• Early REVERSE-IT Data Show Novel Drug Immediately Reverses Ticagrelor’s Effects

    A novel ticagrelor reversal agent showed immediate and sustained reversal of ticagrelor’s antiplatelet effects in patients undergoing invasive procedures or who experience major bleeding, according to new study findings.

    Deepak L. Bhatt, MD, MPH, the executive director of Interventional Cardiovascular Programs at Brigham and Women’s Hospital, Boston, presented results from a prespecified interim analysis of the REVERSE-IT study Monday at the American Heart Association (AHA) Scientific Sessions 2021 virtual meeting.

     

    Background

    Ticagrelor is a U.S. Food and Drug Administration (FDA)-approved oral P2Y12 inhibitor that has demonstrated effectiveness in patients with acute coronary syndromes, prior myocardial infarction, high-risk coronary artery disease, transient ischemic attack and stroke.

    However, as with other antiplatelet drugs, spontaneous major bleeding and bleeding associated with urgent or emergent invasive procedures are concerns, Bhatt said.

    The antiplatelet effects of ticagrelor cannot be reversed with platelet transfusion. Therefore, Bhatt said, a rapid-acting reversal agent would be useful.

    The P2Y12 receptor is activated by adenosine diphosphate (ADP). On platelets, ticagrelor reversibly binds to the P2Y12 receptor, inducing a conformational change that prevents ADP from signaling through the receptor and thereby inhibiting platelet activation, Bhatt explained.

    Bentracimab is a recombinant human IgG1 monoclonal antibody fragment, administered intravenously, which binds to free ticagrelor with high affinity and specificity. This allows ADP to activate platelets while the bentracimab-ticagrelor complex is eliminated from the bloodstream, Bhatt said.

    A Phase I study of healthy volunteers demonstrated immediate (within 5 minutes) and sustained (20-24 hours) ticagrelor reversal with a bolus and prolonged (16 hours) infusion of 18 grams of bentracimab. These findings were confirmed in a Phase 2A study of patients aged 58-80 undergoing dual antiplatelet therapy.

     

    REVERSE-IT study design

    REVERSE-IT is a multicenter, open-label, prospective, single-arm study of the reversal of the antiplatelet effects of ticagrelor in at least 200 patients who present with uncontrolled major or life-threatening bleeding or who required urgent surgery or invasive procedures. Enrollment is ongoing in North America and Europe. Patients who have used ticagrelor within the previous 3 days and who require urgent ticagrelor reversal are eligible for enrollment.

    Bentracimab was granted the Breakthrough Therapy designation by the FDA and the PRIME (priority medicines) designation by the European Medicines Agency. The results presented Monday at AHA were a prespecified interim analysis to support a submission for accelerated conditional approval, Bhatt said.

    The study’s primary reversal endpoint is the minimum percentage inhibition of platelet reactivity units (PRUs) as assessed by a platelet function assay.

    The primary hemostasis point, which will be centrally adjudicated, is achievement of effective hemostasis within 24 hours after the start of bentracimab infection assessed in each population separately, then pooled for primary endpoint analysis. Uncontrolled major bleeding is assessed using prespecified criteria for effective hemostasis for visible and non-visible major bleeding. Urgent surgery or invasive procedure is assessed using prespecified criteria for effective hemostasis derived from the GUSTO clinical bleeding scale.

     

    Results

    According to results reported Monday, 154 patients were enrolled, of whom 150 were treated with bentracimab after screening. Most of the treated patients (142) were enrolled as urgent surgical/procedure, while the remaining eight were enrolled as major bleeding patients.

    At baseline, the patients’ mean age was 65 ± 10.6 years. The major-bleeding patients were older (67 ± 13.4 years) than the surgical patients (64.8 ± 10.5 years). The patients overall were mostly male (77.3%), but the bleeding patients were evenly divided (four male, four female). Most patients were white (83.3%), 80% had hypertension, and 39.3% had diabetes. Overall, 81.3% of study patients had a prior myocardial infarction, but this was true of only half of the major-bleeding patients. Most patients (71.3%) presented within 1 day of their last ticagrelor dose.

    A platelet function assay test showed that the percent inhibition of PRUs was more than 50% before the administration of bentracimab, and it dropped to less than -50% at 4 hours post-dose (p<0.001). At the time of administration, patients had less than 100 PRUs, but this quickly rose to more than 200 PRUs within 10 minutes and to nearly 300 PRUs at 4 hours. The 300-PRU level was sustained through 24 hours (p<0.001 for all time points through 24 hours).

    Platelet reactivity index (PRI) testing showed similar results. PRI percent inhibition fell from more than 50% pre-dose to less than 0% at 4 hours post-dose (p<0.0001). The PRI analysis of reversal showed an increase in PRI from less than 50% pre-dose to nearly 100 within 10 minutes post-dose, a level that was sustained through 12 hours before falling to more than 75 at 24 hours (p<0.0001 across all time points through 24 hours).

    The reversal appeared to be similar in surgical and bleeding patients, the results show.

    Forest plots of the platelet-function assay test showed that overall, the mean difference in percent PRU inhibition from drug administration to 4 hours was -135 (95% confidence interval: -142, -129; p<0.0001). This significance in the reduction of PRU inhibition was maintained across all subgroups.

    Turning to the hemostasis results, 100% of adjudicated surgical patients achieved hemostasis, compared to 95.1% of those reported by study investigators. A total of 56 blood transfusions (39%) and 19 platelet transfusions (13.4%) were performed in these patients. Most surgical patients (74%) were restarted on P2Y12 inhibition at a median of 2 days (interquartile range: 0, 22 days), and four patients (2.8%) died.

    Among the eight major-bleeding patients, seven (77.8%) achieved hemostasis, according to both adjudicated and investigator-reported outcomes. Five of these patients (62.5%) required blood transfusions, and two (25%) received platelet transfusions. Five of the major-bleeding patients (62.5%) restarted P2Y12 inhibition at a median of 5 days (interquartile range: 0, 8 days), and none of these patients died.

    The study’s limitations include that it has no control arm, as the investigators felt it would be challenging to randomize patients eligible for the trial to receive a placebo. The majority of surgical patients underwent cardiac surgery, but Bhatt said there is no reason to think that the study results do not apply to other surgeries or invasive procedures. Also, the number of major-bleeding patients in the prespecified interim analysis was low, although Bhatt said that “surgery is an excellent model of bleeding” and that the bleeding subgroup did show statistically significant results.

    Bhatt concluded that bentracimab’s rates of effective hemostasis were adjudicated as good or excellent in more than 90% of cases, with no drug-related serious adverse events or allergic or infusion-related reactions. He added that the benefits of the ticagrelor reversal agent “were consistent in all prespecified subgroups, including those undergoing surgery and with major bleeding.”

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

    A manuscript will be reported in NEJM Evidence, a new monthly digital journal launching in January 2022 produced by the publisher of The New England Journal of Medicine, when production is complete, Bhatt said.

    The study was funded by PhaseBio Biopharmaceuticals Inc., the manufacturer of bentracimab.

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