Bococizumab Reduced Cardiovascular Events in High-Risk But Not Low-Risk Patients

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.

References

1. 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.
2. 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
3. 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
4. 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
5. 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