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Interim Phase 2 Data Demonstrate Robust Response Rate with Indoximod in Combination with Keytruda® (pembrolizumab) for Patients with Advanced Melanoma at AACR Plenary

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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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.

Nektar Therapeutics Presents New Preclinical Data for its Immuno-Oncology Programs at the American Association for Cancer Research (AACR) Annual Meeting

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.

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.

Kite Presents Promising Preclinical Data from KITE-585, a Fully Human Anti-BCMA CAR T-Cell Product Candidate at the 2017 American Association of Cancer Research (AACR) Annual Meeting

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]).

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.

Ignyta Announces New Data Highlighting Broad Potential of Both RXDX-106 and Entrectinib at the 2017 AACR Annual Meeting

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.

"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.

Cyclacel Presents Identification of Sensitive Target Indications and Synergistic Drug Combinations for Novel PLK1 Inhibitor CYC140

On April 4, 2017 Cyclacel Pharmaceuticals, Inc. (NASDAQ:CYCC) (NASDAQ:CYCCP) (Cyclacel or the Company), reported the presentation of preclinical data outlining the potential therapeutic utility of CYC140, a polo-like kinase (PLK) 1 inhibitor, for the treatment of esophageal cancer and acute leukemia (Press release, Cyclacel, APR 4, 2017, View Source [SID1234518455]). The findings were presented during the American Academy of Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, April 1-5, in Washington, D.C.

"We believe these findings further validate the potential utility of CYC140 and its selection as a clinical candidate," said Spiro Rombotis, President and Chief Executive Officer of Cyclacel. "CYC140 is a potent and selective inhibitor of PLK1, an oncogenic regulator of cell division. These preclinical data suggest that CYC140 can be targeted against esophageal cancer and acute leukemia. In addition, the data demonstrate the potential for CYC140 to be used in synergistic combinations with other targeted agents, including EGFR inhibitors and PI3K pathway inhibitors, to enhance cancer cell death or growth suppression. CYC140 was discovered and developed in-house, drawing on our strong scientific experience in cell cycle biology. Based on these results and the conclusion of IND-directed development we plan to make an Investigational New Drug submission for CYC140."

Esophageal cancer and acute leukemia were identified as highly sensitive cancer indications from a panel of 300 cancer cell lines and non-malignant comparators following short exposure to CYC140. CYC140 demonstrated good selectivity over non-malignant cell lines. Potent, dose-dependent antitumor activity of CYC140 was demonstrated in preclinical xenograft models of esophageal cancer and acute leukemia with tumor growth delay, tumor regression and cures observed.

In esophageal cancer cell lines CYC140 combined synergistically with EGFR inhibitors or PI3K pathway inhibitors and can also be combined with approved cytotoxics such as cisplatin. Consistent with PLK1 inhibition, CYC140 reduced phosphorylation of nucleophosmin, a PLK1 substrate, and caused accumulation of mitotic cells in vitro and in vivo.

The study concluded that CYC140 is a selective PLK1 inhibitor which preferentially induces growth inhibition and cell death in malignant versus non-malignant cells. Identification of several pharmacodynamic markers and demonstration of activity in a majority of malignant cell lines derived from acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and esophageal cancer support prospective clinical development of CYC140, alone and in potential combination with targeted agents.

Abstract: 4178
Title: The novel PLK1 inhibitor, CYC140: Identification of pharmacodynamic markers, sensitive target indications and potential combinations
Date/Time: Tues. April 4, 2017: 1 p.m. – 5 p.m. EDT
Location: Section 7, Poster Board 1
Session Title: Targeting Protein Kinases and DNA
Authors: Sylvie Moureau, Craig MacKay, Chiara Saladino, Elizabeth Pohler, Karin Kroboth, Jonathan Hollick, Daniella Zheleva, Sheelagh Frame, David Blake. Cyclacel Ltd, Dundee, United Kingdom
The abstract can be accessed through the AACR (Free AACR Whitepaper) website, www.aacr.org.

About PLK inhibition

Polo kinases were discovered by Professor David Glover, Cyclacel’s Chief Scientist. They are a family of enzymes that regulate cell cycle progression through mitosis or cell division. PLKs are part of the biological machinery that regulate spindle formation and activation of CDK/cyclin complexes during mitosis. Activity of the mitotic kinase PLK1 is strongly associated with cancer progression. Several studies have shown correlations between elevated PLK1 expression, histological grade and poor prognosis in several types of cancer. PLK1 may have a role in oncogenesis through its regulation of tumor suppressors, such as p53 and BRCA2. Inhibition of PLK1 by small molecules or siRNA has been shown to interfere with several stages of mitosis. PLK1 inhibition offers an opportunity to treat cancer with a targeted anti-mitotic approach.

About CYC140

Cyclacel employed high throughput screening, in silico screening and de novo ligand design approaches to discover multiple PLK1 inhibitor series. The lead series includes potent and highly selective PLK1 inhibitors with broad anti-proliferative activity across a range of tumor cell lines, which are highly active in xenograft models of human cancers when dosed orally. CYC140 was selected as a clinical candidate following optimization for drug-like properties, cellular activity and pharmacokinetic profile. CYC140 has recently completed IND-enabling studies.

A grant of approximately $3.7 million from the U.K. Government’s Biomedical Catalyst has supported IND-directed development of CYC140.