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Puma Biotechnology’s Neratinib Featured in Poster Presentations at the AACR Annual Meeting 2016

On April 20, 2016 Puma Biotechnology, Inc. (NYSE: PBYI), a biopharmaceutical company, reported that its drug candidate neratinib was highlighted in three poster presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 (Press release, Puma Biotechnology, APR 20, 2016, View Source [SID:1234511151]). The AACR (Free AACR Whitepaper) Annual Meeting was held at the Ernest N. Morial Convention Center in New Orleans from April 16 to April 20.

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Abstract Number 298: Amplification of mutant ERBB2 drives resistance to the irreversible kinase inhibitor neratinib in ERBB2-mutated breast cancer patients.

On Sunday April 17th, preclinical data was presented from studies performed to identify possible mechanisms of acquired resistance to neratinib therapy in ERBB2-mutated breast cancers. Data from three breast cancer patients in the ongoing phase II SUMMIT basket study of neratinib in ERBB2-mutant cancers who progressed following initial benefit from neratinib treatment identified a common genomic alteration in their tumors. More specifically, targeted exome sequencing of biopsies collected at time of disease progression revealed increased copy number of the ERBB2-mutant allele. In addition, enhanced receptor activity in the ERBB2-mutant cells correlated with increased formation of ERBB2/ERBB3 dimers, activation of the PI3K/AKT pathway and in vivo tumorigenic potential. Combined ERBB2 and ERBB3 inhibition efficiently inhibited phosphorylation of ERBB2/ERBB3 and cell proliferation. These studies indicate that amplification of mutated ERBB2 may promote increased ERBB2/ERBB3 dimerization, ERBB3 activation, and subsequent downstream signaling activation and that dual ERBB2/ERBB3 blockade may be a potential strategy to delay or prevent resistance to neratinib in ERBB2-mutant breast tumors.

Abstract Number 3140: Differential clonal selection in tumor tissue and cell-free DNA from a neratinib-treated refractory breast cancer patient harboring an activating ERBB2 (HER2) mutation.

On Tuesday April 19th, data was presented from a patient who was part of the ongoing Copenhagen Prospective Personalized Oncology (CoPPO) research program. This program aims to offer patients with limited treatment options targeted treatments against actionable driver mutations that have been identified in circulating cell free DNA in patients by using whole exome sequencing. The poster presented data from a patient with metastatic HER2-negative and estrogen receptor (ER)-positive breast cancer (Luminal A) who had previously been exposed to seven lines of chemotherapy as well as ER antagonists and aromatase inhibitors. After examination by whole exome sequencing, an activating mutation in ERBB2 (S310Y) was found and consequently the patient was treated with neratinib through a compassionate use program. Neratinib caused a rapid decrease in the allelic frequency of ERBB2 (S310Y) cell free DNA after 2 days, with a continuous decline during the next 7 days. Consistent with this neratinib treatment effect, MRI scans showed regression of the liver metastases. After 5 months on neratinib, the patient progressed with the appearance of brain metastases, which were surgically removed and subject to whole exome sequencing. The ERBB2 mutation observed in the liver metastasis could not be identified in the brain metastases. However, more than 300 new variants were exclusively identified in the brain metastases, among these ERBB3 as well as new PIK3CA, and ESR1 mutations, that were not present in the pre-treatment cell free DNA samples. In conclusion, neratinib was able to suppress an activating ERBB2 mutation in a heavily pre-treated ER+ breast cancer patient. However, refractory tumor clones harboring ERBB3, PIK3CA and ESR1 mutations developed in brain. The poster indicated that combining neratinib with fulvestrant or inhibitors of the HER3/PI3K/AKT/mTOR pathway might prove beneficial to overcome potential resistance mechanisms to therapy.

Abstract Number 4760: Efficacy of EGFR/HER2 duel-kinase inhibitors in PDX models harboring known and novel HER2-mutations.

On Wednesday April 20th, preclinical studies to better understand effects of HER2 mutations were presented. Patient-derived xenograft (PDX) tumor models representing colorectal, ovary, pancreas and endometrial cancers were evaluated in vivo, testing the antitumor activity of neratinib, afatinib, lapatinib, trastuzumab and T-DM1 administered on standard treatment regimens. In vivo treatment with neratinib or afatinib resulted in tumor growth inhibition in some tested models including ST022 (HER2G366R/R678Q) ovary and ST204 (HER2A386D) pancreas and tumor regressions were reported with either agent in the ST427 (HER2V777L) colorectal line. Neratinib or afatinib were also found active in one each of four tested endometrial models. Lapatinib, trastuzumab and T-DM1 were inactive in all tested HER2-mutant models.

The abstracts of the three presentations described above are available online at: View Source;DetailItemID=363#.Vusrr-IrKUk.

Preclinical Data Presented at American Association for Cancer Research (AACR) Annual Meeting Demonstrate Enhanced Therapeutic Benefit of Combining a PS-Targeting Antibody With Anti-PD-1 Therapy in Models of Triple Negative Breast Cancer (TNBC)

On April 20, 2016 Peregrine Pharmaceuticals, Inc. (NASDAQ:PPHM) (NASDAQ:PPHMP), a biopharmaceutical company focused on developing therapeutics to stimulate the body’s immune system to fight cancer, reported the presentation of preclinical study data demonstrating enhanced anti-tumor activity and immune activation for a combination of the preclinical bavituximab equivalent (ch1N11) and anti-PD-1 therapy in models of breast cancer including triple negative breast cancer (TNBC) (Press release, Peregrine Pharmaceuticals, APR 20, 2016, View Source [SID:1234511150]). Additionally, new analysis conducted using the nCounter PanCancer Immune Profiling Panel from NanoString Technologies further validated previously reported findings showing that the combination treatment induced a shift in the tumor microenvironment from immunosuppressive to immune active. This was evidenced by a distinct change in immune cell phenotypes, as well as an increase in immune activating cytokines and decrease in immunosuppressive cytokines. These study results, which were presented at the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, provide further support for Peregrine’s strategy of evaluating bavituximab in combination with a range of novel immuno-oncology (I-O) agents for the treatment of various cancers.

"These presented study results, particularly the significant increase in overall survival and immunity to tumor re-challenge seen with the treatment combination as compared to anti-PD-1 therapy alone, continue to strengthen our collection of translational and preclinical data supporting the potential for bavituximab to enhance the therapeutic impact of I-O agents in the treatment of cancer. In doing so, these data provide further rationale for our clinical strategy focused on studying bavituximab in combination with I-O agents targeting the PD-1/PD-L1 pathway in a range of cancers," stated Jeff T. Hutchins, Ph.D., Peregrine’s vice president, preclinical research. "With a wealth of supportive research in hand, we look forward to the continued advancement of our clinical collaborations with AstraZeneca, the National Comprehensive Cancer Network and Memorial Sloan Kettering Cancer Center, to further evaluate the therapeutic potential of bavituximab with novel I-O agent combinations."

Bavituximab is an investigational immunotherapy designed to assist the body’s immune system by targeting and modulating the activity of phosphatidylserine (PS), a highly immune-suppressive signaling molecule expressed broadly on the surface of cells in the tumor microenvironment. Peregrine’s PS signaling pathway inhibitor candidates, including bavituximab, reverse the immunosuppressive environment that many tumors establish in order to proliferate, while also activating immune cells that target and fight cancer. The preclinical equivalent of bavituximab, ch1N11, is used in animal model studies as a guide for clinical development.

As part of the study that was presented at AACR (Free AACR Whitepaper), researchers evaluated the combination of ch1N11 and anti-PD-1 therapy versus anti-PD-1 stand-alone therapy in two well-characterized murine models of TNBC (EMT-6 and E0771). Study data showed that the combination therapy significantly enhanced overall survival (p=0.0155) and was capable of mediating complete tumor regressions in a greater number of subjects compared to single agent treatments (60% vs. 20%). Data also demonstrated that animals receiving combination treatment had significant increases in tumor associated indicators of immune system activation, including CD45+, CD8+ and CD3+ T-cells. Importantly, the combination treatment led to a prolonged anti-tumor immune response which protected the animals that achieved a complete tumor regression against a re-challenge with the same E0771 TNBC model tumor cells. This sustained anti-tumor response demonstrates the ability of the combination treatment to trigger immune system memory and support adaptive immune responses against reemerging disease in this TNBC model. All study animals experienced no signs of adverse effects or weight loss following repeated doses of all therapeutic agents.

About Bavituximab: A Targeted Investigational Immunotherapy
Bavituximab is an investigational chimeric monoclonal antibody that targets phosphatidylserine (PS). Signals from PS inhibit the ability of immune cells to recognize and fight tumors. Bavituximab is believed to override PS mediated immunosuppressive signaling by blocking the engagement of PS with its receptors as well as by sending an alternate immune activating signal. PS targeting antibodies have been shown to shift the functions of immune cells in tumors, resulting in multiple signs of immune activation and anti-tumor immune responses.

Onconova Announces Novel Dual Targeting of ARK5 and CDK4/6 by Pre-clinical Compound, ON 123300, in Presentation at 2016 American Association of Cancer Research (AACR) Annual Meeting

On April 20, 2016 Onconova Therapeutics, Inc. (Nasdaq:ONTX), a clinical-stage biopharmaceutical company focused on discovering and developing novel products to treat cancer, reported the presentation of pre-clinical data for its first-in-class dual inhibitor of ARK5 and CDK4/6 at the 2016 AACR (Free AACR Whitepaper) Annual Meeting being held April 16-20, 2016 at the Ernest N. Morial Convention Center in New Orleans, LA (Press release, Onconova, APR 20, 2016, View Source [SID:1234511149]).

The poster presentation by investigators from the Icahn School of Medicine at Mount Sinai and the University of Nebraska Medical Center, compared the activity of ON 123300 to Ibrance (palbociclib), an FDA approved CDK4/6 inhibitor. The studies revealed that both compounds could inhibit CDK4/6 but only ON 123300 targeted ARK5, a kinase that regulates cancer cell metabolism by increasing glutamine uptake. Using colorectal cancer cells as a model, the researchers demonstrated that ARK5 inhibition by ON 123300 reduced glutamine uptake leading to diminished cellular ATP levels. Most notably, the inhibitory activity of ON 123300 on ARK5 and CDK4/6 resulted in the activation of programmed cell death, while selective CDK4/6 targeting by palbociclib merely resulted in cytostasis.

"This pre-clinical poster adds to previous data demonstrating the important differentiating features of ON 123300," said Manoj Maniar, Ph.D., Senior Vice President for Product Development at Onconova. "We believe that the inhibition of ARK5 and induction of apoptosis by ON 123300 represent an improvement over the current generation of CDK4/6 inhibitors."

A full copy of the AACR (Free AACR Whitepaper) poster titled, "Dual targeting of ARK5 and CDK4 pathways with ON 123300 as a therapeutic strategy," can be accessed by visiting "Posters" in the Investors and Media section of Onconova’s website at www.onconova.com.

OncoMed Presents Biomarker Research for Two Clinical Programs and Demcizumab Mechanism Data at the AACR Annual Meeting 2016

On April 20, 2016 – OncoMed Pharmaceuticals Inc. (NASDAQ:OMED), presented new biomarker research associated with its clinical programs for anti-RSPO3 (OMP-131R10) and vantictumab (anti-FZD7, OMP-18R5), as well as new preclinical mechanism-of-action data for demcizumab (anti-DLL4, OMP-18M21), at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) Meeting (Press release, OncoMed, APR 20, 2016, View Source [SID:1234511148]). All three presentations support ongoing clinical trials: anti-RSPO3 in a Phase1a/b trial in advanced solid tumor and colorectal cancer; vantictumab in a Phase 1b trial in pancreatic cancer; and demcizumab in a Phase 2 randomized study in first-line non-small cell lung cancer (NSCLC).

Based on preclinical work in patient-derived xenograft models that demonstrated a correlation between RSPO3 gene expression and anti-RSPO3 antibody efficacy, researchers at OncoMed set out to develop predictive biomarker assays. A CLIA-validated RSPO3 assay and a gene fusion detection workflow have both been developed and are now being deployed in OncoMed’s Phase 1a/1b dose escalation study of anti-RSPO3 in advanced solid tumors and in combination with FOLFIRI in metastatic colorectal cancer. Data detailing the validation of the predictive biomarker tests were presented in Abstract 404: "Development of a RSPO3 CLIA-validated assay as a predictive biomarker for response to anti-RSPO3 antibody treatment in patients with solid tumors".

Abstract 3129: "Predictive biomarker identification for response to vantictumab (OMP-18R5; anti-Frizzled) using primary patient-derived human pancreatic tumor xenografts" reviewed the identification of a distinct three-gene signature as a predictive biomarker for response to vantictumab combined with gemcitabine plus Abraxane. The three-gene biomarker has been validated in multiple patient-derived xenograft models and is now being utilized in an ongoing Phase 1b study of vantictumab in combination with standard-of-care therapy in patients with previously untreated Stage IV pancreatic cancer.

"Whenever possible, we strive to identify and validate possible predictive biomarkers that may be able to serve as companion diagnostics early on in the clinical development process. We are optimistic about the correlation observed between RSPO3 gene expression and anti-RSPO3’s efficacy and have begun using these assays in our ongoing Phase 1a/1b clinical trial," said Ann Kapoun, PhD, Vice President, Translational Medicine. "Vantictumab is another candidate that has proven amenable to the identification of predictive biomarkers. In addition to the three-gene pancreatic assay now being utilized in our Phase 1b clinical trial, last year we presented data on a six-gene biomarker for breast cancer, which is also now being assessed in the clinic. Data from our ongoing clinical trials of anti-RSPO3 and vantictumab are anticipated later in 2016."

Anti-DLL4 was evaluated in a series of NSCLC patient-derived xenografts to model demcizumab treatment in humans as a single-agent and in combination with standard-of-care carboplatin/pemetrexed. Data presented detailed anti-DLL4’s multi-pronged mechanism of action. Notch pathway and stem-cell related genes were down-regulated and a decrease in tumor-initiating cells was observed in anti-DLL4-treated tumors. Evidence of anti-DLL4’s vascular mechanism of action was affirmed by observations of up-regulation of endothelial-related genes, increases in blood vessel density and modification of hypoxia-related gene expression. Studies in humanized mice, created by engraftment of human hematopoietic stem cells with patient-derived xenograft tumors allowed researchers to observe an increase anti-DLL4’s immune activity in the presence of human lymphocytes, including up-regulation of human CD45+ cells and down-regulation of human CD33+ cells in tumors. Anti-DLL4 showed tumor growth inhibition and the combination with chemotherapy demonstrated improved activity. These findings provide additional evidence supporting demcizumab as a potential treatment for NSCLC. Data were presented in Abstract 4652: "Effects of anti-DLL4 treatment on non-small cell lung cancer (NSCLC) human xenograft tumors". A Phase 2 trial (DENALI) testing demcizumab in combination with chemotherapy is currently enrolling.

MEI Pharma Announces New Clinical Data from First-in-Human Study of ME-401, A Next Generation Oral PI3K Delta Inhibitor

On April 20, 2016 MEI Pharma, Inc. (Nasdaq: MEIP), an oncology company focused on the clinical development of novel therapies for cancer, announced new clinical data from a first-in-human study of MEI Pharma’s investigational drug candidate, ME-401, a next generation oral PI3K delta inhibitor (Press release, MEI Pharma, APR 20, 2016, View Source [SID:1234511147]). The data, presented today at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, suggest that ME-401 has an excellent pharmacokinetic (PK) and pharmacodynamic (PD) profile and the potential for an improved therapeutic window compared to other PI3K delta inhibitors, including the approved drug idelalisib (marketed as Zydelig), with a half-life that supports once-daily dosing.

A copy of the poster presentation, entitled, "Clinical Pharmacokinetics and Pharmacodynamics of ME-401, an Oral, Potent, and Selective Inhibitor of Phosphatidylinositol 3-Kinase P110δ, Following Single Ascending Administration to Healthy Volunteers," is now available at www.meipharma.com.

"PI3K delta is a class of drugs that has shown great promise in the treatment of B-cell malignancies, but with certain toxicities," said Daniel P. Gold, Ph.D., President and Chief Executive Officer of MEI Pharma. "We believe this provides an opportunity for a next-generation drug that can produce therapeutic responses at a safe, effective dose. Thus far, ME-401 has demonstrated all of the attributes we had hoped to see, including linear PK and on-target activity at very low concentrations. Now the goal of our upcoming Phase Ib study will be to show a large therapeutic window in cancer patients. We expect to dose the first patient in this study by the end of June and look forward to providing an update later this year."

The Phase I study was designed to assess the safety and tolerability of ME-401 after single ascending oral doses in healthy volunteers to select the most appropriate dose for further clinical evaluation. The open label study enrolled a total of 15 healthy volunteers in 10, 30, 60, 90 and 150 mg dose levels. ME-401 was well tolerated at all dose levels. One subject experienced two treatment-emergent adverse events that were considered drug-related: pain and headache, graded as mild, after a 60 mg dose.

The first-in-human study of ME-401 was conducted using Quotient Clinical’s Translational Pharmaceutics platform, which collected PK PD data immediately after each dose and allowed for real-time decision making and manufacturing between dose groups.

About ME-401

ME-401 (formerly PWT143) is an orally bioavailable, potent and selective inhibitor of phosphatidylinositol 3 kinase (PI3K) delta, a molecular target that has been shown to play a critical role in the proliferation and survival of certain hematologic cancer cells. ME-401 has a distinct chemical structure from other PI3K delta inhibitors, including idelalisib. Data presented at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in December 2012 demonstrated that ME-401 has superior pre-clinical activity compared to idelalisib. In March 2015, the U.S. Food and Drug Administration approved an Investigational New Drug application for ME-401 in B-cell malignancies. MEI Pharma expects to initiate a Phase Ib dose-escalation study of ME-401 in patients with relapsed refractory chronic lymphocytic leukemia (CLL) or follicular non-Hodgkin’s lymphoma (fNHL) in June 2016. The study is expected to enroll 42-84 patients at approximately 10 sites, with a starting dose of 60 mg.