Effect of a Monoclonal Antibody to PCSK9 on LDL Cholesterol

Stein, Evan A.; Mellis, Scott; Yancopoulos, George D.; Stahl, Neil; Logan, Douglas; Smith, William B.; Lisbon, Eleanor; Gutierrez, Maria; Webb, Cheryle; Wu, Richard; Du, Yunling; Kranz, Therese; Gasparino, Evelyn; Swergold, Gary D.

doi:10.1056/nejmoa1105803

Cited by 665Lipoproteins and Cardiovascular HealthCholesterol and Lipid MetabolismLipid metabolism and disorders

Effect of a Monoclonal Antibody to PCSK9 on LDL Cholesterol

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Stein, Evan A., Mellis, Scott, Yancopoulos, George D., Stahl, Neil, Logan, Douglas, Smith, William B., Lisbon, Eleanor, Gutierrez, Maria +6 more·2012·New England Journal of Medicine

DOI 10.1056/nejmoa1105803

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Abstract

BACKGROUND: Proprotein convertase subtilisin/kexin 9 (PCSK9), one of the serine proteases, binds to low-density lipoprotein (LDL) receptors, leading to their accelerated degradation and to increased LDL cholesterol levels. We report three phase 1 studies of a monoclonal antibody to PCSK9 designated as REGN727/SAR236553 (REGN727). METHODS: In healthy volunteers, we performed two randomized, single ascending-dose studies of REGN727 administered either intravenously (40 subjects) or subcutaneously (32 subjects), as compared with placebo. These studies were followed by a randomized, placebo-controlled, multiple-dose trial in adults with heterozygous familial hypercholesterolemia who were receiving atorvastatin (21 subjects) and those with nonfamilial hypercholesterolemia who were receiving treatment with atorvastatin (30 subjects) (baseline LDL cholesterol, >100 mg per deciliter [2.6 mmol per liter]) or a modified diet alone (10 subjects) (baseline LDL cholesterol, >130 mg per deciliter [3.4 mmol per liter]). REGN727 doses of 50, 100, or 150 mg were administered subcutaneously on days 1, 29, and 43. The primary outcome for all studies was the occurrence of adverse events. The principal secondary outcome was the effect of REGN727 on the lipid profile. RESULTS: Among subjects receiving REGN727, there were no discontinuations because of adverse events. REGN727 significantly lowered LDL cholesterol levels in all the studies. In the multiple-dose study, REGN727 doses of 50, 100, and 150 mg reduced measured LDL cholesterol levels in the combined atorvastatin-treated populations to 77.5 mg per deciliter (2.00 mmol per liter), 61.3 mg per deciliter (1.59 mmol per liter), and 53.8 mg per deciliter (1.39 mmol per liter), for a difference in the change from baseline of -39.2, -53.7, and -61.0 percentage points, respectively, as compared with placebo (P<0.001 for all comparisons). CONCLUSIONS: In three phase 1 trials, a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels in healthy volunteers and in subjects with familial or nonfamilial hypercholesterolemia. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT01026597, NCT01074372, and NCT01161082.).

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Monoclonal antibodies to PCSK9 produce substantial reductions in LDL cholesterol when administered alone or with a statin.
“These findings have led to the development of monoclonal antibodies to PCSK9 that produce substantial reductions in LDL cholesterol when administered alone or with a statin. 8-12”
From Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome (2018) · cites this paper as [8]

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Self-citation

Authors: Stein, E. A., Mellis, S., Yancopoulos, G. D., Stahl, N., Logan, D., Smith, W. B., Lisbon, E., Gutierrez, M., Webb, C., Wu, R., Du, Y., Kranz, T., Gasparino, E., & Swergold, G. D.
Affiliations: Regeneron (United States) (US)
Medpace (United States) (US)
University of Tennessee Medical Center (US)
IQVIA (United States) (US)
ORCID: Stein, Evan A.
Mellis, Scott
Stahl, Neil
Lisbon, Eleanor
Venue: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Published: 2012-03-22
Volume: 366
Issue: 12
Pages: 1108-1118
ISSN: 0028-4793 (ISSN-L)
1533-4406
DOI: 10.1056/nejmoa1105803
OpenAlex: W1989730880
Semantic Scholar: 04c1ea8c55c4bae0da3106e47141bac81e1bb585
Cited by: 664
References: 15
Citations by year: 2026: 12 · 2025: 11 · 2024: 29 · 2023: 22 · 2022: 19 · 2021: 20 · 2020: 38 · 2019: 29 · 2018: 46 · 2017: 58 · 2016: 62 · 2015: 86 · 2014: 83 · 2013: 92 · 2012: 57
FWCI: 103.85
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: New England Journal of Medicine (publishedVersion)
PubMed (publishedVersion)
Funders: Sanofi
Regeneron Pharmaceuticals
Topics: Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords: PCSK9, monoclonal antibodies, LDL cholesterol, LDL receptor degradation, hypercholesterolemia, familial hypercholesterolemia, atorvastatin, lipid profile, adverse events, dose escalation, cholesterol absorption inhibition
MeSH terms: Atorvastatin, Proprotein Convertase 9, Adult, Antibodies, Monoclonal, Anticholesteremic Agents, Dose-Response Relationship, Drug, Drug Therapy, Combination, Female, Heptanoic Acids, Humans, Hypercholesterolemia, Hyperlipoproteinemia Type II, Injections, Intravenous, Injections, Subcutaneous, Lipoproteins, Cholesterol, LDL, Male, Middle Aged, Pyrroles, Receptors, LDL, Serine Endopeptidases, Least-Squares Analysis, Proprotein Convertases, Antibodies, Monoclonal, Humanized

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Effect of a Monoclonal Antibody to PCSK9 on LDL Cholesterol

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