On June 8, 2015 Seattle Genetics and Unum Therapeutics reported that the two companies have entered into a strategic collaboration and license agreement to develop and commercialize novel antibody-coupled T-cell receptor (ACTR) therapies for cancer (Press release, Seattle Genetics, JUN 8, 2015, View Source [SID:1234505377]).

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Unum’s proprietary ACTR technology enables programming of a patient’s T-cells to attack tumor cells when co-administered with tumor-specific therapeutic antibodies. Seattle Genetics, through its extensive work in the field of antibody-drug conjugates (ADCs), has a substantial portfolio of cancer targets and tumor-specific monoclonal antibodies from which programs will be selected for the collaboration.

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"This collaboration is an exciting extension of our work over more than 17 years, empowering antibodies in order to provide new therapeutic options for cancer patients," said Clay B. Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics. "Unum’s innovative technology for a universal, antibody-directed cellular immunotherapy is differentiated from other engineered T-cell approaches, and may have broad applicability across a range of cancer targets. We are pleased to be collaborating with one of the most promising companies in the emerging field of cellular immunotherapy to develop new treatment options for cancer patients with unmet medical needs."

"Unum’s strategy is to develop and commercialize a universal cellular immunotherapy that can be used in combination with a variety of antibodies to attack a wide range of hematological and solid tumors," said Charles Wilson, Ph.D., President and Chief Executive Officer of Unum Therapeutics. "We believe that our unique approach has the potential to advance beyond the safety and efficacy limitations of current generation T-cell approaches. We are delighted to collaborate with Seattle Genetics in the development of ACTR therapies. Their leadership in antibody-based therapies and expertise in the development of cancer treatments will be invaluable as we work together to bring potentially breakthrough therapies to patients."

Under the terms of the agreement, Seattle Genetics will make an upfront payment of $25 million and an equity investment of $5 million in Unum’s next round of private financing. The companies will initially develop two ACTR products incorporating Seattle Genetics’ antibodies, and Seattle Genetics has an option to expand the collaboration to include a third ACTR product. Unum will conduct preclinical research and clinical development activities through phase 1 with funding from Seattle Genetics. The companies will work together to co-develop and jointly fund programs after phase 1 unless either company opts out. Seattle Genetics and Unum will co-commercialize and share profits 50/50 on any co-developed programs in the United States. Seattle Genetics will retain exclusive commercial rights outside of the United States, paying Unum high single to mid-double digit royalties on ex-U.S. sales. Potential option fee and progress-dependent milestone payments to Unum under the collaboration may total up to $615 million across all three ACTR programs.

As a result of the amounts paid up front and the additional development activities expected under this deal, Seattle Genetics will provide revised 2015 financial guidance in connection with announcing its second quarter financial results currently planned for July 30, 2015.

About ACTR Technology

ACTR is a chimeric protein that combines components from receptors normally found on two different human immune cell types – natural killer (NK) cells and T-cells – to create a novel cancer cell killing activity. T-cells bearing the ACTR receptor can be directed to attack tumor cells by providing a monoclonal antibody that binds to antigens on the cancer cell surface and then acts as a bridge to the ACTR T-cell, enabling tumor cell killing. Unum has built a platform for cancer treatment based upon ACTR. In contrast to other approaches that are limited to a single target and treat a narrow set of tumors, Unum’s approach is not restricted by antigen and may have applications for treating many types of cancers.

On June 8, 2015 Idera Pharmaceuticals reported that the company has entered into a strategic clinical research alliance with The University of Texas MD Anderson Cancer Center to advance clinical development of intratumoral TLR9 agonist in combination with checkpoint inhibitors (Press release, Idera Pharmaceuticals, JUN 8, 2015, View Source [SID:1234505376]). IMO-2125 is a TLR9 agonist which has been evaluated subcutaneously in over 80 human subjects, was well tolerated, and was shown to induce immune responses.

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The company intends to initiate the first trial of the research alliance, a Phase 1/2 study to assess the safety and efficacy of Intratumoral IMO-2125 in combination with ipilimumab (a CTLA4 antibody) in patients with metastatic melanoma. In this trial, escalating doses of IMO-2125 will be administered intratumorally into a lesion, with a standard dosing regimen of ipilimumab. The primary objectives of the trial will be to determine the maximum tolerated dose (MTD) and characterize the dose-limiting toxicities (DLTs) of IMO-2125 when administered intratumorally in combination with ipilimumab, as well as to determine the efficacy of the combination utilizing the immune-related response criteria (irRC). The company has already filed and received FDA feedback to a Pre-Investigational New Drug Application (PIND) for IMO-2125 and intends to submit an Investigational New Drug application (IND) and initiate the clinical study in the second half of this year. The trial will enroll approximately 45 patients. The company expects data to be available in 2016. The study will be led by Adi Diab, MD, Assistant Professor, Department of Melanoma Medical Oncology, Division of Cancer Medicine, MD Anderson. Additional trials as part of the broader, clinical research alliance are currently in the planning stages.

"This type of clinical research alliance is important to MD Anderson’s work toward eliminating cancer," said Patrick Hwu, M.D., division head, Cancer Medicine at MD Anderson. "The study to be headed by Dr. Diab will add to our overall efforts in finding new therapies for our patients."

"Being chosen as a strategic research alliance partner by MD Anderson, a world-leading cancer research center to advance the clinical development of intratumoral TLR9 agonists in combination with check-point inhibitors is an important step forward for Idera’s oncology program. We look forward to evaluating in the clinical setting if our targeted intratumoral approach can meaningfully improve patient outcomes," stated Vincent Milano, Chief Executive Officer of Idera Pharmaceuticals. "The pre-clinical data we presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Immunotherapy conference in December demonstrated that the combination of intratumoral TLR9 agonist and systemically administered ipilimumab induced potent anti-tumor activity in both the treated and distant tumors and we look forward to seeing if we can replicate those results in the clinical setting."

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, intratumoral 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 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 from these studies to be presented at an oncology conference in the second half of 2015.

On June 8, 2015 Compugen reported it will disclose an additional novel immune checkpoint target candidate, CGEN-15029, and initial experimental validation data for this candidate at its Analyst and Investor Day in New York City today (Filing, 6-K, Compugen, JUN 8, 2015, View Source [SID:1234505375]).

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In addition, the Company will disclose a new computational infrastructure, LINKS, which is designed for the comprehensive and comparative assessment of drug targets. Initial usage of this new infrastructure resulted in the selection of five target candidates, including CGEN-15029, as the highest priority immune checkpoint target programs to be advanced by the Company.

A live webcast of the Analyst and Investor Day event will be available on the investor section of Compugen’s website beginning at 9:00 a.m. ET today. An archived replay of the webcast will be available on the website for 30 days after the event.

Dr. Cohen-Dayag, Ph.D., President and Chief Executive Officer of Compugen, stated, "We are very excited to disclose the initial validation of this additional novel immune checkpoint candidate, along with identification of its binding partner. These initial biological studies provide a better understanding of the mechanism of action of this candidate and should support a clear path to therapeutic antibody discovery and development."

Dr. Cohen-Dayag continued, "In addition, the recent development and application of our LINKS infrastructure provided new insights into the therapeutic potential of our novel target candidates and further enhanced our capabilities. Establishing our unique target discovery capabilities required many years of pioneering multi-disciplinary research, however, once established, the in silico discovery of multiple B7/CD28-like immune checkpoint candidates took only several months. We believe that further validation and clinical advancement of the multiple target candidates resulting from the initial usage of our discovery infrastructure will continue to demonstrate a level of predictive accuracy that is unprecedented in pharmaceutical research in terms of the quality and quantity of the candidates."

CGEN-15029 is one of eleven novel B7/CD28-like immune checkpoint candidates discovered by Compugen. Initial validation studies show that expression of CGEN-15029 in T-cells inhibits their activation by melanoma cells, consistent with an immune suppressive role of the target in the tumor microenvironment. The target possesses signature immune-checkpoint receptor characteristics, including expression in relevant subsets of T- and NK-cells, with particularly high expression in lymphocytes that populate the tumor microenvironment (known as tumor infiltrating lymphocytes or TILs). A binding partner for CGEN-15029 has also been identified, which enables a clear path towards selection of inhibitory antibodies and their therapeutic development.

The LINKS infrastructure is a novel, proprietary, in silico platform designed to allow comprehensive characterization and differentiation of drug target candidates. LINKS was designed to integrate and analyze extremely large amounts of patients’ disease and clinical data to associate novel drug targets with specific disease conditions, clinical attributes and disease-associated mechanisms of action. During the past several months, this new infrastructure was applied to analyze Compugen’s pipeline of immune checkpoint target candidates and to compare them to one another as well as to differentiate them from known immune checkpoints. This analysis included immune subpopulations, regulatory mechanisms and cancer-specific immune signatures, and enabled Compugen to compare and differentiate its large portfolio of novel immune checkpoint programs, other than the two that are subject to a collaboration agreement with a pharma partner. Based on this assessment, as well as experimental data for the target candidates, Compugen selected five target programs as highest priority, including CGEN-15029, representing various aspects of cellular immune biology and therefore potentially addressing multiple therapeutic applications and indications.

About Immune Checkpoints
Immune checkpoints are inhibitory receptors and their ligands, which are crucial for the maintenance of self-tolerance (that is, the prevention of autoimmunity) and for the protection of tissues from damage when the immune system is responding to pathogenic infection or other injuries. These immune checkpoints, which are "hijacked" by tumors to block the ability of the immune system to destroy the tumor (immune resistance), have emerged as promising targets for cancer immunotherapy, and have shifted the treatment paradigms for several major cancer types. Therapeutic blockade of immune checkpoints boost anti-tumor immunity, enabling the patient’s immune system to recognize and attack the tumor cells, and mount durable anti-tumor responses and tumor destruction. Although to date the blockade of immune checkpoints has proven effective for only a minority of patients in a limited, but growing number of cancer types, it has provided impressive clinical benefits, enabling long-term survival, even for end-stage patients, and is transforming cancer therapeutics.

On June 8, 2015 Celator Pharmaceuticals reported that an investigator-initiated clinical study evaluating CPX-351 (cytarabine:daunorubicin) Liposome Injection in patients with untreated high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), at high risk of treatment-related mortality has met the efficacy and safety criteria to expand the 32units/m2 dose cohort (Press release, Celator Pharmaceuticals, JUN 8, 2015, View Source [SID:1234505374]).

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In order to expand the 32units/m2 cohort, the protocol requires 5 or more complete responses and fewer than five deaths by day 28 in the first 20 patients. CPX-351 resulted in 6 responses in the first 20 patients with 2 early treatment-related deaths by day 28. CPX-351 surpassed both criteria and the number of patients in the cohort was increased from 20 to 30.

Treatment-related mortality (TRM) is a key contributor to overall survival in high risk MDS and AML. This study is evaluating whether CPX-351 is a practical option in patients deemed at high risk of TRM. Patients eligible for this study had TRM scores putting them in the 20 percent of patients at highest risk for early mortality. The rationale for evaluating CPX-351 in these patient populations is based on observations from the earlier conducted and completed Phase 1 and 2 studies with CPX-351, whereby complete responses occurred at dose levels well below the dose being used in the Phase 3 study, with a substantial reduction in early mortality, resulting in an improvement in overall survival in certain patient populations.

Risk assessment for TRM is based on an analysis of 3,365 adults with newly diagnosed AML treated on protocols at Southwest Oncology Group (SWOG) or at MD Anderson Cancer Center. TRM scores provide a means for objectively identifying patients at high-risk for early mortality (treatment-related mortality, or TRM score), such that the higher the TRM score, the greater the risk for treatment-related mortality.

"We are happy to report expansion of this study which seeks an active but safe treatment for patients with AML or MDS at high risk for early treatment-related mortality, who are rarely eligible for conventional chemotherapy," said Roland Walter, MD, PhD, Assistant Member of the Clinical Research Division at the Fred Hutchinson Cancer Research Center, the lead investigator for this study. "The early safety and efficacy observations are encouraging and we look forward to continuing to study CPX-351 in these patient populations."

"As we await the results from the ongoing Phase 3 study in patients with secondary AML, it is important to evaluate the potential benefit of CPX-351 in other patient populations," said Scott Jackson, Chief Executive Officer of Celator Pharmaceuticals. "Working with investigators at leading cancer centers facilitates the broader evaluation of CPX-351 in patient populations in dire need of therapeutic improvements. We are pleased that CPX-351 was selected as one of these potential therapeutic alternatives and are encouraged to see meaningful therapeutic activity of CPX-351 in these patients."