PB1053 - Therapeutic Window of a Synthetic Platelet Nanotechnology in New Zealand White Rabbits

Background: Transfusion of allogeneic platelets is routinely used in the clinic to treat bleeding complications in trauma, surgery, hematology/oncology, and congenital disorders. Clinical studies have shown that early platelet transfusion improves hemostatic and survival outcomes in bleeding complications. However, clinical use of donor-derived platelet products is limited by their portability, high risk of pathogenic contamination, and short shelf-life, often rendering them unavailable in pre-hospital settings.

Aims: We have developed a lyophilizable, shelf-stable synthetic platelet (SP) nanotechnology that mimics some of the primary hemostatic mechanisms of platelets to cover the unmet need for platelet surrogates for in-hospital and pre-hospital management of bleeding complications. Here, we established the therapeutic window of SP by comparing the tolerable dosing limits to efficacious doses in several different models of hemorrhage in New Zealand White (NZW) Rabbits.

Methods: SP was manufactured using established methods, and physicochemical and functional release testing was performed. Single-ascending doses of SP were given to healthy NZW rabbits, and tolerability was assessed via clinical observations, hematology, clinical chemistry, coagulation panel, and organ gross and histopathology (Non-GLP studies). Furthermore, efficacy of SP was assessed in three different hemorrhage models in NZW rabbits: kidney incision after dilutional coagulopathy, splenic + hepatic polytrauma, and ear laceration after busulfan-induction of thrombocytopenia.

Results: The therapeutic window, or the dosage range between a minimum effective therapeutic dose and the minimum toxic dose, of SP was determined to be >200X in NZW rabbits.

Conclusion(s): SP is a fully synthetic, platelet mimicking nanotechnology with a demonstrated >200X therapeutic window in a clinically relevant, non-rodent animal model (NZW rabbits). This information will be used to support dosing in GLP IND-enabling studies and subsequent first-in-human studies.