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Celldex Therapeutics, Inc. Message Board

long_vrts2 76 posts  |  Last Activity: May 26, 2015 1:16 AM Member since: Jul 12, 1999
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  • long_vrts2 long_vrts2 May 26, 2015 1:16 AM Flag

    Agree. We may get more details on the FDA regulatory process for Rindo in vIII GBM during ASCO.

    Sentiment: Strong Buy

  • LGND projected commercial launch for MK-8931 in '18 (at the B of A Merrill Lynch Healthcare conference presentation on May 12 '15).
    Heard through the grapevine: MRK is planning commercial launch in late '18, confirming and specifying LGND's earlier projection. All of this implies continuing positive clinical trial for 8931 in AD, and bodes well for the future revenue prospects of LGND!

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 May 22, 2015 1:08 AM Flag

    The FDA has given Breakthrough Therapy Designation to Rindo, indicating that they have a v. positive view of this treatment and they want to facilitate its approval. The decision will come as a result of a dialogue with the FDA. Rindo approval in relapsed vIII GBM is a virtual lock imo, approval in ndGBM- if it were accorded at the same time as relapsed- would be conditional on the outcome of the current pivotal PIII trial.

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 May 22, 2015 12:58 AM Flag

    1. The title seems pretty self-explanatory, and also by logical extension the consequence of taking out vIII:

    "Pigment Epithelium-Derived Factor (PEDF) Expression Induced by EGFRvIII Promotes Self-renewal and Tumor Progression of Glioma Stem Cells."

    2. There is still the issue of why 15% of vIII GBM pts are alive and well (and cancer free) at 7+ years, when the median survival for vIII+ pts is 1.5 years, and there is no record of any pt living beyond 5 years (unless they received Rindo...). Hmmm...

    3. The approval for Rindo is just a question of time...Rindo will be a practice changing addition to the treatment protocol for vIII+ GBM, and none too soon!

    Sentiment: Strong Buy

  • 1. The incurability of cancer is due to cancer stem cells which renew and repopulate the tumor.
    2. Eliminating cancer stem cells would lead to a cure.
    3. This report shows that EGFRvIII is directly involved in GBM cancer stem cell self-renewal and tumor progression.
    4. Rindo eliminates EGFRvIII+ GBM cells: explains long-term survivors, cancer free even at 7+ years.
    5. This report will have significant implications regarding FDA approval of Rindo, pricing of Rindo treatment, and in the short term the impact of the Rindo ReACT trial results presentation at ASCO.

    PLoS Biol. 2015 May 20;13(5):e1002152. doi: 10.1371/journal.pbio.1002152. eCollection 2015.

    Pigment Epithelium-Derived Factor (PEDF) Expression Induced by EGFRvIII Promotes Self-renewal and Tumor Progression of Glioma Stem Cells.

    Yin J1, et al

    Author information

    Abstract
    Epidermal growth factor receptor variant III (EGFRvIII) has been associated with glioma stemness, but the direct molecular mechanism linking the two is largely unknown. Here, we show that EGFRvIII induces the expression and secretion of pigment epithelium-derived factor (PEDF) via activation of signal transducer and activator of transcription 3 (STAT3), thereby promoting self-renewal and tumor progression of glioma stem cells (GSCs). Mechanistically, PEDF sustained GSC self-renewal by Notch1 cleavage, and the generated intracellular domain of Notch1 (NICD) induced the expression of Sox2 through interaction with its promoter region. Furthermore, a subpopulation with high levels of PEDF was capable of infiltration along corpus callosum. Inhibition of PEDF diminished GSC self-renewal and increased survival of orthotopic tumor-bearing mice. Together, these data indicate the novel role of PEDF as a key regulator of GSC and suggest clinical implications.

    Sentiment: Strong Buy

  • CAMBRIDGE, Mass., May 14, 2015 (GLOBE NEWSWIRE) -- SAGE Therapeutics (SAGE) today announced that SAGE-547 demonstrated robust activity, with a 77 percent response rate in evaluable patients with super-refractory status epilepticus (SRSE), in a successfully completed Phase 1/2 clinical trial. SAGE-547 also demonstrated favorable tolerability and a benefit-risk profile supporting development in this acutely ill patient population. SRSE is a critical condition in which the brain is in a state of persistent seizure, where patients are placed in a medically induced coma in an attempt to stabilize them and where conventional and approved therapies fail to awaken the patients. Currently, there are no therapies specifically approved for SRSE.

    "We believe these results are unprecedented in the treatment of SRSE and have the potential to be profoundly meaningful for patients affected by this devastating disorder. We believe these data help validate our platform, our unique chemistry capabilities and our approach to drug development based on rare disease indications with high unmet needs and rapid development pathways," said Jeff Jonas, M.D., chief executive officer of SAGE.

    Stephen Kanes, M.D., Ph.D., chief medical officer of SAGE, added, "We are extremely pleased by these data, which demonstrate the potential for SAGE-547 as an interventional treatment for patients where all other treatments have failed. Importantly, SAGE-547 also showed clear pharmacodynamic activity as measured by continuous EEG in patients that had previously failed third-line treatment while burst-suppressed under general anesthesia. We would like to thank the patients, their families and the physicians that participated in this trial."

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 May 18, 2015 1:42 AM Flag

    See my reply to mbb above.

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 May 18, 2015 1:39 AM Flag

    I think Wall Street is waiting for the final survival data from ReACT, and more visibility from the Glemba pivotal trial and the PI/II Varli trials. As I posted before, I believe the ReACT survival data will improve as the trial approaches completion- this is based on the respective K-M survival curves for Avastin and Avastin + Rindo which was disclosed in Nov'14. I expect that the Glemba pivotal trial will also be successful, and that Varli will show a clinical benefit in combination with other treatments.

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 May 18, 2015 1:29 AM Flag

    We need more info, especially regarding what CLDX will be charging for an average course of Rindo. As I posted before, the BTD designation and improvement in survival will justify premium pricing, but we need to find out what the numbers will be.

    Sentiment: Strong Buy

  • Reply to

    long Vrts2 -Question on Rindo for frontline GBM

    by sp0rtakus May 15, 2015 2:00 PM
    long_vrts2 long_vrts2 May 18, 2015 1:22 AM Flag

    I think Rindo will show an approx 4 months survival benefit over standard of care in newly diagnosed GBM in ACTIV. The trial is powered to show a 3 month benefit, so there is a 1 month cushion to assure a statistically significant p

    Sentiment: Strong Buy

  • Reply to

    ARRY - long_vrts2

    by swissmilkcow May 15, 2015 1:56 AM
    long_vrts2 long_vrts2 May 18, 2015 1:12 AM Flag

    Agree that they have good momentum. Haven't looked at their science in awhile, I will check it out...

    Sentiment: Strong Buy

  • Endocr Relat Cancer. 2015 Jun;22(3):319-29. doi: 10.1530/ERC-14-0510.

    Carfilzomib is an effective anticancer agent in anaplastic thyroid cancer.

    Mehta A1, Zhang L2, Boufraqech M2, Zhang Y2, Patel D2, Shen M2, Kebebew E3.
    Author information

    Abstract
    Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies. Currently, there is no standard or effective therapy for ATC. Drug repurposing for cancer treatment is an emerging approach for identifying compounds that may have antineoplastic effects. The aim of this study was to use high-throughput drug library screening to identify and subsequently validate novel therapeutic agents with anticancer effects in ATC. We performed quantitative high-throughput screening (qHTS) in ATC cell lines (SW-1736, 8505C, and C-643), using a compound library of 3282 drugs. qHTS identified 100 compounds that were active in all three ATC cell lines. Proteasome inhibitors were one of the most active drug categories according to enrichment analysis. Of the three proteasome inhibitors screened, a second-generation proteasome inhibitor, carfilzomib, was the most active. Treatment of ATC cells with carfilzomib significantly inhibited cellular proliferation and induced G2/M cell cycle arrest and caspase-dependent apoptosis. Mechanistically, carfilzomib increased expression of p27 (CDKN1B) and decreased expression of the anti-apoptotic protein ATF4. Pretreatment with carfilzomib reduced in vivo metastases (lung, bone, liver, and kidney) and disease progression, and decreased N-cadherin expression. Carfilzomib treatment of mice with established, widely metastatic disease significantly increased their survival, without significant toxicity. Our findings support the use or clinical study of carfilzomib as a therapeutic option in patients with advanced and metastatic ATC.

    Sentiment: Strong Buy

  • There are some things which are worth going over a few times, and the ReACT trial and its results fall in that category- it appears that the implications of this trial have yet to sink in with some investors, a couple of the posters on this MB and possibly even AF:

    1. This was a 1:1 randomized, double-blinded and controlled (against active control Avastin) PII trial.

    2. Patients: Avastin naïve pts in 1st or 2nd relapse with EGFRvIII+ GBB, n=72. Status: accrual is complete, study follow-up continues on surviving pts.

    3. Endpoints: 6-month PFS (PFS6; primary), objective response rate (ORR), PFS, OS and safety.

    4. Results:
    - Safety: excellent safety profile, main adverse effect is skin redness at the injection site.

    - Primary endpoint, PFS6= 27% (9/33) vs. 11% (4/35) (p = 0.048, statistically significant).

    So Rindo more than doubled PFS at 6 months, and this was the primary endpoint: the trial has been successfully accomplished. If the trial were stopped right now, with no more follow-up, the results would be the same: a successfully completed trial. "The fat lady has sung", "It is over because it's over", "Game, set, match CLDX", call it whatever you want, this trial is in the bank! The FDA awarded Breakthrough Therapy Designation to Rindo in the wake of these results, and will give accelerated approval to Rindo in vIII+ GBM relapsed patients, and potentially newly diagnosed vIII+ GBM.

    - Secondary endpoint,: OS = 12.0 vs. 8.8 months (HR = 0.47, p = 0.0208)

    Rindo reduces the risk of death by more than 50% and this is statistically significant. There was an improvement in OS going from "early" interim results to "late" interim results, and there is a high probability that the OS will improve further in the "very late" results that will be presented at ASCO.

    So to be perfectly clear: the ReACT trial was successful, the results that will be presented at ASCO will make it even more successful, BTD has been awarded, next step will be FDA approval!

    Sentiment: Strong Buy

  • Median OS in Control= 15.9 mos; in Vandetanib Rx= 16.6 mos (Rindo= +5 mos survival benefit over these OS)

    Clin Cancer Res. 2015 Apr 24. pii: [Epub ahead of print]

    A multicenter, phase II, randomized, non-comparative clinical trial of radiation and temozolomide with or without vandetanib in newly-diagnosed glioblastoma patients.

    Lee EQ1, et al

    Abstract
    PURPOSE:
    Vandetanib, a tyrosine kinase inhibitor of KDR (VEGFR2), EGFR, and RET, may enhance sensitivity to chemotherapy and radiation. We conducted a randomized, non-comparative, phase II study of radiation (RT) and temozolomide (TMZ) with or without vandetanib in patients with newly diagnosed glioblastoma (GBM).
    EXPERIMENTAL DESIGN:
    We planned to randomize a total of 114 newly diagnosed GBM patients in a ratio of 2:1 to standard RT and TMZ with (76 patients) or without (38 patients) vandetanib 100 mg daily. Patients with age ≥ 18, Karnofsky performance status (KPS) ≥ 60, and not on enzyme-inducing antiepileptics were eligible. Primary endpoint was median overall survival (OS) from the date of randomization. Secondary endpoints included median progression-free survival (PFS), 12-month PFS, and safety. Correlative studies included pharmacokinetics as well as tissue and serum biomarker analysis.
    RESULTS:
    The study was terminated early for futility based on the results of an interim analysis. We enrolled 106 pts (36 in the RT/TMZ arm, 70 in the vandetanib/RT/TMZ arm). Median OS was 15.9 months [95% CI, 11.0 months, 22.5 months] in the RT/TMZ arm and 16.6 months [95% CI, 14.9 months, 20.1 months] in the vandetanib/RT/TMZ (log-rank p=0.75).
    CONCLUSIONS:
    The addition of vandetanib at a dose of 100 mg daily to standard chemoradiation in patients with newly diagnosed GBM or GS was associated with potential pharmacodynamic biomarker changes and was reasonably well tolerated. However, the regimen did not significantly prolong overall survival compared to the parallel control arm, leading to early termination of the study.

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 May 5, 2015 1:15 AM Flag

    It's too early to project revenues for CDX-301. There are at least 5 different indications where 301 could be used, and the list will probably grow as basic and applied clinical science catches up to this drug. I think CLDX will use a similar strategy for 301 that they have used for Rintega and Glemba- find the indication with the quickest readout and highest probability of trial success, and ultimately FDA approval, and then expand to other indications.

    Sentiment: Strong Buy

  • Bone Marrow Transplant. 2015 Apr 27. doi: 10.1038/bmt.2015.74. [Epub ahead of print]
    (This was a collaboration among Rockefeller, Harvard, Weill Cornell and CLDX)

    Efficacy and safety of CDX-301, recombinant human Flt3L, at expanding dendritic cells and hematopoietic stem cells in healthy human volunteers.

    Anandasabapathy N1, Breton G2, Hurley A2, Caskey M2, Trumpfheller C2, Sarma P2, Pring J2, Pack M2, Buckley N2, Matei I3, Lyden D3, Green J4, Hawthorne T4, Marsh HC4, Yellin M4, Davis T4, Keler T4, Schlesinger SJ2.

    Author information
    Abstract

    Fms-like tyrosine kinase-3 ligand (Flt3L) uniquely binds the Flt3 (CD135) receptor expressed on hematopoietic stem cells (HSCs), early progenitor cells, immature thymocytes and steady-state dendritic cells (DCs) and induces their proliferation, differentiation, development and mobilization in the bone marrow, peripheral blood and lymphoid organs. CDX-301 has an identical amino-acid sequence and comparable biological activity to the previously tested rhuFlt3L, which ceased clinical development over a decade ago. This Phase 1 trial assessed the safety, pharmacokinetic, pharmacodynamic and immunologic profile of CDX-301, explored alternate dosing regimens and examined the impact of rhuFlt3L on key immune cell subsets. Thirty healthy volunteers received CDX-301 (1-75 μg/kg/day) over 5-10 days. One event of Grade 3 community-acquired pneumonia occurred. There were no other infections, dose-limiting toxicities or serious adverse events. CDX-301 resulted in effective peripheral expansion of monocytes, hematopoietic stem and progenitor cells and key subsets of myeloid DCs and plasmacytoid DCs, with no clear effect on regulatory T cells. These data from healthy volunteers support the potential for CDX-301, as monotherapy or in combination with other agents, in various indications including allogeneic HSC transplantation and immunotherapy, but the effects of CDX-301 will need to be investigated in each of these patient populations.

    Sentiment: Strong Buy

  • Mol Cancer Ther. 2015 Apr 30. pii: molcanther.0028.2015. [Epub ahead of print]
    (PI trial of Dinaciclib + MK-2206 combiantion has started enrolling in pancreatic cancer indication)

    Combined Inhibition of Cyclin-Dependent Kinases (Dinaciclib) and AKT (MK-2206) Blocks Pancreatic Tumor Growth and Metastases in Patient-Derived Xenograft Models.
    Hu C1, Dadon T2, Chenna V3, Yabuuchi S4, Bannerji R5, Booher R5, Strack P5, Azad NA6, Nelkin BD7, Maitra A4.
    Author information
    Abstract

    KRAS is activated by mutation in the vast majority of cases of pancreatic cancer; unfortunately, therapeutic attempts to inhibit KRAS directly have been unsuccessful. Our previous studies showed that inhibition of cyclin-dependent kinase 5 (CDK5), reduces pancreatic cancer growth and progression, through blockage of the centrally important RAL effector pathway, downstream of KRAS. In the current study, the therapeutic effects of combining the CDK inhibitor dinaciclib (SCH727965; MK-7965) with the pan-AKT inhibitor MK-2206 were evaluated using orthotopic and subcutaneous patient-derived human pancreatic cancer xenograft models. The combination of dinaciclib (20 mg/kg, i.p., t.i.w.) and MK-2206 (60 mg/kg, p.o., t.i.w.) dramatically blocked tumor growth and metastasis in all eight pancreatic cancer models examined. Remarkably, several complete responses were induced by the combination treatment of dinaciclib and MK-2206. The striking results obtained in these models demonstrate that the combination of dinaciclib with the pan-AKT inhibitor MK-2206 is promising for therapeutic evaluation in pancreatic cancer, and strongly suggest that blocking RAL in combination with other effector pathways downstream from KRAS may provide increased efficacy in pancreatic cancer. Based on these data, an NCI-CTEP approved multicenter Phase I clinical trial for pancreatic cancer of the combination of dinaciclib and MK-2206 (NCT01783171) has now been opened.

    Sentiment: Strong Buy

  • 1. Cash position as of 3/31/15 is $360 million. At a current burn rate of $30 million/quarter, cash position is sufficient for 3 years, by which time CLDX will have 2 drugs on the market, Rintega and Glemba.

    2. Rintega: "we look forward to presenting updated data from the ReACT study..." at ASCO. CLDX has seen the data, the ASCO review committee has seen the data in the abstract and scheduled it as a platform presentation, the lead investigator will be presenting the results: I think it's fair to say that the data will be positive.

    3. Commercial launch of Rintega was mentioned twice in the PR: '...our ongoing efforts to prepare for the potential commercial launch of RINTEGA" and "RINTEGA and glembatumumab vedotin commercial planning costs in 2015". Rintega hit a grand slam in React and was awarded BTD by the FDA, and Glemba pivotal trial is open label and CLDX is aware of the trial results, so the fact that CLDX is preparing for commercial launch for both drugs is telling.

    4. The breadth of the pipeline, and its progress, is impressive: Rintega, Glemba, Varli, CDX-1401 and CDX-301 are moving forward at a steady clip.

    It appears that CLDX is hitting its stride, and about to turn the corner toward a commercial stage, profitable biotech. The future looks very bright for CLDX and its shareholders.

    Sentiment: Strong Buy

  • long_vrts2 by long_vrts2 Apr 28, 2015 1:59 AM Flag

    So let me guess: CLDN's gene therapy fails (big surprise there because every gene therapy so far has worked...) and AMGN's T-Vec virus-based melanoma treatment got a critical FDA staff review (another big surprise, given that the data going into the review were pretty tenuous to begin with and the FDA staff is paid to raise questions/concerns...), so CLDX is sailing along today until 11a when some genius struck his forehead in an overwhelming Eureka! moment. If CLDN's gene therapy failed and if AMGN is going to get quizzed over its T-Vec virus treatment, that MUST mean that Rintega will fail too. I must admit the logic is crystal clear...No matter that Rintega showed improved OS, PFS, % survival, decreased steroid use in relapsed vIII+ GBM (any of which endpoints would get Rintega FDA approval), no, let's not get the facts get in the way of a good panic response.
    No wonder some people get rich while others become (or stay) poor...

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 Apr 27, 2015 1:21 AM Flag

    Appreciate your posts. The more opinions we get, the better informed we are and the better investment decisions we will make. In fact I encourage you to post more frequently- if nothing else, it will increase the probability that you will get at least one thing right over all these years :-))
    As far as the good news with CLDX, those will keep coming. Drug development is survival of the fittest and involves good science, astute management and deep pockets- CLDX has all three.

    Sentiment: Strong Buy

CLDX
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