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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.

ABSTRACT: 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.

SUBMITTER: Korjian S

PROVIDER: S-EPMC10236524 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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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.

Korjian Serge S Kazmi Syed Hassan A SHA Chi Gerald G Kalayci Arzu A Lee Jane J JJ Talib Usama U Wright Samuel D SD Duffy Danielle D Kingwell Bronwyn A BA Mehran Roxana R Ridker Paul M PM Gibson C Michael CM

European heart journal. Cardiovascular pharmacotherapy 20230601 4

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) ...[more]

PMID: 36787889

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Project description:BackgroundAcute myocardial infarction (AMI) remains a major cause of mortality and morbidity globally, with a high incidence of major adverse cardiovascular events (MACE) post-primary percutaneous coronary intervention (PPCI). The DETERMINE score, derived from electrocardiographic (ECG) markers, has shown promise as a predictor of adverse outcomes, but its clinical utility requires further validation.ObjectiveTo evaluate the predictive value of the DETERMINE score for MACE and provide early clinical warnings for high-risk patients.MethodsThis bidirectional cohort study included AMI patients from the Second Affiliated Hospital of Anhui Medical University between 2019 and 2023. The training cohort comprised 545 patients between January 2019 and January 2023, while the validation cohort consisted of 122 patients between February 2023 and July 2023. The primary endpoint was MACE within one-year post-PPCI. The relationship between the DETERMINE score and MACE was analyzed using Cox regression, trend tests, and restricted cubic splines to assess linear and nonlinear associations. Patients were stratified into risk groups based on tertiles or optimal cutoffs, and Kaplan-Meier survival curves compared MACE incidence across groups. Predictive accuracy was evaluated through time-dependent C-index, ROC curves, decision curve analysis, and calibration, and compared to other prognostic scores, including the Selvester, GRACE, and SYNTAX scores, as well as left ventricular ejection fraction (LVEF). Subgroup analyses by sex, age, and culprit artery involvement were also conducted.ResultsCox multivariate regression indicated that the DETERMINE score was an independent risk factor for MACE (HR = 1.56, 95% CI 1.38-1.75, P < 0.001). Trend test and RCS showed a positive correlation and non-linear relationship between the DETERMINE score and MACE (P-trend < 0.001, P-overall < 0.001, P-nonlinear: 0.003). Kaplan-Meier survival analysis revealed that, in both the training and validation datasets, groups with a higher DETERMINE score showed a higher cumulative risk of MACE. The DETERMINE score outperformed traditional prognostic scores (Selvester, GRACE, SYNTAX) in terms of predictive accuracy, with an AUROC of 0.840 at 12 months in the training cohort. The score also provided a substantial clinical net benefit, particularly over longer follow-up periods. Subgroup analyses confirmed its predictive power across different demographics and clinical presentations.ConclusionThe DETERMINE score has outstanding predictive power for MACE post-PPCI, which can guide the early identification of high-risk patients with poor prognosis of AMI in clinical practice.

Project description:BackgroundHuman 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.MethodsThe 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).ResultsA 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.ConclusionsAmong 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 registrationURL: https://clinicaltrials.gov. Unique identifier: NCT02108262.

Dataset Information

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.

Publications

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.

Similar Datasets

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