Prasugrel Hydrochloride

A class of blood thinners called P2Y12 inhibitors has been used for the last couple decades to treat and prevent a range of cardiovascular conditions, including stroke and heart attack. But the antiplatelet drugs come with a risk of increased bleeding, which can prove fatal — especially for those who need urgent surgery and don’t have time to wean off their medication. PhaseBio is working on a solution for that. And on Monday, the company presented positive Phase III data that could pave the way for a mid-2022 BLA submission. The company’s lead drug bentracimab was shown to reverse the effects of AstraZeneca’s blood thinner Brilinta in an interim analysis of more than 100 patients who needed urgent surgery or an invasive procedure, PhaseBio announced at this year’s American Heart Association conference. Patients who took bentracimab in the pivotal REVERSE-IT trial saw a 135% reduction in platelet inhibition within 5 to 10 minutes of infusion (p<0.001) and saw those effects last over 24 hours, according to PhaseBio. The drug also met its co-primary endpoint, defined as good or excellent hemostasis within 24 hours of administration. Regulators previously told PhaseBio that an interim analysis from the first 100 patients in REVERSE-IT would be sufficient for an accelerated BLA submission, CEO Jonathan Mow told Endpoints News. “When we then looked at the Phase III data and saw that not only did we hit the VerifyNow, platelet biomarker endpoint, we also hit the clinical endpoint — albeit with a slightly larger number of patients, you know, 150 in total — but still, that’s a fantastic achievement for us. One that was not expected at this point in time,” he said. Bentracimab appeared safe, according to PhaseBio. And though 91% of patients reported a treatment-emergent side effect, the most common was pain associated with the surgical procedure. Eight experienced thrombotic events, though none of the cases were tied to bentracimab. “With no approved reversal agents for oral P2Y12 inhibitors, patients who are prescribed these medications to reduce the risk of cardiac events are at increased risk for spontaneous major bleeding events, and physicians are faced with a complex dilemma of balancing bleeding risk and thrombotic risk, should these patients require urgent surgery,” said Deepak Bhatt, executive director of interventional cardiovascular programs at Boston’s Brigham and Women’s Hospital, who presented the study at AHA. Doctors typically recommend patients stop taking P2Y12 inhibitors five to seven days before any type of surgical procedure. But while other P2Y12 inhibitors like Sanofi’s Plavix and Eli Lilly’s Effient aren’t reversible, Brilinta is. That’s because Plavix and Effient bind to the P2Y12 receptor permanently, so to regain functionality, you need to wait for platelet turnover. Brilinta, on the other hand, binds transiently and only has about a 15-minute residence time on the receptor. Bentracimab is a monoclonal antibody fragment that binds to Brilinta when it’s in that off state, and removes it from the platelet environment. “Essentially it just sequesters ticagrelor [Brilinta] from the platelet,” CMO John Lee told Endpoints. The Phase III readout comes just a couple weeks after PhaseBio reported positive topline results for a Phase IIb study evaluating bentracimab in healthy, older volunteers on Brilinta. Earlier results have also shown promise in treating younger volunteers. The news also bodes well for the Italian biotech Alfasigma, which back in June put down up to $245 million for the European rights to bentracimab. PhaseBio originally licensed the drug from MedImmune, the biologics arm of AstraZeneca, in 2017 for an upfront fee of $100,000, with $68 million in potential milestones. A little over a year later, the biotech rode that deal to an IPO with MedImmune owning 5% of the stock. And in 2019, bentracimab received breakthrough therapy designation from the FDA. While bentracimab would be the first antiplatelet reversal therapy for a P2Y12 inhibitor, it would not be the first to address the risk of bleeding in patients on blood thinners. Back in 2018, the FDA approved Portola Pharmaceuticals’ Andexxa as the first reversal agent for Factor Xa inhibitors, such as Janssen’s Xarelto and Bristol Myers Squibb and Pfizer’s Eliquis. PhaseBio is still recruiting patients with uncontrolled major or life-threatening bleeding for the REVERSE-IT trial, and aims to be fully-enrolled as soon as possible.