Another PCSK9-antibody that effectively lowers LDL-c in hypercholesterolaemic subjects
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
Ballantyne CM, Neutel J, Cropp A et al.,
Am J Cardiol. 2015, May 1;doi:10.1016/j.amjcard.2015.02.006
BackgroundThe enzyme protease proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates cholesterol homeostasis, by inducing degradation of the LDL-receptor (LDLR). Inhibition of PCSK9 lowers plasma LDL-c levels and cardiovascular risk .
Bococizumab is a humanised monoclonal antibody that binds to the LDLR-binding domain of PCSK9, thereby preventing PCSK9-mediated degradation of LDLR, which leads to improved LDL clearance . Bococizumab lowered LDL-c levels by up to ~75% in hypercholesterolaemic subjects, in phase 1 and 2a clinical trials, and was generally well tolerated . This is a 24-week dose-ranging phase 2b study to evaluate the LDL-c lowering effect of bococizumab in hypercholesterolaemic adults on stable statin therapy, administered subcutaneously once every 2 weeks (Q14d) or monthly (Q28d). The trial design incorporated the unique strategy to reduce bococizumab dose if persistent LDL-c <25 mg/dL was achieved.
- Overall, of patients randomised to bococizumab 100 mg Q14d, 150 mg Q14d, 200 mg Q28d and 300 Q28d, 16%, 35%, 44% and 39% respectively had their dose reduced during the study. Dose was never reduced in the 50 mg Q14d group.
- From week 2 onwards, Q14d and Q28d dose regimens significantly reduced LDL-c levels.
- At week 12, the primary endpoint of mean absolute change in LDL-c from baseline was largest in subjects receiving bococizumab 150 mgQ14d.
Placebo-adjusted mean change in LDL-c in all subjects, including those with dose reductions, at week 12 ranged from -34.3 to -53.4 mg/dL (-35.0% to -53.1%) with Q14d and from -27.6 to -44.9 mg/dL (-27.0 to -41.1%) with Q28d.
- Before bococizumab dose reductions (up to week 6 for Q14d and week 8 for Q28d), placebo-adjusted mean LDL-c reductions were greater than at week 12.
- LDL-c reductions were maintained between doses in subjects on a Q14d regime, but not with Q28d regimes.
- Non-HDL-c levels were reduced with bococizumab from week 2 through 24, while HDL-c was increased at weeks 12 and 24. Total cholesterol levels and apoB, but not apoA-1 were significantly decreased with both dosing intervals.
- Serious adverse events (SAEs) and AEs were observed at similar frequency in bococizumab- and placebo-treated subjects. Overall, nasopharyngitis and upper respiratory tract infections were the most commonly reported AEs, and the most frequent treatment-related AEs were injection site events, eg erythema.
ConclusionAll doses of bococizumab significantly reduced LDL-c in subjects with hypercholesterolaemia on stable statin therapy, despite protocol-stipulated dose reductions in a large proportion of subjects. LDL-c reductions of up to about 50% were observed and doses of up to 150 mg Q14d and 300 mg Q28d were generally well-tolerated.
Intensive initial lipid-lowering therapy may often be the preferred strategy to reduce CV outcomes in high-risk patients. Dose-reduction at a threshold of 25 mg/dL occurred frequently in this study, which reduced efficacy of bococizumab. Future studies may therefore need to consider lowering the LDL-c threshold at which dose reduction is initiated, to maintain maximal clinical benefit.
Find this article online at The American Journal of Cardiology
1. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006;354:1264e1272.
2. Liang H, Chaparro-Riggers J, Strop P, et al. Proprotein convertase substilisin/kexin type 9 antagonism reduces low-density lipoprotein cholesterol in statin-treated hypercholesterolemic nonhuman primates. J Pharmacol Exp Ther 2012;340:228e236.
3. Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol 2014;11:563e575.