SFJ Pharmaceuticals and SERB Pharmaceuticals have announced positive final results from their pivotal Phase 3 REVERSE-IT trial evaluating bentracimab, a human monoclonal antibody fragment designed to reverse the antiplatelet effects of ticagrelor. The data, presented at the American College of Cardiology Annual Scientific Session on March 29, 2025, demonstrated significant and rapid restoration of platelet function in patients requiring urgent surgery or experiencing major bleeding while on ticagrelor therapy.
The trial enrolled 226 patients across the United States, Canada, the European Union, and China, achieving its primary efficacy endpoint with statistical significance. Bentracimab normalized platelet function within 5-10 minutes of administration and maintained this effect throughout the 16-hour infusion period and for at least 8 hours afterward.
Impressive Efficacy Results
The REVERSE-IT trial's primary endpoint measured the minimum percent inhibition of P2Y12 reactivity units (PRU) within four hours after initiating bentracimab infusion compared to baseline. Results showed a mean difference of -122.94 (P<0.0001), with PRU values increasing from a mean of 91.7 pre-treatment to ≥180 (the lower limit of normal) within 5-10 minutes.
Dr. Deepak L. Bhatt, Director of the Mount Sinai Fuster Heart Hospital and Principal Investigator of the trial, emphasized the clinical significance: "These Phase 3 data demonstrate that bentracimab could be an effective option to manage major or life-threatening bleeding in patients on ticagrelor, with a consistent safety profile."
The trial also achieved its secondary efficacy endpoint, with 94.3% of eligible patients achieving effective hemostasis within 24 hours. This included 100% of patients requiring urgent surgery and 83.1% of patients experiencing major bleeding, as assessed using GUSTO bleeding criteria for the surgery group and Connolly criteria for the bleeding group.
Addressing a Critical Unmet Need
Ticagrelor, marketed as BRILINTA® by AstraZeneca, is a P2Y12 platelet inhibitor widely prescribed to reduce the risk of cardiovascular events in patients with acute coronary syndrome or history of myocardial infarction. However, its antiplatelet effects typically take 3-5 days to dissipate after discontinuation, creating significant challenges for patients requiring urgent surgery or experiencing major bleeding.
"Discontinuation of ticagrelor and waiting for its anti-platelet effects to disappear over three to five days is not always feasible when patients require urgent surgery or are experiencing major bleeding," Dr. Bhatt explained. "Bentracimab's ability to normalize platelet function within 5-10 minutes and maintain normal platelet function throughout the infusion to facilitate hemostasis delivers a much-needed solution to better manage patients in need."
Dr. Barbara White, President and CEO of SFJ Pharmaceuticals, highlighted the drug's unique mechanism: "The rapid onset of action of bentracimab and its relatively short half-life allows for the quick normalization of platelet function when needed. Stopping bentracimab after surgery or once an acute medical event is under control restores the desired anti-platelet effect of ticagrelor. This would allow doctors to manage both the risk of bleeding and the risk of thrombosis."
Favorable Safety Profile
Bentracimab demonstrated an overall favorable safety profile and was generally well tolerated in the trial. No serious adverse reactions or allergic reactions occurred in patients treated with the drug. The rate of thrombotic events (4.0%) was similar to the typical baseline for patients' underlying conditions.
Importantly, ticagrelor was reinitiated or other P2Y12 inhibitors were started in 69.5% of patients within 7 days after bentracimab infusion, allowing for the continuation of necessary antiplatelet therapy once the acute situation was resolved.
Dosing and Administration
In the REVERSE-IT trial, patients received an intravenous infusion comprising an initial IV bolus of 6 grams infused over 10 minutes for rapid reversal, followed immediately by a 6g IV loading infusion over four hours and then a 6g IV maintenance infusion over 12 hours.
Expert Perspectives
Dr. Toby C. Trujillo, Professor of Clinical Pharmacy at the University of Colorado Skaggs School of Pharmacy and member of the ACC cardiovascular team pharmacist workgroup, commented on the potential clinical impact: "The ability to reverse the antiplatelet effect in a clinical situation where you deem that's going to help improve the patient's clinical outcome—either major bleeding or in an urgent surgery—is going to be a really welcome addition to our ability to manage these particular patients."
Vanessa Wolfeler, Chief Executive Officer of SERB Pharmaceuticals, which acquired exclusive U.S. rights to bentracimab (RETRIG) from SFJ in 2023, emphasized the company's commitment: "There is a significant unmet need to reverse ticagrelor's effects in patients who require non-deferrable surgery or experience major bleeding. These results reinforce the promise of bentracimab, and SERB is committed to bringing this product to healthcare providers treating patients facing rare emergencies and conditions."
Regulatory Status and Future Outlook
Bentracimab has received significant regulatory support, including Breakthrough Therapy Designation from the FDA in 2019, Priority Review in 2024, and Orphan Drug Designation on March 18, 2025. These designations reflect the drug's potential to address an important unmet medical need.
The positive Phase 3 results build upon earlier promising data. Phase 1 results were published in the New England Journal of Medicine in 2019, and the first interim analysis of the REVERSE-IT trial appeared in the New England Journal of Medicine Evidence in 2021.
While the study had some limitations, including a relatively small number of Black patients (n = 5) and the absence of a control group, investigators deemed it unethical to include a placebo arm given the life-threatening scenarios involved and the positive data from randomized Phase 1 trials.
If approved, bentracimab could address a key clinical dilemma among healthcare providers: the hesitancy to prescribe ticagrelor despite its benefits due to concerns about uncontrollable bleeding in emergency situations. With a reversal agent demonstrating both safety and efficacy, clinicians may become more confident in prescribing potent antiplatelet therapy where appropriate, potentially improving overall cardiovascular care.
