Ofir Moreno

Abstract CT157: Clinical pharmacokinetics and pharmacodynamics of ME-401, an oral, potent and selective inhibitor of phosphatidylinositol 3-kinase P110δ, following single ascending dose administration to healthy volunteers

Background: ME-401 is a potent and selective inhibitor of the Phosphatidylinositol 3-Kinase p110δ isoform, which demonstrated highly favorable PK from oral administration in preclinical experiments. Preclinical toxicology and safety pharmacology data supported initial clinical assessment of oral ME-401 in healthy volunteers, consistent with its target selectivity profile. Methods: A first-in-human study was conducted using the Translational Pharmaceutics® platform which enables rapid real-time PK/PD analysis and GMP manufacture of drug products between dosing periods, under a flexible protocol. This was an open-label, single dose design, where it was planned to enroll up to 3 sequential groups, comprising 3, 6 and 6 subjects. The planned dose levels were 10, 30, 60 90 and 150 mg. Blood samples were collected to measure plasma concentrations of ME-401, and for testing with a PD assay: basophil activation assessed via CD63 expression by flow cytometry following ex-vivo stimulation with an anti-FCeR1 monoclonal antibody. Results: A total of 15 healthy volunteers were enrolled in the clinical study. ME-401 was orally administered at the planned dose levels. Plasma concentration vs time profiles were consistent with extravascular dosing. There was a linear relationship between both Cmax and AUC as a function of dose (mg). At the 60 mg dose, geometric mean Cmax, AUCinf and half-life were 9.4 ng/ml, 230 ng*h/ml and 28 h, respectively. Half-life appeared dose-independent. Significant inhibition of basophil activation was observed at all dose levels. The individual concentrations and percent inhibition data were fitted to a simple Emax model: E = (Emax*C)/(C+EC50). EC50 and EC90 were 0.6 and 5 ng/mL (1 and 9 nM), respectively. A PK model was fitted to the individual data observed from the 60 mg dose level, and was used to generate steady state trough plasma concentrations from daily dosing of a simulated population of 250 individuals. Statistical analysis indicated a 95% confidence interval of 5.7-6.4 ng/ml for the geometric mean trough plasma levels, which is above the EC90. All doses were generally well tolerated. There were no serious adverse events, severe TEAEs, TEAEs leading to death or TEAEs leading to discontinuation reported. Conclusions: ME-401 is orally bioavailable, exhibiting linear increase in exposure, over the 10-150 mg dose range. Daily dosing of 60 mg, or higher, is expected to afford trough plasma levels that lie above the EC90, on the plateau of the effectiveness dose-response curve. ME-401 was well tolerated when administered to healthy volunteers as a single oral dose up to 150 mg. This highly selective, oral PI3K delta inhibitor is expected to enter a Phase Ib study for the treatment of B-cell malignancies in the first half of 2016. Citation Format: Ofir Moreno, Robert Imani, Vanessa Zann, Pui Leung. Clinical pharmacokinetics and pharmacodynamics of ME-401, an oral, potent and selective inhibitor of phosphatidylinositol 3-kinase P110δ, following single ascending dose administration to healthy volunteers. [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 CT157.

Abstract 2457: Ex vivo analysis of novel isoflavanoids (ME-143 and ME-334) in patient derived triple negative breast cancer tumors.

There is an unmet need for novel effective therapeutics to treat triple negative (ER, PR and Her2 negative) breast cancer in clinics. Phase I clinical studies of 2 novel isoflavonoid investigational drugs, ME-143 and ME-344 have been shown them to be generally well tolerated in patients with solid tumors. ME-143, a next analogue of the investigational anti-cancer drug Phenoxodiol binds at low nanomolar concentrations to a tumor-specific variant of cell surface associated NADH oxidase (tNOX), resulting in caspase activation and apoptotic tumor cell death. ME-344, a second investigational anti-cancer isoflavonoid, is structurally related to ME-143 but functionally distinct. ME-344 is a mitochondrial targeting agent that interferes with tumor cell energy generation resulting in cell death via mitochondrial membrane destabilization and autophagy induction through the disruption of both mTOR1 and mTOR2 upstream and downstream signal transduction pathways. Pre-clinical studies using in vitro cell lines showed significantly high potency for both compounds either when used as single agents or when combined with cytotoxic and targeted anti-cancer agents. The present study investigated the ex vivo efficacy of ME-143 and ME-344 using patient-derived tumor cells from triple negative breast cancer. Tumor tissue was disintegrated into single cell suspension and expanded in mouse as subcutaneous patient-derived xenograft before harvesting for the studies. Mouse tumor cells were disintegrated into single cells and were grown as spheroids to mimic the tumor micro-environment and single agent as well as combination treatments were performed. Using a high content imaging platform, various endpoints were evaluated to compare the efficacies of the drugs. Both ME-143 and ME-344 as single agents showed efficacy in inhibiting cell proliferation as well as colony formation in patient-derived triple negative breast cancer cells while combination of these agents with Cisplatin and Gemcitabine demonstrated additive or synergistic effects. Use of high content imaging has enabled the identification of patient population that has tumor cells resistant to very high doses of drugs. Follow-up studies are planned to characterize the sub-population of cells that are resistant to high dose of these drugs. Citation Format: Kesavan Nair Praveen, Thomas Broudy, Cyrus Mirsaidi, Ofir Moreno, Daniel Gold. Ex vivo analysis of novel isoflavanoids (ME-143 and ME-334) in patient derived triple negative breast cancer tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2457. doi:10.1158/1538-7445.AM2013-2457