On June 22, 2016 Cerulean Pharma Inc. (NASDAQ:CERU), a clinical-stage company developing nanoparticle-drug conjugates (NDCs), reported the publication of preclinical proof of concept data for its lead compound, CRLX101, in the journal Cancer Research (Press release, Cerulean Pharma, JUN 22, 2016, View Source [SID:1234513504]).

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The publication highlights that CRLX101 demonstrated strong antitumor activity, as monotherapy and in combination with Avastin (bevacizumab), leading to complete tumor regression, reduced metastasis, and extended survival of mice with metastatic disease. These preclinical results were derived from mouse models of orthotropic primary triple-negative breast tumor xenografts, including a patient-derived xenograft and a model of post-surgical, advanced metastatic breast cancer. The article was published online.

"CRLX101 in combination with Avastin is a promising combination that has shown compelling antitumor activity in renal cell carcinoma and ovarian cancer, and we are eager to further explore its potential utility in this aggressive and difficult-to-treat form of breast cancer in which patients are at very high risk of recurrence and metastasis," said Christopher D.T. Guiffre, President and Chief Executive Officer of Cerulean. "Consistent with what we observed in previous studies, these preclinical data show that CRLX101 complements and improves concurrent antiangiogenic therapy, and provides strong rationale for continued development in this indication."

In primary xenograft and patient-derived xenograft models, mice on therapy for five to six months of CRLX101 showed tumor growth suppression or regression and reduced lung metastasis. Additionally, Avastin improved both median survival and reduced lung metastasis. Long-term antitumor activity of CRLX101 monotherapy and combination with Avastin was also demonstrated to prevent the emergence of new metastases and caused regression of existing metastases in a model of post-surgical, advanced metastatic breast cancer. Finally, CRLX101 led to improved tumor perfusion and reduced hypoxia, as measured by contrast-enhanced ultrasound and photoacoustic imaging. This improvement in tumor perfusion may contribute to the ability of CRLX101 to effectively and durably suppress HIF-1α.

About CRLX101

CRLX101 is a nanoparticle-drug conjugate (NDC) designed to concentrate in tumors and slowly release its anti-cancer payload, camptothecin, inside tumor cells. CRLX101 inhibits topoisomerase 1 (topo 1), which is involved in cellular replication, and also inhibits hypoxia-inducible factor-1α (HIF-1α), which research suggests is a master regulator of cancer cell survival mechanisms. CRLX101 has shown activity in four different tumor types, both as monotherapy and in combination with other cancer treatments. CRLX101 is in Phase 2 clinical development and has been dosed in more than 350 patients. The U.S. FDA has granted CRLX101 Orphan Drug designation for the treatment of ovarian cancer and Fast Track designation in combination with Avastin in metastatic renal cell carcinoma.

On June 21, 2016, Epizyme, Inc. (the "Company") reported that it entered into a collaboration agreement with Genentech, a member of the Roche Group ("Genentech"), to conduct a phase 1b clinical trial to investigate the anti-cancer effects of the Company’s EZH2 inhibitor, tazemetostat, and Genentech’s recently approved anti-PD-L1 cancer immunotherapy, Tecentriq (atezolizumab), when used in combination (Filing, 8-K, Epizyme, JUN 22, 2016, View Source [SID:1234513503]).

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The trial will evaluate this combination regimen for the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Under the agreement, each company will supply its respective anti-cancer agent to support the trial and share equally in the trial’s costs. Genentech will manage study operations for the trial. The Company expects that patient enrollment in the trial will begin in the second half of 2016.

On June 22, 2016 Incyte Corporation (Nasdaq: INCY) reported that the first patient has been treated in the ECHO-301 study—a Phase 3 trial evaluating epacadostat, Incyte’s investigational, highly potent and selective oral IDO1 inhibitor, in combination with Keytruda (pembrolizumab), Merck’s anti-PD-1 therapy, as first-line treatment for patients with advanced or metastatic melanoma (Press release, Incyte, JUN 22, 2016, View Source [SID:1234513502]). Incyte expects initial data from the ECHO-301 study to be available in 2018.

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"We are very pleased to treat the first patient in the ECHO-301 study and advance the Phase 3 program evaluating epacadostat in combination with pembrolizumab," said Steven Stein, M.D. Incyte’s Chief Medical Officer. "This trial—the first to test this combination in a pivotal study—is part of the larger ECHO program evaluating epacadostat, including combination studies with anti-PD-1 and PD-L1 therapies across multiple tumor types."

Melanoma, the most serious form of skin cancer, strikes adults of all ages. In the U.S., melanoma accounts for approximately five percent of all new cases of cancer each year. The incidence of melanoma continues to rise by almost three percent each year which translates to 76,000 new cases yearly in the U.S. alone.1 In the European Union, there are approximately 41,000 new cases of melanoma per year and approximately 11,000 deaths annually.2

About ECHO-301 (Keynote-252/NCT02752074)
This Phase 3 randomized, double-blind, placebo-controlled study will evaluate pembrolizumab in combination with epacadostat or placebo in patients with unresectable or metastatic melanoma. ECHO-301 will enroll 600 patients, randomized 1:1, who will be stratified by PD-L1 expression (positive versus negative/indeterminate) and BRAF mutation status (BRAF mutant who have received prior BRAF-directed treatment or BRAF mutant with no prior BRAF-directed treatment and BRAF wild type).
The two primary endpoints of the study are progression-free survival and overall survival. Key secondary endpoints include objective response rate, safety and tolerability.

ECHO-301 is co-sponsored by Incyte and Merck. For more information about the study, please visit View Source

About Epacadostat (INCB024360)
Indoleamine 2,3-dioxygenase 1 (IDO1) is a key immunosuppressive enzyme that modulates the anti-tumor immune response by promoting regulatory T cell generation and blocking effector T cell activation, thereby facilitating tumor growth by allowing cancer cells to avoid immune surveillance. Epacadostat is a first-in-class, highly potent and selective oral inhibitor of the IDO1 enzyme that reverses tumor-associated immune suppression and restores effective anti-tumor immune responses. In single-arm studies, the combination of epacadostat and immune checkpoint inhibitors has shown proof-of-concept in patients with unresectable or metastatic melanoma. In these studies, epacadostat combined with the CTLA-4 inhibitor ipilimumab or the PD-1 inhibitor pembrolizumab improved response rates compared with studies of the immune checkpoint inhibitors alone. Ongoing Phase 1 and Phase 2 studies are investigating epacadostat in combination with PD-1 and PD-L1 inhibitors in a variety of other cancer histologies.

On June 22, 2016 The Abramson Cancer Center at the University of Pennsylvania, The Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, and The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai reported the establishment of a research consortium focused on accelerating the discovery and development of novel cancer therapeutics and diagnostics for the benefit of patients (Press release, Celgene, JUN 22, 2016, View Source [SID:1234513493]).

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The consortium aligns four major academic institutions in a unified partnership with the shared goal of creating high-impact research programs to discover new treatments for cancer. The magnitude of the multi-institutional consortium and agreements between Celgene Corporation (NASDAQ:CELG) and each institution will support the rapid delivery of disease-altering programs to the clinic that may ultimately benefit cancer patients, global healthcare systems and society.

Subsequent to establishing the consortium, Celgene entered into four public-private collaboration agreements in which it paid a total of $50 million, $12.5 million to each institution, for the option to enter into future agreements to develop and commercialize novel cancer therapeutics arising from the consortium’s efforts. Over the next ten years the institutions intend to present multiple high-impact research programs to Celgene with the goal of developing new life-saving therapeutics. Subject to Celgene’s decision to opt-in and license the resulting technologies, each program has the potential to be valued at hundreds of millions of dollars.

The four cancer center directors, Steven Burakoff, M.D., of the Icahn School of Medicine at Mount Sinai, Stephen G. Emerson, M.D., Ph.D., of Columbia University, William Nelson, M.D., Ph.D., of Johns Hopkins University and Chi Van Dang, M.D., Ph.D., of the University of Pennsylvania, said in a shared statement, "The active and coordinated engagement, creative thinking and unique perspectives and expertise of each institution have made this collaboration a reality. Our shared vision and unified approach to biomedical research, discovery and development, combined with Celgene’s vast research, development and global commercial expertise, will enable us to accelerate the development and delivery of next-generation cancer therapies to patients worldwide."

In addition to the benefits of long-standing professional relationships among the four cancer center directors, the depth and breadth of the institutions’ combined research and clinical infrastructures provide an exceptional foundation upon which to build this transformative collaboration. The four institutions collectively care for more than 30,000 new cancer patients each year, and have nearly 800 faculty members who are active in basic and clinical research, and clinical care.

"This is a paradigm-shifting collaboration that further strengthens our innovative ecosystem," said Bob Hugin, Executive Chairman of Celgene Corporation. "We remain firmly committed to driving critical advances in cancer and believe the tremendous expertise of our collaboration partner institutions will be invaluable in identifying new therapies for cancer patients."

The four consortium members are among the 69 institutions designated as Cancer Centers by the National Cancer Institute (NCI). These 69 institutions serve as the backbone of NCI’s research in the war against cancer.

The Cancer Trust, a non-profit organization, brought together the four institutions, thereby establishing the multi-institutional research consortium. T.R. Winston & Company, LLC served as the strategic advisor to The Cancer Trust and facilitated negotiations among The Cancer Trust, the institutions and Celgene. The commercialization offices of the four institutions, Columbia Technology Ventures, Johns Hopkins Technology Ventures, Mount Sinai Innovation Partners and the Penn Center for Innovation, subsequently collaborated with Celgene to accelerate this effort to discover and develop new therapies for the treatment of cancer.

"We are extremely proud of what we’ve collectively accomplished through establishing this collaboration and aligning all participants," said Erik Lium, Ph.D., Senior Vice President of Mount Sinai Innovation Partners. "We look forward to continuing to work closely with one another, our colleagues in research and clinical care, and now with Celgene to advance the discovery of new therapies that will dramatically improve the lives of patients worldwide."

On June 22, 2016 Agenus Inc. (NASDAQ: AGEN), an immuno-oncology company developing antibodies including checkpoint inhibitors and other checkpoint modulators, and cancer vaccines, reported that the first patient has been dosed in a Phase 1/2 clinical trial of the anti-GITR agonist antibody INCAGN1876 (Press release, Incyte, JUN 22, 2016, View Source [SID:1234513491]). The trial is being conducted by, and in collaboration with, Incyte Corporation.

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The open-label, dose-escalation portion of the trial will evaluate the safety and tolerability of INCAGN1876 in patients with advanced or metastatic solid tumors and determine the pharmacologically active and/or maximum tolerated dose of INCAGN1876. Part 2 of the trial is planned to further evaluate the recommended dose of INCAGN1876 in selected tumor types, including advanced or metastatic endometrial adenocarcinoma, melanoma, non-small cell lung cancer and renal cell carcinoma.

"This is the second product candidate from our antibody program that has advanced into clinical trials this year," said Garo H. Armen, Ph.D. Chairman and CEO of Agenus. "We expect to initiate additional clinical studies with antibodies as well as other immuno-oncology leads from our comprehensive pipeline in the next twelve months."

INCAGN1876 is an agonist antibody targeting the glucocorticoid-induced TNFR-related protein, or GITR. Upon activation, GITR, a co-stimulatory receptor, can stimulate immune cells to target and potentially destroy cancer cells. This antibody was discovered during an earlier collaboration with Ludwig Cancer Research. INCAGN1876 is being co-developed with Incyte.

"Targeted immunomodulatory therapy including anti-PD-1 and CTLA-4 drugs have demonstrated unprecedented results in cancer, but there remains significant need to improve treatment in cancer patients," said Robert B. Stein, M.D., Ph.D., Agenus’ President, Research & Development. "GITR is a unique co-stimulatory receptor which holds great promise as a new pathway for stimulating immune cells to target cancer and may be effective alone or in combination with other immuno-modulatory approaches."
Additional information about the trial can be found here.

About Checkpoint Antibodies
Promising clinical data from trials employing monoclonal antibodies that bind to checkpoint molecules, such as CTLA-4 and programmed death receptor-1 (PD-1), have generated considerable excitement in the field of cancer immunotherapy. These molecules serve as checks employed by the body to prevent a runaway immune response or allow rapid activation of the immune response when needed. Unfortunately, these necessary mechanisms of control can hinder the anti-cancer immune response. They can be harnessed by cancer cells as a defense against immune attack. Agenus is developing a broad pipeline of antibodies that bind to key checkpoint proteins and activate or block their activities for use in cancer therapy.