title: Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia.
abstract: Bococizumab is a humanized monoclonal antibody binding proprotein convertase subtilisin/kexin type 9, which may be a potential therapeutic option for reducing low-density lipoprotein cholesterol (LDL-C) levels in patients with hypercholesterolemia. In this 24-week, multicenter, double-blind, placebo-controlled, dose-ranging study (NCT01592240), subjects with LDL-C levels≥80 mg/dl on stable statin therapy were randomized to Q14 days subcutaneous placebo or bococizumab 50, 100, or 150 mg or Q28 days subcutaneous placebo or bococizumab 200 or 300 mg. Doses of bococizumab were reduced if LDL-C levels persistently decreased to ≤25 mg/dl. The primary end point was the absolute change in LDL-C levels from baseline to week 12 after placebo or bococizumab administration. Continuation of bococizumab administration through to week 24 enabled the collection of safety data over an extended period. Of the 354 subjects randomized, 351 received treatment (placebo [n=100] or bococizumab [n=251]). The most efficacious bococizumab doses were 150 mg Q14 days and 300 mg Q28 days. Compared with placebo, bococizumab 150 mg Q14 days reduced LDL-C at week 12 by 53.4 mg/dl and bococizumab 300 mg Q28 days reduced LDL-C by 44.9 mg/dl; this was despite dose reductions in 32.5% and 34.2% of subjects at week 10 or 8, respectively. Pharmacokinetic/pharmacodynamic model-based simulation assuming no dose reductions predicted that bococizumab would lower LDL-C levels by 72.2 and 55.4 mg/dl, respectively. Adverse events were similar across placebo and bococizumab groups. Few subjects (n=7; 2%) discontinued treatment because of treatment-related adverse events. In conclusion, bococizumab significantly reduced LDL-C across all doses despite dose reductions in many subjects. Model-based simulations predicted greater LDL-C reduction in the absence of bococizumab dose reduction. The Q14 days regimen is being evaluated in phase 3 clinical trials.
authors.affiliation: Section of Cardiovascular Research, Division of Atherosclerosis, Department of Medicine, Baylor College of Medicine, Houston, Texas; Center for Cardiovascular Research, Houston Methodist DeBakey Heart and Vascular Center, Houston, Texas. Electronic address: cmb@bcm.edu.
authors.forename: Christie M
authors.initials: CM
authors.lastname: Ballantyne
authors.affiliation: Orange County Research Center, Tustin, California.
authors.forename: Joel
authors.initials: J
authors.lastname: Neutel
authors.affiliation: Clinical Sciences, Global Innovative Pharma Business, Pfizer Inc., Groton, Connecticut.
authors.forename: Anne
authors.initials: A
authors.lastname: Cropp
authors.affiliation: Statistics, Global Innovative Pharma Business, Pfizer Inc., Groton, Connecticut.
authors.forename: William
authors.initials: W
authors.lastname: Duggan
authors.affiliation: Clinical Pharmacology, Global Innovative Pharma Business, Pfizer Inc., New York, New York.
authors.forename: Ellen Q
authors.initials: EQ
authors.lastname: Wang
authors.affiliation: Clinical Pharmacology, Global Innovative Pharma Business, Pfizer Inc., Groton, Connecticut.
authors.forename: David
authors.initials: D
authors.lastname: Plowchalk
authors.affiliation: Clinical Pharmacology, Global Innovative Pharma Business, Pfizer Inc., Groton, Connecticut.
authors.forename: Kevin
authors.initials: K
authors.lastname: Sweeney
authors.affiliation: Clinical Pharmacology, Global Innovative Pharma Business, Pfizer Inc., Groton, Connecticut.
authors.forename: Nitin
authors.initials: N
authors.lastname: Kaila
authors.affiliation: Clinical Sciences, Global Innovative Pharma Business, Pfizer Inc., New York, New York.
authors.forename: John
authors.initials: J
authors.lastname: Vincent
authors.affiliation: Louisville Metabolic and Atherosclerosis Research Center, Louisville, Kentucky.
authors.forename: Harold
authors.initials: H
authors.lastname: Bays
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D008078:Cholesterol, LDL / Q000097:blood*; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy*; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000008:administration & dosage* / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C000598888:bococizumab; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases