Abstract C197: Accurins improve the pharmacokinetics, pharmacodynamics, tolerability and anti-tumor activity of the AKT inhibitor MK-2206

Abstract

Abstract Background: BIND-2206 Accurins are novel polymeric nanoparticles encapsulating MK-2206, a Merck AKT inhibitor in phase 2 trials. MK-2206 targets the phosphatidylinositol 3-kinase (PI3K) pathway via AKT inhibition and has demonstrated therapeutic efficacy in the treatment of cancer albeit with dose limiting toxicities. Accurins have shown promise for targeting oncology agents preferentially to tumors, while limiting systemic exposure. To determine if encapsulation of MK-2206 improves therapeutic index, studies were performed to evaluate pharmacokinetics (PK), pharmacodynamics (PD), tolerability and anti-tumor activity compared to parent MK-2206. Materials and Methods: PK of four Accurin formulations with varying in vitro drug release rates was evaluated. Based on these data, two lead Accurins (BIND-2206C and BIND-2206D) were selected for further characterization. Since AKT inhibitors are documented to induce hyperglycemia in mice, blood glucose levels were also evaluated after acute administration of BIND-2206 Accurins or parent MK-2206 as a measure of tolerability. Using a panel of human tumor xenografts (VCaP, SK-OV-3 and BT-474) anti-tumor activity of the Accurins was assessed in mice. When tumors were established mice were dosed orally with parent MK-2206 or intravenously with BIND-2206 Accurins two or three times per week on a three week cycle. Tumor volume was measured post treatment to determine anti-tumor activity. Following final drug administration, tumors were collected for PK and PD evaluation. Extent and duration of tumor target inhibition was evaluated by measuring pAKT and total AKT using a mesoscale discovery method and was correlated to tumor MK-2206 levels. Results: Accurins BIND-2206C and BIND-2206D significantly enhanced the PK profile of parent MK-2206 by increasing Cmax (33 fold) and AUC (222 fold) and decreasing clearance (38 fold) in mice. In addition, both BIND-2206 Accurins improved tolerability as demonstrated by no hyperglycemic response compared to a 300% increase in blood glucose in nude mice treated with parent MK-2206. In the VCaP human prostate cancer tumor model, BIND-2206C inhibited tumor growth by 88% and BIND-2206D induced 16% tumor regression showing significant enhancement of anti-tumor efficacy compared to 55% tumor growth inhibition achieved by parent MK-2206. This correlated with high tumor exposure at 72 hours and prolonged tumor PD at 96 hours post dose for both Accurins compared to parent MK-2206. A similar increase in tumor exposure and prolonged PD response resulted in enhanced anti-tumor efficacy for BIND-2206 Accurins in the SK-OV-3 human ovarian cancer tumor model. In the BT-474 HER2 over-expressing human breast cancer tumor model, BIND-2206 Accurins did not improve efficacy compared to parent drug, although there was significant and prolonged tumor PD correlating with enhanced tumor PK. This suggests that anti-tumor efficacy is model specific and a combination strategy in the BT-474 model may be advantageous. Conclusions: BIND-2206 Accurins showed differentiated PK, increased tumor exposure, prolonged duration of target inhibition, superior efficacy and enhanced tolerability compared to parent MK-2206. These data suggest that nanoparticle formulations of the AKT inhibitor, MK-2206, may provide improved tolerability and therapeutic efficacy in a clinical setting. Citation Format: Louise Cadzow, Michael H. Lam, Young Ho Song, Maria Figueiredo, Hong Wang, David De Witt, Vincenzo Pucci, Jan-Rung Mo, Eric Lewis-Clark, Heidi Ferguson, Marian Gindy, Susan Low, Steve Zale, Jeff Hrkach, Caroline McGregor, Brian J. Long. Accurins improve the pharmacokinetics, pharmacodynamics, tolerability and anti-tumor activity of the AKT inhibitor MK-2206. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C197.