PhaseBio is working toward mitigating the surgical risks for cardiac patients taking antiplatelet therapies with bentracimab, which is currently in Phase III development.
For millions of cardiac patients, antiplatelet therapies (P2Y12 inhibitors) such as ticagrelor (Brilinta) and clopidogrel (Plavix), are a blessing that reduces their risk from blood clots that may cause acute coronary syndrome – typically strokes or heart attacks. If such patients need surgery, they must stop taking the drug for about five days so it can exit their systems. However, if surgery cannot be delayed, that blessing quickly becomes a curse that could cause them to bleed out on the operating table.
“Antiplatelet therapy is doing exactly what it’s supposed to do, but if those patients require surgery, are in an accident or cut themselves, they have a limited ability to stop bleeding,” Jonathan Mow, CEO of PhaseBio Pharmaceuticals pointed out.
PhaseBio is working toward mitigating that risk with a medication in clinical development – bentracimab – that in trials has been shown to quickly reverse the blood-thinning effects of Brilinta. Completed Phase II trials and interim results from Phase III clinical trials met all endpoints and showed that the drug began reversing the antiplatelet effects of Brilinta within five minutes.
In the Phase IIb trial, “The safety profile was completely clean,” Mow said. The Phase III trial is still ongoing, and interim results look good. Interim data indicates surgical patients and patients who were actively bleeding achieved immediate, sustained reversal of Brilinta, which allowed platelets to function normally and their blood, therefore, to coagulate. More than 90% achieved clinical homeostasis, and the drug was well-tolerated with no reported serious adverse events.
“100% of patients had a reversal of their platelet function and had normalization of their platelet function. They went from completely inhibited to completely normal platelet function,” Mow said. “We’re getting the effects we’re looking for. We’re very happy.
“Obviously there are adverse events associated with surgery because a lot of our patients are surgical patients or are actively bleeding,” he noted. “They lead complicated lives, but the safety profile of the drug in and of itself is very clean. We had very high hurdles for safety and efficacy,” because a drug reversing agent like this shouldn’t give physicians cause for concern.
Cardiovascular disease accounts for approximately 32% of all deaths globally, according to the World Health Organization. The Centers for Disease Control and Prevention says heart disease is the leading cause of death in the U.S., accountable for 25% of all deaths.
Between 4 and 5 million patients are prescribed dual antiplatelet therapy in the United States each year. Brilinta – “the last remaining branded drug in the P2Y12 space” – has about 10 to 15% of that market. Of those patients, 10 to 15% will require surgery, and another 5% will have a spontaneous bleeding event, like an accident or an intracranial hemorrhage. Those patients need an immediate solution to quell the bleeding and allow medical intervention. Bentracimab appears to be that solution, but – importantly – it only works against Brilinta.
As Mow explained, the other antiplatelet therapies permanently bind to the P2Y12 receptor, so the platelet is forever deactivated. “AstraZeneca’s Brilinta, in contrast, transiently binds to that receptor but still deactivates the platelets. It has a half-life of approximately six hours, but the actual effect of the drug lasts for days.” Medical guidelines advise at least a five-day washout period for the antiplatelet drug to leave the body.
In contrast, “Bentracimab, can deactivate the Brilinta when it’s not on the receptor, therefore restoring platelet function,” Mow explained. This means physicians can administer bentracimab minutes before surgery and put their patients back on Brilinta immediately afterward.
This approach has been in development for several years. PhaseBio licensed all rights for bentracimab in 2017 from AstraZeneca. If bentracimab is approved by the FDA, the ability to reverse Brilinta could become a competitive advantage for that company as well.
If approved, PhaseBio plans to make this product available on a global basis, just as Brilinta is available worldwide. Bentracimab holds Breakthrough Designation from the U.S. Food and Drug Administration, Prime Designation from the European Medicines Agency and Breakthrough Designation from the Chinese regulatory authority. Therefore, Mow said he expects this therapy to have an expedited review process in each of those regions.
“We plan to submit our Biologics License Agreement to the FDA early fourth quarter of this year,” he said, which makes a regulatory decision in the U.S. possible as early as mid-2023.
If bentracimab is approved as a reversal agent for Brilinta, a mid-2023 approval timeline would mean this reversal agent could potentially be on the market 12 to 18 months before Brilinta goes off patent. At that point, Brilinta would (presumably) be priced competitively with other generic antiplatelet therapies. That combination means the market for both Brilinta and bentracimab could soar.
