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

Background

The 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 [1].
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 [2]. Bococizumab lowered LDL-c levels by up to ~75% in hypercholesterolaemic subjects, in phase 1 and 2a clinical trials, and was generally well tolerated [3]. 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.

Main results

• 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.

Conclusion

All 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

References

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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.