He said the developmental game plan for the ticagrelor reversal agent is initially to get it approved by the Food and Drug Administration for ticagrelor-related catastrophic bleeding, such as intracranial hemorrhage, since there is a recognized major unmet need in such situations. But as shown in the phase 1 study, BP2452 is potentially titratable by varying the size of the initial bolus dose and the dosing and duration of the subsequent infusion. So after initial approval for catastrophic bleeding, it makes sense to branch out and conduct further studies establishing the reversal agent’s value for prevention of bleeding complications caused by ticagrelor. An example might be a patient on ticagrelor because she recently received a stent in her left main coronary artery who falls and breaks her hip, and her surgeon says she needs surgery right away.
“If someone on ticagrelor came in with an intracranial hemorrhage, you’d want rapid reversal and have it sustained for as many days as the neurologist advises, whereas maybe if someone came in on ticagrelor after placement of a left main stent and you needed to do a lumbar puncture, you’d want to reverse the antiplatelet effect for the LP, and then if things go smoothly you’d want to get the ticagrelor back on board so the stent doesn’t thrombose. But that type of more precise dosing will require further work,” according to the cardiologist.
Discussant Barbara S. Wiggins, PharmD, commented, “We’ve been fortunate to have reversal agents come out for oral anticoagulants, but in terms of antiplatelet activity we’ve not been able to be successful with platelet transfusions. So having a reversal agent added to our armamentarium certainly is something that’s desirable.”
The phase 1 study of PB2452 indicates the monoclonal antibody checks the key boxes one looks for in a reversal agent: quick onset, long duration of effect, lack of a rebound in platelet activity after drug cessation, and potential for tailored titration. Of course, data on efficacy outcomes will also be necessary, noted Dr. Wiggins, a clinical pharmacologist at the Medical University of South Carolina, Charleston.
She added that she was favorably impressed that Dr. Bhatt and his coinvestigators went to the trouble of convincingly demonstrating reversal of ticagrelor’s antiplatelet effects using three different assays: light transmission aggregometry, which is considered the standard, as well as the point-of-care VerifyNow P2Y12 assay and the modified CY-QUANT assay.
The phase 1 study was funded by PhaseBio Pharmaceuticals. Dr. Bhatt reported the company provided a research grant directly to Brigham and Women’s Hospital.
Simultaneous with Dr. Bhatt’s presentation, the study results were published online (N Engl J Med. 2019 Mar 17. doi: 10.1056/NEJMoa1901778).
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