Journal Article

Development of CER-001: Preclinical Dose Selection Through to Phase I Clinical Findings

Keyserling, Constance H., Dasseux, Jean-Louis, Benghozi, Renee, Barbaras, Ronald

2017

Overview

Background CER-001 comprises recombinant human apolipoprotein A-I complexed with phospholipids that mimics natural, nascent, pre-β high-density lipoprotein (HDL). We present animal model data showing dose-dependent increases in cholesterol efflux with CER-001 and its subsequent elimination by reverse lipid transport, together with inhibition of atherosclerotic plaque progression. We report the first phase I study results with CER-001 in humans, starting at 0.25 mg/kg, which is 1/80th of the safe dose (20 mg/kg) established in 4-week multiple-dose animal studies dosed every second day. Methods Healthy volunteers, 18–55 years old with a low-density lipoprotein-cholesterol:HDL-cholesterol ratio greater than 3.0, received single intravenous escalating doses of CER-001 (0.25–45.0 mg/kg) and placebo in a double-blind randomised cross-over fashion. Subjects were followed up for 3 weeks post-dose. Assessments included adverse event monitoring, blood sampling, and clinical laboratory measurements. Results Thirty-two subjects were enrolled. All CER-001 doses (0.25–45 mg/kg) were safe and well tolerated, with an adverse event profile similar to placebo. Effects on clinical chemistry, haematology and coagulation parameters were comparable to placebo. No adverse effects of CER-001 on electrocardiograms were observed. No antibodies to apolipoprotein A-I were detected following single-dose administration of CER-001. Plasma apolipoprotein A-I levels increased in a dose-related manner and returned to baseline by 24 h post-dose for doses up to 10 mg/kg but remained in circulation for >72 h post-dose for doses >10 mg/kg. CER-001 caused elevations in plasma cholesterol and total and unesterified cholesterol in the HDL fraction. Mobilisation of unesterified cholesterol in the HDL fraction was seen with CER-001 at doses as low as 2 mg/kg. Conclusion CER-001 is well tolerated when administered to humans as single doses up to 45 mg/kg and mobilises and eliminates cholesterol via reverse lipid transport.

• Publisher: Springer International Publishing,Springer Nature B.V
• Subject: Acute coronary syndromes / Adult / Animals / Apolipoprotein A-I - blood / Apolipoprotein A-I - pharmacology / Apolipoprotein A-I - therapeutic use / Apolipoproteins / Atherosclerosis / Carotid arteries / Cholesterol / Cholesterol - blood / Cholesterol, HDL - antagonists & inhibitors / Cholesterol, HDL - blood / Cholesterol, LDL - antagonists & inhibitors / Cholesterol, LDL - blood / Cross-Over Studies / Dose-Response Relationship, Drug / Double-Blind Method / Drug Evaluation, Preclinical - methods / Female / Humans / Internal Medicine / Lipids / Low density lipoprotein / Male / Medicine / Medicine & Public Health / Mice / Mice, Knockout / Middle Aged / Original / Original Research Article / Pharmacology/Toxicology / Pharmacotherapy / Phospholipids - pharmacology / Phospholipids - therapeutic use / Rabbits / Recombinant Proteins - pharmacology / Recombinant Proteins - therapeutic use / Rodents