Development of a POEGMA Aptamer rapid onset anticoagulant that eliminates antigenicity to anti PEG antibodies

ABSTRACT The objective of this STTR proposal is to reformulate a promising PEG aptamer rapid onset anticoagulant ROA by applying a novel PEG like POEGMA polymer brush technology capable of eliminating anti PEG antigenicity The importance of this proposal is highlighted by the early termination of a recent Phase III clinical trial of the original PEG aptamer conjugate in which severe allergic reactions occurred in individuals with high levels of pre existing anti PEG antibodies As evidenced by this halted clinical trial the effect of circulating anti PEG antibodies is a growing concern due to the prevalence of anti PEG found in individuals who are naive to PEGylated therapeutics it has been suggested that the free PEGs present in commonly used consumer products are a likely source of these interfering anti PEG antibodies Our PEG like POEGMA polymer brush technology has been shown to confer the same PD PK advantages of traditional PEG conjugates while simultaneously eliminating anti PEG antigenicity We have shown that POEGMA which breaks up the long sequences of repeating ethylene glycol units found in PEG and presents much shorter oligo ethylene glycol sequences does not interact with anti PEG antibodies We expect that the application of POEGMA technology to the aptamer based ROA described here will allow for an effective therapeutic that does not suffer from a harmful interaction with pre existing anti PEG antibodies Reformulating this aptamer ROA represents a useful application of the POEGMA technology as there is an unmet clinical need for anticoagulants that can be rapidly reversed Currently approximately million Americans per year require intravenous infusion of a highly potent rapid onset anticoagulant to perform clinical procedures that are highly prothrombotic including percutaneous coronary intervention PCI angioplasty coronary artery bypass graft CABG surgery and other surgeries as well as dialysis Significant disadvantages of current FDA approved ROAs unfractionated heparin UFH lepirudin bivalirudin and argatroban have prompted efforts to identify ROAs that eliminate the toxicity and drug induced bleeding associated with these ROAs The PEG aptamer sequence described here together with the complementary antidote sequence capable of titrating and rapidly reversing anticoagulant activity has been evaluated in andgt patients in Phase Phase and Phase clinical trials with phase studies suggesting that this aptamer antidote pair can reduce ischemic events and limit bleeding in PCI patients compared to heparin Based on these promising results we propose to eliminate the potential for the negative anti PEG interactions that have stopped the development of this once promising PEG aptamer therapeutic by developing a POEGMA aptamer conjugate NARRATIVE Twelve million Americans per year require intravenous infusion of a highly potent rapid onset anticoagulant ROA in order to receive treatment with a number of clinical procedures that are highly prothrombotic including percutaneous coronary intervention PCI angioplasty coronary artery bypass graft CABG surgery and other surgeries as well as dialysis Significant disadvantages of the FDA approved ROAs unfractionated heparin UFH lepirudin bivalirudin and argatroban have prompted efforts to identify ROAs that eliminate the toxicity and drug induced bleeding associated with these approved ROAs A recently developed PEG aptamer ROA showed promising results toward the goal of a more controlled treatment until trials were halted due to severe allergic reactions caused by interactions of the PEG aptamer with pre existing anti PEG antibodies This application proposes to eliminate the negative interaction of this promising aptamer therapeutic with anti PEG antibodies by developing PEG like POEGMA conjugates that do not interact with anti PEG antibodies