On November 11, 2016 Idera Pharmaceuticals, Inc. (NASDAQ:IDRA), a clinical-stage biopharmaceutical company developing toll-like receptor and RNA therapeutics for patients with cancer and rare diseases, is reporting translational data supporting the mechanism of action of intratumoral IMO-2125, a Toll-like receptor (TLR) 9 agonist from the ongoing Phase 1 dose escalating clinical trial (Press release, Idera Pharmaceuticals, NOV 11, 2016, View Source;p=RssLanding&cat=news&id=2221857 [SID1234516527]). In this trial, IMO-2125 is being evaluated in combination with ipilimumab for treatment of patients with metastatic melanoma with disease that is refractory to anti-PD-1 inhibitors, and have minimal options and low expectation of clinical response with ipilimumab treatment alone. Taken together, the previously reported early clinical responses and the supporting mechanism of action translational data being presented today, indicate that intratumoral IMO-2125 is a potent agent for the stimulation of the tumor microenvironment.
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In the oral presentation at the 2016 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting (SITC) (Free SITC Whitepaper), entitled "Reactivating the anti-tumor immune response by targeting innate and adaptive immunity in a phase I/II study of intratumoral IMO-2125 in combination with systemic ipilimumab in patients with anti-PD-1 refractory metastatic melanoma," Cara Haymaker, Ph.D., from the University of Texas, MD Anderson Cancer Center, presented an overview of the modulation of the tumor microenvironment through the unique mechanism of action of intratumoral IMO-2125 and provided an update on the initial findings of the translational data through the first cohorts of the trial. Immunological analysis of the biopsy taken from the lesion injected with IMO-2125 showed rapid dendritic cell maturation which is a critical first step in the induction of the immune cascade within the tumor microenvironment. During the treatment period, T-cell expansion and activation and importantly, immune infiltration was observed in the biopsied distant lesions of the responding patients, demonstrating the abscopal effect.
From a clinical perspective, through all dosing cohorts tested to date, no dose-limiting toxicity has been seen. Preliminary clinical activity is also encouraging in this population with disease that is refractory to PD-1 inhibitors as 3 responses (including one CR) have already been recorded. The trial continues to dose escalate and enrollment into the planned anti-PD-1 inhibitor combination arm has also commenced.
"We hypothesized that the intratumoral injection of IMO-2125 into a single tumor lesion would stimulate dendritic cells to produce interferon and the downstream immune cascade in the tumor microenvironment, resulting in the recruitment and activation of tumor-killing T-cells in both the injected and non-injected tumors," said Joanna Horobin, M.B., Ch.B., Idera’s Chief Medical Officer. "When combined with a systemic checkpoint inhibitor, this change in the tumor microenvironment was expected to affect tumor responses in both injected and distant tumors. Today Dr. Haymaker presented analyses of serial biopsies from the tumors of patients with anti-PD-1 refractory melanoma in our ongoing phase 1 dose escalation trial of intratumoral IMO-2125 which clearly demonstrated these beneficial changes in the tumor microenvironment, essentially turning "cold" tumors "hot" in responding patients. We are thrilled to see what we believe to be, the clear translation of our hypothesis in patients. Moreover, in three patients the investigator has reported substantial tumor shrinkage with 2 partial and one complete response."
A copy of the slides from today’s presentation as well as a copy of a related poster presentation are currently available on Idera’s corporate website at View Source
These early results are from the phase 1 portion of study IMO-2125-204 (NCT02644967) in which cohorts of patients with metastatic melanoma unresponsive to PD-1 inhibitor therapy are being administered escalating doses of IMO-2125 ranging from 4 mg/kg through 32 mg/kg. IMO-2125 is injected intra-tumorally into a designated tumor lesion together with a standard dosing regimen of ipilimumab. The trial has recently been amended to also study the combination of IMO-2125 and pembrolizumab given intravenously. Following determination of the recommended phase 2 doses (RP2D) additional patients will be treated in an expansion phase 2 portion of the study. The primary objective of the phase 1 portion of the trial is to characterize the safety and determine a RP2D of IMO-2125 when administered intra-tumorally in combination with ipilimumab or pembrolizumab. The primary objective of the phase 2 portion is to assess the clinical activity of IMO-2125 in each combination at the respective RP2Ds. Assessment will be based on the immune-related response criteria (irRC) and additionally the traditional RECIST criteria. Serial biopsies are being taken of selected injected and non-injected tumor lesions to assess immune changes and correlate with clinical response assessments. The trial will enroll approximately 60 patients. The study is being conducted at MD Anderson and is being led by Adi Diab, MD, Assistant Professor, Department of Melanoma Medical Oncology, Division of Cancer Medicine, MD Anderson as part of a strategic research alliance announced by Idera and MD Anderson in 2015.
Additionally at SITC (Free SITC Whitepaper), on November 9th, Idera’s Oncology Lead, Mark Cornfeld, M.D., M.P.H., presented an overview of IMO-2125’s unique mechanism of action in an oral presentation, entitled "IMO-2125, An Investigational Intratumoral Toll-Like Receptor 9 Agonist, Modulates the Tumor Microenvironment to Enhance Anti-Tumor Immunity" during a session focused on New Clinical Agents in Development. A copy of the slides from this presentation is currently available on Idera’s corporate website at View Source
About Toll-like Receptors and Idera’s Immuno-Oncology Research Program
Toll-like receptors (TLRs) play a central role in the innate immune system, the body’s first line of defense against invading pathogens, as well as damaged or dysfunctional cells including cancer cells. The innate immune system is also involved in activating the adaptive immune system, which marshals highly specific immune responses to target pathogens or tissue. Cancer cells may exploit regulatory checkpoint pathways to avoid being recognized by the immune system, thereby shielding the tumor from immune attack. Checkpoint inhibitors such as agents targeting CTLA4 or programmed cell death protein 1 (PD1) are designed to enable the immune system to recognize tumor cells. In this setting, intra-tumoral TLR9 agonist administration may increase the tumor-infiltrating lymphocytes (TILs), and thereby potentiate anti-cancer activity of checkpoint inhibitors in the injected tumor as well as systemically.
Idera’s TLR9 agonists, IMO-2125 and IMO-2055, have been created using the company’s proprietary chemistry-based discovery platform. IMO-2125 has been shown in various scientific presentations and publications to activate dendritic cells and induce interferon. Idera selected IMO-2125 to advance into clinical development in combination with checkpoint inhibitors based on this immunological profile. In previously completed clinical trials, subcutaneous administration of IMO-2125 was generally well tolerated in about 80 patients with hepatitis C. Idera has conducted further preclinical research evaluating the potential of IMO-2125 to enhance the anti-tumor activity of other checkpoint inhibitors in cancer immunotherapy with data being presented at several medical conferences during the past twelve months. The posters from these presentations can be found at View Source
About Metastatic Melanoma
Melanoma is a type of skin cancer that begins in a type of skin cell called melanocytes. As is the case in many forms of cancer, melanoma becomes more difficult to treat once the disease has spread beyond the skin to other parts of the body such as by through the lymphatic system (metastatic disease). Melanoma accounts for only one percent of skin cancer cases, but causes a large majority of skin cancer deaths. The American Cancer Society estimates that in 2016, there will be 76,380 new cases of melanoma in the U.S., and about 10,130 will die of this disease.