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

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 rever...

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Autores principales: Keyserling, Constance H., Barbaras, Ronald, Benghozi, Renee, Dasseux, Jean-Louis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394142/
https://www.ncbi.nlm.nih.gov/pubmed/28213743
http://dx.doi.org/10.1007/s40261-017-0506-3
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author Keyserling, Constance H.
Barbaras, Ronald
Benghozi, Renee
Dasseux, Jean-Louis
author_facet Keyserling, Constance H.
Barbaras, Ronald
Benghozi, Renee
Dasseux, Jean-Louis
author_sort Keyserling, Constance H.
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40261-017-0506-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-53941422017-05-03 Development of CER-001: Preclinical Dose Selection Through to Phase I Clinical Findings Keyserling, Constance H. Barbaras, Ronald Benghozi, Renee Dasseux, Jean-Louis Clin Drug Investig Original Research Article 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s40261-017-0506-3) contains supplementary material, which is available to authorized users. Springer International Publishing 2017-02-17 2017 /pmc/articles/PMC5394142/ /pubmed/28213743 http://dx.doi.org/10.1007/s40261-017-0506-3 Text en © The Author(s) 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Research Article
Keyserling, Constance H.
Barbaras, Ronald
Benghozi, Renee
Dasseux, Jean-Louis
Development of CER-001: Preclinical Dose Selection Through to Phase I Clinical Findings
title Development of CER-001: Preclinical Dose Selection Through to Phase I Clinical Findings
title_full Development of CER-001: Preclinical Dose Selection Through to Phase I Clinical Findings
title_fullStr Development of CER-001: Preclinical Dose Selection Through to Phase I Clinical Findings
title_full_unstemmed Development of CER-001: Preclinical Dose Selection Through to Phase I Clinical Findings
title_short Development of CER-001: Preclinical Dose Selection Through to Phase I Clinical Findings
title_sort development of cer-001: preclinical dose selection through to phase i clinical findings
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394142/
https://www.ncbi.nlm.nih.gov/pubmed/28213743
http://dx.doi.org/10.1007/s40261-017-0506-3
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