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Celldex Therapeutics, Inc. Message Board

long_vrts2 13 posts  |  Last Activity: Aug 22, 2016 1:41 PM Member since: Jul 12, 1999
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  • Mol Cancer Ther. 2016 Aug 17. pii: molcanther.0921.2015. [Epub ahead of print]
    Bazedoxifene as a Novel GP130 Inhibitor for Pancreatic Cancer Therapy.
    Wu X1, Cao Y2, Xiao H2, Li C3, Lin J4.
    Author information
    The IL-6/GP130/STAT3 pathway is crucial for tumorigenesis in multiple cancer types, including pancreatic cancer and presents as a viable target for cancer therapy. We reported Bazedoxifene, which is approved as a selective estrogen modulator by FDA, as a novel inhibitor of IL-6/GP130 protein-protein interactions using multiple ligand simultaneous docking and drug repositioning approaches. STAT3 is one of the major downstream effectors of IL-6/GP130. Here, we observed Bazedoxifene inhibited STAT3 phosphorylation and STAT3 DNA binding, induced apoptosis, and suppressed tumor growth in pancreatic cancer cells with persistent IL-6/GP130/STAT3 signaling in vitro and in vivo. In addition, IL-6 but not INF-γ rescued Bazedoxifene-mediated reduction of cell viability. Bazedoxifene also inhibited STAT3 phosphorylation induced by IL-6 and IL-11, but not by OSM or STAT1 phosphorylation induced by INF-γ in pancreatic cancer cells, suggesting that Bazedoxifene inhibits GP130/STAT3 pathway mediated by IL-6 and IL-11. Furthermore, Bazedoxifene combined with paclitaxel or gemcitabine synergistically inhibited cell viability and cell migration in pancreatic cancer cells. These results indicate that Bazedoxifene is a potential agent and can generate synergism when combined with conventional chemotherapy in human pancreatic cancer cells and tumor Xenograft in mice. Therefore, our results support that Bazedoxifene as a novel inhibitor of GP130 signaling and may be a potential and safe therapeutic agent for human pancreatic cancer therapy.

    Sentiment: Strong Buy

  • Reply to

    New Glemba paper just published

    by fludyspnea Aug 17, 2016 11:56 PM
    long_vrts2 long_vrts2 Aug 18, 2016 10:19 PM Flag

    "Hopefully it will be quite a bit higher particularly in the BRAF mutation patients who have already been on a BRAF/MEK inhibitor. "

    There is evidence that GPNMB is an upstream activator of MEK/ERK pathways so sequential treatment with BRAF/MEK inhibitor first, followed by Glemba, will probably not produce an additive clinical response. Combination treatment (concurrently) with Glemba is more likely to have an additive effect, and I suspect this will be the next step in the clinical testing of Glemba in melanoma pts.

    Speaking of combination treatments: I ran into one of the CDX-1401 clinical trial investigators at a conference and he mentioned that CDX-1401 alone only produced modest clinical responses (which was already pretty evident to anybody who follows CLDX...). However, he said that it appears that in combination with checkpoint inhibitors or immune activators there is a more robust response. So of the 8 clinical trials with CDX-1401, IMO the ones where 1401 is used as monotherapy are not likely to advance to the next stage of testing, but combination treatments with checkpoint inhibitors/immune activators ( Ipi, Pembro, Varli, ID01 inhibitor, 301...) look better positioned to move to the next phase. CLDX needs to start nailing clinical trials, especially after Rintega flame out- it's not sufficient to have a subset of pts showing good responses and long-term survival, the overall trial stats need to pan out.

    Sentiment: Strong Buy

  • CLDX a collaborator on this project, manufactured 3BNC117 and did patient PK; not currently licensed, CLDX to license once Tx optimized (?) :

    Nature. 2016 Jun 22. doi: 10.1038/nature18929. [Epub ahead of print]

    HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption.

    Scheid JF1,2, Horwitz JA1, Bar-On Y1, Kreider EF3, Lorenzi JC1, Feldmann A4, Shimeliovich I1, Patel R1, Burke L5, Cohen YZ1, Witmer-Pack M1, Juelg B7, Keler T8, Hawthorne T8, Zingman B9, Gulick RM5, Pfeifer N4, Learn GH3, Seaman MS10, Klein F1,11,12, Schlesinger SJ1, Walker BD7,13, Hahn BH3, Nussenzweig MC1, Caskey M1.

    Interruption of combination antiretroviral therapy (ART) in HIV-1-infected individuals leads to rapid viral rebound. Here we report the results of a phase IIa open label clinical trial evaluating 3BNC117, a broad and potent neutralizing antibody (bNAb) against the CD4 binding site of HIV-1 Env1, in the setting of analytical treatment interruption (ATI) in 13 HIV-1-infected individuals. Participants with 3BNC117-sensitive virus outgrowth cultures were enrolled. Two or four 30 mg/kg infusions of 3BNC117, separated by 3 or 2 weeks, respectively, were generally well tolerated. The infusions were associated with a delay in viral rebound for 5-9 weeks after 2 infusions, and up to 19 weeks after 4 infusions, or an average of 6.7 and 9.9 weeks respectively, compared with 2.6 weeks for historical controls (p=

    Sentiment: Strong Buy

  • June 22, 2016
    Marinus Pharmaceuticals Doses First Subject in Phase 1 Clinical Trial for Ganaxolone IV Ganaxolone IV Program Aimed at Status Epilepticus Target Indication
    RADNOR, Pa., June 22, 2016 (GLOBE NEWSWIRE) -- Marinus Pharmaceuticals, Inc. (Nasdaq:MRNS), a biopharmaceutical
    company dedicated to the development of innovative therapeutics to treat epilepsy and neuropsychiatric disorders, today
    announced that it has dosed the first subject in its Phase 1 clinical trial of ganaxolone IV, an intravenous (IV) formulation of
    Marinus' CNS-selective GABA modulator, for the treatment of status epilepticus (SE). The study is designed to evaluate the A
    safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ganaxolone IV in healthy volunteers, with data anticipated in the second half of 2016.
    Albena Patroneva, M.D., chief medical officer of Marinus Pharmaceuticals, commented, "Status epilepticus is a life- threatening medical emergency associated with high mortality and limited treatments. Typically, single or combination IV antiepileptic drugs are used in an attempt to break the seizures, however there are approximately 45,000 patients in the U.S. who do not respond to treatment and progress to established SE. Our preclinical research suggests ganaxolone IV could be a promising therapeutic in this difficult to treat seizure disorder, especially after first-line benzodiazepine treatment fails to halt the seizures. We look forward to reporting the results on this Phase 1 study later this year."
    Christopher M. Cashman, chief executive officer of Marinus Pharmaceuticals, added, "Dosing the first subject with ganaxolone IV in SE is an important event for Marinus as we focus the development of ganaxolone on target patient populations where we believe there to be a strong mechanistic rationale for a therapeutic benefit with ganaxolone. Strategically, we believe that ganaxolone IV in combination with our convenient oral capsule and liquid formulations, has the potential to

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 Jun 21, 2016 2:02 PM Flag

    "not sure whether or not to read anything into this"

    The definition for "Disease control rate" that CLDX provided is the standard definition for DCR so I wouldn't read too much into this.

    "This small 38 patient study continues to attract significant interest"

    The increase to 124 sites with 65 investigators is significant, as investigators gravitate towards treatments where there is a reasonable probability of clinical benefit for the patients they enroll in a trial. This is consistent with the Glemba trial in advanced TN breast cancer patients where Glemba demonstrated clinical benefit. So Glemba has shown efficacy, the question is whether the trial(s) will hit the required stats, in TNBC, as well as other indications. The pivotal TNBC trial is open label so CLDX is aware of results as the trial progresses- the fact that they have expanded Glemba into other cancer indications, and continue to increase sites+investigators in those additional indications, suggest positive results at this stage of Glemba's clinical testing.

    Sentiment: Strong Buy

  • June 16, 2016
    Oncobiologics Announces First CTA Approvals For Global Phase 3 Clinical Program For ONS-3010 (Humira® Biosimilar)
    Clinical Program Designed to Enable Interchangeability with Humira in U.S.
    CRANBURY, N.J., June 16, 2016 (GLOBE NEWSWIRE) -- Oncobiologics, Inc. (NASDAQ:ONS), a clinical-stage biopharmaceutical company focused on identifying, developing, manufacturing and commercializing complex monoclonal antibody (mAb) biosimilar therapeutics, today announced that its Phase 3 clinical plan for ONS-3010 (Humira® biosimilar) has received the first of its European Union (EU) clinical trial authorization (CTA) approvals, including in the United Kingdom, Germany and Spain, for the biosimilarity study portion of the Phase 3 clinical program.
    The global Phase 3 clinical program for ONS-3010 is expected to include recruitment and treatment of patients in approximately 20 countries, including the United States and various member states of the EU. The program study design is based on input from multiple Health Authorities including the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA), and will include testing intended to enable interchangeability for Humira® in the United States. The Phase 3 program will be conducted in patients with moderate to severe plaque psoriasis and is anticipated to begin dosing patients later in 2016.
    “We are excited to move to this final clinical confirmatory stage to demonstrate that ONS-3010 is biosimilar to Humira,” said Kenneth Bahrt, M.D., Chief Medical Officer of Oncobiologics. “This study marks the beginning of our first Phase 3 program and is supported by positive data from our previous Phase 1 study of ONS-3010.”
    Oncobiologics Chairman and Chief Executive Officer Pankaj Mohan, Ph.D., added, “These CTA approvals are another important step for Oncobiologics as we move to this final clinical confirmatory stage to demonstrate that ONS-3010 is biosimil

    Sentiment: Strong Buy

  • BioDrugs. 2016 Jun;30(3):173-94. doi: 10.1007/s40259-016-0168-3.
    Future Therapeutics in Alzheimer's Disease: Development Status of BACE Inhibitors.
    Evin G1.
    Author information
    Alzheimer's disease (AD) is the primary cause of dementia in the elderly. It remains incurable and poses a huge socio-economic challenge for developed countries with an aging population. AD manifests by progressive decline in cognitive functions and alterations in behaviour, which are the result of the extensive degeneration of brain neurons. The AD pathogenic mechanism involves the accumulation of amyloid beta peptide (Aβ), an aggregating protein fragment that self-associates to form neurotoxic fibrils that trigger a cascade of cellular events leading to neuronal injury and death. Researchers from academia and the pharmaceutical industry have pursued a rational approach to AD drug discovery and targeted the amyloid cascade. Schemes have been devised to prevent the overproduction and accumulation of Aβ in the brain. The extensive efforts of the past 20 years have been translated into bringing new drugs to advanced clinical trials. The most progressed mechanism-based therapies to date consist of immunological interventions to clear Aβ oligomers, and pharmacological drugs to inhibit the secretase enzymes that produce Aβ, namely β-site amyloid precursor-cleaving enzyme (BACE) and γ-secretase. After giving an update on the development and current status of new AD therapeutics, this review will focus on BACE inhibitors and, in particular, will discuss the prospects of verubecestat (MK-8931), which has reached phase III clinical trials.

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 Jun 14, 2016 2:03 AM Flag

    "Rindo is dead unless CLDX figures what went wrong on the control arm. "

    True for ndGBM in ACTIV trial. However, the ReACT trial for relapsed patients is still ongoing as they follow long term survivors. If the absolute survival rate with Avastin+ Rindo exceeds the (well established) absolute survival with Avastin alone, then CLDX would be in position to re-open a discussion with the FDA regarding regulatory prospects for Rindo in relapsed GBM. Time- and survival rates- will tell...

    Sentiment: Strong Buy

  • Neuro Oncol. 2016 Jun 10. pii: now113. [Epub ahead of print]
    Bearing on positive results seen in ReACT w Bev+Rindo:

    EGFRvIII mutations can emerge as late and heterogenous events in glioblastoma development and promote angiogenesis through Src activation.
    Eskilsson E1, et al
    Author information
    Amplification of the epidermal growth factor receptor (EGFR) and its mutant EGFRvIII are among the most common genetic alterations in glioblastoma (GBM), the most frequent and most aggressive primary brain tumor.
    In the present work, we analyzed the clonal evolution of these major EGFR aberrations in a small cohort of GBM patients using a unique surgical multisampling technique. Furthermore, we overexpressed both receptors separately and together in 2 patient-derived GBM stem cell lines (GSCs) to analyze their functions in vivo in orthotopic xenograft models.
    In human GBM biopsies, we identified EGFR amplification as an early event because EGFRvIII mutations emerge from intratumoral heterogeneity later in tumor development. To investigate the biological relevance of this distinct developmental pattern, we established experimental model systems. In these models, EGFR+ tumor cells showed activation of classical downstream signaling pathways upon EGF stimulation and displayed enhanced invasive growth without evidence of angiogenesis in vivo. In contrast, EGFRvIII+ tumors were driven by activation of the prototypical Src family kinase c-Src that promoted VEGF secretion leading to angiogenic tumor growth.
    The presented work shows that sequential EGFR amplification and EGFRvIII mutations might represent concerted evolutionary events that drive the aggressive nature of GBM by promoting invasion and angiogenesis via distinct signaling pathways. In particular, c-SRC may be an attractive therapeutic target for tumors harboring EGFRvIII as we identified this protein specifically mediating angiogenic tumor growth downstream of EGFRvIII.

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 Jun 2, 2016 2:08 PM Flag


    There is speculation that this may have been a response by the FDA to the Eteplirsen situation. It appears that CLDX will be able to get reimbursement for the cost of Rintega Rx through its current expanded access program, but I don't think there will be a "profit" as would be the case from typical commercial distribution. Comment from RBC analyst re SRPT interpretation:

    "RBC Capital analyst Simos Simeonidis was the latest to weigh in on Sarepta Therapeutic (NASDAQ: SRPT) amid the FDA's expanded access guidance. He says this outlines a potential way out for the FDA as it could provide the drug to DMD community without approving right now.

    Sarepta commented, "The FDA documents released today lay out a potential path whereby eteplirsen could become available to DMD patients, at cost, without jeopardizing the integrity of the FDA approval process. Making a drug like eteplirsen available through an expanded access process was already possible and had been considered for a while, but many questions lingered, including process, timing, cost, reimbursement. Today's guidance by FDA helped answer a number of these questions. Most importantly, it provided a simple roadmap by which the drug could get to patients quickly, thus relieving the significant political pressure being felt by the agency, without FDA having to approve the drug prior to the completion of randomized controlled trials. Thus, we view this development as consistent with our thesis that eteplirsen will not be approved by FDA and as an incremental negative for SRPT"

    Sentiment: Strong Buy

  • For Immediate Release
    June 2, 2016
    Today, the U.S. Food and Drug Administration finalized its efforts to streamline the process used by physicians to request expanded access, often called “compassionate use,” to investigational drugs and biologics for their patients. As a physician, I understand the importance of being able to access investigational treatments for a patient when there are no other options to treat their serious disease or condition.
    Access to investigational treatments requires the active cooperation of the FDA, industry, and health care professionals in order to be successful. But we know that navigating that process can be challenging and time consuming, and we are committed to reducing the procedural burdens on physicians and patients whenever possible.

    One way we hope to make things simpler for physicians is to reduce the amount of time they spend filling out a request for access to an investigational drug. That’s why today we are releasing the final Individual Patient Expanded Access Investigational New Drug Application - Form FDA 3926. The new form can be used by physicians to request expanded access to investigational drugs for individual patients who suffer from serious or immediately life-threatening diseases and for whom no comparable or satisfactory alternative therapy is available. It is much shorter than the form previously used for individual patient expanded access requests and is designed specifically for these requests. It should take about 45 minutes for a physician to complete the new form. Along with the new form we are also releasing step-by-step instructions on how to complete it.

    We want the expanded access process to be as clear as possible. That is why the agency is also releasing two additional final guidance documents today. One is in a question and answer format and explains what expand access is, when and how to request expanded access, and the type of information that should be included in requests.

    Sentiment: Strong Buy

  • Amgen Gets CHMP's Positive Opinion To Extend Indication Of Kyprolis For Relapsed Multiple Myeloma Treatment
    Benzinga By R. Chandrasekaran
    May 27, 2016 12:09 PM
    Amgen (NASDAQ: AMGN) revealed that the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has adopted a favorable opinion to extend the current indication for Kyprolis. That meant it can be included in treatment in combination with dexamethasone alone for adult patients with multiple myeloma who have get a minimum of one prior therapy.

    The company's EVP of R&D, Sean Harper, commented, "In the first ever comparative Phase 3 head-to-head study of two proteasome inhibitors in relapsed multiple myeloma, Kyprolis in combination with dexamethasone nearly doubled progression-free survival compared to a current standard of care regimen. We are pleased that the CHMP has recognized these robust data with a positive opinion, and we look forward to ensuring approval of this extended indication of Kyprolis."

    Amgen said the CHMP positive opinion was based on data from the final stage head-to-head ENDEAVOR trial in which patients with multiple myeloma treated with Kyprolis plus dexamethasone achieved superior progression-free survival (PFS) of 18.7 months compared to 9.4 months in those receiving Velcade plus dexamethasone, (HR=0.53; 95 percent CI: 0.44,0.65 p

    The company also indicated the most common adverse reactions that happened in greater than 20 percent of patients in the Kyprolis arm were anemia, fatigue, diarrhea, thrombocytopenia, nausea, pyrexia, dyspnea, respiratory tract infection, cough and peripheral edema.

    The drug maker said the CHMP positive opinion would now be reviewed by the European Commission (EC). The company believes that if granted, the marketing authorization would be extended to include Kyprolis in combination with dexamethasone in the 28 member countries of the European Union, as well as Iceland, Lichtenstein and Norway.

    Sentiment: Strong Buy

  • Send to:
    Antimicrob Agents Chemother. 2016 May 23. pii: AAC.00647-16. [Epub ahead of print]
    In vivo Pharmacodynamic Target Assessment of Delafloxacin against Staphylococcus aureus, Streptococcus pneumoniae, and Klebsiella pneumoniae in the Murine Lung Infection Model.
    Lepak AJ1, Andes DR2.
    Author information
    1Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
    2Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI, USA William S. Middleton Memorial VA Hospital, Madison, WI, USA
    Delafloxacin is a broad-spectrum anionic fluoroquinolone under development for the treatment of bacterial pneumonia. The goal of the study was to determine the PK/PD targets in the murine lung infection model for S. aureus, S. pneumoniae, and K. pneumoniae.
    Four isolates of each species were utilized for in vivo studies: S. aureus (1 methicillin-susceptible, 3 methicillin-resistant), S. pneumoniae (2 penicillin-susceptible, 2 penicillin-resistant), K. pneumoniae (3 extended spectrum beta-lactamase producing, 1 wild-type). Minimum inhibitory concentrations (MICs) were determined using CLSI methods. A neutropenic murine lung infection model was utilized for all treatment studies and drug dosing was by subcutaneous route. Single dose plasma pharmacokinetics was determined in the mouse model after administration of 2.5, 10, 40 and 160 mg/kg. For in vivo studies, four-fold increasing doses of delafloxacin (range 0.03 to 160 mg/kg) were administered q6h to infected mice. Treatment outcome was measured by determining organism burden in the lung (CFU) at the end of each experiment (24 h). The Emax Hill equation was used to model the dose-response data. The magnitude of the PK/PD index AUC/MIC associated with net stasis and 1-log kill were determined in the lung

    Sentiment: Strong Buy

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