A phase 1 study to evaluate the safety and LDL cholesterol-lowering effects of RG7652, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9
| Autor: | Amos Baruch, Robert Kahn, Andrew S. Peterson, Cecilia P.C. Chiu, Whittemore G. Tingley, Nageshwar Budha, Daniel Kirchhofer, Kyra J. Cowan, Yan Wu, Diana Luca, Maya Leabman, John C. Davis |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
business.industry Cholesterol PCSK9 Atorvastatin General Medicine 030204 cardiovascular system & hematology Pharmacology 03 medical and health sciences Subcutaneous injection chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Pharmacokinetics chemistry LDL receptor Medicine Kexin lipids (amino acids peptides and proteins) Cardiology and Cardiovascular Medicine business Lipoprotein medicine.drug |
| Zdroj: | Clinical Cardiology. 40:503-511 |
| ISSN: | 0160-9289 |
| DOI: | 10.1002/clc.22687 |
| Popis: | Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) downregulates low-density lipoprotein (LDL) receptors, thereby leading to a rise in circulating LDL cholesterol (LDL-C). RG7652 is a fully human monoclonal antibody against PCSK9. This placebo-controlled, phase 1 ascending-dose study in healthy subjects evaluated the safety of RG7652 and its efficacy as a potential LDL-C–lowering drug. Hypothesis Anti-PCSK9 antibody therapy safely and effectively reduces LDL-C. Methods Subjects (N = 80) were randomized into 10 cohorts. Six sequential single-dose cohorts received 10, 40, 150, 300, 600, or 800 mg of RG7652 via subcutaneous injection. Four multiple-dose cohorts received 40 or 150 mg of RG7652 once weekly for 4 weeks, either with or without statin therapy (atorvastatin). Results Adverse events (AEs) were generally mild; the most common AEs were temporary injection-site reactions. No serious AEs, severe AEs, AEs leading to study-drug discontinuation, or dose-limiting toxicities were reported. RG7652 monotherapy reduced mean LDL-C levels by up to 64% and as much as 100 mg/dL at week 2; the effect magnitude and duration increased with dose (≥57 days following a single RG7652 dose ≥300 mg). Exploratory analyses showed reduced oxidized LDL, lipoprotein(a), and lipoprotein-associated phospholipase A2 with RG7652. Antidrug antibody against RG7652 tested positive in 2 of 60 (3.3%) RG7652-treated and in 4 of 20 (20.0%) placebo-treated subjects. Simultaneous atorvastatin administration did not appear to impact the pharmacokinetic profile or lipid-lowering effects of RG7652. Conclusions Overall, RG7652 elicited substantial and sustained dose-related LDL-C reductions with an acceptable safety profile and minimal immunogenicity. |
| Databáze: | OpenAIRE |
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