Eribulin ORA: A novel oral formulation of eribulin based on combination with the P-gp inhibitor HM30181A.

Abstract

e12577 Background: Eribulin is a potent synthetic derivative of the marine sponge natural product Halichondrin B that uniquely targets microtubule growth to induce apoptotic cell death. Eribulin is currently administered intravenously (IV) to treat patients with breast cancer and liposarcoma refractory to taxane therapy due to its superior efficacy in taxane resistant tumor types. Methods: Utilizing a proprietary Orascovery platform, Eribulin ORA, a novel orally-administered eribulin formulation has been developed, which combines the P-glycoprotein (P-gp) inhibitor, HM30181A, with oral eribulin. Results: HM30181A significantly improves the systemic exposure of oral eribulin in rodents, which enables remarkable tumor regression in murine xenografts. HM30181A improves eribulin plasma exposure > 5-fold in mouse model (AUC0-24hr = 8224 ng*hr/mL with HM30181A vs. 1516 ng*hr/mL without HM30181A) and also improves eribulin oral bioavailability in the rat (%F = 35.0 with HM30181A vs. 16.1 without HM30181A). In vitro cell viability assays of MCF-7 and MDA-MB-231 breast cancer cell lines show eribulin is synergistic with other microtubule disrupting agents, including common first-line breast cancer therapy paclitaxel. In mice bearing orthotopic MDA-MB-231 breast tumor xenografts, oral eribulin with HM30181A was administered at eribulin doses of 0.5, 1.0, and 1.5 mg/kg Q2Dx3 (M,W,F)/week for four weeks. Only mice treated with 1.5 mg/kg (highest dose) eribulin had weight loss during treatment, with the observed weight loss was < 10%, (except for one mouse). All eribulin doses tested induced tumor regression, with 7/9 tumors in the 1.5 mg/kg eribulin group experiencing durable complete regression until study end, two-weeks post administration. Of the tumors in the Eribulin ORA-treated groups that resumed growth after treatment, the degree of tumor growth was minimal. Overall, Eribulin ORA was well tolerated and showed potent efficacy against breast cancer tumors, exhibiting nearly 100% growth inhibition at all dose levels tested. Conclusions: Eribulin ORA showed good oral absorption, efficacious systemic exposure, and importantly, excellent anti-cancer activity in a breast cancer model. In vitro studies demonstrated the synergistic potential of eribulin in combination with paclitaxel. Accordingly, the combination of Eribulin ORA with Oraxol (oral paclitaxel that has shown promising clinical data) may represent an excellent metronomic oral combination chemotherapy that warrants further investigation for patients with advanced breast cancer.