The SPIRE development program of the humanized PCSK9 inhibitor bococizumab has shown that the development of antidrug antibodies in 15-20 percent of patients attenuated the substantial reduction in LDL cholesterol (LDL-C) and that in terms of cardiovascular outcomes there was benefit in patients with a baseline LDL-C >100 mg/dL but not for a baseline LDL-C <100 mg/dL. The results of the multinational trials were presented by Paul M. Ridker, MD, March 17 at ACC.17 and published simultaneously in the New England Journal of Medicine. The cardiovascular outcomes studies, SPIRE-1 and SPIRE-2 were stopped prematurely in November 2016 after the lipid-lowering trial results led the sponsor to discontinue the drug's development.

Lipid-lowering results were reported for 4,449 high-risk patients (mean age 61 years, 42 percent women, LDL-C 122 mg/dL) who were treated with maximally tolerated doses of a statin (86 percent on high-intensity statin) and bococizumab 150 mg subcutaneously every two weeks or placebo. The 54.2 percent reduction in LDL-C seen at 12 weeks with bococizumab was attenuated to 43 percent at 52 weeks – and in the 16 percent of patients who developed antibodies this attenuation was greater at 31 percent. The attenuation in LDL-C reduction was greater with higher antibody levels. Further, the reductions in LDL-C were highly variable within patients, regardless of antibody status. In the lipid-lowering studies, there was a similar rate of major adverse cardiovascular events with bococizumab and placebo at 2.5 percent and 2.7 percent, respectively.

In the SPIRE-1 outcomes study of 16,817 patients with an LDL-C >70 mg/dL, at seven months there was no difference in the primary endpoint of non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina requiring urgent revascularization or cardiovascular death. However, in the SPIRE-2 study of 10,621 patients with an LDL-C >100 mg/dL, at 12 months there was a 21 percent reduction in the primary endpoint. Analyses of the combined results for SPIRE-1 and SPIRE-2 revealed that a larger reduction in LDL cholesterol and a longer duration of treatment were both associated with significantly better outcomes.

The investigators stated that the clinical benefits were greater and statistically significant in subgroup analyses in patients who had and sustained greater absolute and proportionate reductions in LDL-C and that this is consistent with the "lower is better for longer" hypothesis. They also state their data support the use of PCSK9 inhibitors on top of aggressive statin therapy in selected patients.

"In addition to supporting the general hypothesis that PCSK9 inhibitors can lower cardiovascular event rates, differences in this medication class between fully human and humanized therapeutic monoclonal antibodies may be important to consider," Ridker said. "We believe genetic analyses could be very helpful to determine who does and does not develop antidrug antibodies to bococizumab."

Keywords: ACC17, ACC Annual Scientific Session, Angina, Unstable, Diabetes Mellitus, Lipoatrophic, Antibodies, Monoclonal, Humanized, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipids, Maximum Tolerated Dose, Myocardial Infarction, Peripheral Vascular Diseases, Primary Prevention, Renal Insufficiency, Chronic, Secondary Prevention, Stroke, ACC Scientific Session Newspaper

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