ZIOPHARM, Intrexon Offer Clinical, Preclinical Data from Immuno-Oncology Programs: Showed Anti-Cancer Activity, Planning Phase 1b/@ Trial AD-RTS-HIL-12 with Veledimex

ZIOPHARM Oncology, Inc.

, a biopharmaceutical company focused on the development and commercialization of new cancer therapies, and Intrexon Corporation

, a leader in synthetic biology, today announced the presentation of clinical and preclinical studies from their immuno-oncology programs at the American Association for Cancer Research (AACR) 2014 Immunology and Immunotherapy Meeting taking place December 1-4, 2014 in Orlando, Florida. Presentations include: * Clinical results from the Ad-RTS-hIL-12 + veledimex studies in patients with advanced breast cancer and melanoma demonstrating local and systemic IL-12-mediated anti-cancer activity, as well as safety through control of both immune- and IL-12-mediated toxicity with use of the RheoSwitch Therapeutic System^® (RTS^®) gene switch (Abstract #B11); * Preclinical data supporting the potential for cytolytic activity against solid tumor targets with allogeneic, genetically-modified stem cells enabled for controlled release of cell-linking moieties (CLMs) within the tumor micro-environment (Abstract #B25); and * Preclinical data describing the development of a novel, high-throughput screening technology for rapidly identifying bi-specific antibodies capable of inducing targeted immunologic activity through the activation of T-cells or other immune cells against tumors (Abstract #B16). "The goal of immuno-oncology is to produce powerful immune responses to cancer. Controlling these immune responses and being able to keep patients out of the ICU during treatment would be an important advance," said James Armitage, M.D., Professor, Department of Internal Medicine, Joe Shapiro Distinguished Chair of Oncology, University of Nebraska Medical Center, ZIOPHARM Medical Board member, and Past President of ASCO and the American Society for Blood and Marrow Transplantation. "A key to achieving this is to tightly control immune system effectors, activating and modulating the intensity of the response as necessary. These data demonstrate the ability to do just that, showing novel control over effector expression, not only in the lab, but also in the clinic." Interim clinical trial results continue to validate dose-dependent oral veledimex control of the Interleukin-12 (IL-12) gene program module and the rapid reversibility of cytokine expression and associated adverse events in patients upon withdrawal of the activator ligand. Together the Companies intend to integrate this RTS-hIL-12 veledimex-controlled cytokine module into a suite of next generation cellular products armed with tumor specific targeting and signaling through chimeric antigen receptor (CAR), T-Cell Receptor (TCR), and cell linking moiety (CLM) platforms. "Through the rational design of molecularly directed T-cell therapies, such as CAR-T and CLM, and controlled expression of cytokine adjuvants with our clinically validated RTS^® platform, we plan to advance cellular therapies that overcome the challenges of treating solid tumor malignancies and improve upon the limitations of current hematologic approaches within immuno-oncology," stated Gregory Frost, Ph.D., Senior Vice President and Head of Intrexon's Health Sector. Results in detail "Ad-RTS-hIL-12 + Veledimex Regulation of IL-12 Expression in Advanced Breast Cancer (BC) and Melanoma Patients" (Abstract #B11) In two open-label Phase II clinical studies, twelve patients with metastatic advanced stage breast cancer and twenty-six patients with metastatic melanoma were administered Ad-RTS-hIL-12, a novel DNA-based therapeutic candidate for the controlled expression of IL-12, a potent cytokine for stimulating an anti-cancer T-cell immune response. Following intra-tumoral injection of Ad‑RTS‑hIL‑12, expression of IL-12 within patients was controlled by the RheoSwitch Therapeutic System^® (RTS^®) gene switch using the oral activator ligand, veledimex, at doses ranging from 5mg to 160mg. All subjects had heavy tumor burden and disease progression at the time of enrollment, with mean number of prior therapies at 14 and 10 for breast cancer and melanoma patients, respectively. Treatment with Ad-RTS-hIL-12 + veledimex resulted in an increase in the immune cytokine IL-12 and downstream cytokines, IFNg, IP-10 and IL-10, resulting in a significant increase in the number of CD8+ T-cells. Among seven evaluable subjects in the Phase II clinical study of Ad-RTS-IL-12 + veledimex in patients with recurrent or metastatic breast cancer, three had stable disease, including one triple negative BC subject who crossed the primary endpoint of 16 week progression free survival, for a disease control rate (stable disease or better) of 43%. Target lesions and tumor burden were significantly reduced in approximately 40% of patients. In the Phase I/II study of Ad-RTS-hIL-12 + veledimex in subjects with unresectable stage III/IV melanoma, of eighteen evaluable subjects, one had a partial response and six had stable disease, for a disease control rate of 39%. In melanoma patients for whom a response was observed, there was evidence of local and systemic anti-cancer activity. The adverse event profile of Ad-RTS-hIL-12 + veledimex in both melanoma and breast cancer was predictable, reversible and characteristic of immune activation. The most common ≥ Grade 3 treatment emergent adverse events (TEAEs) in breast cancer and melanoma included neutropenia and electrolyte abnormalities (21%) each, LFTs increased (16%), leukopenia (13%) and pyrexia, hypotension, lymphopenia, anemia, and cytokine release syndrome (11%) each. Importantly, all TEAEs and SAEs ≥ Grade 3 reversed rapidly upon discontinuation of veledimex oral dosing. Based on these results, ZIOPHARM expects to initiate a Phase 1b/2 clinical trial of Ad-RTS-hIL-12 + veledimex in conjunction with standard-of-care treatment in subjects with earlier-stage, locally advanced or metastatic breast cancer. The Company also continues to work with regulators toward the initiation of a Phase I trial of Ad-RTS-IL-12 as a single agent in the treatment of patients with Glioblastoma Multiforme, anticipated to begin in the first half of 2015, and is exploring additional applications using the RTS^® control system for IL-12 cell-based therapies. "With potent, systemic anti-cancer immune activity and control of both immune- and IL-12-mediated toxicity established in heavily pretreated breast cancer and melanoma patients, our development strategy for this novel therapy is in sharp focus," said Francois Lebel, M.D., Senior Vice President, Clinical Development and Medical Operations at ZIOPHARM. "These findings will be translated into a study of patients with early metastatic breast cancer responding to standard therapy, where an increase in tumor specific CD8+ T-cells may improve clinical outcomes. As we evolve this platform, we look forward to exploring its further clinical application in cancers where an IL-12 driven immune response is associated with anti-cancer immunity and where combination therapy may deliver significantly improved outcomes for patients." "Development of a High-Throughput Imaging Screen for the Functional Assessment of Cell-Linking Moieties Using Effector And Target Cells In A Cell Kill Assay" (Abstract #B16) and "Controlled Production of a Bispecific Antibody by a Genetically-modified Stem Cell Triggers T-cell Activation and Cytolysis in Non-small Cell Lung Carcinoma" (Abstract #B25) Cell Linking Moieties (CLMs) are small bi-specific antibody fragments capable of directing potent T-cell mediated tumor lysis by bridging the immunologic synapses of T-cells and surface targets on tumor cells. Previous studies have shown that the systemic distribution and pharmacokinetic profile of bi-specific antibodies limit their utility for many target/effector combinations. In two preclinical studies, Intrexon and ZIOPHARM researchers interrogated a large number of CLM-based effectors for their ability to activate white blood cells from peripheral blood and lyse receptor target-positive tumor cells. Allogeneic, tumor targeting stem cells were then genetically modified to express CLMs within the tumor microenvironment using the RheoSwitch Therapeutic System^® platform as a mechanism for providing spatial and temporal control. The first study demonstrates the ability of Intrexon's proprietary image-based screening systems and rapid DNA assembly to screen a large number of EGFR and HER2 receptor-targeted CLM variants for their ability to recruit CD3+ T-cells and mediate selective cell killing against target positive cells in peripheral blood co-cultures. The image-based screening platform allows for real time target cell killing information to be obtained, as well as kinetic cell morphologic analyses to understand the dynamics of killing activity, thereby shortening the developmental timeline to lead candidate selection. The second study validated these CLM candidates in scalable, allogeneic endometrial regenerative cells (ERCs) genetically modified to express an anti-CD3-anti-EGFR CLM under RTS^® ligand inducible control. Expression of CLMs under the RTS^® inducible promoter provided effective control of CLM secretion and modulation of killing activity, with veledimex-dependent cytotoxicity of greater than 80% against an EGFR+ KRAS mutant lung cancer cell model. CLM-expressing ERCs were found to be effective in co-culture killing assays at cellular doses as low as 1% of target cells. These data support the feasibility of localized cytolytic activity of CLM-secreting allogeneic cell therapy products against EGFR+ KRAS mutant solid tumor malignancies.