番茄社区

This article is a collaboration between 番茄社区 and:

WASHINGTON -- Novel PCSK9 inhibitor bococizumab actually prevented cardiovascular events in the higher-risk population studied in the SPIRE-2 trial before the drug's manufacturer halted the development program, researchers said here.

last November, citing trial data showing a decline in LDL effects over time and more adverse events than others in the class.

In the SPIRE-2 trial, in which 10,621 patients with LDL initially at least 100 mg/dL were treated for a median of 12 months, the drug succeeded on the primary endpoint of nonfatal MI, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or CV death compared with placebo atop statin therapy (179 vs 224 events, HR 0.79; 95% CI 0.65-0.97).

But the effect wasn't significant in the lower-risk population in the parallel phase III SPIRE-1 trial with 16,817 patients with LDL of at least 70 mg/dL for a median 7 months (HR 0.99, 95% CI 0.80-1.22), Paul Ridker, MD, of Brigham and Women's Hospital in Boston, reported here at the American College of Cardiology meeting and simultaneously online in the New England Journal of Medicine.

But both trials affirmed what the six multinational lipid-lowering trials of bococizumab he also reported showed: The LDL effect of the drug wore off over time as antidrug antibodies developed in 48% of patients by 52 weeks, and even among patients with no such antibodies, "there was wide variability in the reduction in LDL cholesterol levels at both 12 weeks and 52 weeks."

Due to those effects and the higher likelihood of injection site reactions, again tied to antidrug antibody development, Pfizer called off development before even interim results of SPIRE's cardiovascular outcome trial program were known.

By comparison, in the 27,500-patient FOURIER trial that reported a significant reduction in major adverse cardiovascular events at the conference, no patients developed neutralizing antibody to evolocumab (Repatha).

Ridker chalked up bococizumab's troubles to the fact that it was not a fully human monoclonal antibody and thus retains some mouse material, unlike evolocumab and alirocumab (Praluent).

ACC president , who moderated the late-breaking clinical trial session and press conference, said the findings were encouraging for a cardiovascular event-reducing class effect of LDL reduction of the magnitude seen with the PCSK9 inhibitors, "although the SPIRE trial results, with the attenuation based on the difference on the agent with antibody formation means we can't treat them exactly the same."

"We believe this effect is specific to bococizumab, a humanized monoclonal antibody, and that it has not been seen with alirocumab or evolocumab, which are fully human monoclonal antibodies," Ridker said at the session.

He and all others on the session panel agreed that one key piece of information from the trial was that it reinforced that lower is better for cardiovascular outcomes when it comes to LDL.

The other was with regard to monitoring of PCSK9 treatment, Ridker said. "On-treatment levels of LDL cholesterol may well be important for clinical practice as we monitor who truly benefits from these drugs, whether or not similar individual variability in response is present for alirocumab and evolocumab is uncertain."

, of Mount Sinai Hospital in New York City, said that she would like to see bococizumab revived based on the SPIRE-2 results as a third competitor to bring costs down, although antidrug antibody development would be "a deterrent" to clinicians.

However, Ridker suggested it was a business decision that likely makes sense because there didn't seem to be any plateau in the attenuation of LDL lowering over time in the trial. That might be a hassle physicians wouldn't want to deal with, given the struggle to get a PCSK9 inhibitor covered for the patient in the first place.

Pfizer spokesperson Steven Danehy said in an email to 番茄社区 that the drug would not, in fact, be revived despite SPIRE-2.

"We feel these data validate our decision to discontinue the program," he wrote. "Taken together with the evolving treatment and market landscape for lipid-lowering agents, these data confirm that bococizumab is not likely to provide value to patients, physicians, or our shareholders."