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Ligand Pharmaceuticals Incorporated Message Board

long_vrts2 12 posts  |  Last Activity: Sep 23, 2016 3:56 PM Member since: Jul 12, 1999
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  • long_vrts2 long_vrts2 Sep 23, 2016 3:56 PM Flag

    Agree. I think CLDX is getting closer to becoming a commercial stage biotech, driven primarily by Glemba at this stage. The ESMO abstract on Glemba in Stage IV melanoma will be published on Wed 9/28, and next day (Thurs 9/29) AM and TD are at Leerink roundtable- unlikely this is pure coincidence, but we'll find out soon enough.

    Also, Glemba is being tested in a couple of indications where a 10%+ ORR would be sufficient for regulatory approval due to lack of effective treatment options. CLDX management needs to maintain a laser focus on prioritizing drug candidates that have the highest probability of going into commercial phase.

    Sentiment: Strong Buy

  • Oncotarget. 2016 Sep 15. doi: 10.18632/oncotarget.12048. [Epub ahead of print]
    Second-generation proteasome inhibitor carfilzomib enhances doxorubicin-induced cytotoxicity and apoptosis in breast cancer cells.
    Shi Y1,2,3, Yu Y3,4, Wang Z2,3,5, Wang H2,3,6, Bieerkehazhi S2,3,7, Zhao Y8, Suzuk L1, Zhang H2,3.
    Author information
    Proteasome inhibition is an attractive approach for anticancer therapy. Doxorubicin (DOX) is widely used for treatment in a number of cancers including breast cancer; however, the development of DOX resistance largely limits its clinical application. One of the possible mechanisms of DOX-resistance is that DOX might induce the activation of NF-κB. In this case, proteasome inhibitors could inhibit the activation of NF-κB by blocking inhibitory factor κB (IκB) degradation. Carfilzomib, a second-generation proteasome inhibitor, overcomes bortezomib resistance and lessens its side-effects. Currently, the effect of carfilzomib on breast cancer cell proliferation remains unclear. In this study, we exploited the role of carfilzomib in seven breast cancer cell lines, MCF7, T-47D, MDA-MB-361, HCC1954, MDA-MB-468, MDA-MB-231, and BT-549, representing all major molecular subtypes of breast cancer. We found that carfilzomib alone had cytotoxic effects on the breast cancer cells and it increased DOX-induced cytotoxic effects and apoptosis in combination by enhancing DOX-induced JNK phosphorylation and inhibiting DOX-induced IκBα degradation. The results suggest that carfilzomib has potent antitumor effects on breast cancer in vitro and can sensitize breast cancer cells to DOX treatment. DOX in combination with carfilzomib may be an effective and feasible therapeutic option in the clinical trials for treating breast cancer.

    Sentiment: Strong Buy

  • Oncotarget. 2016 Sep 17.

    Comprehensive adipocytic and neurogenic tissue microarray analysis of NY-ESO-1 expression - a promising immunotherapy target in malignant peripheral nerve sheath tumor and liposarcoma.

    Shurell E1, et al

    Immunotherapy targeting cancer-testis antigen NY-ESO-1 shows promise for tumors with poor response to chemoradiation. Malignant peripheral nerve sheath tumors (MPNSTs) and liposarcomas (LPS) are chemoresistant and have few effective treatment options.
    Using a comprehensive tissue microarray (TMA) of both benign and malignant tumors in primary, recurrent, and metastatic samples, we examined NY-ESO-1 expression in peripheral nerve sheath tumor (PNST) and adipocytic tumors. The PNST TMA included 42 MPNSTs (spontaneous n = 26, NF1-associated n = 16), 35 neurofibromas (spontaneous n = 22, NF-1 associated n = 13), 11 schwannomas, and 18 normal nerves. The LPS TMA included 48 well-differentiated/dedifferentiated (WD/DD) LPS, 13 myxoid/round cell LPS, 3 pleomorphic LPS, 8 lipomas, 1 myelolipoma, and 3 normal adipocytic tissue samples.
    NY-ESO-1 expression was exclusive to malignant tumors. 100% of myxoid/round cell LPS demonstrated NY-ESO-1 expression, while only 6% of WD/DD LPS showed protein expression, one of which was WD LPS. Of MPNST, 4/26 (15%) spontaneous and 2/16 (12%) NF1-associated MPNSTs demonstrated NY-ESO-1 expression. Strong NY-ESO-1 expression was observed in myxoid/round cell and dedifferentiated LPS, and MPNST in primary, neoadjuvant, and metastatic settings.
    We found higher prevalence of NY-ESO-1 expression in MPNSTs than previously reported, highlighting a subset of MPNST patients who may benefit from immunotherapy. This study expands our understanding of NY-ESO-1 in WD/DD LPS and is the first demonstration of staining in a WD LPS and metastatic/recurrent MxThese results suggest immunotherapy targeting NY-ESO-1 may benefit patients with aggressive tumors resistant to conventi

    Sentiment: Strong Buy

  • Cancer. 2016 Aug 17. doi: 10.1002/cncr.30258. [Epub ahead of print]
    Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies.
    Algazi AP1, et al
    Antibodies inhibiting the programmed death receptor 1 (PD-1) have demonstrated significant activity in the treatment of advanced cutaneous melanoma. The efficacy and safety of PD-1 blockade in patients with uveal melanoma has not been well characterized.
    Fifty-eight patients with stage IV uveal melanoma received PD-1 or PD-1 ligand (PD-L1) antibodies between 2009 and 2015 at 9 academic centers. Patients who were evaluable for response were eligible for the analysis. Imaging was performed every 12 weeks and at the investigators' discretion. Safety and clinical efficacy outcomes, including the best overall response, progression-free survival (PFS), and overall survival (OS), were retrospectively determined.
    Of 56 eligible patients, 48 (86%) had received prior therapy, and 35 (63%) had received treatment with ipilimumab. Three patients had an objective response to ipilimumab, and 8 had stable disease as their best response. Thirty-eight patients (68%) received pembrolizumab, 16 (29%) received nivolumab, and 2 (4%) received atezolizumab. Objective tumor responses were observed in 2 patients for an overall response rate of 3.6% (95% confidence interval [CI], 1.8%-22.5%). Stable disease (≥6 months) was observed in 5 patients (9%). The median PFS was 2.6 months (95% CI, 2.4-2.8 months), and the median OS was 7.6 months (95% CI, 0.7-14.6 months). There was no association between prior treatment with ipilimumab or liver-directed therapy and PFS or OS. Treatment was well tolerated, and only 1 patient discontinued treatment because of toxicity.
    PD-1 and PD-L1 antibodies rarely confer durable remissions in patients with metastatic uveal melanoma. Clinical trial enrollment should be prioritized in this population. Cancer 2016. © 2016 American Cancer Society

    Sentiment: Strong Buy

  • Catlin acquired 10,000 sh @ $2.8 on 9-2-16.

    Good to see CTO and CFO buying, but rest of senior management + board needs to step up and show leadership by buying shares.

    Sentiment: Strong Buy

  • Reply to

    Form 4 Filed...

    by mybestbehavior Sep 6, 2016 1:20 PM
    long_vrts2 long_vrts2 Sep 6, 2016 3:01 PM Flag

    It's a start, but management (across the board, CEO, CMO, CFO, all other SR VP's/VP's) have to start buying shares. That's what leadership is about, putting your money where your mouth is!

    Sentiment: Strong Buy

  • Reply to

    glemba in TNBC anecdote

    by whippersnapper65 Sep 4, 2016 11:23 PM
    long_vrts2 long_vrts2 Sep 6, 2016 2:48 PM Flag

    This is consistent with earlier trial data presented at ASCO'10 from the Glemba dose finding PI/II in unresectable, Stage III/IV melanoma pts:

    1. Patient 4191, advanced/metastatic, Tx at 1.5 mg/kg q2/3w: overall 88% shrinkage of tumor burden (100% disappearance of pancreatic lesion, 81% shrinkage of gastric lesion).

    2. Patient 2219, a/m, Tx at 1.0 mg/kg qw: overall 81% shrinkage of tumor burden, disappearance of thigh lesions.

    3. Skin rash of any severity occurs in ~60 % of pts; grade 3 or greater in ~20%. Skin rash appears to correlate with treatment outcome, with pts showing skin rash responding with greater efficacy.

    4. Best response rate was observed in pts with strong GPNMB expression:
    - any tumor shrinkage: 86% of pts
    - ORR; 29%
    - PR/SD of 12 wks or greater: 86%
    - median PFS: 4.9 mos (this is double the avg median PFS for adv/mts melanoma pts)

    Looking forward to PII trial results in high GPNMB expressing, unresectable adv/met Melanoma pts to be presented at ESMO'16.

    Sentiment: Strong Buy

  • Reply to

    ACT IV on SNO 2016 Preliminary Program Nov 18

    by fludyspnea Aug 30, 2016 11:05 AM
    long_vrts2 long_vrts2 Sep 1, 2016 3:00 PM Flag


    "I was a little surprised that the Opening Plenary session of SNO 2016 included a 15 min discussion of ACT IV, a "failed" study. There must be something in the sub group analysis."

    1. There is a growing consensus that EGFRVIII- with current SOC of Surg+TMZ+RT- is not a risk factor in the first 2 years for ndGBM pts. However, the OS curves start separating after 2 yrs and vIII+ becomes a risk factor at 2+ yrs into survival.

    2. Rindo PIII trial didn't show a significant difference in the first 2 yrs, which is consistent with #1 above, and vIII not being a risk factor in this time frame. However, there is the possibility that Rindo shows a survival benefit in yrs 3 and 4 (and beyond...) when vIII is a risk factor.

    3. Included in the primary outcome measure for Rindo PIII was OS out to 5 yrs (and possibly longer since survivors continue to receive Rindo on an expanded access basis):

    "Primary Outcome Measures:
    Overall Survival [ Time Frame: During treatment and every three months from end of treatment through end of study or approximately up to 5 years. ] "

    So it's possible that there is an OS advantage with Rindo at yrs 3, 4 and further out from the PIII, consistent with long-term survival of 10+ yrs from previous Rindo trials.

    4. Dr. Mark Gilbert at the Nat'l Cancer Institute is continuing to enroll (under expanded access) rGBM pts who receive Avastin + Rindo tx. So there is the possibility of clinical efficacy in the rGBM pts who are on Avas + Rindo combo treatment.

    5. How would all of this play into the regulatory picture regarding the FDA? Hard to say at this point, all we know is what Marucci stated during the last CC, which is that the conversation with the FDA is ongoing. I think public pressure from the GBM community could be a factor, but CLDX has been lacking in mounting a public campaign- as Sarepta has done, for example- to have an effect on the FDA in terms of looking at the whole clinical picture and not just mean OS at 2 yrs.

    Sentiment: Strong Buy

  • Leukemia. 2016 Aug 5. doi: 10.1038/leu.2016.186. [Epub ahead of print]
    Impact of prior treatment on patients with relapsed multiple myeloma treated with carfilzomib and dexamethasone vs bortezomib and dexamethasone in the phase 3 ENDEAVOR study.
    Moreau P1, Joshua D2, Chng WJ3, Palumbo A4, Goldschmidt H5, Hájek R6, Facon T7, Ludwig H8, Pour L9, Niesvizky R10, Oriol A11, Rosiñol L12, Suvorov A13, Gaidano G14, Pika T15, Weisel K16, Goranova-Marinova V17, Gillenwater HH18, Mohamed N18, Aggarwal S18, Feng S18, Dimopoulos MA19.
    Author information
    The randomized phase 3 ENDEAVOR study (N=929) compared carfilzomib and dexamethasone (Kd) with bortezomib and dexamethasone (Vd) in relapsed multiple myeloma (RMM). We performed a subgroup analysis from ENDEAVOR in patients categorized by number of prior lines of therapy or by prior treatment. Median progression-free survival (PFS) for patients with one prior line was 22.2 months for Kd vs 10.1 months for Vd, and median PFS for patients with ⩾2 prior lines was 14.9 months for Kd vs 8.4 months for Vd. For patients with prior bortezomib exposure, the median PFS was 15.6 months for Kd vs 8.1 months for Vd, and for patients with prior lenalidomide exposure the median PFS was 12.9 months for Kd vs 7.3 months for Vd. Overall response rates (Kd vs Vd) were 81.9 vs 65.5% (one prior line), 72.0 vs 59.7% (⩾2 prior lines), 71.2 vs 60.3% (prior bortezomib) and 70.1 vs 59.3% (prior lenalidomide). The safety profile in the prior lines subgroups was qualitatively similar to that in the broader ENDEAVOR population. In RMM, outcomes are improved when receiving treatment with carfilzomib compared with bortezomib, regardless of the number of prior therapy lines or prior exposure to bortezomib or lenalidomide.Leukemia advance online publication, 5 August 2016;

    Sentiment: Strong Buy

  • 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

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