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.

Description:

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.

Interpretation:

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.

References:

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.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Vascular Medicine, Lipid Metabolism, Nonstatins, Novel Agents, Statins

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


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