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

Abstract

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.

• Authors: Constance H Keyserling, Ronald Barbaras, Renee Benghozi, Jean-Louis Dasseux
• Journal: Clinical drug investigation (Clin Drug Investig) Vol. 37 Issue 5 Pg. 483-491 (May 2017) ISSN: 1179-1918 [Electronic] New Zealand
• PMID: 28213743 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial)

Chemical References

• APOA1 protein, human
• Apolipoprotein A-I
• CER-001
• Cholesterol, HDL
• Cholesterol, LDL
• Phospholipids
• Recombinant Proteins
• Cholesterol

Topics

• Adult
• Animals
• Apolipoprotein A-I (blood, pharmacology, therapeutic use)
• Cholesterol (blood)
• Cholesterol, HDL (antagonists & inhibitors, blood)
• Cholesterol, LDL (antagonists & inhibitors, blood)
• Cross-Over Studies
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Evaluation, Preclinical (methods)
• Female
• Humans
• Male
• Mice
• Mice, Knockout
• Middle Aged
• Phospholipids (pharmacology, therapeutic use)
• Rabbits
• Recombinant Proteins (pharmacology, therapeutic use)