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Ligand Pharmaceuticals Incorporated Message Board

long_vrts2 16 posts  |  Last Activity: 17 hours ago Member since: Jul 12, 1999
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  • long_vrts2 long_vrts2 17 hours ago Flag

    If Glemba were already approved in another indication like TN breast cancer, then I would say yes. But for a first approval they may need to do another trial. The FDA is considering going to a "cancer target" approval model, i.e. Glemba would be approved for all GPNMB+ cancers, whatever the origin of that cancer may be (breast, skin, lung...), but that protocol hasn't been implemented yet.

    Sentiment: Strong Buy

  • The data published in the abstract are from earlier in the year (May'16), updated results will be provided at the time of presentation in October.

    1. Trial design:
    - Glemba, an ADC targeted against GPNMB which is expressed in approx 80% of melanomas.
    - Patient population: refractory to checkpoint inhibitor/BRAF inhibitor; 62 pts enrolled, 57 evaluated at time of abstract submission.
    - Primary endpoint: objective response rate (ORR).

    2. Results:
    - ORR = 14%, with 1 complete response and 7 partial responses.
    - 1 single time point PR (not included in ORR).
    - Stable disease = 46% (26 patients, duration 6-51 weeks with 11 ongoing as of 5/16).
    - adverse effects: consistent with an ADC, manageable.

    My take on these results:
    - Glemba ORR inferior to Keytruda/Opdivo immunotherapies, and targeted BRAF/MEK inhibitors.
    - comparable to Yervoy and IL- 2 which produce an ORR of 11-16% in similar melanoma patients.
    - Glemba has an advantage re toxicity because Yervoy produces life threatening effects in ~15% of pts plus long-term liver and GI problems, IL-2 very toxic during Tx to most organs and requires ICU setting in Tx.
    - superior to chemo which produces an ORR of ~8% in these pts (used mostly for symptomatic relief these days).

    - regulatory aspect: good probability of FDA approval based on efficacy, AE profile, mechanism of action and unmet need for advanced melanoma pts who progressed through checkpoint and BRAF/MEK inhibitors.

    - clinical indication: 2nd/3rd line intervention in BRAF mutant/GPNMB+ advanced melanoma pts with heavy tumor burden who progressed through BRAF/MEK inhibitors.

    Conclusion: Glemba has demonstrated clear evidence of efficacy in checkpoint/BRAF inhibitor refractory advanced melanoma patients. Relatively modest clinical market as 2nd/3rd line intervention in GPNMB+, advanced melanoma patients, CP/BRAF inh refractory. CLDX is testing Glemba+Varli in melanoma pts and this combo would need to produce a signify higher ORR for GV+V to become 1st line

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 Sep 26, 2016 1:06 AM Flag

    There is significant potential for CLDX in cancers which don't have effective treatment options.
    For example, Glemba is being tested in uveal melanoma. An ORR of 10% would probably be sufficient to get AA because there are no good treatment options currently for this cancer.

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 Sep 26, 2016 1:01 AM Flag

    "I'd really like to know more on their intended Varli strategy. "

    I think if Varli proves itself as an immune activator in combo with chemo, checkpoint inhibitors, vaccines, etc, in the current PI/II trials, then they will need to partner because the cost of testing the various permutations will be prohibitive for an R&D stage biotech like CLDX.

    On the other hand, big pharma is on the hunt for smaller bios with promising drug candidates. Wouldn't be surprised if we saw a Medarex 2.0, this time with CLDX, especially since BMY's trial with Opdivo as first line in NSCLC didn't pan out.

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 Sep 26, 2016 12:45 AM Flag

    Can't rule out the possibility of an oral presentation-yes, in that case we would have to wait until 10/5.

    Sentiment: Strong Buy

  • 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
    Abstract
    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

    BACKGROUND:
    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.
    MATERIALS METHODS:
    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.
    RESULTS:
    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.
    CONCLUSIONS:
    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
    Abstract
    BACKGROUND:
    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.
    METHODS:
    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.
    RESULTS:
    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.
    CONCLUSIONS:
    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

    fludyspnea,

    "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
    Abstract
    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
    Abstract
    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

    flu,
    "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

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