WASHINGTON, DC — Findings from the discontinued SPIRE (Studies of PCSK9 Inhibition and the Reduction of Vascular Events; ClinicalTrials.gov identifiers: NCT01975376 and NCT01975389) trials were presented at the 66th Annual Scientific Session & Expo of the American College of Cardiology in Washington, DC.1,2
In terms of reducing the risk of major cardiovascular (CV) events, no benefit was found for lower-risk patients, but a significant benefit was observed in higher-risk patients.
Previous results showed that the fully human monoclonal antibodies evolocumab and alirocumab, which inhibit proprotein convertase subtilisin–kexin type 9 (PCSK9), reduce low-density lipoprotein cholesterol (LDL-C) levels and CV events,3,4 and large-scale trials involving these agents are currently underway.
The randomized, double-blind SPIRE-1 and SPIRE-2 trials aimed to examine the safety and efficacy of bococizumab, which is a PCSK9 inhibitor that is a humanized monoclonal antibody with a small portion of murine antibody, in patients with high CV risk.
When data from 6 related lipid-lowering trials revealed a link between bococizumab and high levels of antidrug antibodies, however, Pfizer discontinued development of the drug as well as the SPIRE-1 and SPIRE-2 trials.2,5 Data from those trials through the point at which they were discontinued (14 weeks) were simultaneously reported in the New England Journal of Medicine.2,5
Patients (N=27,438) were assigned to 1 of 2 conditions: 150 mg of bococizumab administered subcutaneously every 2 weeks, or matching placebo. SPIRE-1 involved a shorter observation period (7-month median follow-up) and lower-risk patients (baseline LDL-C level ≥70 mg/dL; 1.8 mmol/L), while SPIRE-2 involved a longer observation period (12-month median follow-up) and higher-risk patients (baseline LDL-C level ≥100 mg/dL; 2.6 mmol/L).
The results were as follows:
- In the combined trials, the mean change in LDL-C levels from baseline was −56.0% in the bococizumab group and +2.9% in the placebo group, representing a median reduction of 64.2% and a between-group difference of –59.0 percentage points (both P <.001).
- In the SPIRE-1 trial, 173 patients in each group experienced major CV events (hazard ratio [HR]: 0.99; 95% CI, 0.80-1.22; P =.94).
- In the SPIRE-2 trial, 179 patients in the bococizumab group and 224 patients in the placebo group experienced major CV events (HR: 0.79; 95% CI, 0.65-0.97; P =.02).
- In the combined trials, the HR for the primary end point (nonfatal myocardial infarction or stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death) was 0.88 (95% CI, 0.76-1.02; P =.08).
In summary, the results of these prematurely terminated trials demonstrate no benefit of bococizumab in reducing major CV events in lower-risk patients, while showing a significant benefit in higher-risk patients.
“The idea that the magnitude of risk and the duration of treatment may explain the differences between the 2 trials is supported by 3 additional analyses that were planned after the trial was stopped but before unblinding,” the researchers reported.2
Disclosures: The SPIRE trials were funded by Pfizer. The authors’ disclosures are listed online at NEJM.
- Ridker PM for the SPIRE Cardiovascular Outcome Investigators. Safety and cardiovascular efficacy of bococizumab among 27,000 high risk patients. Joint ACC/JACC Late-Breaking Clinical Trials. Presented at: the 66th Annual Scientific Session & Expo of the American College of Cardiology. March 17-19, 2017; Washington, DC.
- Ridker PM, Revkin J, Amarenco P, et al; for the SPIRE Cardiovascular Outcome Investigators. Cardiovascular efficacy and safety of bococizumab in high-risk patients [published online March 17, 2017]. N Engl J Med. doi:10.1056/NEJMoa1701488
- Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500-1509. doi:10.1056/NEJMoa1500858
- Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015; 372:1489-1499. doi:10.1056/NEJMoa1501031
- Ridker PM, Tardif J-C, Amarenco P, et al; for the SPIRE Cardiovascular Outcome Investigators. Lipid-reduction variability and antidrug antibody formation with bococizumab [published online March 17, 2017]. N Engl J Med. doi:10.1056/NEJMoa1614062