizing effect on atherosclerotic plaque. We provide a detailed overview of these mechanisms, in addition to information on the composition of CSL112 and how it is manufactured.

Recombinant human lecithin-cholesterol acyltransferase in patients with atherosclerosis: phase 2a primary results and phase 2b design.

AIMS: Reverse cholesterol transport (RCT) removes cholesterol and stabilizes vulnerable plaques. In addition, high-density lipoprotein (HDL) may be cardioprotective in acute myocardial infarction (MI). Lecithin-cholesterol acyltransferase (LCAT) may enhance RCT. The objective of this study was to investigate the pharmacokinetics, pharmacodynamics, and safety of multiple ascending doses of recombinant human LCAT (MEDI6012) to inform a Phase 2b programme. METHODS AND RESULTS: This was a randomized, blinded, placebo-controlled, dose-escalation Phase 2a study of MEDI6012. Patients were randomized into one of four cohorts (40, 120, 300 mg IV weekly ×3 doses, or 300 mg IV-push, 150 mg at 48 h and 100 mg at 7 days). All cohorts were planned to randomize 6:2 (MEDI6012 vs. placebo). The primary endpoints were baseline-adjusted area under the curve (AUC) from 0 to 96 h post dose 3 (AUC 0-96 h) for HDL-C, HDL cholesteryl ester (HDL-CE), and total cholesteryl ester (CE). The primary safety endpoints were treatment-emergent adverse events. A total of 32 patients were randomized. MEDI6012 significantly increased AUC 0-96 h for HDL-C, HDL-CE and CE in a graded fashion with increasing doses. Relative to placebo, MEDI6012 increased HDL-C at Day 19 by 66% (95% CI 33-99, P = 0.014) with 120 mg and 144% (95% CI 108-181, P < 0.001) with 300 mg. An IV-push increased HDL-C by 40.8% at 30 min. Overall adverse events were similar between groups with no severe, life-threatening/fatal adverse events, or neutralizing antibodies. CONCLUSIONS: Multiple ascending doses of MEDI6012 were safe and well tolerated and significantly increased HDL-C, HDL-CE and CE in a dose-related manner. These data support the ongoing Phase 2b programme investigating MEDI6012 in ST-elevation MI.

TTC39B destabilizes retinoblastoma protein promoting hepatic lipogenesis in a sex-specific fashion.

BACKGROUND & AIMS: Molecular mechanisms underlying the different susceptibility of men and women to non-alcoholic fatty liver disease (NAFLD) are poorly understood. The TTC39B locus encodes a scaffolding protein, associates with gynecological disorders and its deletion protects mice from diet-induced steatohepatitis. This study aimed to elucidate the molecular mechanisms linking TTC39B (T39) to the expression of lipogenic genes and to explore sex-specific effects. METHODS: Co-expression in HEK293A cells validated the novel T39/pRb interaction predicted by a protein-protein interaction algorithm. T39 was knocked down using an antisense oligonucleotide (ASO) in mice with dietary NAFLD and a genetic deficiency of pRb or its downstream effector E2F1, as well as in primary human hepatocytes. RESULTS: T39 interacts with pRb via its C-terminal TPR domain and promotes its proteasomal degradation. In female mice, T39 deficiency reduces the mRNA of lipogenic genes, especially Pnpla3, in a pRb- and E2F1-dependent manner. In contrast, in male mice, T39 deficiency results in a much smaller reduction in lipogenic gene expression that is independent of pRb/E2F1. T39 also interacts with VAPB via an N-terminal FFAT motif and stabilizes the interaction of VAPB with SCAP. Ovariectomy abolishes the effect of T39 knockdown on the hepatic pRb/E2F1/Pnpla3 axis. In both sexes T39 knockdown reduces SCAP independently of pRb. In primary human hepatocytes, T39 knockdown reduces expression of PNPLA3 and other lipogenic genes in women but not men. CONCLUSIONS: We have uncovered a conserved sexual dimorphism in the regulation of hepatic lipogenic genes, with effects of T39 mediated through pRb/E2F1 in females and VAPB/SCAP in both sexes. T39 inhibition could be a novel strategy to downregulate PNPLA3 and treat NAFLD in women. LAY SUMMARY: In females, the protein TTC39B degrades a tumor suppressor in the liver to promote the synthesis of new fat and the expression of a major genetic risk factor for non-alcoholic fatty liver disease. TTC39B is a potential therapeutic target for non-alcoholic fatty liver disease, especially in women.

High density lipoproteins and oxidative stress in breast cancer.

Breast cancer is one of the main leading causes of women death. In recent years, attention has been focused on the role of lipoproteins, alterations of cholesterol metabolism and oxidative stress in the molecular mechanism of breast cancer. A role for high density lipoproteins (HDL) has been proposed, in fact, in addition to the role of reverse cholesterol transport (RCT), HDL exert antioxidant and anti-inflammatory properties, modulate intracellular cholesterol homeostasis, signal transduction and proliferation. Low levels of HDL-Cholesterol (HDL-C) have been demonstrated in patients affected by breast cancer and it has been suggested that low levels of HDL-C could represent a risk factor of breast cancer. Contrasting results have been observed by other authors. Recent studies have demonstrated alterations of the activity of some enzymes associated to HDL surface such as Paraoxonase (PON1), Lecithin-Cholesterol Acyltransferase (LCAT) and Phospholipase A2 (PLA2). Higher levels of markers of lipid peroxidation in plasma or serum of patients have also been observed and suggest dysfunctional HDL in breast cancer patients. The review summarizes results on levels of markers of oxidative stress of plasma lipids and on alterations of enzymes associated to HDL in patients affected by breast cancer. The effects of normal and dysfunctional HDL on human breast cancer cells and molecular mechanisms potentially involved will be also reviewed.

MEDI6012: Recombinant Human Lecithin Cholesterol Acyltransferase, High-Density Lipoprotein, and Low-Density Lipoprotein Receptor-Mediated Reverse Cholesterol Transport.

Background MEDI6012 is recombinant human lecithin cholesterol acyltransferase, the rate-limiting enzyme in reverse cholesterol transport. Infusions of lecithin cholesterol acyltransferase have the potential to enhance reverse cholesterol transport and benefit patients with coronary heart disease. The purpose of this study was to test the safety, pharmacokinetic, and pharmacodynamic profile of MEDI6012. Methods and Results This phase 2a double-blind study randomized 48 subjects with stable coronary heart disease on a statin to a single dose of MEDI6012 or placebo (6:2) (NCT02601560) with ascending doses administered intravenously (24, 80, 240, and 800 mg) and subcutaneously (80 and 600 mg). MEDI6012 demonstrated rates of treatment-emergent adverse events that were similar to those of placebo. Dose-dependent increases in high-density lipoprotein cholesterol were observed with area under the concentration-time curves from 0 to 96 hours of 728, 1640, 3035, and 5318 should be: mg·h/mL in the intravenous dose groups and 422 and 2845 mg·h/mL in the subcutaneous dose groups. Peak mean high-density lipoprotein cholesterol percent change was 31.4%, 71.4%, 125%, and 177.8% in the intravenous dose groups and 18.3% and 111.2% in the subcutaneous dose groups, and was accompanied by increases in endogenous apoA1 (apolipoprotein A1) and non-ATP-binding cassette transporter A1 cholesterol efflux capacity. Decreases in apoB (apolipoprotein B) were observed across all dose levels and decreases in atherogenic small low-density lipoprotein particles by 41%, 88%, and 79% at the 80-, 240-, and 800-mg IV doses, respectively. Conclusions MEDI6012 demonstrated an acceptable safety profile and increased high-density lipoprotein cholesterol, endogenous apoA1, and non-ATP-binding cassette transporter A1 cholesterol efflux capacity while reducing the number of atherogenic low-density lipoprotein particles. These findings are supportive of enhanced reverse cholesterol transport and a functional high-density lipoprotein phenotype. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02601560.

Rationale and design of ApoA-I Event Reducing in Ischemic Syndromes II (AEGIS-II): A phase 3, multicenter, double-blind, randomized, placebo-controlled, parallel-group study to investigate the efficacy and safety of CSL112 in subjects after acute myocardial infarction.

Acute myocardial infarction (MI) patients remain at high risk for recurrent events. Cholesterol efflux, mediated by apolipoprotein A-I, removes excess cholesterol from atherosclerotic plaque and transports it to the liver for excretion. Impaired cholesterol efflux is associated with higher cardiovascular (CV) event rates among both patients with stable coronary artery disease and recent MI. CSL112, a novel intravenous formulation of apolipoprotein A-I (human) derived from human plasma, increases cholesterol efflux capacity. AEGIS-II is a phase 3, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial investigating the efficacy and safety of CSL112 compared to placebo among high-risk acute MI participants. Eligibility criteria include age ≥ 18 years with type 1 (spontaneous) MI, evidence of multivessel stable coronary artery disease, and presence of diabetes requiring pharmacotherapy, or ≥2 of the following: age ≥ 65 years, prior MI, or peripheral artery disease. A target sample of 17,400 participants will be randomized 1:1 to receive 4 weekly infusions of CSL112 6 g or placebo, initiated prior to or on the day of discharge and within 5 days of first medical contact. The primary outcome is the time to first occurrence of the composite of CV death, MI, or stroke through 90 days. Key secondary outcomes include the total number of hospitalizations for coronary, cerebral, or peripheral ischemia through 90 days and time to first occurrence of the composite primary outcome through 180 and 365 days. AEGIS-II will be the first trial to formally test whether enhancing cholesterol efflux can reduce the rate of recurrent major adverse CV events.

HDL-Targeted Therapies During Myocardial Infarction.

It is now apparent that a variety of deleterious mechanisms intrinsic to myocardial infarction (MI) exists and underlies its high residual lethality. Indeed, despite effective coronary patency therapies, ischemia and reperfusion (I/R) injury accounts for about 50% of the infarcted mass. In this context, recent studies in animal models have demonstrated that coronary reperfusion with high-density lipoproteins (HDL) may reduce MI size in up to 30%. A spectrum of mechanisms mediated by either HDL-related apolipoproteins or phospholipids attenuates myocardial cell death. Hence, promising therapeutic approaches such as infusion of reconstituted HDL particles, new HDL by genomic therapy, or the infusion of apoA-I mimetic peptides have been sought as a way of ensuring protection against I/R injury. In this review, we will explore the limitations and potential therapeutic effects of HDL therapies during the acute phase of MI.

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/1.73 m2 ) and 16 age-, sex-, and weight-matched subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m2 ) were randomized 3:1 to receive a single infusion of CSL112 2 g (n = 6) or placebo (n = 2), or CSL112 6 g (n = 6) or placebo (n = 2). PK sampling was at prespecified times from 48 hours prior to 144 hours following infusions, with final safety assessments at 90 days. Renal and hepatic safety, and adverse events (AEs) were monitored throughout the study. Plasma apoA-I and PC PK profiles were similar between renal function cohorts at both doses. For CSL112 6 g mean ± SD apoA-I AUC0-last was 7670 ± 1900 and 9170 ± 2910 mg·h/dL in normal renal function and moderate RI subjects, respectively. Renal apoA-I clearance was <1% of CSL112 dose. In moderate RI, sucrose clearance was slower; however, approximately 70% was excreted within 48 hours in both renal function cohorts. No CSL112-related serious AEs or clinically significant renal or hepatic safety changes were observed. Dose adjustment of CSL112 is not required in subjects with moderate RI, supporting its further investigation in AMI patients with moderate RI.

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. Sixteen subjects with moderate renal impairment and 16 age-, sex-, and weight-matched subjects with normal renal function participated in the study. Within each renal function cohort, subjects were randomized 3:1 to receive a single intravenous infusion of CSL112 2 g (n = 6) or placebo (n = 2) or CSL112 6 g (n = 6) or placebo (n = 2). At baseline, subjects with moderate renal impairment versus normal renal function had higher total cholesterol efflux, ABCA1-dependent cholesterol efflux capacity, and pre-ß1-high-density lipoprotein (HDL) levels. Infusing CSL112 resulted in similar, immediate, robust, dose-dependent elevations in apoA-I and cholesterol efflux capacity in both renal function cohorts and significantly greater elevations in pre-ß1-HDL (P < .05) in moderate renal impairment. Lecithin-cholesterol acyltransferase activity, demonstrated by a time-dependent change in the ratio of unesterified to esterified cholesterol, did not differ by renal function. No meaningful changes in proatherogenic lipid levels were observed. Moderate renal impairment did not impact the ability of CSL112 to enhance cholesterol efflux capacity. CSL112 may represent a novel therapy to reduce the risk of early recurrent cardiovascular events following acute myocardial infarction in patients with or without moderate renal impairment.

The CSL112-2001 trial: Safety and tolerability of multiple doses of CSL112 (apolipoprotein A-I [human]), an intravenous formulation of plasma-derived apolipoprotein A-I, among subjects with moderate renal impairment after acute myocardial infarction.

BACKGROUND: CSL112 (apolipoprotein A-I [human]) is a plasma-derived apolipoprotein A-I developed for early reduction of cardiovascular risk following an acute myocardial infarction (AMI). The safety of CSL112 among AMI subjects with moderate, stage 3 chronic kidney disease (CKD) is unknown. METHODS: CSL112_2001, a multicenter, placebo-controlled, parallel-group, double-blind, randomized phase 2 trial, enrolled patients with moderate CKD within 7 days following AMI. Enrollment was stratified on the basis of estimated glomerular filtration rate and presence of diabetes requiring treatment. Patients were randomized in a 2:1 ratio to receive 4 weekly infusions of CSL112 6 g or placebo. The co-primary safety end points were renal serious adverse events (SAEs) and acute kidney injury, defined as an increase ≥26.5 µmol/L in baseline serum creatinine for more than 24 hours, during the treatment period. RESULTS: A total of 83 patients were randomized (55 CSL112 vs 28 placebo). No increase in renal SAEs was observed in the CSL112 group compared with placebo (CSL112 = 1 [1.9%], placebo = 4 [14.3%]). Similarly, no increase in acute kidney injury events was observed (CSL112 = 2 [4.0%], placebo = 4 [14.3%]). Rates of other SAEs were similar between groups. CSL112 administration resulted in increases in ApoA-I and cholesterol efflux similar to those observed in patients with AMI and normal renal function or stage 2 CKD enrolled in the ApoA-I Event Reducing in Ischemic Syndromes I trial. CONCLUSIONS: These results demonstrate the acceptable safety of the 6-g dose of CSL112 among AMI subjects with moderate stage 3 CKD and support inclusion of these patients in a phase 3 cardiovascular outcomes trial powered to assess efficacy.

CSL112, a reconstituted, infusible, plasma-derived apolipoprotein A-I: safety and tolerability profiles and implications for management in patients with myocardial infarction.

INTRODUCTION: The risk of major adverse cardiac events (MACE) remains elevated soon after a coronary event. High-density lipoprotein (HDL) cholesterol has been proposed as a target to reduce cardiovascular endpoints, but there is growing recognition that increasing the function of HDL may be more important than merely increasing its concentration. CSL112 is a reconstituted, infusible human plasma-derived apolipoprotein A-I (apoA-I) that increases cholesterol efflux capacity - an ex vivo measure of the ability of HDL to accept cholesterol from macrophages. AREAS COVERED: This article reviews the pharmacology of CSL112 and its current clinical development status. EXPERT OPINION: Clinical trials provide clear evidence that LDL cholesterol is involved in the mechanism of atherogenesis, but data for the protective role of HDL cholesterol remains inconclusive. The AEGIS-I trial suggests that the CSL112 elevates the quantity and the functionality of the apoA-I pool. The number of MACE in the AEGIS-I trial was low, but the study was not powered for efficacy. In aggregate, the favorable safety results of the AEGIS-I study encouraged the initiation of a large-scale phase 3 outcomes trial. Any benefit of CSL112, if proven on a large scale, must be weighed against the costs of the compound.

Psoriasis-associated vascular disease: the role of HDL.

Psoriasis is a chronic inflammatory systemic disease with a prevalence of 2-3%. Overwhelming evidence show an epidemiological association between psoriasis, cardiovascular disease and atherosclerosis. Cardiovascular disease is the most frequent cause of death in patients with severe psoriasis. Several cardiovascular disease classical risk factors are also increased in psoriasis but the psoriasis-associated risk persists after adjusting for other risk factors.Investigation has focused on finding explanations for these epidemiological data. Several studies have demonstrated significant lipid metabolism and HDL composition and function alterations in psoriatic patients. Altered HDL function is clearly one of the mechanisms involved, as these particles are of the utmost importance in atherosclerosis defense. Recent data indicate that biologic therapy can reverse both structural and functional HDL alterations in psoriasis, reinforcing their therapeutic potential.

Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, After Acute Myocardial Infarction: The AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I).

BACKGROUND: Human or recombinant apolipoprotein A-I (apoA-I) has been shown to increase high-density lipoprotein-mediated cholesterol efflux capacity and to regress atherosclerotic disease in animal and clinical studies. CSL112 is an infusible, plasma-derived apoA-I that has been studied in normal subjects or those with stable coronary artery disease. This study aimed to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of CSL112 in patients with a recent acute myocardial infarction. METHODS: The AEGIS-I trial (Apo-I Event Reducing in Ischemic Syndromes I) was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 2b trial. Patients with myocardial infarction were stratified by renal function and randomized 1:1:1 to CSL112 (2 g apoA-I per dose) and high-dose CSL112 (6 g apoA-I per dose), or placebo for 4 consecutive weekly infusions. Coprimary safety end points were occurrence of either a hepatic safety event (an increase in alanine transaminase >3 times the upper limit of normal or an increase in total bilirubin >2 times the upper limit of normal) or a renal safety event (an increase in serum creatinine >1.5 times the baseline value or a new requirement for renal replacement therapy). RESULTS: A total of 1258 patients were randomized, and 91.2% received all 4 infusions. The difference in incidence rates for an increase in alanine transaminase or total bilirubin between both CSL112 arms and placebo was within the protocol-defined noninferiority margin of 4%. Similarly, the difference in incidence rates for an increase in serum creatinine or a new requirement for renal replacement therapy was within the protocol-defined noninferiority margin of 5%. CSL112 was associated with increases in apoA-I and ex vivo cholesterol efflux similar to that achieved in patients with stable coronary artery disease. In regard to the secondary efficacy end point, the risk for the composite of major adverse cardiovascular events among the groups was similar. CONCLUSIONS: Among patients with acute myocardial infarction, 4 weekly infusions of CSL112 are feasible, well tolerated, and not associated with any significant alterations in liver or kidney function or other safety concern. The ability of CSL112 to acutely enhance cholesterol efflux was confirmed. The potential benefit of CSL112 to reduce major adverse cardiovascular events needs to be assessed in an adequately powered phase 3 trial. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT02108262.

Rationale and design of Apo-I Event Reduction in Ischemic Syndromes I (AEGIS-I): A phase 2b, randomized, placebo-controlled, dose-ranging trial to investigate the safety and tolerability of CSL112, a reconstituted, infusible, human apoA-I, after acute myocardial infarction.

BACKGROUND: Despite aggressive pharmacotherapy and stenting, there is a residual risk of major adverse cardiovascular events among patients with acute coronary syndrome. High-density lipoprotein (HDL) has been a major target for secondary acute coronary syndrome prevention; however, a better understanding of the physiologic function of HDL has demonstrated that a high cholesterol efflux capacity, rather than high HDL concentrations alone, may be critical to improving outcomes. CSL112, a reconstituted, infusible human apolipoprotein A-I, has been demonstrated to increase cholesterol efflux capacity and to have a protective effect in experimental models of atherosclerotic cardiovascular disease. DESIGN: The AEGIS-I trial (ClinicalTrials.govNCT02108262) is a phase 2b, multicenter, randomized, placebo-controlled, dose-ranging clinical trial to evaluate the hepatic and renal safety of multiple administrations of 2 doses of CSL112 among subjects with acute myocardial infarction (AMI). Approximately 1,200 subjects (400 per treatment group) with either normal renal function or mild renal impairment will be enrolled up to 7 days after an AMI and will be stratified by renal function and randomized in a 1:1:1 ratio to either 1 of 2 doses of CSL112 (either 2 g or 6 g) or placebo as a weekly 2-hour infusion over the course of 4 consecutive weeks. The coprimary safety endpoints will be the incidence of hepatic and renal toxicity, defined as either confirmed ALT >3 × ULN, total bilirubin >2 × ULN, serum creatinine ≥1.5×baseline value, or a new requirement for renal replacement therapy through the end of the active treatment period. SUMMARY: The AEGIS-I trial will characterize the safety profile of CSL112, a reconstituted formulation of apolipoprotein A-I, and will assess if administration to patients with a recent AMI is associated with a clinically significant alteration in either liver or kidney function when compared with placebo.

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 (1.7, 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.

Remodelamento de partículas lipoprotéicas de alta densidade (HDL) e atividade antioxidante entre pacientes diabéticos e não diabéticos com doença aterosclerótica coronária / Remodeling of high-density lipoprotein particles (HDL) and antioxidant activity between diabetic and non-diabetic patients with coronary artery disease

sendo a doença aterosclerótica a de maior morbimortalidade. Além disso, a aterosclerose pode manifestar-se precocemente dada a presença de dislipidemias, processos inflamatórios e alterações metabólicas como a diabetes. OBJETIVO: avaliar se existem diferenças no remodelamento da HDL e atividade antioxidante entre pacientes diabéticos e não diabéticos com doença aterosclerótica. Ainda, identificar, quantificar e estimar biomarcadores relacionados ao remodelamento de partículas lipoprotéicas e ao risco cardiovascular em função da concentração de colesterol na HDL, colesterol livre total,LDL-C, apoB, apoA-I, atividade da paraoxonase 1 (PON1), razões de risco como TG/HDL-C, LDL-C/ApoB, HDL-C/apoA-I, PON1/apoA-I, apoA-I/ApoB e tamanho estimado de partículas de HDL, LDL, glicemia, insulina e HbA1c. MÉTODOS: foram selecionados por conveniência 69 pacientes do sexo masculino, entre 18 e 75 anos,oriundos da enfermaria de cardiologia do Hospital Ana Neri, subdivididos em dois subgrupos: diabéticos e não diabéticos, ambos, com doença aterosclerótica coronária.Foram utilizadas metodologias enzimáticas, imunoturbidimétricas e nefelometricas nesse estudo. RESULTADOS: dos achados da comparação direta entre os grupos apenas a glicemia de jejum foi significativamente diferente (Teste t; p<0,05). Embora não significante o valor do colesterol não esterificado (CL) foi, em média, quatro vezes maior nos diabéticos quando comparado aos não diabéticos. A análise de correlação linear mostrou achados importantes do ponto de vista fisiológico, como correlação positiva entre CL e HDL-C (r=0,617; p<0,01083) e razão apoA-I/apoB e insulina (r=0,489; p<0,02095) nos diabéticos, e correlação negativa entre PON1/apoA-I com CL (r=-0,499; p<0,0065) e HDL-C com HbA1c (r=-0,444; p<0,0324) nos pacientes não diabéticos. CONCLUSÃO: Os achados desse estudo mostram que o cálculo das razões utilizadas para a análise de risco cardiovascular foram importantes indicadores quando correlacionados com marcadores séricos sugestivos de risco cardiovascular na população masculina diabética deste estudo.

Introduction: cardiovascular diseases affect thousands of people around the world, and atherosclerotic disease is the one with the greatest morbidity and mortality. Furthermore, atherosclerosis may manifest early by the presence of dyslipidemia, inflammatory processes and metabolic disorders such as diabetes. Objective: to assess whether there are differences between HDL remodeling and antioxidant activity from diabetic and nondiabetic patients with coronary artery disease. Also, identify, quantify and evaluate biomarkers related to lipoprotein particles remodeling and cardiovascular risk depending on HDL cholesterol concentration, total free cholesterol, LDL-C, apoB, apoA-I, paraoxonase activity 1 (PON1), and risk ratios like TG/HDL-C, LDL-C/ApoB, HDLC/apoA-I, PON1/apoA-I, apoA-I/ApoB, HDL and LDL estimated particles size, glucose, insulin and HbA1c. Methods: we selected by convenience 69 male patients between 18 and 75 years, from the Cardiology Unit of Hospital Ana Neri, they were subdivided into two groups: diabetic and non-diabetic patients, both with coronary atherosclerosis. In these study were used enzymatic, immunoturbidimetric and nephelometric methodologies. Results: From the findings of the direct comparison between groups only fasting glucose was significantly different (t test; p <0.05). Although not significant, the value of non-esterified cholesterol (CL) was on average, four times higher in diabetics when compared to non-diabetics. Linear correlation analysis showed significant findings, from a physiological point of view, as positive correlation between CL and HDL-C (r = 0.617, p <0.01083) and apoA-I ratio/apoB and insulin (r = 0.489, p <0.02095) in diabetics, and negative correlation between PON1/apoA-I with CL (r = -0.499; p <0.0065) and HDL-C with HbA1c (r = -0.444; p <0.0324) in patients non-diabetic. Conclusion: the findings shows that the calculated ratio´s used for cardiovascular risk analysis were important indicators when correlated to serum markers suggestive of cardiovascular risk in the study diabetic male population.

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. 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.

Efficient systemic delivery of siRNA by using high-density lipoprotein-mimicking peptide lipid nanoparticles.

UNLABELLED: The main challenge for RNAi therapeutics lies in systemic delivery of siRNA to the correct tissues and transporting them into the cytoplasm of targeted cells, at safe, therapeutic levels. Recently, we developed a high-density lipoprotein-mimicking peptide-phospholipid scaffold (HPPS) and demonstrated its direct cytosolic delivery of siRNA in vitro, thereby bypassing endosomal trapping. AIM: We investigate the in vivo implementation of HPPS for siRNA delivery. METHOD & RESULTS: After systemic administration in KB tumor-bearing mice, HPPS prolonged the blood circulation time of cholesterol-modified siRNA (chol-siRNA) by a factor of four, improved its biodistribution and facilitated its uptake in scavenger receptor class B type I overexpressed tumors. For therapeutic targeting to the bcl-2 gene, the HPPS-chol-si-bcl-2 nanoparticles downregulated Bcl-2 protein, induced enhanced apoptosis (2.5-fold) in tumors when compared with controls (saline, HPPS, HPPS-chol-si-scramble and chol-si-bcl-2) and significantly inhibited tumor growth with no adverse effect. CONCLUSION: HPPS is a safe, efficient nanocarrier for RNAi therapeutics in vivo.

Reconstituted HDL in acute coronary syndromes.

OBJECTIVES: The strong inverse relationship between plasma high-density lipoprotein (HDL)-cholesterol and atherosclerotic cardiovascular disease provides the epidemiological basis that HDL is atheroprotective. Since HDL enhances cholesterol efflux and exhibits potent antiinflammatory properties, the aim of the present study was to investigate whether infusion of reconstituted HDL (rHDL) impacts on vascular function, a well-established surrogate of atherosclerotic vascular disease, as well as markers of inflammation and oxidative stress in patients with acute coronary syndromes (ACS). METHODS: Twenty-nine patients with ACS were randomized to double-blind treatment with rHDL or albumin. Endothelium-dependent and independent vasodilatation to intraarterial acetylcholine and sodium nitroprusside were measured by forearm venous occlusion plethysmography. In addition, oxidized LDL and high-sensitivity C-reactive protein were determined as markers of oxidative stress and vascular inflammation. RESULTS: rHDL infusion increased plasma HDL (P < 0.0001) and decreased LDL (P < 0.0001). Oxidized LDL (P= 0.11), high-sensitivity C-reactive protein (P= 0.12) and the response to endothelium-dependent and -independent vasodilatators remained unchanged after rHDL compared to albumin infusion (14.9 ± 9.2 versus 14.5 ± 12.4, P= 0.93 and 12.8 ± 7.1 versus 13.2 ± 9.6, P= 0.27, respectively). CONCLUSIONS: An increase of HDL and a reduction of LDL notwithstanding, human rHDL did not improve vascular function in patients with ACS thus further challenging the clinical benefit of interventions, which rapidly raise HDL in ACS, particularly with the infusion of reconstituted HDL.

High-density lipoprotein: does it have a dark side?

There are proven pleiotropic anti-atherogenic actions of high-density lipoprotein (HDL). However, in systemic inflammation, HDL can have pro-inflammatory properties that may contribute to accelerated atherosclerosis, likely mediated by a change in the structure of HDL to pro-inflammatory HDL (PiHDL). Validation of the technically challenging assay for PiHDL, and confirmation of an association of PiHDL in multiple populations with known risk for atherosclerosis will eventually provide a useful biomarker. Identification of PiHDL in patients with rheumatic disease may help identify patients at risk of accelerated atherosclerosis, and focus our therapeutic interventions.