Studies of PSCK9 Inhibition and the Reduction of Vascular Events - SPIRE-1 and SPIRE-2

Contribution To Literature:

The SPIRE-1 and -2 trials failed to show a consistent and sustained reduction in LDL-C from bococizumab compared with placebo.


The goal of the trial was to evaluate the efficacy and safety of bococizumab, a PCSK9 inhibitor (humanized antibody, >90% human), among subjects at elevated risk or with established cardiovascular disease on statin therapy.

Study Design

  • Randomized
  • Parallel
  • Double-blind
  • Placebo

Patients with established or at high risk for cardiovascular disease on statin therapy were randomized to bococizumab 150 mg subcutaneous every 2 weeks (n = 13,720) versus placebo every 2 weeks (n = 13,718).

Inclusion criteria:

  • Cardiovascular disease defined as prior myocardial infarction (MI), prior stroke, or symptomatic peripheral arterial disease (PAD) (secondary prevention cohort)
  • High risk for cardiovascular disease defined as diabetes, chronic kidney disease, or asymptomatic PAD (primary prevention cohort)
  • On statin therapy for the last 4 weeks with low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dl (SPIRE-1) or LDL-C ≥100 mg/dl (SPIRE-2)
  • Total number of enrollees: 27,438 patients
  • Duration of follow-up: median 12 months
  • Mean patient age: 63 years
  • Percentage female: 30%
  • Percentage with diabetes: 48%
  • Mean LDL-C: 109 mg/dl

Principal Findings:

Due to lipid-lowering data, the sponsor decided to prematurely stop the SPIRE-1 and SPIRE-2 outcome trials on November 2016.

The primary outcome, incidence of cardiovascular death, MI, stroke, or hospitalization for unstable angina requiring revascularization: HRSPIRE-1 0.99 (p = 0.94) and HRSPIRE-2 0.79 (p = 0.021) and HRSPIRE-1 and -2 0.88 (p = 0.08) for bococizumab versus placebo

Secondary outcomes: There was a marked initial reduction in LDL-C (55-60%) with bococizumab versus placebo; however, there was wide individual variability with benefit that diminished over the follow-up period. Any serious adverse event: 19.6% with bococizumab versus 19.7% with placebo.


Among patients with elevated cardiovascular risk on statin therapy, bococizumab versus placebo reduced LDL-C; however, this benefit diminished over time due to development of antidrug antibodies. Adverse cardiovascular events were reduced with bococizumab versus placebo in the SPIRE-2 trial, but not in the SPIRE-1 trial. Serious adverse events were similar between treatment groups. Bococizumab is not ready for clinical use.


Ridker PM, Revkin J, Amarenco P, et al., on behalf of the SPIRE Cardiovascular Outcome Investigators. Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients. N Engl J Med 2017;376:1527-39.

Ridker PM, Tardif JC, Amarenco P, et al., on behalf of the SPIRE Investigators. Lipid-Reduction Variability and Antidrug-Antibody Formation With Bococizumab. N Engl J Med 2017;376:1517-26.

Presented by Dr. Paul M. Ridker at the American College of Cardiology Annual Scientific Session (ACC 2017), Washington, DC, March 17, 2017.

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

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