SPIRE 1 and 2: Support for PCSK9 Inhibition but Not Bococizumab

WASHINGTON, DC—Although unexpected rates of immunogenicity observed over time will prevent the novel PCSK9 inhibitor bococizumab from ever being used in clinical practice, data from the SPIRE clinical trial program show the benefit of using this class of drug as an adjunct to statin therapy in patients with high LDL cholesterol, experts said here.

In November, Pfizer announced the discontinuation of its bococizumab program in part due to the “unanticipated attenuation of LDL-cholesterol lowering over time” based on shorter-term SPIRE lipid-lowering studies The humanized monocolonal antibody was on track to compete with the two fully human monoclonal antibodies alirocumab (Praluent, Sanofi/Regeneron) and evolocumab (Repatha, Amgen), which have already been approved by the US Food and Drug Administration for the treatment of high LDL cholesterol levels.

Presenting results of the earlier studies as well as the two cardiovascular outcomes trials (SPIRE 1 and 2) today at the American College of Cardiology (ACC) 2017 Scientific Session, Paul Ridker, MD, MPH (Brigham and Women’s Hospital, Boston, MA), remarked that sharing the data in a high-profile, late-breaking clinical trial session “honors the altruism” of the tens of thousands of patients who enrolled in the SPIRE trials and “contributes to our understanding of PCSK9 inhibition and cardiovascular health.”

Results were simultaneously published in the New England Journal of Medicine.

Before the SPIRE 1 and 2 trials were stopped, they had enrolled 16,817 lower-risk patients (LDL ≥ 70 mg/dL or non-HDL ≥ 100 mg/dL) and 10,621 higher-risk patients (LDL ≥ 100 mg/dL or non-HDL ≥ 130 mg/dL), respectively. Both groups experienced attenuation in LDL cholesterol reduction over time and the wide individual variability previously seen in the short-term lipid lowering trials.

While bococizumab did not affect the rate of the primary endpoint (nonfatal MI, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death) for the lower-risk patients in SPIRE 1 compared with placebo (HR 0.99; 95% CI 0.80-1.22), there was a reduction for higher-risk patients in SPIRE 2 taking the drug, even during the shortened time frame of the study (HR 0.79; 95% CI 0.65-0.97).

When the patients from the two trials were combined, those who had higher than the median percentage of LDL reduction saw a 25% decrease in primary endpoint events (HR 0.75; 95% CI 0.61-0.92). Additionally, when these patients were stratified by length of treatment, those who had a longer duration of exposure (mean 13.6 months) had a 17% reduction in events (HR 0.83; 95% CI 0.70-0.98), but there was no benefit observed in patients on bococizumab for a shorter duration of time (mean 5.6 months).

Ridker pointed out that other outcomes results were similar to what was observed in the FOURIER trial for evolocumab, also presented at ACC today, except for a higher incidence of significant adverse events leading to drug discontinuation in those on bococizumab compared with placebo (6.3% vs 4.2%; P < 0.001). This difference was primarily driven by a higher rate of injection site reaction in the study arm (10.4% vs 1.3%; P < 0.001), which Ridker acknowledged makes sense given the higher rates of immunogenicity seen across the SPIRE program.

‘Important for Scientific Transparency’

Particularly given the fact that bococizumab is associated with wide individual variability in LDL response even among those who do not develop antidrug antibodies, Ridker stressed the importance of measuring on-treatment LDL cholesterol in everyday practice. It remains “uncertain” whether or not this variability exists for evolocumab and alirocumab, he said. Even so, Ridker urged physicians to closely monitor their patients, especially given the high cost of these drugs.

Consistent with the “lower is better for longer” hypothesis, Ridker commented that regardless of the shortcomings apparent with bococizumab, “clinical benefits were greater and statistically significant in analyses of those who achieved and sustained greater absolute as well as relative reductions in LDL cholesterol. These data thus support the use of PCSK9 inhibitors in selected patients as an adjunct to aggressive statin therapy.”

In a discussion following the study presentation, panelist Sidney Smith Jr, MD (University of North Carolina School of Medicine, Chapel Hill), praised the study investigators for presenting data “absolutely essential” for scientific dialogue. Panelist Jennifer Robinson, MD, MPH (University of Iowa, Iowa City), also said the findings of SPIRE 1 and 2 are “important for scientific transparency.”       

Other Antidrug Antibodies

In an editorial accompanying the studies, Eli Roth, MD (Sterling Research Group, Cincinnati, OH), and colleagues explain that immunogenicity is more likely to occur for “murine-derived antibodies humanized by artificially engineering them in vitro, as compared with fully human antibodies that are produced with the use of mice with genetically humanized immune systems.”

Roth and colleagues conducted an additional analysis of more than 4,700 patients from 10 trials on the effect of antidrug antibodies on the efficacy and safety of alirocumab and its ability to reduce LDL cholesterol.

“According to regulatory guidance, we reasoned that the presence of persistent antidrug antibodies would most likely influence efficacy,” they write. “However, we found that substantial reductions in LDL cholesterol levels were maintained over the course of the studies, regardless of antidrug-antibody status, although for some time points, nominally significant differences (not adjusted for multiple testing) were noted.”

Notably, no patients in FOURIER, according to that trial’s lead investigator, reported any antidrug antibodies.