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.