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BACKGROUND

Obatoclax Biodistribution in MLL Leukemia NOG Mouse Model is Predicted by Modeling and Simulation and Shows High Tissue Penetration at Clinically Important Sites . Mice injected with 1.3 million leukemia cells . 3 weeks post-injection.

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BACKGROUND

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  1. Obatoclax Biodistribution in MLL Leukemia NOG Mouse Model is Predicted by Modeling and Simulation and Shows High Tissue Penetration at Clinically Important Sites Mice injected with 1.3 million leukemia cells 3 weeks post-injection Alena Y. Zhang1, Jeffrey S. Barrett1,2, Gwenn Danet-Desoyers2, Anthony Secreto2, Vu T. Nguyen, Cathy Keefer2, Xiaochuan Shan, 2 Ralph Bunte2, Manon Lavoie3, Pierre Beauparlant3 , Carolyn A. Felix1,21The Children’s Hospital of Philadelphia, 2University of Pennsylvania, Philadelphia, PA. 3Gemin X Pharmaceuticals, Inc., Montreal, Canada Diseased Mice n = 42 1.2 mg/kg n = 21 4.8 mg/kg n = 21 PK sampling at 0.08, 0.25, 1, 2, 4, 8, 24 hr (3 mice per time point per dose level) DESIGN / METHODS (continued) RESULTS (continued) BACKGROUND Tissue sampling • MLL translocations (MLL+) , which are chemotherapy resistant, occur in ~80% of infant ALL and AML and are a poor prognostic factor in infant ALL. MLL translocations also occur in secondary leukemias after exposure to chemotherapeutic topoisomerase II poisons. • Cell death pathways are desired targets of small molecule inhibitors since their deregulation plays an important role in chemotherapy resistance; e.g. imbalanced expression of BCL-2 family proteins leads to deregulated homeostatic binding between pro- and anti-apoptotic BCL-2 family members and impairs cell death. • Obatoclax inhibits pro- and anti- apoptotic BCL-2 family protein interactions by binding to the BH3 pocket of the anti-apoptotic proteins. • Obatoclax haspotent single agent in vitro activity in MLL+ leukemias and cell lines. Adult phase I CLL trials indicate single agent activity with minimal toxicity. • NOD-scid-IL-2Rnull(NOG) mice lack natural killer cell activity, resulting in superior engraftment of human leukemia xenografts compared to other immuno-deficient mouse strains. • Performed simulations based on obatoclax pop-PK models in diseased NOG and healthy Balb/C mice • Compared simulated secondary PK parameters using WinNonLin (Pharsight, Mountain View, CA) IC90 IC50 PBPK model (PK Sim®) Pop-PK model (NONMEM) Figure 3. Diagnostic plots of pop-PK model fit with observed concentrations in NOG mice. Left:Observed data versus population predicted (PRED) plasma concentrations. Right:Weighted residuals (WRES) versus population predicted (PRED) plasma concentrations. Figure 2. Bi-phasic obatoclax disposition after IV bolus dosing in diseased NOG mice. Note good proportionality at both doses. Blue lines indicate in vitro obatoclax activity. Single-dose IV bolus PK study 1.2 mg/kg 4.8 mg/kg • II. Simulated pop-PK models show similar obatoclax exposure between mouse strains but slower elimination in the NOG • Similar AUC24hr between strains at both doses. • Greater than 3-fold longer half-life in NOG mice, suggesting slower elimination due either to strain differences, disease burden, or analytical detection limit at the lower concentration. NOG Balb/C • II. MLL+ Leukemia Xenografts • Established NOG mouse xenograft model of infant MLL/ENL+ bilineal leukemia that recapitulates the hyperleukocytosis and involvement of the CNS and other extramedullary sites in human MLL+ leukemia III. Experimental Design Figure 1: Schema of the PK study.NOG mice with established xenografts received single IV bolus dose of 1.2 or 4.8 mg/kg obatoclax. Concentrations were measured in plasma, spleen, liver, kidney and brain at indicated times using a validated LC-MS method Figure 4. Simulation of pop-PK models in mouse strains. Simulated plasma concentration-time profiles (n=100) illustrate median (solid line), 10th and 90th percentile (dotted lines) of the pop-PK models. • To construct obatoclax dose-exposure and tissue distribution relationships in NOG mouse xenograft model of MLL+ leukemia using an experimental design based on prior PK data from other strains of mice and adult Phase 1 trial target exposure data • To determine the effect of leukemia and mouse strain on drug disposition Spleen Liver • III. Obatoclax biodistribution is extensive and sustained in murine equivalent sites of MLL+ leukemia • Sustained drug retention in spleen, liver and brain, which are desired target sites of anti-leukemia activity. • Brain:plasma ratios  2-10, indicate substantial CNS penetration. • Higher ratios in the kidney for 1.2 mg/kg dose group suggest the potential for saturable elimination. • Increasing tissue to plasma ratios with time in liver relative to other target organs with more consistent accumulation. • Equilibrium of splenic uptake at 8 hours forms rationale for pre-treating with obatoclax 4 hours prior to chemotherapy to achieve chemosensitization in the upcoming preclinical diseased NOG mouse efficacy study. • I. Modeling Approach • Previously had constructed a pop-PK model using TK data from 3 single-dose studies in healthy Balb/C mice (courtesy of GeminX) via NONMEM with FO method (version 5, level 1.1, Globomax, Hanover, MD) (Zhang, 2007 ACCP Annual Meeting) • Simulated obatoclax exposure in the NOG mouse based on adult CLL phase I target exposure (AUC24hr180 ng•hr/mL) associated with peak ODNA release • Assumptions based on model: 1.2 mg/kg and 4.8 mg/kg would achieve 100% and 400% of the target exposure • Optimal sampling schedule to yield model-predicted parameters based on 7 time point design with “big rat” approach (destructive sampling consideration) • Performed PK study in leukemia-bearing NOG mice and used NONMEM to develop a pop-PK model from experimental data Brain Kidney RESULTS • I. Pop-PK Model in MLL+ Leukemia NOG Mice • A 2-compartment PK model best describes the distribution/elimination of obatoclax in NOG mice, similar to Balb/C. • Exponential inter-individual variability model for CL, V1, Q and V2 and proportional error model for residual variability afford unbiased predictions of drug concentrations. Figure 5. Obatoclax tissue biodistribution in diseased NOG mice.

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