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FDA grants breakthrough therapy designation for ticagrelor reversal agent
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The FDA has granted breakthrough therapy designation for a novel reversal agent for the antiplatelet drug ticagrelor, according to an announcement from PhaseBio Pharmaceuticals Inc.
The FDA’s breakthrough therapy designation is designed to expedite the development and review of drugs that are intended to treat a serious condition and for which preliminary clinical evidence indicates the drug may demonstrate substantial improvement over available therapy.
The ticagrelor (Brilinta, AstraZeneca) reversal agent, known as PB2452, is a recombinant human monoclonal antibody antigen-binding fragment designed to reverse the antiplatelet activity of ticagrelor in major bleeding and urgent surgery situations.
“Breakthrough therapy designation for PB2452 highlights the critical unmet need for a therapy to reverse the antiplatelet activity of ticagrelor, which is widely prescribed to patients with acute coronary syndrome or a history of heart attack,” John Lee, MD, chief medical officer of PhaseBio Pharmaceuticals, stated in the company release.
Phase 1 data
The first randomized human experience of a ticagrelor reversal agent was presented by Deepak L. Bhatt, MD, MPH, at the American College of Cardiology Scientific Session and simultaneously published in The New England Journal of Medicine.
The randomized, double-blind, placebo-controlled, phase 1 trial was designed to assess platelet function in healthy volunteers aged 18 to 50 years before and after 48 hours of ticagrelor pretreatment and again after administration of the reversal agent (n = 48) or placebo (n = 16). PB2452 was administered as an initial IV bolus, followed by a prolonged infusion of 8, 12 or 16 hours. Twenty-one patients in the study received the highest study drug dose (18 g). The researchers used light transmission aggregometry, a point-of-care P2Y12 assay (VerifyNow) and a vasodilator-stimulated phosphoprotein assay to assess platelet function.
Platelet aggregation was suppressed by 80% to 85% after 48 hours of ticagrelor pretreatment. The reversal agent yielded a significantly greater increase in platelet function compared with placebo. Overall, ticagrelor reversal occurred within 5 minutes after initiation of PB2452, and reversal was sustained for more than 20 hours (P < .001). The researchers reported no evidence of a rebound in platelet reactivity after cessation of the study drug, according to the results.
The researchers also reported no deaths, dose-limiting toxic effects, infusion-related reactions or adverse events leading to discontinuation of the study drug or hospitalization.
Discussing the results with Cardiology Today, Bhatt said, “It appears that if a patient had a bleeding problem, such as an intracranial hemorrhage, this [reversal agent] could be a really useful option, if approved.”
Chandan Devireddy, MD, FACC, FSCAI, associate professor of medicine and associate fellowship director at Emory University, discussed the phase 1 data with Cardiology Today.
“In studies looking at use of antiplatelet agents, there is a finite risk of gastrointestinal events, cerebral events, emergency cardiac surgery and so on. There’s a promise that this agent could have a niche use that would be applied in certain circumstances,” Devireddy said.
Novel agent
There are currently no approved reversal agents for ticagrelor or any other antiplatelet drugs.
“The antiplatelet effects of ticagrelor cannot be reversed with platelet transfusion. Therefore, a rapid-acting reversal agent would be useful,” Bhatt said. “Unlike other P2Y12 antagonists, ticagrelor is a reversible inhibitor, which makes development of a specific reversal agent for ticagrelor feasible.” – by Katie Kalvaitis
References:
Bhatt DL. Featured Clinical Research II: Interventional. Presented at: American College of Cardiology Scientific Session; March 16-18, 2019; New Orleans.
Bhatt DL, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1901778.
Disclosures: The study was supported by PhaseBio Pharmaceuticals. Bhatt reports he received grants and other from PhaseBio Pharmaceuticals during the conduct of the study and grants from AstraZeneca. Devireddy reports no relevant financial disclosures.