Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients

Abstract

BACKGROUNDBococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. METHODSIn two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow-up was 10 months. RESULTSAt 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of −56.0% in the bococizumab group and +2.9% in the placebo group, for a between-group difference of -59.0 percentage points (P<0.001) and a median reduction from baseline of 64.2% (P<0.001). In the lower-risk, shorter-duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [1.8 mmol per liter] and the median follow-up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P = 0.94). In the higher-risk, longer-duration trial (in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [2.6 mmol per liter] and the median follow-up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P = 0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P = 0.08). Injection-site reactions were more common in the bococizumab group than in the placebo group (10.4% vs.

Effect of PCSK9 Inhibitors on Clinical Outcomes in Patients With Hypercholesterolemia: A Meta‐Analysis of 35 Randomized Controlled Trials

“…The 2 cardiovascular outcome trials, SPIRE‐1 and SPIRE‐2, collectively enrolled 16 187 patients with variable baseline lipid‐lowering therapy (including patients with statin intolerance) and ASCVD status (including patients in the high‐risk, primary prevention setting) before the trial was terminated 9. Bococizumab showed a propensity for development of antidrug antibodies, which may explain the high individual variability in percentage of change in LDL‐C, attenuation in LDL‐C reduction over time, and comparatively high rate of injection‐site reactions.…”

“…For phase 2 studies, only dosing regimens that were also tested in phase 3 studies were included. During the study‐selection phase of the trial, the phase 3 clinical development program for the PCSK9 inhibitor bococizumab (SPIRE [Studies of PCSK9 Inhibition and the Reduction of Vascular Events]) was discontinued without plans for future marketing of this drug; therefore, 3 published trials of bococizumab8, 9 were not included in our quantitative synthesis, so as to maintain the clinical relevance of our findings.…”

Vaccine against PCSK9: the natural strategy from passive to active immunization for the prevention of atherosclerosis

“…Non-LDL cholesterol potential functions of PCSK9 have been recently reviewed by Banerjee et al and include: hepatic regeneration; pancreatic integrity; glucose homeostasis; antiviral activity; antimalarial activity; regulation of different cell signaling pathways; cortical neural differentiation; and neuronal apoptosis (20). At present, data from homozygous subjects for PCSK9 null alleles with absence of PCSK9 from birth (21), and from large clinical trial with monoclonal antibodies against PCSK9 do not show any dangerous signal (18,19), but continuous monitoring of these populations in coming years will solve this important issue. Furthermore, as PCSK9 is a cell surface molecule, an active immunization has a potential antibody-dependent cell-mediated cytotoxicity or complement-dependent cell lysis with nonspecific destruction of these cells (13).…”

“…Moreover, gain of function mutations in PCSK9 produced familial hypercholesterolemia (16), and loss of function genetic variation in PCSK9 are associated with low LDL cholesterol and reduced cardiovascular risk (17). Recently, two large clinical trials with evolocumab and bococizumab, two different human PCSK9 monoclonal antibodies, have demonstrated the clinical benefit of passive immunization against PCSK9 on top of statins in subjects very high cardiovascular risk without any relevant side effect associated with treatment (18,19). However, the costs of monoclonals and their inconvenience for the patient could be major impediments for their extensive use.…”

Comment on de Carvalho et al. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors and Incident Type 2 Diabetes: A Systematic Review and Meta-analysis With Over 96,000 Patient-Years. Diabetes Care 2018;41:364–367

“…In fact, unlike evolocumab and alirocumab, bococizumab is not a fully humanized monoclonal antibody; it contains ;3% of the murine sequence in the antigen-binding complementaritydetermining region (2). During bococizumab treatment, nearly half the patients developed antidrug antibodies, and 29% of patients had neutralizing antibodies that reduced the clinical efficacy, which never occurred in evolocumab and alirocumab therapy.…”