Abstract 126: Non‐Clinical Risk Assessment of Co‐Administration of Thrombolytics and Scp776, a Targeted IGF‐1 Neuroprotectant for Stroke

Introduction/Purpose Scp776 is a first‐in‐class targeted growth factor therapeutic in development for treatment of acute ischemic stroke (AIS) patients. The therapeutic hypothesis for scp776 neuroprotection in stroke is targeted delivery of a potent growth factor (IGF‐1) alongside standard‐of‐care flow restoration will protect tissue from damage by promoting apoptosis escape. In the ARPEGGIO study of scp776 in patients undergoing endovascular thrombectomy (EVT), those receiving intravenous thrombolytics (IVT) are excluded. Before expanding testing of scp776 into the broader patient population (i.e., including IVT and IVT/EVT patients), we characterized the compatibility of scp776 with IVTs in an array of non‐clinical studies. We present tests of compatibility and propose criteria for acceptable test results to allow the safe introduction of adjuvants (e.g., neuroprotectants) to the significant population of stroke patients receiving thrombolytics. Materials/Methods The potential for interference with tPA‐mediated clot lysis by scp776 was tested in a plate‐based assay using clots derived from rat blood. The susceptibility of scp776 to proteolysis and/or inactivation by tPA or downstream effectors (e.g., plasmin) was assessed by co‐administration pharmacokinetic experiments in monkeys and a binding assay. The risk of increased bleeding in animals after co‐administration of scp776 and tPA was assessed using a mouse tail snip model. Results In the clot lysis assay, supra‐clinical concentrations of scp776 did not affect the rate or extent of clot lysis by tPA (50% Lysis Time, 40 nM tPA = 17.5±0.6 min; 40 nM tPA+100 µg/mL scp776 = 16.5±0.6 min), while the inclusion of protease inhibitors abrogated clot lysis. Scp776 remained intact, with an unchanged pharmacokinetic profile for 48 hours (~6 half‐lives) following co‐administration of 4 mg/kg scp776 with 0.9 mg/kg tPA in monkeys. The targeting function of scp776, phosphatidylserine binding, was unaffected by incubation with tPA in an in vitro binding assay (relative binding, 101%; 95% CI, 94‐109%). In the tail snip model, mice that received 5, 10, or 20 mg/kg scp776 did not have increased blood loss compared to negative controls, while mice that received 10 mg/kg tPA showed a non‐significant increase in blood loss. Mice that received 10 mg/kg tPA with 20 mg/kg scp776 showed a similar non‐significant increase in blood loss compared to negative controls. The tPA only and scp776 + tPA groups were not significantly different. Conclusion We propose a non‐clinical testing scheme for the assessment of pharmacocompatibility of novel adjuvant therapies with standard‐of‐care thrombolytics. Under this paradigm, the proposed neuroprotectant scp776 did not evidence either bidirectional drug‐drug interactions or potential synergy in dysregulation of hemostasis. Scp776 did not interfere with tPA‐mediated clot lysis in an ex vivo assay. Studies in animals and assay plates revealed that scp776 pharmacokinetics, integrity, and targeting function were not affected by tPA. Together, these results indicate that a drug‐drug interaction is unlikely in patients that receive both drugs. Co‐administration of scp776 and tPA in mice did not induce significant changes in blood loss compared to mice that received tPA only or saline. These data support future human testing of scp776 in AIS patients receiving thrombolytic therapies.