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Ligand Pharmaceuticals Incorporated Message Board

long_vrts2 63 posts  |  Last Activity: Feb 24, 2015 1:43 AM Member since: Jul 12, 1999
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  • 1. The BTD is for the treatment of all vIII GBM pts, newly diagnosed as well as recurrent.

    2. The path is set for CLDX to apply for accelerated approval for Rindo in recurrent vIII+ GBM based on ReACT, and it is a lock for expedited approval by the FDA. There is also the potential to apply for conditional approval of Rindo as frontline in ndGBM, since the BTD is also a recognition of Rindo efficacy/safety in newly diagnosed pts.

    3. There will be significant off-label use of Rindo in ndGBM if the FDA wants to see the results of ACTIV before full approval.

    4. The BTD allows for filing on a rolling basis, so as the results come in CLDX can forward them to the FDA without waiting for completing the whole package.

    5. The BTD designation will give CLDX the opportunity to negotiate premium Rindo pricing with payers, something that is also justified by the clinical efficacy reflected in improved OS, PFS, steroid use, etc. in a cancer that had one of the worst prognosis across the cancer spectrum.

    6. CLDX needs to define the rate of vIII+ in other cancers such as head-and-neck, lung and breast cancer. There are over 50,000 new cases every year of HNCC alone in the US, so even at a 10% vIII rate, that's 5,000 pts (and an equal number in EU).

    7, The successful progress of Rindo both in the clinical and regulatory arena indicates that CLDX knows what it's doing and bodes well for the prospects of the other candidates in the pipeline: Glemba, Varli, CDX-1401 and CDX-301.

    Sentiment: Strong Buy

  • Menopause. 2015
    A 7-year randomized, placebo-controlled trial assessing the long-term efficacy and safety of bazedoxifene in postmenopausal women with osteoporosis

    Palacios S1,et al on behalf of the Bazedoxifene Study Group.

    OBJECTIVE:
    In a 3-year randomized, double-blind, osteoporosis treatment study (N = 7,492), bazedoxifene 20 mg and bazedoxifene 40 mg significantly (P

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 Feb 18, 2015 12:42 AM Flag

    Rindo will be given in combination with Avastin in relapsed EGFRvIII GBM pts based on the ReACT trial protocol:

    1. Avastin revenue in relapsed GBM for US+EU+ROW (Japan, S. Korea, Australia, NZ) = ~$300 Million/yr

    2. Approx 30% of GBM pts are vIII+ so this would indicate a $100 Million/yr market for Rindo in relapsed pts.

    3. There are 2 factors that are harder to predict at this point: what will be peak penetration in the vIII population, and how much of an "efficacy premium" in pricing can Rindo command over Avastin, given that Rindo is showing a clear survival and PFS benefit compared to Avastin.

    After Rindo receives accelerated approval in relapsed GBM- followed by approval as first line in newly diagnosed GBM based on ACTIV trial- CLDX will need to re-position Rindo from a GBM immunotherapy to an anti-EGFRvIII cancer treatment to expand indications and include vIII+ head-and-neck, breast and lung cancers.

    (If you detected that I said "when" - not "if" - Rindo is approved, you are on the right track, because Rindo would've been approved if it provided only symptomatic benefit in relapsed GBM, let alone OS, PFS, reduced steroids, etc, and all this with zero toxicity!)

    Sentiment: Strong Buy

  • Br J Haematol. 2015 Feb 13. doi: 10.1111/bjh.13296. [Epub ahead of print]

    Phase Ib/II trial of CYKLONE (cyclophosphamide, carfilzomib, thalidomide and dexamethasone) for newly diagnosed myeloma.

    Mikhael JR1, Reeder CB, Libby EN, Costa LJ, Bergsagel PL, Buadi F, Mayo A, Nagi Reddy SK, Gano K, Dueck AC, Stewart AK.
    Author information

    1Mayo Clinic, Scottsdale, AZ, USA.

    Abstract

    Sixty-four transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) received carfilzomib (days 1, 2, 8, 9, 15, 16), 300 mg/m2 cyclophosphamide (days 1, 8, 15), 100 mg thalidomide (days 1-28) and 40 mg dexamethasone (days 1, 8, 15, 22) in 28-day cycles (CYKLONE regimen). Carfilzomib was dose-escalated to 15/20, 20/27, 20/36 and 20/45 mg/m2 to determine the maximum tolerated dose (MTD), which was 20/36 mg/m2 . Regardless of attribution, common Grade 3 or higher adverse events were lymphopenia (38%), neutropenia (23%) and anaemia (20%). All peripheral neuropathy (31%) was Grade 1 and considered most likely to be thalidomide-related. Common cardiac or pulmonary events of any grade in ≥5% of patients included dyspnoea (20%) and cough (6%). Overall (N = 64), 91% of patients achieved a best response of partial response or better across all cycles of treatment, including five patients with complete responses. At the MTD (n = 29), 59% of patients achieved a very good partial response or better after four cycles (primary end point). Stem cell collection was successful in all patients in whom it was attempted (n = 42). Progression-free survival and overall survival at 24 months was 76% and 96%, respectively (median follow-up of 17·5 months). CYKLONE appears highly efficacious in NDMM patients, with manageable toxicities.

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 Feb 11, 2015 1:18 AM Flag

    There are 55,000 cases of HNSCC in the US a year, so even a 10% EGFRvIII rate would mean more than a doubling in the current market size for Rindo. The technology is available to nail down conclusively the % of vIII+ cancer in HNSCC (and also BC and lung). The same group that published the paper above also found a correlation between vIII and worse outcome in HNSCC due to STAT activation:

    Oncogene. 2010 Sep 16;29(37):5135-45.

    Epidermal growth factor receptor variant III mediates head and neck cancer cell invasion via STAT3 activation.
    Wheeler SE1et al

    Abstract

    Epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) where aberrant signaling downstream of this receptor contributes to tumor growth. EGFR variant III (EGFRvIII) is the most commonly altered form of EGFR and contains a truncated ligand-binding domain. We previously reported that EGFRvIII is expressed in up to 40% of HNSCC tumors where it is associated with increased proliferation, tumor growth and chemoresistance to antitumor drugs including the EGFR-targeting monoclonal antibody cetuximab. Cetuximab was FDA-approved in 2006 for HNSCC but has not been shown to prevent invasion or metastasis. This study was undertaken to evaluate the mechanisms of EGFRvIII-mediated cell motility and invasion in HNSCC. We found that EGFRvIII induced HNSCC cell migration and invasion in conjunction with increased signal transducer and activator of transcription 3 (STAT3) activation, which was not abrogated by cetuximab treatment. Further investigation showed that EGF-induced expression of the STAT3 target gene HIF1-α, was abolished by cetuximab in HNSCC cells expressing wild-type EGFR under hypoxic conditions, but not in EGFRvIII-expressing HNSCC cells. These results suggest that EGFRvIII mediates HNSCC cell migration and invasion by increased STAT3 activation and induction of HIF1-α, which contribute to cetuximab resistance in EGFRvIII-expressing HNSCC tumors.

    Sentiment: Strong Buy

  • PLoS One. 2015 Feb

    Challenges in EGFRvIII Detection in Head and Neck Squamous Cell Carcinoma.
    Wheeler SE et al

    Abstract

    Head and neck squamous cell carcinoma (HNSCC) accounts for more than 5% of all cancers worldwide. The mortality rate of HNSCC has remained unchanged (approximately 50%) over the last few decades. Ubiquitous overexpression of wild type EGFR in many solid tumors has led to the development of EGFR targeted therapies. EGFR can be constitutively activated via several mechanisms including the truncated, EGFR variant III isoform (EGFRvIII). EGFRvIII lacks exons 2-7 and has been reported to be present in up to 20-40% of HNSCC. EGFRvIII has been shown to contribute to cetuximab resistance. The mechanisms leading to EGFRvIII expression in HNSCC are unknown. The present investigation was undertaken to determine the etiology of EGFRvIII in HNSCC.

    MATERIALS AND METHODS:
    Fixed HNSCC and glioma tissues were analyzed by fluorescence in situ hybridization for EGFR amplification. DNA and RNA from fresh frozen specimens were used to determine the presence of EGFRvIII transcripts and the mechanisms of expression via PCR, RT-PCR and RNA sequencing.

    RESULTS:
    Unlike glioma, EGFRvIII expression in HNSCC did not correlate with EGFR amplification. We found evidence of genomic deletion of the exon 2-7 in 6 of 7 HNSCC cases examined, however, the presence of genomic deletion did not always result in mRNA expression of EGFRvIII. RNA sequencing with automated alignment did not identify EGFRvIII due to microhomology between intron 1 and exon 8. RNA sequencing analyzed by manual alignment methods did not correlate well with RT-PCR and PCR findings.

    CONCLUSION:
    These findings suggest that genomic deletion as well as additional regulatory mechanisms may contribute to EGFRvIII expression in HNSCC. Further, large scale automated alignment of sequencing are unlikely to identify EGFRvIII and an assay specifically designed to detect EGFRvIII may be necessary to detect this altere

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 Feb 2, 2015 1:20 AM Flag

    "Do you suspect we will see a Rindo-Varli trial in the future?"

    Based on the clinical evidence with Rindo in glioblastoma, there is clear causality between a robust immune response to vIII and efficacy in GBM pts. So any intervention that boosts the immune response with Rindo treatment will also increase clinical efficacy- Varli would be a good candidate to test in this context, and Rindo+Varli combo trials are likely in the future,

    Sentiment: Strong Buy

  • Expert Opin Investig Drugs. 2015 Jan 21:1-10. [Epub ahead of print]
    (Delafloxacin is completing PIII trials and is licensed by LGND to Melinta Therapeutics).

    Delafloxacin for the treatment of respiratory and skin infections.

    Bassetti M1, Della Siega P, Pecori D, Scarparo C, Righi E.

    Author information

    Abstract

    Introduction: There has been a striking increase in the emergence of multidrug-resistant pathogens in recent times. Delafloxacin is a novel, broad-spectrum fluoroquinolone with antimicrobial activity against resistant Gram-positive, Gram-negative and anaerobic organisms. It has the potential to treat a variety of infections including complicated skin and skin structure infections and respiratory tract infections. Areas covered: In this review, the authors report the microbiological spectrum of activity of delafloxacin as well as its pharmacokinetic characteristics. They also report the results of recent studies investigating its safety and efficacy. Expert opinion: The profile of delafloxacin offers several advantages. Delafloxacin presents a broad spectrum of activity against pathogens involved in respiratory infections and complicated skin and skin structure infections (SSSIs), including methicillin-resistant Staphylococcus aureus. It has also shown activity against Gram-negative pathogens, such as quinolone-susceptible and -resistant strains of Escherichia coli and Klebsiella pneumoniae and quinolone-susceptible Pseudomonas aeruginosa. The availability of an oral formulation supports its use in sequential therapy. The efficacy and tolerability of delafloxacin have been demonstrated in Phase II clinical trials in comparison with moxifloxacin for respiratory infections and linezolid and vancomycin in SSSIs. Compared with other quinolones such as moxifloxacin, delafloxacin showed comparable efficacy and a lower rate of adverse effects. The results of new Phase III studies are awaited to confirm delafloxacin's future applications in the treatment of SSSIs.

    Sentiment: Strong Buy

  • Hum Vaccin Immunother. doi: 10.4161/21645515.2014.983002.

    The evolution of the EGFRvIII (rindopepimut) immunotherapy for glioblastoma multiforme patients.

    Paff M1, Alexandru-Abrams D, Hsu FP, Bota DA.

    Author information
    1a Department of Neurological Surgery ; University of California, Irvine ; Orange , CA USA.

    Abstract

    Glioblastoma Multiforme (GBM) is the most common type of brain tumor and it is uniformly fatal. The community standard of treatment for this disease is gross or subtotal resection of the tumor, followed by radiation and temozolomide. At recurrence bevacizumab can be added for increased progression free survival. Many challenges are encountered while trying to devise new drugs to treat GBM, such as the presence of the blood brain barrier which is impermeable to most drugs. Therefore in the past few years attention was turned to immunological means for the treatment of this devastating disease. EGFRvIII targeting has proven a good way to attack glioblastoma cells by using the immune system. Although still in development, this approach holds the promise as a great first step toward immune-tailored drugs for the treatment of brain cancers.

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 Jan 30, 2015 12:50 AM Flag

    This is definitely good news. Blackrock was one of the early investors in CLDX, so they already have a 2-3 fold return on their investment. If they are doubling down at these pps levels, it's not because they 're looking for an incremental 10% return.

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 Jan 28, 2015 1:33 AM Flag

    "What do you think the market potential is for Varli (including all possible line extensinos and combinations)??"

    Given your assumptions, In the neighborhood of $8 Billion at peak penetration.

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 Jan 27, 2015 1:46 AM Flag

    Yes, combination therapy may prove to be the most lucrative segment for Varli. The excellent safety profile of Varli means that it can be combined with a great number of complementary immunotherapies, chemotherapies and perhaps even radiation therapy (as is being tested in the Univ of Virginia trial already underway).

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 Jan 27, 2015 1:33 AM Flag

    Yes, demand for KLH has been growing rapidly... but it's still considered a commodity, with many suppliers pushing product to the market. However, if a shortage develops due to overharvesting, then we may see upward pressure on pricing.

    Sentiment: Strong Buy

  • Three implications relevant to CLDX and CDX-1127:

    1. Validation from independent research group of CDX-1127 mechanism of action.
    2. Combination therapy shows synergy over monotherapy with the CD27 antibody or the dendritic cell vaccine. The way CLDX could apply this combo would be 1127 plus 1401 which is CLDX's dendritic vaccine.
    3. Should create additional interest in combining 1127 w cancer immunotherapies.

    Int Surg. 2015 Jan-Feb;100(1):155-63.
    Anti-CD27 Antibody Potentiates Antitumor Effect of Dendritic Cell-Based Vaccine in Prostate Cancer-Bearing Mice.
    Wei SM1 et al

    Abstract

    In the current study, we investigated whether anti-CD27 monoclonal antibody can enhance the antitumor efficacy of a dendritic cell-based vaccine in prostate cancer-bearing mice. The overall therapeutic effect of a dendritic cell-based vaccine for prostate cancer remains moderate. A prostate cancer model was established by subcutaneous injection of RM-1 tumor cells into male C57BL/6 mice on day 0. After 4 days, tumor-bearing mice were treated with RM-1 tumor lysate-pulsed dendritic cells (i.e., dendritic cell-based vaccine), anti-CD27 monoclonal antibody, or a combination of RM-1 tumor lysate-pulsed dendritic cells with anti-CD27 monoclonal antibody. Mice were killed at 21 days after tumor cell implantation. Tumor size was measured for assessment of antitumor effect. Spleens were collected for analysis of antitumor immune responses. The antitumor immune responses were evaluated by measuring the proliferation and activity of T cells, which have the ability to kill tumor cells. The combination therapy with RM-1 tumor lysate-pulsed dendritic cells and anti-CD27 antibody significantly enhanced T-cell proliferation and activity, and significantly reduced tumor growth, compared with monotherapy with RM-1 tumor lysate-pulsed dendritic cells or anti-CD27 antibody. Our results suggest that combined treatment can strengthen antitumor efficacy by improving T-cell proliferation and activity.

    Sentiment: Strong Buy

  • Semin Hematol. 2015 Jan;52(1):31-37. doi: 10.1053/j.seminhematol.2014.10.002.

    Eltrombopag in Aplastic Anemia.

    Desmond R1, Townsley DM2, Dunbar C2, Young NS2.
    Author information
    Abstract

    The treatment of aplastic anemia is currently with immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and cyclosporine, to which two thirds of patients respond. However, a significant proportion of these responders relapse and many have persistent cytopenias. The management of these patients is challenging. Modifications to this standard approach using alternative immunosuppressive agents or adding hematopoietic cytokines such as granulocyte colony-stimulating factor (G-CSF) and erythropoietin (EPO) have not improved outcome. A recent trial has shown that eltrombopag, a thrombopoeitin mimetic, is efficacious in the treatment of patients with severe aplastic anemia (SAA) refractory to IST. There is evidence that this drug works by directly stimulating marrow stem and progenitor cells thereby promoting hematopoietic recovery in patients with bone marrow failure. Several trials are ongoing in our institution using this very promising drug in combination therapy in the upfront treatment of SAA, in IST-refractory SAA and in moderate disease.

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 Jan 20, 2015 1:05 AM Flag

    I think there is a very high probability for Rindo approval in relapsed vIII+ GBM:
    - there is a severe unmet need
    - Rindo is targeted immunotherapy
    - outstanding safety profile
    - validated mechanism of action
    - global support for Rindo from neuro-oncologists
    - the regulatory process involves an ongoing dialogue with the FDA, from IND to FDA approval, and I believe that CLDX has had positive feedback on Rindo from the FDA

    I think there is also a strong rationale for granting early approval for Rindo in newly diagnosed vIII+ GBM:
    - excellent safety profile in ndGBM, so there is negligible risk of AE to patients
    - there are several successful trials with long term survivors that supports efficacy
    - the largest trial in ndGBM, ACTIV, will be providing pivotal results in a reasonable time frame

    Another way to look at it: even if Rindo doesn't get early approval in ndGBM, pts will still end up receiving Rindo because they inevitable relapse on SOC in about a year. So sooner or later- and sooner would be better than later from a disease management point of view- vIII GBM pts will be on Rindo.

    Sentiment: Strong Buy

  • Leukemia. 2015 Jan 12. doi: 10.1038/leu.2015.10. [Epub ahead of print]

    CDK9 inhibition by dinaciclib potently suppresses Mcl-1 to induce durable apoptotic responses in aggressive MYC-driven B-cell lymphoma in vivo.

    Gregory GP1, Hogg SJ2, Kats LM2, Vidacs E2, Baker AJ2, Gilan O3, Lefebure M2, Martin BP2, Dawson MA3, Johnstone RW2, Shortt J4.

    From the report:

    "In conclusion, our findings indicate that CDK9 inhibition by dinaciclib is highly
    effective in aggressive MYC-driven lymphomas, including ‘poor-risk’ p53-deficient
    clones, via selective inhibition of critical MYC-targets including Mcl-1 (which is
    currently undruggable with existing BH3 mimetics).13,14 Our data suggest a linear and
    druggable dependency between MYC and Mcl-1 that is contingent on CDK9
    signaling. These findings are of particular interest in the context of a recent
    publication by Kelly et al. further highlighting the dependency of MYC-driven B-cell
    lymphoma to Mcl-1.15 Rapid clinical translation of CDK9 inhibitors to MYC dysregulated
    lymphoid malignancy should now be considered."

    Sentiment: Strong Buy

  • gerald_p already posted the ACTIII abstract earlier, but it's instructive to compare the critical endpoints with the trial results from the German Glioblastoma Network'14 study:

    1. The GGN study was led by Michael Weller and the goal was to model the enrollment for ACTIV. ndGBM pts were stratified according to vIII status and received SOC (surgery, radiotherapy and TMZ). The results of the trial were published in 2014.

    2, Rindo ACT III results vs SOC in GGN:
    - median overall survival: Rindo produced a 50% survival improvement (21.8 mos vs 14 mos).
    - % survival at 36-months: Rindo improved % survival by 50% (26% vs 17%).

    3. The last thing that I want to mention is the reported immune response of 85%. As I posted previously, the threshold for successful vaccine immunotherapy is 80%, so Rindo meets this criterion.

    Rindo continues to demonstrate robust clinical benefit- including significantly improved survival over current SOC- in newly diagnosed vIII+ GBM. The combination of efficacy and outstanding safety makes Rindo an optimal candidate for frontline treatment in ndGBM.

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 Jan 15, 2015 12:46 AM Flag

    Based on earnings projections, LGND will double every ~2 years for the next 6 years. Will be around $400/sh by 2020-21. And that's not including the Alzheimer drug.

    Sentiment: Strong Buy

  • Reply to

    BMY and CLDX start 1127 Trial-BMY to Announce?

    by maximus06906 Jan 12, 2015 2:01 PM
    long_vrts2 long_vrts2 Jan 14, 2015 12:41 AM Flag

    The Varli + Nivo trial has been posted on ClinicalTrials.gov but hasn't started enrolling yet. CLDX is the sponsor, so I expect they will issue a PR when enrollment starts. BMY put most of the emphasis on immuno-oncology in its JPMH presentation, this sector is really heating up. All the big boys are prioritizing I-O, CLDX in strong position to ride the wave!

    Sentiment: Strong Buy

LGND
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