Abstract 2094: Translating EPHARNA (DOPC nanoliposomal EphA2-targeted siRNA) to the clinic

Introduction: To address the need for efficient and biocompatible delivery systems for systemic siRNA delivery, we have developed a 1,2-Dioleoyl-sn-Glycero-3-Phosphatidylcholine (DOPC) nanoliposomal EphA2-targeted therapeutic (EPHARNA). We have previously demonstrated the efficacy of EPHARNA in multiple tumor models. Here, following FDA guidance, we performed safety studies of EPHARNA in murine and primate models. Methods: Single dosing of EPHARNA was tested at 5 concentrations in mice (N = 15 per group) and groups of animals were sacrificed on days 1, 14, and 28 for evaluation of clinical pathology and organ toxicity. Multiple dosing of EPHARNA was tested in mice twice weekly for 1 month (N = 10 per group) and in Rhesus macaques weekly (N = 4 per group) at two dose levels in each model. Possible effects on hematologic parameters, serum chemistry, coagulation, and organ toxicity were assessed in all animals. Results: Following single dose EPHARNA administration to mice, no gross pathological or dose-related microscopic findings were observed in either the acute (24 hrs) or recovery (14 and 28 days) phases of this study. The no-observed-adverse-effect level (NOAEL) for EPHARNA is considered > 225 μg/kg when administered as a single injection intravenously in CD-1 male and female mice. With twice weekly injection, EPHARNA appeared to stimulate a mild to moderate inflammatory response in a dose-related fashion. In addition, there appeared to be a mild hemolytic reaction in the female mice. Systemic toxicity related to both the DOPC formulation as well as EphA2 silencing was assessed in Rhesus macaques due to the near 100% homology between Rhesus and human EphA2. One animal developed signs consistent with an infusion reaction on its first administration, and was dosed with a slow infusion over 15-30 minutes with subsequent infusions. Minimal to moderate infiltration of mononuclear cells was found in some organs including the GI tract, heart, and kidney in all Rhesus macaques in all groups. The significance of these infiltrates to the general health of the animals is unknown. One female in the control group and one in the high dose group had ovarian mineralization, which was considered incidental in this study. No differences attributed to EPHARNA were observed in the hematologic or anatomic parameters assessed. Conclusion: These results demonstrate that EPHARNA is well tolerated at all doses tested without significant complications. These data, combined with previously published validation studies demonstrating siRNA as an effective therapeutic in vivo, led to the development of a first in human Phase I clinical trial that is currently underway (NCT01591356). Citation Format: Michael J. Wagner, Rahul Mitra, Wallace Baze, Kirstin Barnhart, Robert L. Coleman, Gabriel Lopez-Berestein, Anil K. Sood. Translating EPHARNA (DOPC nanoliposomal EphA2-targeted siRNA) to the clinic. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2094.