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Acetylon Announces the Presentation of Preclinical Data at AACR Supporting the Use of Selective HDAC6 Inhibition to Modulate Chronic Lymphocytic Leukemia (CLL) Immunobiology

On April 20, 2016 Acetylon Pharmaceuticals, Inc., the leader in the development of selective histone deacetylase (HDAC) inhibitors for enhanced therapeutic outcomes, reported the presentation of data demonstrating that selective HDAC6 inhibition results in dosedependent increases in cell killing as a single treatment and in combination with Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib (Imbruvica), in patient-derived cell lines and preclinical models of chronic lymphocytic leukemia (CLL) (Press release, Acetylon, APR 20, 2016, View Source [SID:1234511168]). The studies were completed in collaboration with the laboratory of Javier Pinilla-Ibarz, M.D., Ph.D. at the Moffitt Cancer Center and the data were presented by Moffitt investigator, Eva Sahakian, Ph.D., in a poster presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans.

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In CLL, malignant B cells evade immune detection and lead to immune suppression. Recently, histone deacetylases (HDACs) have been shown to play an active role in the regulation of pathogenesis and immune-related pathways in CLL, although their role in B-cell receptor signaling remains unknown. Previously, aberrant overexpression of HDAC6 has been demonstrated in CLL cell lines and patient samples, and the authors sought to understand the mechanistic role of HDAC6 in CLL.

In collaboration with Acetylon scientists, the authors demonstrated that selective HDAC6 inhibition in CLL cell lines resulted in dose-dependent reductions in IL-10, a cytokine that regulates cell proliferation in CLL, as well as dose-dependent increases in cell death and a synergistic reduction in cell viability in combination with the BTK inhibitor, ibrutinib. Genetic knockdown of HDAC6 in CLL cells reduced expression of PD-L1 and other immune checkpoint markers, while increasing markers related to antigen presentation, including MHC II. Using an animal model of CLL, the authors then demonstrated with systemic administration of a selective HDAC6 inhibitor, a reduction in disease burden and increased survival in parallel with diminished expression of immune checkpoint markers on T-cells and B-cells, as well as a reduction in the number of immunosuppressive T-cells (Tregs).

"The preclinical findings presented at AACR (Free AACR Whitepaper) today demonstrate that selective HDAC6 inhibition may provide a successful combination immunotherapeutic strategy for the treatment of CLL," said Steven Quayle, Ph.D., Senior Scientist at Acetylon.
"Overall these data further support the broad versatility and immunomodulatory capability of our selective HDAC6 inhibitors in multiple drug combinations across a breadth of oncology applications, including hematologic as well as solid tumor indications," said Simon S. Jones, Ph.D., Senior Vice President, Head of Research and Preclinical Development at Acetylon.

Details of the presentation are as follows:

Date: Wednesday, April 20, 2016
Time: 7:30 AM -11:00 AM CDT
Location: Section 4
Session: Epigenetic Biomarkers and Therapies
Poster Board Number: 29
Abstract Number: 4485
Title: Regulation of chronic lymphocytic leukemia (CLL) immunobiology by histone deacetylase 6 (HDAC6)

About HDAC6 Inhibition
Ricolinostat (ACY-1215) and ACY-241 selectively inhibit the intracellular enzyme HDAC6, which leads to an accumulation of excess protein and in addition may disrupt critical proliferative signals in malignant cells. Disruption of these molecular processes in cancer cells triggers programmed cell death, called "apoptosis," with little or no effect on normal cells. Currently available HDAC drugs also affect the expression of numerous other genes in normal cells as well as cancer cells, which can result in side effects such as gastrointestinal dysfunction, lowered blood platelet levels and risk of hemorrhage and profound fatigue as well as potential for significant cardiac toxicity. Selective inhibition of HDAC6 is expected to reduce or eliminate these often-severe side effects associated with non-selective HDAC inhibition and may enable the development of optimized treatment regimens, including maximally effective combination drug therapies.

Molecular Pathways: Targeting the Cyclin D-CDK4/6 Axis for Cancer Treatment.

Cancer cells bypass normal controls over mitotic cell-cycle progression to achieve a deregulated state of proliferation. The retinoblastoma tumor suppressor protein (pRb) governs a key cell-cycle checkpoint that normally prevents G1-phase cells from entering S-phase in the absence of appropriate mitogenic signals. Cancer cells frequently overcome pRb-dependent growth suppression via constitutive phosphorylation and inactivation of pRb function by cyclin-dependent kinase (CDK) 4 or CDK6 partnered with D-type cyclins. Three selective CDK4/6 inhibitors, palbociclib (Ibrance; Pfizer), ribociclib (Novartis), and abemaciclib (Lilly), are in various stages of development in a variety of pRb-positive tumor types, including breast cancer, melanoma, liposarcoma, and non-small cell lung cancer. The emerging, positive clinical data obtained to date finally validate the two decades-old hypothesis that the cyclin D-CDK4/6 pathway is a rational target for cancer therapy.
©2015 American Association for Cancer Research (AACR) (Free AACR Whitepaper).

Mirna Therapeutics Announces Data Presentations at the Annual Meeting of the American Association for Cancer Research

On April 20, 2016 Mirna Therapeutics, Inc. (Nasdaq:MIRN), a clinical stage biopharmaceutical company developing a broad pipeline of microRNA-based oncology therapeutics, reported the presentation of new preclinical data at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans (Press release, Mirna Therapeutics, APR 20, 2016, View Source [SID:1234511166]). Researchers reported results in two poster presentations from experiments demonstrating that the Company’s lead microRNA therapeutic, MRX34 (miR-34), is synergistic with widely used cancer chemotherapies and next-generation tyrosine kinase inhibitors (TKIs).

"These in vitro data suggest that MRX34 has strong potential in combination with other cancer drugs," commented Miguel Barbosa, Ph.D., Mirna’s Chief Scientific Officer. "The ability of miR-34 to control multiple oncogenic pathways may overcome both primary and acquired resistance when used in combination with chemotherapy or TKIs."

In a poster (#4829) entitled, "miRNA Combination Therapy: in vitro Anticancer Synergy Between miR-34a Mimic and Cytotoxic Chemotherapy (CT) in NSCLC," researchers from Mirna and the University of Texas Health Science Center at San Antonio reported:

Synergistic anticancer effects were observed between miR-34a and platinum and other commonly used cytotoxic chemotherapy drugs, across a range of non-small cell lung cancer (NSCLC) cell lines with varying degrees of resistance.
The synergy observed suggests the potential for lower, less toxic doses of chemotherapy than currently used in the clinic when in combination with miR-34a.
In a second poster (#4814) entitled, "MicroRNA (miRNA) Combination Therapy: in vitro Anticancer Synergy Between miR-34a Mimic and Next Generation EGFR Tyrosine Kinase Inhibitors (TKIs) in NSCLC," researchers from Mirna reported:

Synergistic anticancer effects were shown between miR-34a and next-generation EGFR TKIs afatinib and rociletinib against a range of wild-type and mutant NSCLC cell lines. These results extend similar findings with the first-generation EGFR TKI erlotinib (Zhao et al, PLoS ONE 9(2):e89105).
Results support the potential of MRX34 and EGFR TKI combinations to overcome both primary and acquired resistance to EGFR TKIs in patients with NSCLC.
Mirna is a grant recipient of the Cancer Prevention Research Institute of Texas (CPRIT) for preclinical and clinical testing of microRNA and targeted drug combination therapies, and also of the National Institutes of Health (NIH) for the study of combination molecular therapies for lung cancer, as well as miRNAs in combination with standard of care chemotherapy.

The posters may be accessed from the Events & Presentations section of the Company’s website.

Kolltan Pharmaceuticals Presents Preclinical Data at the 2016 American Association for Cancer Research (AACR) Annual Meeting

On April 20, 2016 Kolltan Pharmaceuticals, Inc., a privately held clinical-stage company focused on the discovery and development of novel antibody-based drugs targeting receptor tyrosine kinases (RTKs) for use in oncology and immunology, reported the presentation of preclinical data relating to its KTN3379 and KTN0073 drug development programs at the AACR (Free AACR Whitepaper) Annual Meeting, taking place in New Orleans, Louisiana, April 16-20, 2016 (Press release, Kolltan Pharmaceuticals, APR 20, 2016, View Source [SID:1234511164]).

"This new preclinical data with KTN3379, along with emerging clinical results to date, support our plans to initiate a Phase 2 study in squamous cell tumors of the head and neck. Separately, we have identified KTN0073 as a unique antibody targeting the Met receptor tyrosine kinase with novel mechanisms of action. We are actively seeking a partner for the KTN0073 program to assist in the development of this novel and differentiated antibody drug candidate," stated Gerald McMahon, Ph.D., President and Chief Executive Officer of Kolltan.

"KTN3379 has shown broad anti-tumor activity in preclinical models, is potent, and binds to a unique epitope on ErbB3 or HER3. We presented scientific data supporting the potential use of KTN3379 for treatment of squamous cell tumors of the head and neck (HNSCC) and we continue to explore additional tumor indications where ErbB3 plays a role in driving the tumor or limiting therapies due to pathway resistance. The data presented shows anti-tumor activity of KTN3379 in HNSCC models in combination with the standard of care, cetuximab and radiation, and the anti-tumor activity correlated with several measurable parameters related to activation of the ErbB3 or EGF receptors. HNSCC cancer enriches for these parameters, and we are measuring these endpoints in ongoing and future clinical studies to guide patient selection and drug effectiveness," said Theresa LaVallee, Ph.D., Senior Vice President, Translational Medicine and Product Development at Kolltan.

Following are key data and results from the four poster presentations at AACR (Free AACR Whitepaper) relating to KTN3379 and KTN0073:

KTN3379
KTN3379 is an IgG1 monoclonal antibody that effectively locks ErbB3 in an inactive conformation by binding to a unique epitope, which may contribute to the antibody’s high potency and dual mechanism of action.

On Monday, April 18, "Combination of neuregulin with EGFR activation signatures predict activity of the anti-ErbB3 antibody KTN3379 in SCCHN" (Abstract Number 1196) was presented in a poster session.

The poster presentation reported the following data and results:

ErbB3 and its ligand neuregulin (NRG) are highly expressed in HNSCC and HER2, not EGFR, catalyzes ErbB3 activation in the presence of NRG;

Database analyses of HNSCC patient samples indicated that NRG expression is highly correlated with the expression of the EGFR ligands amphiregulin (AREG) and transforming growth factor α (TGFα), but not other EGFR ligands;

Using NRG-positive cell lines, KTN3379 anti-tumor activity correlated with the level of secreted AREG and TGFα and EGFR homodimer levels; and

The combined measurement of NRG with EGFR activation is a potential biomarker for KTN3379 activity.
On Tuesday, April 19, "Dual targeting of HER3 and PIK3CA has potent anti-tumor effects in pre-clinical models of HNSCC" (Abstract Number 2979) was presented in a poster session.

The poster presentation featured the following data and results:

Combined administration of KTN3379 and BYL719, a PIK3Cα inhibitor, enhanced anti-tumor activity over single agent administration in HNSCC models;

Inhibition of PI3K led to upregulation of ErbB3 activity;

ErbB3 upregulation attenuated PI3K inhibition suggesting ErbB3 is playing a role in resistance as a compensatory pathway; and
Dual targeting of the ErbB3 and PI3K pathways led to synergistic anti-tumor activity in vitro and in vivo.

On Tuesday, April 19, "Inhibition of heregulin-mediated ErbB3 signaling as a radiosensitization therapy for head and neck cancers" (Abstract Number 3053) was presented in a poster session.

The poster presentation reported the following data and results:

Two different HNSCC models of cetuximab resistance were generated using A431 and FaDu cell lines by exposure to increasing doses of cetuximab over 14 weeks;

In these models, ErbB3 levels and signaling were upregulated and KTN3379 effectively blocked elevated ErbB3 signaling and overcame the cetuximab resistance in the A431 and FaDu models;

In a panel of six HNSCC cell lines, KTN3379 enhanced the anti-tumor activity of radiation alone or the combination of radiation and cetuximab in most of the cell lines; and

These results suggest that combining KTN3379 with standard of care treatments in HNSCC, including cetuximab and radiation, may enhance anti-tumor activity and may overcome resistance.

KTN0073
KTN0073 is a humanized, IgG2 monoclonal antibody that inhibits Met-dependent tumor growth in preclinical models when activated by HGF, Met gene amplification, or mutations in exon 14.

On Tuesday, April 19, "An anti-Met IgG2 monoclonal antibody degrades both wild-type and exon 14 mutant MET receptor tyrosine kinase through a novel exon 14-independent mechanism and inhibits tumor growth" (Abstract Number 3835) was presented in a poster session.

The poster presentation highlighted the following data and results:
KTN0073 was identified as a potent anti-Met antibody with broad anti-tumor activity in HGF-driven and Met amplified tumors;

KTN0073 induced potent degradation of oncogenic exon 14-mutant Met, which propagates prolonged Met signaling due to a defect in receptor degradation;

Conversion of the antibody from IgG1 to IgG2 surprisingly resulted in enhanced anti-tumor activity in vitro and in vivo; and

KTN0073 demonstrated broad anti-tumor activity through multiple mechanisms of action in HGF-driven, Met-amplified, and exon 14-mutated tumors.

The posters are available on the Kolltan website.

About KTN3379
KTN3379 is a human monoclonal antibody designed to block the activity of ErbB3 (HER3), a receptor tyrosine kinase (RTK) that belongs to the epidermal growth factor receptor, or EGFR, family. ErbB3 is believed to be an important receptor regulating cancer cell growth and survival. ErbB3 is expressed in many cancers, including head and neck, breast, lung, gastric, and melanoma. Kolltan is conducting multiple clinical trials evaluating KTN3379 in the treatment of solid tumors (NCT02014909, NCT02456701, and NCT02473731).

Kolltan Pharmaceuticals Announces Presentations of Anti-KIT Antibody Preclinical Data at the 2016 American Association for Cancer Research (AACR) Annual Meeting

On April 20, 2016 Kolltan Pharmaceuticals, Inc., a privately held clinical-stage company focused on the discovery and development of novel antibody-based drugs targeting receptor tyrosine kinases (RTKs) for use in oncology and immunology, reported the presentation of preclinical data relating to its KTN0158 drug development program at the AACR (Free AACR Whitepaper) Annual Meeting, taking place in New Orleans, Louisiana, April 16-20, 2016 (Press release, Kolltan Pharmaceuticals, APR 20, 2016, View Source [SID:1234511162]). KTN0158 is a proprietary, clinical-stage, humanized anti-KIT IgG1 monoclonal antibody drug candidate that selectively and potently inhibits KIT and is being developed as a potential therapy for cancer and mast cell-related diseases.

"The compelling preclinical data that were presented at AACR (Free AACR Whitepaper) support our plans to evaluate KTN0158 in combination with T-cell checkpoint inhibitors in the clinic near-term. This expands our current clinical focus beyond gastrointestinal stromal tumors (GIST) and further broadens the opportunity to investigate the treatment of cancer patients through targeting KIT, with potential to affect immunosuppressive mast cells and myeloid cells. Developing innovative biologics with a focus on RTKs expressed on innate immune cells is an exciting new area for Kolltan with KTN0158 in clinical development," stated Gerald McMahon, Ph.D., President and Chief Executive Officer of Kolltan.

Rich Gedrich, Ph.D., Senior Director of Translational Medicine of Kolltan, added, "KTN0158 represents a novel approach to inhibit KIT on tumor cells by blocking the dimerization of the receptor through an allosteric mechanism. Previous preclinical data have shown significant anti-tumor activity in KIT-driven tumors such as GIST, targeted in our Phase 1 trial of KTN0158, and now the current findings in combination with anti-PD-1 and anti-CTLA4 antibodies support a second distinct approach to develop KTN0158 as an anti-cancer therapy."

Following are the key data and results from the two presentations at AACR (Free AACR Whitepaper) relating to KTN0158:
On Sunday, April 17, KTN0158 was highlighted as a novel experimental treatment approach for GIST in an oral presentation titled "Experimental Treatment Options for Gastrointestinal Stromal Tumors with Primary or Secondary Resistance to Tyrosine Kinase Inhibitors". The presentation reviewed previously disclosed preclinical data including:

An overview of KTN0158’s unique mechanism of action which inhibits KIT activation by blocking receptor dimerization; and
The preclinical activity of KTN0158 in GIST models with activating KIT mutations and also activity in dogs with spontaneous mast cell tumors driven by KIT activation.

On Tuesday, April 19, "Inhibition of KIT In Vivo Modifies Immune Cell Populations to Improve the Efficacy of Checkpoint Inhibitors in Syngeneic Mouse Tumor Models" (Abstract Number 4020), was presented in a poster session.

The poster presentation reported the following data and results:

Enhanced anti-tumor activity with the combination of a surrogate mouse anti-KIT monoclonal antibody with either anti-PD-1 or anti-CTLA4 monoclonal antibodies in several syngeneic mouse tumor models; and

Mechanistic studies showed a significant decrease in monocytic myeloid-derived suppressor cells (mMDSCs) in the tumor and in the spleen of the anti-KIT antibody treated groups. High levels of circulating mMDSCs have been associated with reduced survival in melanoma patients treated with ipilimumab or nivolumab.

The poster is available on the Kolltan website.

About KTN0158

KTN0158 is a proprietary, humanized monoclonal antibody designed using structure-based approaches to block the activation of KIT, an RTK that is expressed on many cancers and mast cells. There are currently no KIT-targeting antibodies on the market for any disease indication. In oncology, KIT is expressed in tumors such as GIST, melanoma, acute myeloid leukemia (AML), small cell lung cancer (SCLC), and others. Additionally, KIT is expressed in immune suppressive cells in the tumor microenvironment and thus may provide a novel combination treatment for immuno-oncology. Kolltan has initiated a Phase 1 study for the treatment of GIST and other KIT-expressing tumors (NCT02642016) and plans to move into combination studies with other targeted therapies and T cell checkpoint inhibitors.