番茄社区

Bentracimab reversed the antiplatelet effects of P2Y12 inhibitor ticagrelor (Brilinta) in the vast majority of patients on dual anti-platelet therapy (DAPT) who were set to undergo urgent surgery or treatment for hemorrhage, according to interim results from the REVERSE-IT trial.

For the study's primary endpoint of immediate and sustained reversal of ticagrelor's antiplatelet effects -- as measured by a point-of-care platelet function assay (VerifyNow) -- bentracimab led to a significant reduction in platelet inhibition within minutes of initiation (P<0.001), which was sustained through all timepoints over a 24-hour period, reported Deepak Bhatt, MD, MPH, of Brigham and Women's Hospital/Harvard Medical School in Boston.

And clinical hemostasis (the study's co-primary endpoint) was adjudicated as good or excellent in more than 90% of patients, he said during a presentation at the American Heart Association virtual meeting.

"Bentracimab appears to be a very promising option for ticagrelor reversal," said Bhatt.

There were "no drug-related serious adverse events or allergic or infusion-related reactions," he said. "The benefits were consistent in all prespecified subgroups, including those undergoing surgery and with major bleeding."

Bhatt explained how ticagrelor reversibly binds to the P2Y12 receptor on platelets, preventing ADP from signaling through to the P2Y12 receptor and blocking platelets from activating their clotting effect. Bentracimab, meanwhile, binds to ticagrelor and blocks its antiplatelet effects until the drug passes from the patient's system. Bentracimab is delivered as a bolus followed by an infusion.

REVERSE-IT is a multicenter, open-label, prospective single-arm study of bentracimab for the reversal of the antiplatelet effects of ticagrelor in patients who present with uncontrolled major or life-threatening bleeding, or who require urgent surgery or invasive procedures. Enrollment is ongoing in North America and Europe with a target goal of 200 patients (150 have been enrolled to date). Patients with use of ticagrelor within the prior 3 days who require urgent ticagrelor reversal are eligible for enrollment.

Bhatt pointed out that bentracimab was granted a status by the FDA (in 2019) and (in 2020) by the European Medicines Agency (EMA), "and in consultation with them, we performed this prespecified, interim analysis to support a submission for an accelerated approval."

The current analysis included DAPT reversal activity in 142 patients who were being treated for emergency or urgent surgery, mainly coronary artery bypass graft (CABG) procedures. It also included eight patients with uncontrolled bleeding (brain bleeds in four patients).

"The number of patients with bleeding in this prespecified interim analysis was low, though surgery is an excellent model of bleeding, and the bleeding subgroup showed statistically significant benefits," said Bhatt. He added that while most of the surgical patients underwent cardiac surgery, "there is no reason to think the results don't apply to other surgeries and invasive procedures."

In this interim analysis, about 75% of patients were able to restart DAPT at a median of 2 days after surgery, according to Bhatt. There were four deaths, he reported.

Bhatt noted that bentracimab's safety had been demonstrated in , both of which had control arms, while the current phase III trial does not have a control arm. However, Bhatt said the FDA and EMA recognize that many investigators will not want to randomize very sick patients.

B. Hadley Wilson, MD, vice-president elect of the American College of Cardiology, called REVERSE-IT "a great trial."

Bentracimab is the only "agent for reversal of DAPT with ticagrelor that we have," he told 番茄社区. "It is very active and very promising, and encouraging, and it is certainly something that we need to help with our patients who need urgent surgery."

Wilson, who is at the Sanger Heart & Vascular Institute in Charlotte, North Carolina, estimated that about 10% of patients on DAPT to prevent blood clotting after various procedures may require urgent surgery during the course of their treatment -- typically a person who has had stents implanted in the coronary arteries, but then requires urgent CABG because of deteriorating conditions. Given the high volume of patients who undergo stent and valve implants, which require months of DAPT, there is a huge unmet need for a ticagrelor reversal agent, he added. Ticagrelor is currently the favored anti-platelet therapy.

These interim results of REVERSE-IT have been in NEJM Evidence, according to PhaseBio Pharmaceuticals, bentracimab's developer.

Comment