On December 5, 2016 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported data on new product candidate CDX-1140, a fully human antibody targeted to CD40 that has demonstrated potent agonist and anti-lymphoma activity (Press release, Celldex Therapeutics, DEC 5, 2016, View Source [SID1234516926]). Found on antigen presenting cells, such as dendritic cells, macrophages and B cells, CD40 is a key activator of the immune response and is expressed on many cancer cells, in particular B cell lymphomas. The data were presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting on Saturday, December 3 in a poster titled "CDX-1140, A Novel Agonist CD40 Antibody with Potent Anti-lymphoma Activity" (Abstract #1848). CDX-1140 is expected to be ready to enter clinical studies in patients with advanced cancers, including lymphoma, in 2017.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"We have previously characterized CDX-1140 as possessing a needed balance between its agonist activity and its safety profile to allow for systemic dosing at levels that provide good tissue and tumor penetration, which we believe to be important in order to fully capture the benefit of CD40 immunotherapy," said Tibor Keler, Ph.D., Executive Vice President and Chief Scientific Officer of Celldex Therapeutics. "With this study in preclinical lymphoma tumor models, we show both direct and indirect anti-lymphoma activity as well as synergistic anti-lymphoma activity with our CD27 agonist varlilumab, supporting potential combination treatment in this setting."

The poster features detailed analyses of the anti-lymphoma efficacy of CDX-1140 both as a single-agent and in combination with varlilumab, Celldex’s agonist antibody that binds and activates CD27, or with human immune cells. It is available on the "Publications" page of the "Science" section of the Celldex website. Key findings include:

CDX-1140 elicits direct anti-tumor activity against CD40-positive lymphomas in preclinical tumor models.
The addition of human peripheral blood mononuclear cells (PBMCs) to the tumor models enhances the anti-tumor activity of CDX-1140 compared to the administration of either human PBMC or CDX-1140 alone, indicating an activated anti-tumor immune response by CDX-1140 in addition to direct anti-tumor activity.
The combination of CDX-1140 and varlilumab, elicited greater anti-tumor activity than either antibody alone.
Celldex is currently performing manufacturing and IND-enabling studies to support Phase 1 dose-escalation studies of CDX-1140. The Company believes that the potential for CDX-1140 will be best defined in combination studies with other immunotherapies or conventional cancer treatments.

Additionally, data from investigator sponsored research with varlilumab, CDX-301 and CDX-1401 were/will be presented by Celldex’s collaborating investigators during the ASH (Free ASH Whitepaper) Annual Meeting.

Varlilumab: "Anti-CD27 Enhances Lymphoma Immunotherapy through Profound Myeloid Cell Recruitment" was presented in a poster session on Sunday, December 4 (Abstract #3024). This poster was selected for discussion in a Special-Interest Session called, "Novel Approaches to Immunotherapy — Not Just Checkpoint" to be held on Monday, December 5, 2016 from 12:15-1:15 pm PST.
CDX-301: "Combining In Situ Vaccination with Immune Checkpoint Blockade Induces Long-Term Regression of Lymphoma Tumors" was presented in an oral session on Sunday, December 4 (Abstract #465).

CDX-1401: "Vaccination with NY-ESO-1 in Combination with Decitabine for Patients with MDS" will be presented in a poster session on Monday, December 5 (Abstract #4326)

On December 5, 2016 Aduro Biotech, Inc. (Nasdaq:ADRO), a biopharmaceutical company with three distinct immunotherapy technologies, reported that an anti-CD27 antibody developed by Aduro Biotech Europe and derived from its proprietary B-select technology has been selected to be advanced into clinical development by Merck & Co., Inc., Kenilworth, NJ, USA (known as MSD outside the U.S. and Canada), through a subsidiary (Press release, Aduro BioTech, DEC 5, 2016, View Source [SID1234516924]). CD27 has been recognized as having a critical role in activating a productive anti-cancer immune response and has demonstrated the potential to be combined with checkpoint inhibitors in pre-clinical studies.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"Pre-clinical studies have shown that an anti-CD27 agonist can induce a T cell-mediated anti-cancer immune response, and in combination with PD-1 immune checkpoint inhibitors complete tumor eradication can be achieved," said Hans van Eenennaam, Ph.D., chief operational officer, Aduro Biotech Europe.

The CD27 antibody was licensed by MSD to advance as a part of their successful immunotherapy development program and was identified in close collaboration with Prof. Jannie Borst, Ph.D., professor at the University of Amsterdam and division head at the Netherlands Cancer Institute, through Aduro’s B-select monoclonal antibody technology. This technology includes a proprietary ultra-selective functional screening process to identify antibodies with unique binding properties against a broad repertoire of targets that can modulate the innate and adaptive arms of the immune system.

"In 2014, prior to the acquisition by Aduro Biotech, BioNovion entered into a worldwide license agreement with MSD that covers the product candidate’s development and advancement through commercialization," said Andrea van Elsas, Ph.D., chief scientific officer of Aduro Biotech Europe. "Both companies recognized the significant potential of targeting CD27 as a new and distinct mechanism in cancer immunotherapy, especially in the context of PD-1 checkpoint inhibitors, and were strongly committed to accelerate a quality candidate into the clinic."

Conference Call with Management
Aduro’s management will host a conference call to review this announcement and provide a program update, including STELLAR, today at 5:30 a.m. PT/ 8:30 a.m. ET. To participate in the conference call, please dial (844) 309-0604 (domestic) or (574) 990-9932 (international) and refer to conference ID 31336163. Live audio of the conference call will be simultaneously webcast and will be available to members of the news media, investors and the general public at View Source

About the Aduro – MSD Collaboration
BioNovion B.V. and MSD, through a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, entered into a worldwide license agreement in 2014 for the development and commercialization of CD27 antibody agonists, and BioNovion received an up-front payment of $15 million. In 2015, BioNovion was acquired by Aduro Biotech and became its subsidiary, Aduro Biotech Europe B.V.

Under the agreement, a Joint Research Committee was formed to advance the program. Aduro has been reimbursed for certain research activities and is eligible to receive future development, commercial and net sales milestone payments. In addition, Aduro is eligible to receive royalties in the mid-single digits to low teens based on any net sales of the product, if it is approved for marketing.

On December 5, 2016 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported that it has initiated a study of its NY‑ESO SPEAR T‑cells in myxoid/round cell liposarcoma (MRCLS) (Press release, Adaptimmune, DEC 5, 2016, View Source [SID1234516923]). Patient screening is underway, and the results from this study in up to 15 patients will inform a potential future registration trial. The initiation of screening in this study meets a milestone set forth in the Company’s strategic collaboration agreement with GlaxoSmithKline plc (LSE/NYSE: GSK).

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

This is an open-label pilot study in patients to assess preliminary safety and efficacy in this new indication. Initially, 10 patients will be enrolled. If further characterization of the treatment is required, up to 5 additional patients may be enrolled. Eligible patients will be HLA-A*02:01, HLA‑A*02:05 and/or HLA-A*02:06 with advanced (metastatic or inoperable) high grade MRCLS whose tumor shows positive NY-ESO-1 expression defined as ≥30 percent of cells that are 2+ or 3+ by immunohistochemistry. Patients will receive preconditioning with fludarabine and cyclophosphamide at the same dose that is being used in Cohort 4 of the Company’s ongoing synovial sarcoma study.

About MRCLS
Soft tissue sarcomas can develop from tissues like fat, muscle, nerves, fibrous tissues, blood vessels, or deep skin tissues. There are approximately 50 types of soft tissue sarcomas, including MRCLS. Myxoid/round cell liposarcoma is associated with specific chromosomal translocations and represents about 30 to 35 percent of liposarcomas and 5 to 10 percent of all adult soft tissue sarcomas. Myxoid/round cell liposarcoma commonly presents at an age ranging from 35 to 55 years.

On December 5, 2016 Sunesis Pharmaceuticals, Inc. (Nasdaq:SNSS) reported the presentation of results from the Company’s Phase 1A study in healthy volunteers evaluating oral non-covalent reversible BTK inhibitor SNS-062 (Press release, Sunesis, DEC 5, 2016, View Source [SID1234516922]). The results were presented in a poster session titled "CLL: Therapy, excluding Transplantation: Poster I" on Saturday, December 3, at the 58th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in San Diego, California. The presentation, titled "First-in-Human Phase 1a Study of the Safety, Pharmacokinetics, and Pharmacodynamics of the Noncovalent Bruton’s Tyrosine Kinase (BTK) Inhibitor SNS-062 in Healthy Subjects," is available at www.sunesis.com.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

"These final results from the Phase 1A Healthy Volunteer study suggest that SNS-062, with a favorable safety, pharmacokinetic (PK) and pharmacodynamic (PD) profile, and its improved PK properties over ibrutinib and acalabrutinib, has significant potential to become a new treatment option for patients with B-cell malignancies," said Linda Neuman, M.D., Vice President, Clinical Development of Sunesis. "Additionally, as a non-covalent BTK inhibitor with a distinct reversible binding profile, SNS-062 may overcome the acquired resistance to ibrutinib and other covalent clinical-stage BTK inhibitors resulting from a point mutation (C481S) in the active site."

"The safety profile, extent of SNS-062 exposure, and duration of BTK inhibition from these study results are encouraging and support our plans for a Phase 1B/2 study to assess safety and efficacy in patients with advanced B-cell malignancies after prior ibrutinib exposure, both with and without a BTK C481 mutation," said Daniel Swisher, President and Chief Executive Officer of Sunesis. "We are preparing an IND filing for this year as we work closely with our identified clinical sites for this study, and expect to begin dosing patients within the first half of 2017."

The reported data from this Phase 1A randomized, double-blind, placebo-controlled, single-dose study are from four sequential cohorts of 8 subjects each who were randomly assigned to receive progressively higher single oral administrations of SNS-062 at doses of 25, 50, 100, 200, and 300 mg (n=6 per cohort) or placebo (n=2 per cohort).

For the primary endpoint of safety in stage 1, investigators were blinded to treatment arm for assessment of relatedness. Overall, AEs were reported for 8 (33%) subjects who received SNS-062 and for 3 (38%) subjects who received placebo. In the unblinded stages 2 and 3 of the trial, a similar pattern and rate of AEs were observed. Overall, no obvious pattern of dose-dependent toxicity was observed. All AEs were transient and low grade. None of the AEs, laboratory abnormalities, or ECG or telemetry findings were considered clinically meaningful. No SAEs were reported.

SNS-062 was rapidly absorbed and had mean plasma half-life values across all dose cohorts of 6.9 to 17 hours. SNS-062 demonstrated rapid, profound (~100%), and prolonged inhibition of BTK at all dose levels support investigation of a twice-daily dosing regimen in B-cell malignancies with or without an acquired BTK resistance mutation.

Furthermore in stage 2, food had no impact on the extent of absorption or elimination of SNS-062, suggesting that it may be administered to patients without regard to food. In stage 3, SNS-062, similar to ibrutinib, is a sensitive substrate of CYP3A4 and administration with moderate/strong CYP3A4 inhibitors or inducers is not recommended.

About SNS-062

SNS-062 is a novel, second-generation BTK inhibitor, a class of kinase inhibitors that selectively inhibits the enzyme Bruton’s tyrosine kinase (BTK). This target mediates signaling through the B-cell receptor, which is critical for adhesion, migration, proliferation and survival of normal and malignant B-lineage lymphoid cells. Unlike other drugs in its class, SNS-062 binds non-covalently and reversibly to the BTK enzyme. Its binding profile along with improved PK/PD properties potentially provide SNS-062 an opportunity to address the leading acquired resistance to ibrutinib, a mutation in the enzyme’s binding site required for covalent binding. In preclinical studies, SNS-062 demonstrated potent activity against C481S mutated B-cell malignancies, and has been studied in healthy subjects in a completed Phase 1A, randomized, double-blind, placebo-controlled dose-ranging study to investigate the drug’s safety, pharmacokinetics, and pharmacodynamics. With the reported successful study outcome, SNS-062 is proceeding to a Phase 1B/2 study in patients with B-cell malignancies.

On December 5, 2016 Omeros Corporation (NASDAQ: OMER) reported that its small-molecule inhibitors against GPR174, an orphan G protein-coupled receptor (GPCR) narrowly expressed in immune cells and linked to cancers, substantially and statistically significantly boost levels of cytokines and reduce the population of a subset of T cells known as regulatory T cells (Tregs), both activities known to be important in cancer immunotherapy (Press release, Omeros, DEC 5, 2016, View Source [SID1234516917]). Based on these findings, the compounds being advanced by Omeros hold potential advantages over both chimeric antigen receptor (CAR) T-cell therapy and checkpoint inhibitors, each highly touted immunotherapies in development for the treatment of multiple cancers. Part of its orphan GPCR program, Omeros believes that the company alone has identified compounds that inhibit GPR174, and Omeros is establishing a broad patent position directed to any GPR174 inhibitor for the treatment of cancer.

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

                  Schedule Your 30 min Free Demo!

In assays with human peripheral blood mononuclear cells (PBMCs) evaluating T-cell proliferation and survival following T-cell stimulation, Omeros discovered that small-molecule GPR174 inhibitors increase, with statistical significance, the levels of cytokines interleukin 2 (IL-2) and interferon gamma (IFN-γ) multiple-fold and nearly doubled interleukin 10 (IL-10). Moreover, GPR174 inhibition statistically significantly reduced by approximately 40 percent the population of Tregs, a subset of T-cells elevated in a large number of cancers. Data from GPR174 inhibition in mouse PBMCs are consistent with the human PBMC findings. Importantly, the compound effects were not observed in PBMCs derived from mice genetically lacking GPR174, indicating that the robust Omeros compound effects are the result of "on-target" interaction with the orphan receptor.

These results demonstrate that GPR174 inhibition potentiates the activity of effector T cells, which produce cytokines and are known to be integral to combatting cancer. Also, reducing the level of Tregs is a key objective in cancer immunotherapy, and high levels of Tregs in solid tumors frequently correlates with poor patient outcomes. In addition, signaling and mechanistic studies support that GPR174 suppresses anti-tumor activity, and inhibitors of GPR174 are expected to counteract that detrimental suppression.

"The data from Omeros’ GPR174 program are exciting, as they may lead to a new approach to increase immune function through simultaneous modulation of multiple immune cell subsets," stated Marc Gavin, Ph.D., Research Associate Member, Benaroya Research Institute. "GPR174 inhibition represents a wholly new mechanism in cancer immunotherapy, one that may offer the combined effects of cytokine stimulation and Treg reduction across a wide variety of cancers. This unique mechanism together with Omeros’ development of small-molecule inhibitors targeting GPR174 could provide meaningful benefits over other cancer immunotherapies and a significant advance for patients."

Based on the collective data, small-molecule inhibitors of GPR174 could provide a significant advance in cancer immunotherapy with meaningful potential advantages over current cancer immunotherapies in development, including CAR-T cell therapy and checkpoint inhibitors. Small molecules, unlike antibodies, can be formulated for oral, intravenous, intralesional and topical delivery, addressing some of the administration and procedural limitations of other immunotherapies. Small-molecule compounds, because of their shorter half-life than antibodies, should not have the same safety concerns (e.g., acute, life-threatening immune reactions due to extended duration of drug activity) associated with CAR-T cell and checkpoint therapies. GPR174 inhibitors act on both CD4 (helper) and CD8 (cytotoxic) T-cells and should not rely on the presence of specific tumor cell-surface receptors to be effective as do checkpoint inhibitors. GPR174 inhibitors represent a class of agents that could treat a broad range of cancers – the primary mechanistic limitation of a GPR174 inhibitor is expected to be a cancer cell that is recognized by the body’s immune system as fully "self," i.e., a cancer cell without mutation, which is quite rare.

"Omeros’ proprietary orphan GPCR program continues to generate new drug targets, and GPR174 is one of our current areas of focus," stated Gregory A. Demopulos, M.D., chairman and chief executive officer of Omeros Corporation. "The company’s development of GPR174 inhibitors and related target-based intellectual property position expands our therapeutic assets to oncology and, specifically, to the rapidly progressing and high-interest field of cancer immunotherapy."

About Omeros’ GPCR Program

Omeros uses its proprietary high-throughput CRA to identify small-molecule agonists and antagonists for orphan GPCRs, or GPCRs without known functionally active compounds (i.e., ligands), unlocking them to drug development. Omeros believes that it is the first to possess the capability to unlock orphan GPCRs in high-throughput, and that currently there is no other comparable technology. Omeros has screened a large number of orphan GPCRs against its small-molecule chemical libraries using its proprietary, high-throughput CRA technology. The CRA detects receptor antagonists, agonists and inverse agonists. Omeros has identified and confirmed sets of compounds that interact selectively with 54 of the 81 Class A orphan receptors linked to metabolic, cardiovascular and immunologic disorders, oncology, and disorders of the central nervous system. Omeros has also demonstrated that the CRA is effective in identifying ligands for Class B GPCRs.

GPCRs, which mediate key physiological processes in the body, are one of the most valuable families of drug targets. According to Insight Pharma Reports, GPCR-targeting drugs represent 30 to 40 percent of marketed pharmaceuticals. Examples include Claritin (allergy), Zantac (ulcers and reflux), OxyContin (pain), Lopressor (high blood pressure), Imitrex (migraine headache), Reglan (nausea) and Abilify (schizophrenia, bipolar disease and depression) as well as all other antihistamines, opioids, alpha and beta blockers, and compounds acting through serotonin and dopamine receptors.

The industry focuses its GPCR drug discovery efforts mostly on non-sensory GPCRs. Of the 363 total non-sensory GPCRs, approximately 240 have known ligands with nearly half of those targeted either by marketed drugs (46 GPCRs) or by drugs in development (about 82 GPCRs). There are approximately 120 orphan GPCRs, which have no known ligands. Without a known ligand, drug development for a given receptor is extremely difficult.