Development of another PCSK9 inhibitor for hyperlipidemia

Renzo Gonzalez, Mercer University College of Pharmacy

It has been shown that lowering low density lipoprotein cholesterol (LDL-C) will reduce cardiovascular (CV) risk. [1] Statins effectively reduce LDL-C levels, but individual responses may vary. [2-3] Bococizumab is a monoclonal antibody that targets proprotein convertase subtilisin-kexin type 9 (PCSK9).  Unlike the two existing PCSK9 inhibitors Praluent® (alirocumab) and Repatha® (evolocumab), bococizumab is a humanized monoclonal antibody, rather than a fully human one.  Fully human monoclonal antibodies (mAbs) have binding sites composed of fully human sequences, whereas humanized mAbs still contain trace amount of mouse sequences.  Given that bococizumab is a humanized mAb, the likelihood of forming antidrug antibodies is higher compared to the existing PCSK9 inhibitors. [4] These agents are very potent in lowering LDL-C, [5,6] but there is uncertainty in the variability and durability of its LDL-C lowering effect.

Lipid Reduction Variability and Antidrug-Antibody Formation with Bococizumab [7]
Design Six parallel, multinational trials (35 countries); N= 4,449
Objective To evaluate changes in lipid levels, durability of effect, safety, and incidence of CV events during treatment with bococizumab
Study Groups Placebo (n= 2,058); bococizumab (n= 2,377)
Methods This study was part of the SPIRE (studies of PCSK9 inhibition and reduction of vascular events) program for the development of bococizumab.  Each of the six trials had slightly different inclusion criteria, and sample sizes ranging from 184 patients to 2,139.  Patients received either bococizumab 150 mg subcutaneously (SQ) every two weeks, or matching placebo.  In one of the six trials, there was a third arm where patients received atorvastatin 40 mg daily.  Patient response to changes in lipid panel was assessed at 12 weeks and again at 52 weeks.  Special attention was given to the development of antidrug antibodies (ADA) and how it impacted treatment response.  Patients were placed in one of four groups based on their ADA titer: ADA negative, ADA < 1.1176 (patients in lower third and middle third of max ADA titer), ADA ≥ 1.1176 (patients in upper third of max ADA titer), and ADA ≥ 1.5674 (patients with titers in top 10%).
Duration 52 weeks
Primary Outcome Measure Percent change from baseline in fasting LDL-C levels at 12 weeks


Secondary Outcome Measure Persistence of LDL-C reduction throughout 52 weeks

Relationship between LDL-C reduction and ADA development

Baseline Characteristics
Mean age, years 61.3
Female, % 41.7
Diabetes, % 53.3
Hypertension, % 78.3
Current smoking, % 19.4
Familial hypercholesterolemia, % 12.1
History of statin use, % 99.8
Baseline LDL-C, mg/dL 122
Baseline total cholesterol, mg/dL 195.2

  Bococizumab Placebo Difference p-value
Change in low-density lipoprotein cholesterol (LDL-C)
12 weeks -54.2% +1% -55.2% < 0.001
52 weeks -40.4% +2.1% -42.5% < 0.001
Change in total cholesterol (TC)
12 weeks -35.5% +0.1% -36% < 0.001
52 weeks -27.4% -0.2% -27.1% < 0.001
Change in triglycerides
12 weeks -12.1% +1.9% -14.2% < 0.001
52 weeks -11% -0.6% -10.9% < 0.001
Change in high-density lipoprotein cholesterol (HDL-C)
12 weeks +6.4% +0.6% +6.2% < 0.001
52 weeks +6% +1.3% +4.6% < 0.001
  ADA negative ADA < 1:1176 ADA ≥ 1:1176 ADA ≥ 1:5674
LDL-C reduction at 52 weeks -42.5% -43.1% -30.7% -12.3%
Adverse Events Common Adverse Events: injection site reactions (11%), arthralgia (4%)
Serious Adverse Events: N/A
Percentage that Discontinued due to Adverse Events: < 1%
Study Author Conclusions Bococizumab reduced LDL-C levels at 12 weeks and 52 weeks, but the development of antidrug antibodies attenuated LDL-C reduction at 52 weeks.

The presence of antidrug antibodies evidently caused attenuation of LDL-C reduction, however, even patients who didn’t develop antidrug antibodies had marked variability in LDL-C reduction at 12 weeks and 52 weeks.  Although not originally included as outcomes, the difference in major CV events (defined as first occurrence of nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or cardiovascular death) was not statistically significant between groups.  The data from this trial showed the immunogenic tendencies of bococizumab and how that negatively impacted clinical outcomes.  Based on these results, the sponsor decided to discontinue further development of bococizumab.



[1] Cholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012; 380: 581-90.

[2] Boekholdt SM, Hovingh GK, Mora S, et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. J Am Coll Cardiol 2014; 64: 485-94.

[3] Ridker PM, Mora S, Rose L. Percent reduction in LDL cholesterol following high-intensity statin therapy: potential implications for guidelines and for the prescription of emerging lipid-lowering agents. Eur Heart J 2016; 37: 1373-9.

[4] Foltz IN, Karow M, Wasserman SM. Evolution and emergence of therapeutic monoclonal antibodies: what cardiologists need to know. Circulation 2013; 127: 2222- 30.

[5] Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372: 1489-99.

[6] Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372: 1500-9.

[7] Ridker PM, Tardif J-C, Amarenco P, Duggan W, Glynn RJ, Jukema JW, Kastelein JJP, Kim AM, Koenig W, Nissen S, Revkin J, Rose LM, Santos RD, Schwartz PF, Shear CL, Yunis C. Lipid-Reduction Variability and Antidrug-Antibody Formation with Bococizumab. New England Journal of Medicine. 2017;376(16):1517-1526. doi:10.1056/NEJMoa1614062.


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