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]).

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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.

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).

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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.

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.

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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.

On April 20, 2016 Medivation, Inc. (NASDAQ: MDVN) reported that data from an investigator-sponsored Phase II study of enzalutamide, an androgen receptor inhibitor, was presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2016 in New Orleans (Press release, Medivation, APR 20, 2016, View Source [SID:1234511146]). Preliminary data from a 12-patient subset demonstrated that treatment with enzalutamide alone resulted in potential immune-activating properties in patients with non-metastatic castration sensitive prostate cancer. The primary objective of the study was to evaluate the effect of a short-course of enzalutamide (three months) alone or in combination with a therapeutic cancer vaccine (PROSTVAC) on prostate specific antigen kinetics four months after completing enzalutamide. Data from 12 patients treated with enzalutamide alone was presented by the study’s lead investigator Ravi Madan, M.D., Principal Investigator of the Study and Clinical Director, Genitourinary Malignancies Branch at the National Cancer Institute.

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"Existing literature already suggests that inhibition of androgen receptor signaling can potentiate the function of the thymus and improve the profile of the immune system. These new data suggest that in prostate cancer patients, enzalutamide may also enhance immune cell killing of prostate cancer cells throughout the body," said David Hung M.D., Founder, President and Chief Executive Officer of Medivation. "We are very encouraged by these new data and believe that the potential immune-activating properties of enzalutamide warrant further investigation, particularly in combination with other immunotherapy agents."

The effect of enzalutamide on peripheral immune cells was measured in 12 patients who were receiving enzalutamide alone (160 mg daily for 84 days, without androgen deprivation therapy). Measurements of CD4+ and CD8+ T cells, T-regulatory cells (Treg), B cells, conventional and plasmacytoid dendritic cells (cDC, pDC), natural killer cells (NK), natural killer T cells (NKT), and myeloid derived suppressor cells (MDSC), as well as 114 subsets related to immune cell maturation and function, were evaluated. Peripheral blood mononuclear cells were also assessed for T cell receptor excision circles (TREC) to identity recent thymic emigrants and to determine changes in global gene expression.

Results showed that treatment with enzalutamide induced several notable alterations in immune cells consistent with general immune activation. These changes occurred early following treatment, and included an increase in NK cells, decreased frequencies of MDSCs with a suppressive phenotype and decreased frequencies of both CD4+ and CD8+ T-lymphocytes expressing the immune inhibitory checkpoint molecule CTLA4. Additionally, treatment with enzalutamide increased TREC levels by more than 75% in 7 of 12 patients compared with pre-therapy levels (p=0.012). Gene expression analysis of PBMCs corroborated these findings, showing that enzalutamide increased activation of interferon-gamma signaling and related immune-activating pathways. These immune-activating activities for enzalutamide support evaluating the drug in combination with a number of immune-stimulating treatments including checkpoint inhibitors and vaccines.

Enzalutamide is being developed through a collaboration between Medivation and Astellas. Enzalutamide, which is known by the brand name XTANDI, is currently approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

About XTANDI
XTANDI (enzalutamide) capsules is an androgen receptor inhibitor that blocks multiple steps in the androgen receptor signaling pathway within the tumor cell. In preclinical studies, enzalutamide has been shown to competitively inhibit androgen binding to androgen receptors, and inhibit androgen receptor nuclear translocation and interaction with DNA. The clinical significance of this MOA is unknown.

XTANDI is approved by the U.S. Food and Drug Administration for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC).

Important Safety Information
Contraindications XTANDI is not indicated for women and is contraindicated in women who are or may become pregnant. XTANDI can cause fetal harm when administered to a pregnant woman.

Warnings and Precautions
Seizure In Study 1, conducted in patients with metastatic castration-resistant prostate cancer (CRPC) who previously received docetaxel, seizure occurred in 0.9% of XTANDI patients and 0% of placebo patients. In Study 2, conducted in patients with chemotherapy-naive metastatic CRPC, seizure occurred in 0.1% of XTANDI patients and 0.1% of placebo patients. There is no clinical trial experience re-administering XTANDI to patients who experienced a seizure, and limited safety data are available in patients with predisposing factors for seizure. Study 1 excluded the use of concomitant medications that may lower threshold; Study 2 permitted the use of these medications. Because of the risk of seizure associated with XTANDI use, patients should be advised of the risk of engaging in any activity during which sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment.

Posterior Reversible Encephalopathy Syndrome (PRES) In post approval use, there have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES.

Adverse Reactions
The most common adverse reactions ( ≥ 10%) reported from two combined clinical studies that occurred more commonly ( ≥ 2% over placebo) in XTANDI patients were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, and dizziness/vertigo.

In Study 1, Grade 3 and higher adverse reactions were reported among 47% of XTANDI patients and 53% of placebo patients. Discontinuations due to adverse events were reported for 16% of XTANDI patients and 18% of placebo patients. In Study 2, Grade 3-4 adverse reactions were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to adverse events were reported for 6% of both study groups.

Lab Abnormalities: Grade 1-4 neutropenia occurred in 15% of XTANDI patients (1% Grade 3-4) and 6% of placebo patients (0.5% Grade 3-4). Grade 1-4 thrombocytopenia occurred in 6% of XTANDI patients (0.3% Grade 3-4) and 5% of placebo patients (0.5% Grade 3-4). Grade 1-4 elevations in ALT occurred in 10% of XTANDI patients (0.2% Grade 3-4) and 16% of placebo patients (0.2% Grade 3-4). Grade 1-4 elevations in bilirubin occurred in 3% of XTANDI patients (0.1% Grade 3-4) and 2% of placebo patients (no Grade 3-4).
Infections: In Study 1, 1% of XTANDI patients compared to 0.3% of placebo patients died from infections or sepsis. In Study 2, 1 patient in each treatment group (0.1%) had an infection resulting in death.

Falls (including fall-related injuries), occurred in 9% of XTANDI patients and 4% of placebo patients. Falls were not associated with loss of consciousness or seizure. Fall-related injuries were more severe in XTANDI patients, and included non-pathologic fractures, joint injuries, and hematomas.

Hypertension occurred in 11% of XTANDI patients and 4% of placebo patients. No patients experienced hypertensive crisis. Medical history of hypertension was balanced between arms. Hypertension led to study discontinuation in < 1% of all patients.
Drug Interactions

Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI. If co-administration is necessary, reduce the dose of XTANDI.

Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If co-administration is necessary, increase the dose of XTANDI.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs. If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.

For Full Prescribing Information for XTANDI (enzalutamide) capsules, please visit View Source

You are encouraged to report negative side effects of prescription drugs to the FDA.
Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

On April 20, 2016 Geron Corporation (Nasdaq:GERN) reported two poster presentations of data from non-clinical studies of the telomerase inhibitor, imetelstat, at the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting held in New Orleans, Louisiana (Press release, Geron, APR 20, 2016, View Source;p=RssLanding&cat=news&id=2158608 [SID:1234511145]). The first poster presentation described results that treating acute myeloid leukemia (AML) cell lines with imetelstat enhanced the effects of agents currently used for the treatment of AML. These data extend the rationale from prior non-clinical studies for the potential use of imetelstat in hematologic myeloid malignancies, such as AML, including in combination with standard therapies. The second poster presentation described results from non-clinical studies that provide further evidence of potential on-target mechanisms of telomerase inhibition by imetelstat underlying the reduction in platelets observed in previously conducted imetelstat clinical trials.

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The non-clinical studies were conducted by scientists at Janssen Research & Development, LLC and academic collaborators under the terms of the exclusive worldwide imetelstat license and collaboration agreement between Geron and Janssen Biotech, Inc. The poster presentations are available on Geron’s website at www.geron.com/presentations.

Impact of hypomethylating agents on hTERT expression and synergistic effect in combination with imetelstat, a telomerase inhibitor, in AML cell lines

AML cells express high levels of the telomerase catalytic subunit (hTERT). The expression of hTERT may be regulated through chemical changes to DNA, known as epigenetic modifications, such as the addition of a methyl group (methylation). Non-clinical studies by various cancer biologists have suggested a correlation between hTERT overexpression and hypermethylation in some cancers. Two compounds that are currently used for the treatment of AML, decitabine and 5-azacitidine, act as hypomethylating agents by inhibiting DNA methylating enzymes. Furthermore, these compounds have been reported to also reduce hTERT expression in AML cells in addition to inhibiting cell growth.

The aim of the non-clinical study in the AACR (Free AACR Whitepaper) poster was to determine whether combining hypomethylating agents and imetelstat can further inhibit AML cell viability in vitro compared with either agent alone. Combination treatment of the AML cell lines with either decitabine or 5-azacitidine followed by imetelstat, resulted in a greater reduction in cell viability or slower recovery of growth, respectively, than when a hypomethylating agent was administered alone. Similarly, when AML cell lines were treated with decitabine or 5-azacitidine followed by imetelstat, apoptosis, or cell death, increased in a dose-dependent manner.

Rusbuldt J, et al. 2016 AACR (Free AACR Whitepaper)

Myelosuppression in patients treated with the telomerase inhibitor imetelstat is not mediated through activation of toll-like receptors

Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns to trigger innate immune responses. For example, synthetic, single-stranded oligonucleotides with certain properties characteristic of bacteria and virus genomes activate the innate immune response through TLR9 signaling. In addition, TLR activation has been associated with lipopolysaccharide-induced thrombocytopenia in animal models.

The aim of the non-clinical study in the AACR (Free AACR Whitepaper) poster was to test a recent hypothesis that the thrombocytopenia observed in patients with myeloproliferative neoplasms (MPN) treated with imetelstat might occur through off-target effects by binding to and activating TLRs, such as TLR9. Results from the study suggest that the thrombocytopenia associated with imetelstat is not likely to be driven via interactions with TLRs. First, the oligonucleotide imetelstat is shorter and lacks certain features in its sequence required to activate TLR9. Second, in an assay for TLR activity, treatment with imetelstat at clinically relevant concentrations had no stimulatory effect on the majority of TLRs tested, including TLR9. Although a small induction of TLR8 was observed in the assay, such activity was not believed to be relevant because the induction was substantially lower than the positive control used in the experiment, and TLR8 has not been reported to be associated with thrombocytopenia.

The poster also cites results from previous non-clinical studies which suggest potential on-target mechanisms of telomerase inhibition for the observed thrombocytopenia in patients treated with imetelstat. Since telomerase activity is required for the differentiation of megakaryocyte progenitors into mature platelet-producing cells, previous ex vivo studies used cells taken from MPN patients and healthy individuals to show that treatment with imetelstat decreases hTERT expression and inhibits telomerase activity, which is concurrent with blocking the terminal maturation of normal megakaryocyte precursors, reducing the number of mature megakaryocytes available to produce platelets. Other prior ex vivo studies also included in the poster showed that imetelstat selectively inhibits the proliferation of malignant megakaryocyte progenitors from patients with essential thrombocythemia compared to normal progenitors from healthy individuals, suggesting that imetelstat may regulate telomerase differently in malignant versus normal cells.

Baerlocher GM, et al. 2016 AACR (Free AACR Whitepaper)

About Imetelstat

Imetelstat (GRN163L; JNJ-63935937) is a potent and specific inhibitor of telomerase that is administered by intravenous infusion. This first-in-class compound, discovered by Geron, is a specially designed and modified short oligonucleotide, which targets and binds directly with high affinity to the active site of telomerase. Preliminary clinical data suggest imetelstat has disease-modifying activity by inhibiting the progenitor cells of the malignant clones associated with hematologic myeloid malignancies in a relatively select manner. Most commonly reported adverse events in imetelstat clinical studies conducted previously by Geron included fatigue, gastrointestinal symptoms and cytopenias. Patients in those studies also experienced elevated liver enzymes, which resolved to normal or baseline in the majority of patients after imetelstat treatment was withdrawn. Imetelstat has not been approved for marketing by any regulatory authority.

About the Collaboration with Janssen

On November 13, 2014, Geron entered into an exclusive worldwide license and collaboration agreement with Janssen to develop and commercialize imetelstat for oncology, including hematologic myeloid malignancies, and all other human therapeutics uses. Under the terms of the agreement, Geron received an upfront payment of $35 million and is eligible to receive additional payments up to a potential total of $900 million for the achievement of development, regulatory and commercial milestones, as well as royalties on worldwide net sales. Certain regulatory, development, manufacturing and promotional activities are being managed through a joint governance structure, with Janssen responsible for these activities.

Janssen is conducting two imetelstat clinical trials: a Phase 2 clinical trial in patients with intermediate-2 and high risk myelofibrosis (MF) and a Phase 2/3 clinical trial in patients with low and intermediate-1 risk myelodysplastic syndromes (MDS). For more information about these clinical trials, please visit www.clinicaltrials.gov.