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

ABSTRACT: 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. Patients (n?=?44) on aspirin (75-325 mg/day) and either clopidogrel (75 mg/day, n?=?37) or prasugrel (10 mg/day, n?=?7) for >?30 days alongside standard-of-care therapy were randomised to a single dose of placebo or CSL112: 1.7, 3.4, or 6.8 g. Light transmission aggregometry was used to assess platelet aggregation in response to 2 mM arachidonic acid, 5 and 20 µM adenosine diphosphate, and 4 µg/mL collagen, pre-dose (baseline) and up to 48 h post-dosing. Compared to placebo, CSL112 had no clinically meaningful time- or dose-dependent effects on maximum platelet aggregation in response to any agonist, by either dose or renal function subgroup (p?>?0.05). Coagulation parameters showed little variation over time or between treatment groups (p?>?0.05). CSL112, when co-administered with standard DAPT, did not significantly influence platelet aggregation in response to agonists and is, therefore, not expected to significantly increase bleeding risk when administered with antiplatelet therapies.

SUBMITTER: Gurbel PA

PROVIDER: S-EPMC5889770 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Gurbel Paul A PA Tantry Udaya S US D'Andrea Denise D Chung Thomas T Alexander John H JH Bliden Kevin P KP Wright Samuel D SD Tricoci Pierluigi P

Journal of thrombosis and thrombolysis 20180501 4

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 ...[more]

PMID: 29582212

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Project description:BackgroundCSL112 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 resultsPatients 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).ConclusionsCSL112 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 registrationURL: http://www.ClinicalTrials.gov. Unique identifier: NCT01499420.

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

Publications

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

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