The effects of single- and multiple-dose administration of bococizumab (RN316/PF-04950615), a humanized IgG2Δa monoclonal antibody binding proprotein convertase subtilisin/kexin type 9, in hypercholesterolemic subjects treated with and without atorvastatin: Results from four phase I studies.

Abstract

AIMS:

Three single-dose and one multiple-dose phase I studies were conducted in subjects with primary hypercholesterolemia to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of bococizumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.

METHODS:

The dosing schedules for hypercholesterolemic subjects randomized in the four phase I studies were (1) ascending, single, intravenous (IV) bococizumab (0.3, 1, 3, 6, 12, or 18 mg/kg), or placebo (N = 48; baseline low-density lipoprotein cholesterol [LDL-C] ≥130 mg/dL); (2) single, IV bococizumab (0.5 or 4 mg/kg; no placebo) added to ongoing atorvastatin 40 mg/day (N = 24); (3) single, fixed, subcutaneous (SC) bococizumab (100 or 200 mg), or IV bococizumab (200 mg; no placebo; N = 49; baseline LDL-C ≥130 mg/dL); and (4) weekly IV bococizumab (0.25, 0.5, 1, or 1.5 mg/kg) or placebo for 4 weeks (N = 67; baseline LDL-C ≥130 mg/dL).

RESULTS:

Bococizumab pharmacokinetics were well characterized following single IV or SC doses and following multiple IV doses. Exposure to single-dose bococizumab increased slightly greater than dose-proportionally and clearance decreased with increasing dose. In the single-dose studies, maximal mean percent reductions from baseline in LDL-C ranged from 43% (0.3 mg/kg) to 84% (18 mg/kg) in bococizumab-treated subjects, compared with 2% for placebo. For the multiple-dose study, maximal reductions in LDL-C ranged from 55% (0.25 mg/kg) to 66% (1 mg/kg) in bococizumab-treated subjects, compared with 9% for placebo. In all studies, adverse events were infrequent, transient, and not dose-related.

CONCLUSIONS:

Bococizumab was generally safe and well tolerated. Bococizumab lowered LDL-C levels substantially in all four studies.

• Authors: Barry Gumbiner, Tenshang Joh, Hong Liang, Hong Wan, Matteo Levisetti, Alicia M Vana, David L Shelton, Philippe Forgues, Stephan Billotte, Jaume Pons, Charles M Baum, Pamela D Garzone
• Journal: Cardiovascular therapeutics (Cardiovasc Ther) Vol. 36 Issue 1 (Feb 2018) ISSN: 1755-5922 [Electronic] England
• PMID: 29078037 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial)
• Copyright: © 2017 John Wiley & Sons Ltd.

Chemical References

• Antibodies, Monoclonal, Humanized
• Anticholesteremic Agents
• Biomarkers
• Cholesterol, LDL
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• PCSK9 Inhibitors
• Serine Proteinase Inhibitors
• bococizumab
• Atorvastatin
• PCSK9 protein, human
• Proprotein Convertase 9

Topics

• Administration, Intravenous
• Adult
• Aged
• Antibodies, Monoclonal, Humanized (administration & dosage, adverse effects, pharmacokinetics)
• Anticholesteremic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Atorvastatin (administration & dosage, adverse effects)
• Biomarkers (blood)
• Cholesterol, LDL (blood)
• Down-Regulation
• Drug Administration Schedule
• Drug Therapy, Combination
• Female
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (administration & dosage, adverse effects)
• Hypercholesterolemia (blood, drug therapy, enzymology, genetics)
• Male
• Middle Aged
• PCSK9 Inhibitors
• Proprotein Convertase 9 (metabolism)
• Serine Proteinase Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Time Factors
• Treatment Outcome