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Bococizumab yields varying effects on CV events, LDL in SPIRE trials
WASHINGTON — PCSK9 inhibition with bococizumab was safe in high-risk patients with LDL levels exceeding 100 mg/dL, but yielded mixed results on efficacy due to attenuation of LDL lowering, variation in individual response, antidrug antibody production and early termination of drug development.
At the American College of Cardiology Scientific Session, Paul M. Ridker, MD, Eugene Braunwald professor of medicine at Harvard Medical School and director of the Center for Cardiovascular Disease Prevention, reported data from eight parallel bococizumab trials in the SPIRE clinical trial program. The SPIRE-1 and SPIRE-2 CV outcome trials were halted early in November when Pfizer made the decision to discontinue development of bococizumab after high rates of antidrug antibodies and unanticipated attenuation of LDL lowering over time were observed in six lipid-lowering studies.
Lipid-lowering studies
The lipid-lowering studies enrolled 4,449 patients with hyperlipidemia who were randomly assigned bococizumab 150 mg or placebo every 2 weeks via subcutaneous injection, on top of maximally tolerated statin therapy. Follow-up was 12 months.
At 12 weeks, LDL was reduced by 54.2% from baseline in the bococizumab group and increased by 1% in the placebo group (between-group difference, –55.2 percentage points; median between-group difference, –59.2 percentage points). At 52 weeks, the magnitude of percent reduction in LDL was attenuated across the trials (between-group difference, –42.5 percentage points).
“However, high-titer antidrug antibodies developed in a substantial proportion of the patients who received bococizumab, which markedly diminished the magnitude and durability of the reduction in LDL cholesterol levels,” Ridker and colleagues wrote in The New England Journal of Medicine.
At 52 weeks, antidrug antibodies were detected in 48% of patients assigned bococizumab and neutralizing antibodies in 29%, most of which developed after 12 weeks. In patients with high-titer antidrug antibodies, the mean reduction in LDL from baseline to 52 weeks was 31%.
In the group with no antidrug antibodies, reductions in LDL at 12 weeks and 52 weeks varied widely, and the mean reduction in LDL from baseline to 52 weeks was 43%.
CV outcome studies
The parallel SPIRE-1 and SPIRE-2 trials included 27,438 patients assigned to the same treatment regimen. Therapy was administered on top of statin therapy in 93% of patients at baseline.
The primary endpoint was Major adverse CV events, including nonfatal MI, nonfatal stroke, hospitalization for unstable angina or CV death.
The two outcome trials differed in their enrollment criteria. SPIRE-1 included patients with LDL 70 mg/dL with a median follow-up of 7 months, whereas SPIRE-2 included patients with LDL 100 mg/dL with a median follow-up of 12 months.
At 14 weeks, the mean LDL change from baseline was –56% in the bococizumab group vs. an increase of 2.9% in the placebo group (between-group difference, –59 percentage points [P < .001]; median reduction from baseline, 64.2% [P < .001]). Twenty-eight percent of patients assigned bococizumab had LDL 25 mg/dL at 14 weeks.
Bococizumab significantly reduced CV event rates in the higher-risk SPIRE-2 trial of patients with LDL 100 mg/dL, but not in the lower-risk SPIRE-1 trial of those with LDL 70 mg/dL, Ridker said.
- In SPIRE-1, major adverse CV events occurred in 173 patients in the bococizumab group vs. 173 patients in the placebo group (HR = 0.99; 95% CI, 0.8-1.22).
- In SPIRE-2, major adverse CV events occurred in 179 patients in the bococizumab group vs. 224 patients in the placebo group (HR = 0.79; 95% CI, 0.65-0.97).
- The HR for major adverse CV events in the combined trials was 0.88 (95% CI, 0.76-1.02).
- Absolute risk for major adverse CV events was lower in SPIRE-1 vs. SPIRE-2 (3.02 events per 100 person-years vs. 4.19 events per 100 person-years).
Implications of new data
Development of bococizumab was discontinued last year, but there are currently two other PCSK9 inhibitors on the market: alirocumab (Praluent, Sanofi/Regeneron) and evolocumab (Repatha, Amgen). Ridker noted that there are differences between these three inhibitors. Bococizumab is a humanized monoclonal antibody, rather than a fully human monoclonal antibody.
“PCSK9 inhibition with bococizumab reduces LDL by 55% to 60% when given as an adjunct to statin therapy, but this effect is significantly attenuated over time in 10% to 15% of patients due to the development of antidrug antibodies. This effect is specific to bococizumab and has not been seen with either evolocumab or alirocumab. This immunogenicity also explains the higher rate of injection-site reactions observed with bococizumab,” Ridker said.
Across all studies, injection-site reaction was the most commonly observed adverse event, and rates were higher than with placebo. The researchers observed no significant increases in cataracts or new-onset diabetes with bococizumab.
Regarding the wide variability in treatment response observed in these trials, “if similar variability is found to exist for other PCSK9 inhibitors, the individual LDL cholesterol response may be a useful measure to monitor as physicians seek to find the most appropriate selection criteria for the use of these agents,” the researchers wrote in NEJM.
Further, Ridker noted that, “consistent with the hypothesis that ‘lower is better for longer,’ clinical benefits were greater and statistically significant in analyses of those who achieved and sustained greater absolute as well as relative reductions in LDL. These data thus support the use of PCSK9 inhibitors in selected patients as an adjunct to aggressive statin therapy.” – by Katie Kalvaitis
References:
Ridker PM. Opening Session and the Joint American College of Cardiology and Journal of American College of Cardiology Late-Breaking Clinical Trials. Presented at: American College of Cardiology Scientific Session; March 17-19, 2017; Washington, D.C.
Ridker PM, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1701488.
Ridker PM, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1614062.
Disclosure: The SPIRE studies were funded by Pfizer. Ridker reports receiving consultant fees/honoraria from AstraZeneca, CSL Behring, Pfizer, Sanofi and Teva; research grants from Kowa Pharmaceuticals, NHLBI, Novartis and Pfizer; and ownership interest/partnership/principal with Brigham and Women's Hospital.
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