MALVERN, Pa. & SAN DIEGO—PhaseBio Pharmaceuticals, Inc. recently reported the expansion of its pivotal Phase 3 REVERSE-IT trial for bentracimab (formerly PB2452) into Canada. The first patients have been enrolled and dosed.
“Bentracimab (PB2452) is a novel recombinant human monoclonal antibody antigen-binding fragment, designed to reverse the antiplatelet activity of ticagrelor in the event of major bleeding, or when urgent surgery is required,” says Jonathan P. Mow, chief executive officer of PhaseBio. “The American College of Cardiology, American Heart Association and European Society of Cardiology guidelines recognize ticagrelor as the preferred antiplatelet therapy for ACS. Ticagrelor is also indicated for to reduce the risk of a first myocardial infarction or stroke in patients with coronary artery disease (CAD) at high risk for such events.”
“Ticagrelor binds to platelets to prevent them from forming blood clots that could restrict blood flow. In addition, patients on ticagrelor who need urgent surgery often cannot wait the recommended five days for ticagrelor’s effect to dissipate, meaning they are at increased risk of major bleeding during and after surgery,” Mow notes. “Bentracimab binds to ticagrelor with high affinity and specificity to reverse the antiplatelet activity of ticagrelor by deactivating ticagrelor’s ability to bind to the platelet, as illustrated by data from the Phase 1 and Phase 2a clinical trials.”
Bentracimab has demonstrated in Phase 1 and 2 clinical trials the immediate and sustained reversal of ticagrelor. In a translational study, bentracimab achieved equivalent reversal of both branded ticagrelor and multiple ticagrelor generics. This could potentially mitigate concerns of bleeding risks associated with the use of antiplatelet drugs.
“Patients taking antiplatelet therapy have impaired clotting function, and any type of bleeding event can become serious or potentially life threatening. In Phase 1 and Phase 2a trials, bentracimab has demonstrated the ability to restore platelet function to normal within 5 minutes in patients treated with ticagrelor, which could help allow the normal function of platelets to stop an uncontrolled bleeding event,” explains Mow. “Bentracimab could enable ticagrelor patients to have urgent surgical procedures without having to go through the recommended 5 day washout protocol, while allowing the resumption of antiplatelet therapy as soon as the risk of surgery-related bleeding has subsided.”
“Phase 1 and Phase 2 clinical trials have demonstrated that bentracimab restores platelet function for approximately 24 hours with the current dose and dosing regimen. Shorter or longer infusion cycles could facilitate shorter or longer durations of reversal, but would need to be studied in a clinical trial before being approved for use,” he continues.
The Phase 3 REVERSE-IT study is targeting around 200 patients for enrollment worldwide. Patients who report use of ticagrelor within 3 days prior who require urgent reversal will be eligible for enrollment.
“With cardiovascular disease representing a leading cause of death in Canada, as in the rest of the world, we expect to continue to see widespread utilization of P2Y12 inhibitors like ticagrelor to help prevent adverse cardiovascular events in vulnerable patients. While ticagrelor is highly efficacious it poses increased risk of serious bleeding, like other P2Y12 inhibitors,” said Subodh Verma, M.D., Ph.D., a cardiac surgeon and professor at the University of Toronto, and a member of the REVERSE-IT steering committee and Canadian national lead investigator.
“The promise of a potential reversal agent addresses a significant unmet clinical need for a large number of patients at risk of severe bleeding or those who may suffer a serious bleeding episode while on ticagrelor,” Verma continued. “I am delighted that about 20 sites in Canada will participate in this important and potentially practice-changing clinical trial.”
Mow tells DDN that the REVERSE-IT trial is currently enrolling in the U.S. and Canada, and plans to begin recruiting patients in the European Union in the near future. The trial is also expected to expand into China in 2021.
“With a generic version of Brilinta under regulatory review in Canada and a best-in-class efficacy profile relative to other P2Y12 inhibitors, we anticipate significant growth in market share for ticagrelor in Canada and a growing need for a novel reversal agent like bentracimab,” he stated. “We view the expansion of REVERSE-IT enrollment into Canada as an important milestone for the global bentracimab program.”
“PhaseBio plans to file a BLA with the FDA and other regulatory agencies, and to build a commercial organization to support the launch of bentracimab in the United States. The company is actively in negotiations with prospective partners for territories outside the United States,” concludes Mow.