Effects of 12 weeks of treatment with intravenously administered bococizumab, a humanized monoclonal antibody blocking proprotein convertase subtilisin/kexin type 9, in hypercholesterolemic subjects on high-dose statin

Sergio Fazio, David G. Robertson, Tenshang Joh, Hong Wan, Tom Riel, Philippe Forgues, Charles M. Baum, Pamela D. Garzone, Barry Gumbiner

    Research output: Contribution to journalArticle

    4 Citations (Scopus)

    Abstract

    Aims: Two multiple-dose phase II studies were conducted in subjects with primary hypercholesterolemia to evaluate the LDL-C lowering efficacy, safety, and tolerability of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. Methods: The results from the two phase II, double-blinded, randomized, placebo-controlled, multicenter studies conducted in the USA and Canada were combined. In Study 1, 90 subjects with LDL-C ≥100 mg/dL received intravenous (IV) placebo or bococizumab 0.25, 1, 3, or 6 mg/kg. In Study 2, 45 subjects with LDL-C ≥80 mg/dL received IV placebo or bococizumab 1 or 3 mg/kg. Subjects were treated every 4 weeks for 12 weeks. Dosing was interrupted if LDL-C dipped to ≤25 mg/dL and resumed if LDL-C returned to ≥40 mg/dL. The primary endpoint was percent LDL-C reduction from baseline at Week 12. Results: At Week 12, the reductions from baseline in LDL-C vs placebo in the bococizumab 0.25, 1, 3, and 6 mg/kg groups were 9.3%, 10.2%, 41.6%, and 52.0%, respectively (P < .001 vs placebo for all). LDL-C reductions were greater (69.9%) in subjects who received all three doses of bococizumab 6 mg/kg (P < .001 vs placebo). Pharmacogenomic analysis revealed that 15% of hyperlipidemic subjects carried polymorphisms associated with familial hypercholesterolemia, with maximal LDL-C reductions being similar between carriers and noncarriers. Adverse events were mild, unrelated to bococizumab, and resolved by Week 12. Conclusions: These studies demonstrated that bococizumab safely and effectively lowered LDL-C in hypercholesterolemic subjects on high doses of statin.

    Original languageEnglish (US)
    JournalCardiovascular Therapeutics
    DOIs
    StateAccepted/In press - Jan 1 2017

    Fingerprint

    Antibodies, Monoclonal, Humanized
    Hydroxymethylglutaryl-CoA Reductase Inhibitors
    Blocking Antibodies
    Placebos
    Therapeutics
    Hyperlipoproteinemia Type II
    oxidized low density lipoprotein
    Proprotein Convertase 9
    bococizumab
    Hypercholesterolemia
    Multicenter Studies
    Canada
    Safety

    Keywords

    • Bococizumab
    • Humanized monoclonal antibody
    • Hypercholesterolemia
    • Low-density lipoprotein cholesterol
    • Phase II clinical trial
    • Proprotein convertase subtilisin/kexin type 9 inhibitor

    ASJC Scopus subject areas

    • Pharmacology
    • Cardiology and Cardiovascular Medicine
    • Pharmacology (medical)

    Cite this

    Effects of 12 weeks of treatment with intravenously administered bococizumab, a humanized monoclonal antibody blocking proprotein convertase subtilisin/kexin type 9, in hypercholesterolemic subjects on high-dose statin. / Fazio, Sergio; Robertson, David G.; Joh, Tenshang; Wan, Hong; Riel, Tom; Forgues, Philippe; Baum, Charles M.; Garzone, Pamela D.; Gumbiner, Barry.

    In: Cardiovascular Therapeutics, 01.01.2017.

    Research output: Contribution to journalArticle

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    title = "Effects of 12 weeks of treatment with intravenously administered bococizumab, a humanized monoclonal antibody blocking proprotein convertase subtilisin/kexin type 9, in hypercholesterolemic subjects on high-dose statin",
    abstract = "Aims: Two multiple-dose phase II studies were conducted in subjects with primary hypercholesterolemia to evaluate the LDL-C lowering efficacy, safety, and tolerability of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. Methods: The results from the two phase II, double-blinded, randomized, placebo-controlled, multicenter studies conducted in the USA and Canada were combined. In Study 1, 90 subjects with LDL-C ≥100 mg/dL received intravenous (IV) placebo or bococizumab 0.25, 1, 3, or 6 mg/kg. In Study 2, 45 subjects with LDL-C ≥80 mg/dL received IV placebo or bococizumab 1 or 3 mg/kg. Subjects were treated every 4 weeks for 12 weeks. Dosing was interrupted if LDL-C dipped to ≤25 mg/dL and resumed if LDL-C returned to ≥40 mg/dL. The primary endpoint was percent LDL-C reduction from baseline at Week 12. Results: At Week 12, the reductions from baseline in LDL-C vs placebo in the bococizumab 0.25, 1, 3, and 6 mg/kg groups were 9.3{\%}, 10.2{\%}, 41.6{\%}, and 52.0{\%}, respectively (P < .001 vs placebo for all). LDL-C reductions were greater (69.9{\%}) in subjects who received all three doses of bococizumab 6 mg/kg (P < .001 vs placebo). Pharmacogenomic analysis revealed that 15{\%} of hyperlipidemic subjects carried polymorphisms associated with familial hypercholesterolemia, with maximal LDL-C reductions being similar between carriers and noncarriers. Adverse events were mild, unrelated to bococizumab, and resolved by Week 12. Conclusions: These studies demonstrated that bococizumab safely and effectively lowered LDL-C in hypercholesterolemic subjects on high doses of statin.",
    keywords = "Bococizumab, Humanized monoclonal antibody, Hypercholesterolemia, Low-density lipoprotein cholesterol, Phase II clinical trial, Proprotein convertase subtilisin/kexin type 9 inhibitor",
    author = "Sergio Fazio and Robertson, {David G.} and Tenshang Joh and Hong Wan and Tom Riel and Philippe Forgues and Baum, {Charles M.} and Garzone, {Pamela D.} and Barry Gumbiner",
    year = "2017",
    month = "1",
    day = "1",
    doi = "10.1111/1755-5922.12308",
    language = "English (US)",
    journal = "Cardiovascular Therapeutics",
    issn = "1755-5914",
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    T1 - Effects of 12 weeks of treatment with intravenously administered bococizumab, a humanized monoclonal antibody blocking proprotein convertase subtilisin/kexin type 9, in hypercholesterolemic subjects on high-dose statin

    AU - Fazio, Sergio

    AU - Robertson, David G.

    AU - Joh, Tenshang

    AU - Wan, Hong

    AU - Riel, Tom

    AU - Forgues, Philippe

    AU - Baum, Charles M.

    AU - Garzone, Pamela D.

    AU - Gumbiner, Barry

    PY - 2017/1/1

    Y1 - 2017/1/1

    N2 - Aims: Two multiple-dose phase II studies were conducted in subjects with primary hypercholesterolemia to evaluate the LDL-C lowering efficacy, safety, and tolerability of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. Methods: The results from the two phase II, double-blinded, randomized, placebo-controlled, multicenter studies conducted in the USA and Canada were combined. In Study 1, 90 subjects with LDL-C ≥100 mg/dL received intravenous (IV) placebo or bococizumab 0.25, 1, 3, or 6 mg/kg. In Study 2, 45 subjects with LDL-C ≥80 mg/dL received IV placebo or bococizumab 1 or 3 mg/kg. Subjects were treated every 4 weeks for 12 weeks. Dosing was interrupted if LDL-C dipped to ≤25 mg/dL and resumed if LDL-C returned to ≥40 mg/dL. The primary endpoint was percent LDL-C reduction from baseline at Week 12. Results: At Week 12, the reductions from baseline in LDL-C vs placebo in the bococizumab 0.25, 1, 3, and 6 mg/kg groups were 9.3%, 10.2%, 41.6%, and 52.0%, respectively (P < .001 vs placebo for all). LDL-C reductions were greater (69.9%) in subjects who received all three doses of bococizumab 6 mg/kg (P < .001 vs placebo). Pharmacogenomic analysis revealed that 15% of hyperlipidemic subjects carried polymorphisms associated with familial hypercholesterolemia, with maximal LDL-C reductions being similar between carriers and noncarriers. Adverse events were mild, unrelated to bococizumab, and resolved by Week 12. Conclusions: These studies demonstrated that bococizumab safely and effectively lowered LDL-C in hypercholesterolemic subjects on high doses of statin.

    AB - Aims: Two multiple-dose phase II studies were conducted in subjects with primary hypercholesterolemia to evaluate the LDL-C lowering efficacy, safety, and tolerability of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. Methods: The results from the two phase II, double-blinded, randomized, placebo-controlled, multicenter studies conducted in the USA and Canada were combined. In Study 1, 90 subjects with LDL-C ≥100 mg/dL received intravenous (IV) placebo or bococizumab 0.25, 1, 3, or 6 mg/kg. In Study 2, 45 subjects with LDL-C ≥80 mg/dL received IV placebo or bococizumab 1 or 3 mg/kg. Subjects were treated every 4 weeks for 12 weeks. Dosing was interrupted if LDL-C dipped to ≤25 mg/dL and resumed if LDL-C returned to ≥40 mg/dL. The primary endpoint was percent LDL-C reduction from baseline at Week 12. Results: At Week 12, the reductions from baseline in LDL-C vs placebo in the bococizumab 0.25, 1, 3, and 6 mg/kg groups were 9.3%, 10.2%, 41.6%, and 52.0%, respectively (P < .001 vs placebo for all). LDL-C reductions were greater (69.9%) in subjects who received all three doses of bococizumab 6 mg/kg (P < .001 vs placebo). Pharmacogenomic analysis revealed that 15% of hyperlipidemic subjects carried polymorphisms associated with familial hypercholesterolemia, with maximal LDL-C reductions being similar between carriers and noncarriers. Adverse events were mild, unrelated to bococizumab, and resolved by Week 12. Conclusions: These studies demonstrated that bococizumab safely and effectively lowered LDL-C in hypercholesterolemic subjects on high doses of statin.

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    KW - Humanized monoclonal antibody

    KW - Hypercholesterolemia

    KW - Low-density lipoprotein cholesterol

    KW - Phase II clinical trial

    KW - Proprotein convertase subtilisin/kexin type 9 inhibitor

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