Principal Investigator/Program Director (Last, First, Middle: Chen, Ridong Abstract There remains a crucial unmet medical need in acute ischemic stroke (AIS) treatment: Approximately 20% of 795,000 patients die within one year and 15-30% are permanently disabled, making AIS the fourth leading cause of death and the leading cause of adult disability in the USA with an estimated cost range of $69-74 billion annually. Recombinant tissue plasminogen activator (rt-PA) is the only drug approved by the FDA for restoring cerebral blood flow and improving patient's functional outcome with no survival improvement. Currently, only 5% of AIS patients receive rt-PA as its use is limited by narrow time-window of administration (up to 4.5 hours post symptom) and 6-7 fold increased intracranial hemorrhage. Recently, endovascular treatment with retrievable stents has been shown to improve the outcomes in small subpopulation of patients with proximal vessel occlusion. The failures of numerous neuroprotective therapies in clinical trials suggest that neuroprotection alone without restoration of tissue perfusion may not be adequate for treatment of stroke. Thus, developing the combinational therapy of rt-PA and/or retrievable stents with human apyrase as a safe adjunctive antithrombotic that also will attenuate reperfusion and rt-PA related hemorrhagic transformation will be of great importance for stroke patients that promises to extend the time window and improve clinical outcome and survival. APT102 is a proprietary and optimized human apyrase which is a homolog of CD39. Administration of multi-functional APT102 scavenges pro-thrombotic ADP and pro-inflammatory ATP, which are both released at sites of thrombosis and injury. Hence, co-administration of APT102 with rt-PA will prevent thrombotic re- occlusion and maintain vascular integrity necessary to prevent hemorrhagic transformation. The efficacy and safety of APT102 in combination with rt-PA has been demonstrated in the clinically relevant models of thrombo-embolic stroke, adult and aged animals, in two independent laboratories as recommended by the Stroke Therapy Academic Industry Roundtable (funded by a Phase II SBIR grant: R44NS060175). Therefore, this CRP project is well-positioned to successfully advance APT102 to IND. Specifically, we propose: 1). Develop APT102 production process and validate IND-enabling study plan with FDA; 2) Establish protocols for manufacturing cGMP (Current Good Manufacturing Practice) drug product for toxicology and IND filing; 3) Evaluate APT102 for safety in nonclinical toxicology studies; and 4) Prepare and file IND application.. With the successful filing of IND, we will perform Phase I clinical trials of APT102 to obtain safety, pharmacokinetic, and pharmacodynamic/biomarker data in healthy volunteers and then Phase II and III trials for stroke patients. The long-term goal of this project is to market APT102 as combination treatment with r-tPA to provide a highly effective and safe acute therapy for AIS with at least a 6h treatment window. This treatment regimen could be used by emergency room physicians and even in a mobile stroke unit to achieve faster prehospital treatment with rt-PA for over 40% of AIS patients to improve functional outcomes as well as survival, a dramatic increase from the 3-5% of AIS patients currently treated with r-tPA which does not provide survival benefit.
Chen, Ridong Narrative The efficacy and safety of combining an optimized human apyrase with r-tPA has been demonstrated unequivocally in several relevant models of thrombo-embolic stroke, including in the stroke model of aged rats. With a strong interdisciplinary drug development team, we propose to complete activities necessary to enable IND filing.
