On April 4, 2017 Onconova Therapeutics, Inc. (Nasdaq: ONTX), a Phase 3 stage biopharmaceutical company focused on discovering and developing small molecule drug candidates to treat cancer, with a primary focus on Myelodysplastic Syndromes, reported promising pre-clinical data for first-in-class dual inhibitor of CDK4/6 + ARK5, as well as a Type 1 novel inhibitor of FLT3 and Src pathways as a novel strategy for Acute Myeloid Leukemia (AML) therapy at the 2017 AACR (Free AACR Whitepaper) Annual Meeting (Press release, Onconova, APR 4, 2017, View Source [SID1234518461]). The Company presented its findings in two poster presentations on April 3, 2017.

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ON 123300, an orally administered novel CDK4/6 + ARK5 inhibitor, exhibits potent antitumor activity in vivo: comparative studies with Palbociclib

ON 123300, a third-generation potent CDK4/6 inhibitor that also inhibits ARK5 with low nanomolar potency, was found to be as effective as Palbociclib (Pfizer’s Ibrance) in an Rb + ve xenograft model. Moreover, the molecule may have the potential advantage of reduced neutropenia when compared to Palbociclib. Both compounds decreased RBC and platelet counts, however in this model system, Palbociclib had a more prominent and statistically significant (P≤0.05) inhibitory effect on neutrophil counts when compared to ON 123300 (30.70 ± 3.55 vs. 45.10 ± 2.04).

"There is a need for next-generation CDK4/6 inhibitors such as ON 123300, given the limitations of second-generation compounds that depend on a second molecule for therapeutic use. We are particularly excited about ON 123300 because of its potential to act as a single agent, as a dual inhibitor of CDK 4/6 + ARK 5 and which could be suitable for indications that may not be amenable to Palbociclib-like compounds," said Dr. Ramesh Kumar, CEO of Onconova.

A full copy of the above AACR (Free AACR Whitepaper) poster can be accessed by visiting "Scientific Presentations" in the Investors and Media section of Onconova’s website.

Dual inhibition of FLT3 and Src pathways by ON 150030, a type 1 inhibitor, as a novel strategy for relapsed and refractory AML

Biological studies at the Icahn School of Mount Sinai reveal that ON 150030 specifically inhibits the growth of MV4-11 cells harboring the FLT3-ITD mutation (GI50: 10nM). Western blot analysis demonstrates that MAPK and PI3K/AKT pathways in these cells are inhibited with increasing dose of ON 150030. The JAK independent phosphorylation of STAT5 seen in the context of FLT3-ITD is also reduced in response to ON 150030. The poor survival rate among FLT3-ITD positive AML patients and the resistance associated with current treatment regimens highlight a need for a novel FLT3 inhibitor that will be effective in cells resistant to Quizartinib.

"We are excited by the positive data on these two preclinical compounds, which address dual targeting strategy to address difficult to treat diseases. These promising results underscore the depth of our clinical pipeline, which is led by rigosertib, an advanced Phase 3 stage innovation for the treatment of patients with myelodysplastic syndromes. Following the advancement of our late stage trials in 2016, rigosertib is positioned for multiple key milestones in 2017," concluded Dr. Kumar.

On April 4, 2017 NewLink Genetics Corporation (NASDAQ:NLNK), a biopharmaceutical company focused on bringing novel immuno-oncology therapies to patients with cancer, reported interim results from NLG2103, a Phase 2 study evaluating its IDO pathway inhibitor, indoximod, in combination with checkpoint inhibitors for the treatment of patients with advanced melanoma (Press release, NewLink Genetics, APR 4, 2017, View Source [SID1234518460]).

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An infographic accompanying this release is available at
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These data report on a cohort of 60 evaluable patients (including patients with ocular melanoma) who received the combination of indoximod plus pembrolizumab which demonstrated a 52% (31/60) ORR and a 73% (44/60) DCR. Patients with non-ocular melanoma achieved a 59% (30/51) ORR and an 80% (41/51) DCR. The combination was generally well tolerated with low rates of Grade 3 or higher adverse events. These data will be presented today in the Clinical Trials Plenary Session at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2017 Annual Meeting in Washington, D.C.

"These data are impressive and demonstrate the potential of this combination to improve response rates of the currently available therapy for patients with advanced melanoma. Importantly, our combination therapy was well tolerated without an appreciable increase in toxicity," said Dr. Yousef Zakharia, M.D., Assistant Professor of Medicine, Division of Hematology, Oncology and Blood & Marrow Transplantation at the University of Iowa and Holden Comprehensive Cancer Center, a leading investigator on the trial.

Nicholas Vahanian, M.D., President and Chief Medical Officer said, "These new data further underscore the potential for indoximod in combination with other agents. The ORR and DCR are highly encouraging and further validate indoximod as a promising IDO pathway inhibitor."

Charles J. Link, Jr., M.D., Chairman and Chief Executive Officer said, "Currently approved immunotherapies are transforming cancer treatment. We believe targeting the IDO pathway is key to enhancing the efficacy of existing and future treatment regimens. NewLink Genetics has two distinct IDO pathway inhibitors in development that represent separate and independent opportunities. We expect further clinical validation of the IDO pathway as an immuno-oncology target throughout 2017."

NLG2103 is a Phase 2 study evaluating the addition of indoximod to the standard of care checkpoint inhibitors approved for patients with advanced melanoma (pembrolizumab, ipilimumab, or nivolumab). The interim data represent a cohort of 60 evaluable patients who received indoximod plus pembrolizumab. Evaluable patients were defined as those having at least one on-treatment imaging study. The primary outcome measure of the trial is objective response rate (ORR) and secondary outcome measures include disease control rate (DCR) and evaluation of safety and tolerability.

Key findings:

The ORR, by site reported RECIST criteria, for all patients was 52% (31/60) with a 73% (44/60) DCR.
Patients with non-ocular melanoma achieved a 59% (30/51) ORR and a DCR of 80% (41/51).
The majority of responses reported have been durable.
The occurrence of Grade 3 or greater adverse events was low with no apparent increase for the combination over what would be expected with pembrolizumab alone.
About Indoximod
Indoximod is an investigational, orally available small molecule targeting the IDO Pathway. The IDO Pathway is one of the key immuno-oncology targets involved in regulating the tumor microenvironment and immune escape.

NewLink Genetics is currently evaluating indoximod in multiple combination studies for patients with various types of cancer. These include melanoma, acute myeloid leukemia, pancreatic cancer and prostate cancer.

On April 4, 2017 Nektar Therapeutics (Nasdaq: NKTR) reported five preclinical data presentations for its immuno-oncology programs made at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2017 (Press release, Nektar Therapeutics, APR 4, 2017, View Source [SID1234518459]). The presentations featured new preclinical data on NKTR-214, the Company’s immuno-stimulatory CD122-biased agonist, as well as on NKTR-255, the Company’s IL-15 therapeutic candidate.

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Stephen Doberstein, Ph.D., Nektar’s Senior Vice President and Chief Scientific Officer commented, "The preclinical studies presented at AACR (Free AACR Whitepaper) by both Nektar scientists and our academic collaborators highlight the unique mechanistic profiles of Nektar’s two novel cytokine therapies, NKTR-214 and NKTR-255, including their ability to stimulate multiple cancer-killing CD8+ T cell subtypes within the tumor micro-environment. These data showcase how Nektar’s technology can be leveraged to target the IL-2 and IL-15 pathways in new ways in order to stimulate the body’s immune system to fight cancer."

NKTR-214 is a CD122-biased agonist designed to grow specific cancer-killing T cells and natural killer (NK) cell populations in the body which fight cancer, which are known as endogenous tumor-infiltrating lymphocytes (TILs). NKTR-214 stimulates these cancer-killing immune cells in the body by targeting CD122 specific receptors found on the surface of these cancer-killing immune cells, known as CD8+ effector T cells and Natural Killer (NK) cells. NKTR-214 is currently in Phase 1/2 clinical development.

NKTR-255 is a memory T cell stimulating cytokine designed to engage the IL-15 pathway to induce long-term T cell activation and improve the quality of T cell memory response to treat cancer. Through optimal engagement of the IL-15Rα/IL-2Rγ receptor complex, NKTR-255 stimulates proliferation and survival of CD8+ T cells, natural killer (NK) cells and enhances formation of long-term immunological memory which may lead to sustained anti-tumor immune response.

Details of the five preclinical presentations made at AACR (Free AACR Whitepaper) are as follows:

Presenter: Seema Nagpal, M.D., Stanford University, Department of Neurology
Abstract 1598/Poster 6: "Single agent NKTR-214, an engineered IL2 pathway agonist, localizes in tumor tissue, increases immune infiltrates and prolongs survival in rodent (rattus) glioblastoma (GBM)"
Session: Cytokines: The First Modern Immunotherapies

NKTR-214 single agent provides durable responses as a single agent in an aggressive orthotopic rat brain tumor model.
Treatment of even very large tumors is effective with NKTR-214, prolonging survival in a significant proportion of animals; CD8+ T cells infiltrate into the brain tumors after NKTR-214 therapy.
The marked increase in survival in this aggressive rodent brain tumor model after treatment with single agent NKTR-214 suggests its potential benefit for the treatment of human malignant glioma.
Presenter: Michael J. McNamara, Ph.D., Earle A. Chiles Research Institute, Providence Portland Medical Center
Abstract 1604/Poster 12: "NKTR-214 Synergizes with Radiotherapy to Drive Tumor Regression"
Session: Cytokines: The First Modern Immunotherapies

NKTR-214 combines positively with radiation therapy which is a standard of care for multiple tumor types and is a readily available therapy.
Gene expression patterns reveal a strong T cell activation signature including up-regulation of tumor-killing granzymes and perforins.
Combined therapy increased the frequency of tumor-reactive CD8 T cells in the target (irradiated) tumors as measured by increased TCR ligation (Nur77-GFP+) and AH1-A5 tetramer staining.
Presenter: Giulia Parisi, Ph.D., Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles (UCLA)
Abstract 2671/Poster 30: "Antitumor activity of NKTR-214 in combination with Adopted Cell Transfer (ACT) in an aggressive murine melanoma"
Session: Immune Response to Hematopoietic Tumors: New Development in Tumor Immunology

NKTR-214 improves the antitumor activity of adoptive cellular therapy in an aggressive murine melanoma model.
Treatment with NKTR-214 + ACT robustly mobilizes T cells into the tumor where they durably persist.
The robust and long-lasting effect of NKTR-214 supports its potential use in combination with cell-based therapeutics.
Presenter: Samira Khalili, Ph.D., Nektar Therapeutics
Abstract 1617/Poster 25: "Mechanistic modeling of the pharmacokinetics, pharmacodynamics and receptor pharmacology of NKTR-214: A kinetically-controlled CD122 agonist for cancer immunotherapy"
Session: Cytokines: The First Modern Immunotherapies

NKTR-214 significantly favors occupancy at IL-2 receptor βγ compared to the IL-2 receptor αβγ.
NKTR-214 delivers a controlled, sustained, and biased signal through the IL-2 receptor complex.
Presenter: Peiwen Kuo, Ph.D., Nektar Therapeutics
Abstract 1603/Poster 11: "NKTR-255 engages the IL-15 pathway driving CD8 T cell survival and CD8 memory T cell proliferation"
Session: Cytokines: The First Modern Immunotherapies

NKTR-255 induces multiple memory CD8+ T cell subtypes, including effector, central and stem memory populations.
Single dose NKTR-255 results in sustained IL-15-mediated activity not achievable with conventional IL-15.
NKTR-255 has single agent ef­ficacy in the CT-26 lung metastatic model, demonstrating signifi­cant lung nodule inhibition.

On April 4, 2017 Kite Pharma, Inc. (Nasdaq:KITE) reported new data presentations from preclinical studies related to KITE-585, a fully human anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell product candidate for the treatment of multiple myeloma (MM) at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in Washington D.C (Press release, Kite Pharma, APR 4, 2017, View Source [SID1234518458]).

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In today’s oral presentation (Abstract #4979), "Development of KITE-585: A fully human anti-BCMA CAR T-cell therapy for the treatment of multiple myeloma," KITE-585 demonstrated potent in vitro and in vivo activity against MM cell lines. CAR T cells were active in the presence of soluble BCMA and also eradicated established MM tumors in mice. KITE-585 contains a proprietary linker with the CD28 costimulatory domain. This configuration resulted in polyfunctional activation and proliferation of T-cells in the presence of MM cell lines, with no evidence of tonic signaling in the absence of target cells.

In the poster presentation (Abstract #2135), "Selectivity and specificity of engineered T cells expressing KITE-585, a chimeric antigen receptor targeting B-cell maturation antigen (BCMA)," the selectivity of KITE-585’s novel single-chain variable fragment (scFv) for BCMA was assessed using Retrogenix cell microarray technology. The results demonstrated the specificity of KITE-585 for BCMA expressing target cells.

"These promising preclinical data presented at AACR (Free AACR Whitepaper) suggest the potential of KITE-585 to offer a one-time treatment to address the high unmet need in multiple myeloma, an incurable blood cancer," said David Chang, M.D., Ph.D., Executive Vice President, Research and Development, and Chief Medical Officer. "The roadmap developed for the clinical development and manufacturing expertise of axicabtagene ciloleucel will be invaluable as we accelerate KITE-585 into the clinic later this year."

About Multiple Myeloma

Multiple myeloma (MM) is a rare and aggressive cancer. In 2016, there were an estimated 30,330 new cases of MM and 12,650 disease-related deaths in the U.S. alone.1 Nearly 95,000 people are either living with, or in remission from, MM.2 Treatment is chronic for most patients, usually with multi-therapy combinations, and most patients will eventually relapse.3 The median overall survival for high risk disease is 24-36 months.4

About KITE-585

KITE-585 is an investigational therapy in which a patient’s T cells are engineered to express a chimeric antigen receptor (CAR) to target the B cell maturation antigen (BCMA), a protein expressed on the cell surface of multiple myelomas (MM), and redirect the T cells to kill cancer cells. Kite expects to file an investigational new drug application (IND) for KITE-585 and initiate a Phase 1 clinical trial of KITE-585 in 2017.

On April 4, 2017 Ignyta, Inc. (Nasdaq: RXDX), a biotechnology company focused on precision medicine in oncology, reported that preclinical data on RXDX-106 – which represents a novel class of immunomodulatory agents that appears to restore innate immunity in preclinical models via potent inhibition of the TYRO3, AXL and MER (or TAM) family of receptors – will be presented at the 2017 Annual Meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) in Washington D.C (Press release, Ignyta, APR 4, 2017, View Source [SID1234518457]). In addition, the company will also showcase its first ever data in hematological malignancies for entrectinib – an orally available, CNS-active tyrosine kinase inhibitor targeting tumors that harbor TRK, ROS1 or ALK fusions – in molecularly defined acute myeloid leukemia (AML). Entrectinib is currently being studied in a registration-enabling Phase 2 clinical trial known as STARTRK-2.

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"We continue to be excited by our pipeline progress, including the emerging preclinical profile of RXDX-106 and its potential to restore and enhance a patient’s immune response to cancer," said Jonathan Lim, M.D., Chairman and CEO of Ignyta. "Our preclinical data confirm TAM receptors as novel immuno-oncologic targets in the fight against cancer, highlighting both the single agent activity of RXDX-106, as well as a possible synergistic effect when combined with other immuno-oncology treatments such as checkpoint inhibitors. Furthermore, the preclinical data on entrectinib activity in AML highlight the rationale for studying entrectinib in molecularly defined hematological malignancies in a clinical setting, in addition to the ongoing clinical studies of entrectinib in solid tumors."

In the RXDX-106 data to be presented, researchers studied the activity of RXDX-106 in a commonly studied syngeneic mouse colon carcinoma model in matched immunocompetent and immunocompromised mice, finding that RXDX-106 had greater tumor growth inhibition in the immunocompetent animals, which suggested that RXDX-106 effects in this system were modulated by the immune system. Immuno-phenotypic modulation by RXDX-106 was also observed in the mouse model, including an increase in tumor infiltrating lymphocytes (TILs), an increase in the ratio of M1/M2 macrophages, and an increase in expression of CD69 and PD-1 on CD8 T Cells. In another syngeneic mouse model, RXDX-106 inhibited tumor growth as a single agent and demonstrated further tumor growth inhibition in combination with anti-PD-1 or anti-CTLA-4 antibodies, which was accompanied by increased levels of IFNɣ in the blood. In a separate preclinical investigation of RXDX-106 targets, AXL and MER fusion proteins were shown to independently act as oncodrivers and, therefore, may be viable therapeutic targets for patients harboring such molecular alterations. The preclinical data to be presented at the AACR (Free AACR Whitepaper) Annual Meeting suggest that RXDX-106 can act as both an anti-tumor immuno-modulator and TAM oncodriver inhibitor and support clinical development of RXDX-106 in a wide variety of cancers (Abstract number 4698; Abstract number 4191).

Researchers will also present new preclinical data investigating entrectinib as a potential treatment for patients with NTRK rearranged acute myeloid leukemias. Entrectinib treatment inhibited cell proliferation in vitro with sub-nanomolar EC50 values. In a mouse model, entrectinib treatment at clinically relevant doses resulted in tumor regression, which was accompanied by elimination of residual cancer cells from the bone marrow (Abstract number 5158). Based on these data, we intend to evaluaute entrectinib further in molecularly defined hematological malignancies.