How durable are the lipid-lowering effects of bococizumab?
Ridker et al. conducted six parallel, multinational lipid-lowering trials enrolling 4300 patients with hyperlipidemia who were randomly assigned to receive 150 mg of bococizumab or placebo subcutaneously every 2 weeks and who were followed for up to 12 months.
Q. What is bococizumab and how does it work?
A. Inhibitors of proprotein convertase subtilisin–kexin type 9 (PCSK9) reduce plasma low-density lipoprotein (LDL) cholesterol levels by slowing PCSK9-mediated degradation of the LDL receptor. Bococizumab is one of three monoclonal antibodies targeting PCSK9. In a dose-finding study among statin-treated patients, bococizumab lowered LDL cholesterol levels by approximately 55 mg per deciliter (1.4 mmol per liter) from baseline when administered in a regimen of 150 mg subcutaneously every 2 weeks.
Q. How does bococizumab differ from the PCSK9 inhibitors alirocumab and evolocumab?
A. Fully human monoclonal antibodies such as alirocumab and evolocumab that interfere with the LDL receptor–binding domain of PCSK9 reduce circulating LDL cholesterol levels by approximately 60% and are promising agents for further reductions in cardiovascular events. Unlike alirocumab and evolocumab, however, bococizumab is a humanized, rather than a fully human, therapeutic monoclonal antibody with approximately 3% murine sequence remaining in the antigen-binding complementarity- determining regions and as such may be more likely to induce the development of antidrug antibodies.
Morning Report Questions
Q: How durable are the lipid-lowering effects of bococizumab?
A: Ridker et al. reported that bococizumab at a dose of 150 mg subcutaneously every 2 weeks reduced LDL cholesterol levels at 12 weeks by 55.2 percentage points as compared with placebo, with significant reductions in other atherogenic lipid fractions as well. However, this early benefit was substantially attenuated over time among the 16% of patients in whom high-titer anti–bococizumab antibodies developed during the study. At 1 year, 48% of the patients who received bococizumab had detectable antidrug antibodies; most of the antibodies developed after week 12. For the patients who received bococizumab and who were in the lowest third and middle third of maximum titers of antidrug antibodies (<1:1176), the observed mean change in the LDL cholesterol level at 52 weeks (−43.1%) was virtually identical to that observed among those who did not have detectable antidrug antibodies (−42.5%). However, at 52 weeks, among the 16% of the patients who received bococizumab and who had antidrug-antibody titers in the top third of maximum titers (≥1:1176), the mean change in the LDL cholesterol level was −30.7%. In the subgroup of patients with antidrug-antibody titers in the top 10% (≥1:5674), the mean change in LDL cholesterol level was −12.3%.
Q: How variable is the individual response with respect to LDL cholesterol levels among patients who receive bococizumab?
A: Ridker et al. reported that although the average group effect of bococizumab on LDL cholesterol levels at 12 weeks was large, waterfall plots showed wide variation among the patients, such that 4% had no reduction in LDL cholesterol levels, 28% had a reduction in LDL cholesterol levels of less than 50%, and 68% had a reduction of 50% or more. Wide individual variation in LDL cholesterol response was observed at 52 weeks among patients who did not have an antidrug-antibody response. The clinical and genetic determinants of this variation are currently uncertain.
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