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Celldex Therapeutics, Inc. Message Board

long_vrts2 66 posts  |  Last Activity: Jul 1, 2015 3:39 PM Member since: Jul 12, 1999
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  • Future Microbiol. 2015 Jun 29:1-13. [Epub ahead of print]

    Delafloxacin, a non-zwitterionic fluoroquinolone in Phase III of clinical development: evaluation of its pharmacology, pharmacokinetics, pharmacodynamics and clinical efficacy.

    Van Bambeke F1.

    Author information
    1Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Avenue E Mounier 73 B1.73.05, 1200 Brussels, Belgium.

    Abstract
    ABSTRACT  Delafloxacin is a fluoroquinolone lacking a basic substituent in position 7. It shows MICs remarkably low against Gram-positive organisms and anaerobes and similar to those of ciprofloxacin against Gram-negative bacteria. It remains active against most fluoroquinolone-resistant strains, except enterococci. Its potency is further increased in acidic environments (found in many infection sites). Delafloxacin is active on staphylococci growing intracellularly or in biofilms. It is currently evaluated as an intravenous and intravenous/oral stepdown therapy in Phase III trials for the treatment of complicated skin/skin structure infections. It was also granted as Qualified Infectious Disease Product for the treatment of acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia, due to its high activity on pneumococci and atypical pathogens.

    Sentiment: Strong Buy

  • Reply to

    Holding up

    by soldaround Jun 25, 2015 9:36 AM
    long_vrts2 long_vrts2 Jun 25, 2015 2:50 PM Flag

    "Wonder If the Merck phase 3 trial is leaking out good news"

    yes.

    Sentiment: Strong Buy

  • Immunotherapy. 2015 Jun 22:1-13. [Epub ahead of print]

    Targeting the T-cell co-stimulatory CD27/CD70 pathway in cancer immunotherapy: rationale and potential.

    van de Ven K1, Borst J1.

    Abstract
    In 2013, cancer immunotherapy was named 'breakthrough of the year' based on the outcome of clinical trials with blocking antibodies to the T-cell co-inhibitory receptors CTLA-4 and PD-1. This success has emphasized that cytotoxic T-cell responses to cancer can occur, but are limited by peripheral tolerance and by immunosuppression in the tumor microenvironment. Targeting of CTLA-4, PD-1 or its ligands partly overcomes these limitations and can now be applied in multiple immunogenic cancer types. Furthermore, an increased success rate is expected from combining CTLA-4 and/or PD-1 blocking with deliberate engagement of T-cell co-stimulatory receptors, particularly TNF receptor (R) family members. The TNFR family includes CD27 (Tnfrsf7), for which an agonistic antibody has recently entered clinical trials. In this review, we describe how CD27 co-stimulation impacts the T cell response, with the purpose to illuminate how CD27 agonism can be exploited in cancer immunotherapy.

    From the Conclusion, consistent with the strategy taken by CLDX to combine Varli with other immunomodulatory drugs to produce an additive or synergistic effect:

    "...Combining agonistic mAb CD27 with blocking mAb to CTLA-4 or PD-1/-L1 is expected to have an additive or even synergistic effect on the antitumor response. CD27 agonism and CTLA-4 blocking are expected to have a combined effect on the T cell response, since αCTLA-4 promotes CD28 co-stimulation [19]. CD27 agonism and PD-1/-L1 blocking are expected to have a combined effect on the T-cell response, because the latter will alleviate suppression of CTLs in the tumor microenvironment. Ideally, an agonist mAb is used that has CD27 stimulatory activity in absence of Fc receptor binding, thus decreasing the risk of immune cell depletion…."

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 Jun 19, 2015 12:36 AM Flag

    The Rindo clinical trials are closed to further enrollment. So the only way newly diagnosed GBM pts, and/or recurrent GBM pts, can get Rindo is if the FDA approves this treatment. For the sake of GBM pts, the sooner the FDA approves Rindo, the better...

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 Jun 19, 2015 12:30 AM Flag

    Don,

    Agree. The unfolding of the GPNMB/Glemba story reflects fundamentally sound decision making by CLDX management:

    1. A few years ago we were debating on this MB whether, and to what degree, GPNMB in an oncogene. That matter has been laid to rest with clear evidence that GPNMB is an oncogene in breast and skin cancer.

    2. The current report demonstrates that GPNMB is also an oncogene in colorectal and gastric cancer. Wouldn't surprise me if GPNMB is shown to be an oncogene in other cancers in addition to these four.

    3. CLDX owns the IP on GPNMB. With each new development regarding GPNMB, the IP becomes more valuable.

    4. Glemba is an effective drug with a relatively mild adverse effect profile. I think there is a very high probability that the current pivotal trial with Glemba in TNBC pts will be positive and Glemba will receive marketing approval from the FDA, initially in TNBC, and then expanding to several other indications.

    I believe CLDX is on track to be a very successful biotech company, and as the clinical trial results and subsequent FDA approvals roll in, valuation will follow.

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 Jun 19, 2015 12:11 AM Flag

    Nick,

    The situation for both newly diagnosed and recurrent GBM patients is so dire that- as I posted before- even if Rindo only decreased steroid use, or improved quality of life, it would still be approved by the FDA. When you look at the whole package, Rindo is the poster child for what the Oncology division of the FDA is looking for:
    - severe unmet need
    - targeted therapy
    - safe (actually, Rindo's safety is outstanding)
    - proven efficacy: Rindo increases OS, PFS, % survival, etc
    - a highly supportive community of patients, families and physicians, including leading neuro-oncologists worldwide, who will see to it that the FDA makes the right decision

    It's only a matter of time...

    Sentiment: Strong Buy

  • Reply to

    Question for LV

    by xxjssxx Jun 17, 2015 3:28 PM
    long_vrts2 long_vrts2 Jun 18, 2015 11:50 PM Flag

    X,
    No, I don't follow the field of gene therapy. I was always of the opinion that it's high risk- it appears that more recently there has been an improvement in the science, and that should lower the risk somewhat regarding efficacy. However, I still have concerns regarding safety- all it takes is a couple of deaths for patients who are receiving gene therapy and it will crash and burn like a few years ago.

    Sentiment: Strong Buy

  • (CLDX owns the IP on GPNMB as a cancer target: this report will have a significant impact IMO)

    Cancer Med. 2015 Jun 16. doi: 10.1002/cam4.480. [Epub ahead of print]

    Clinical significance of glycoprotein nonmetastatic B and its association with HER2 in breast cancer.

    Kanematsu M1 et al

    Glycoprotein nonmetastatic B (GPNMB) is a potential oncogene that is particularly expressed in melanoma and breast cancer (BC). To clarify its clinical significance in BC, we measured serum GPNMB in vivo and investigated its cross talk with human epidermal growth factor 2 (HER2). GPNMB was expressed in four of six breast cell lines (SK-BR-3, BT-474, MDA-MD-231, and MDA-MD-157), two of six colorectal cell lines, and two of four gastric cancer (GC) cell lines. We established a GPNMB quantification system using enzyme-linked immunosorbent assay (ELISA) for these cell lines. We measured serum GPNMB in vivo in 162 consecutive BC patients and in 88 controls (50 colorectal cancer [CC] and 38 GC patients). The GPNMB concentration in BC, CC and GC was 8.163, 5.751 and 6.55 ng/mL, respectively. The GPNMB level was significantly higher in BC patients than in CC patients (P = 0.021). The HER2-rich subtype of BC patients had significantly higher GPNMB levels than other subtypes (vs. Luminal; P = 0.038; vs. DCIS; P = 0.0195). These high GPNMB levels decreased after treatment (surgery/chemotherapy). Next, we examined the relationship between GPNMB and HER2 in vitro using SK-BR3 and BT-474 (HER2-positive/GPNMB-positive) cells. GPNMB depletion by small interfering RNA (siRNA) increased both HER2 expression and phosphorylation. Trastuzumab (Tra) in combination with docetaxel promoted cell growth inhibition, and treatment with Tra or an Extracellular signal-related kinase (ERK) inhibitor enhanced GPNMB expression. These results indicate that GPNMB might be a surrogate marker for BC and may cross talk with the HER2 signal pathway. GPNMB may therefore emerge as an important player in anti-HER therapy.

    Sentiment: Strong Buy

  • (couldn't fit in the whole article, posting the last half)

    Neurosurgery
    Issue: Volume 76(6), June 2015, p N17
    Copyright: Copyright © by the Congress of Neurological Surgeons

    Outcomes of the ACT III Study: Rindopepimut (CDX-110) Therapy for Glioblastoma

    Zussman, Benjamin M. MD; Engh, Johnathan A. MD

    Author Information
    University of Pittsburgh, Pittsburgh, Pennsylvania

    ...For patients treated with rindopepimut, the median PFS was 9.2 months (95% confidence interval, 7.4-11.3) and median OS was 21.8 months (95% confidence interval, 17.9-26.5) from study entry (ie, approximately 3 months after diagnosis; Figure). In comparison, the “matched” RTOG cohort patients showed a median OS of 16.0 months after randomization. The authors found that anti-EGFRvIII antibody titers increased 4-fold over baseline levels in 85% patients treated with rindopepimut, demonstrating robust, specific, and durable immune responses, despite concurrent temozolomide therapy. In general, rindopepimut was well tolerated: There were no fatal adverse events, no cumulative toxicity over time (median duration of rindopepimut treatment was 7.4 months), and primarily mild to moderate injection site reactions, including erythema and pruritus. Finally, a subanalysis of tumor samples taken from 10 rindopepimut patients with tumor recurrence showed that many of these tumors no longer expressed EGFRvIII.


    The 3 existing phase II trials of rindopepimut (including this study) demonstrate a pooled median PFS of 12.3 to 15.3 months from diagnosis and a median OS of 24 months from diagnosis.5 We eagerly await the results of the double-blind, phase III trial (ACT IV), which will randomize patients with resected EGFRvIII+ GBM to receive either rindopepimut or a control injection.

    Sentiment: Strong Buy

  • Melinta Therapeutics Announces $67M Series 4 Financing

    - Proceeds to Fund the Completion of Final Phase 3 Clinical Study for Delafloxacin and Drive Pipeline of Infectious Disease Therapies -

    NEW HAVEN, Conn – June 10, 2015 -- Melinta Therapeutics, a privately held Phase 3 company developing novel antibiotics to treat bacterial infections, today announced the successful completion of a $67 million Series 4 equity financing. Malin Corporation plc led the round and was joined by other existing investors, including Vatera Healthcare Partners.

    “Melinta has developed a novel multi-product portfolio, including the advancement of delafloxacin through its first Phase 3 ABSSSI trial, presenting the type of compelling investment that our firm seeks to be a part of,” said Sean Murphy, Malin Corporation plc Board Director and appointee to the Melinta Board. “With a proven management team that has outstanding experience commercializing anti-infective therapies for underserved patient populations, Melinta is poised for success.”

    Proceeds from the financing will be used to complete the final Phase 3 study of delafloxacin, an investigational fluoroquinolone, currently undergoing a confirmatory Phase 3 study for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI). Funds will also support the potential submission of a New Drug Application (NDA) for delafloxacin for the lead indication, pursuing new indications for delafloxacin including hospital-treated community-acquired bacterial pneumonia (hCABP), and advancing a lead candidate for the company’s ESKAPE pathogen program.

    Sentiment: Strong Buy

  • Br J Haematol. 2015 May 27. doi: 10.1111/bjh.13517. [Epub ahead of print]
    Phase I study of carfilzomib, lenalidomide, vorinostat, and dexamethasone in patients with relapsed and/or refractory multiple myeloma.

    Vesole DH1, Bilotti E1, Richter JR1, McNeill A1, McBride L1, Raucci L1, Anand P1, Bednarz U1, Ivanovski K1, Smith J1, Batra V1, Aleman A1, Sims T1, Guerrero L1, Mato A1, Siegel DS1.

    Abstract
    Research has shown that proteasome inhibitors (e.g., carfilzomib), immunomodulatory agents (e.g., lenalidomide), histone deacetylase inhibitors (e.g., vorinostat) and corticosteroids (e.g., dexamethasone) have synergistic anti-multiple myeloma (MM) activity. This phase I dose-escalation study evaluated a regimen combining carfilzomib, lenalidomide, vorinostat and dexamethasone (QUAD) in patients with relapsed and/or refractory MM. Seventeen patients received carfilzomib (15, 20, or 20/27 mg/m2 ; 30-min infusion; days 1, 2, 8, 9, 15, 16), lenalidomide (15 or 25 mg; days 1-21), vorinostat (300 or 400 mg; days 1-7, 15-21), and dexamethasone (40 mg; days 1, 8, 15, 22) in 28-d cycles. No dose-limiting toxicities were observed; the maximum tolerated dose was not reached. The maximum administered dose was carfilzomib 20/27 mg/m2 , lenalidomide 25 mg, vorinostat 400 mg, and dexamethasone 40 mg. Common grade ≥3 adverse events included neutropenia (53%), thrombocytopenia (53%) and anaemia (41%). The overall response rate was 53%: 12% of patients achieved a very good partial response (PR) and 41% of patients achieved a PR. At a median follow-up of 10 months, median progression-free survival was 12 months and median overall survival was not reached. Treatment with QUAD was feasible and had encouraging activity in patients with relapsed and/or refractory MM.

    Sentiment: Strong Buy

  • Reply to

    Rintega:

    by long_vrts2 Jun 2, 2015 1:54 AM
    long_vrts2 long_vrts2 Jun 8, 2015 1:03 AM Flag

    Doubters have been known to become the most ardent believers- that will be case here as well.

    Sentiment: Strong Buy

  • Reply to

    Rintega:

    by long_vrts2 Jun 2, 2015 1:54 AM
    long_vrts2 long_vrts2 Jun 8, 2015 12:55 AM Flag

    "Given the future price of treatment with Rintega (still cheaper than other cancer drugs"

    I think Rintega will be priced in the $120-150K range per year- so while not inexpensive, it will be good value because of the survival benefit and the significant percentage of long-term survivors.

    "will Drs be able to use it off-label (on other patients that test vIII+ for other cancers)?"

    The FDA is considering shifting cancer treatment from organ specific cancers (eg, lung, pancreas, brain, etc) to marker specific (vIII+, BRAF, etc). So in that case a pt who tests vIII+ would be eligible for Rintega treatment- this would eliminate the on-label vs off-label question. In the meantime, off- label decisions will be made on a case-by-case basis.

    Sentiment: Strong Buy

  • long_vrts2 long_vrts2 Jun 5, 2015 1:24 PM Flag

    Better yet, if the diabetes drug looks robust, LGND should develop it further on its own given its current cash position:

    1. LGND could use CRO's to take it to PII or even PIII. Even big biotechs like Genenetech use CRO's, and it's a cost effective way to develop a drug candidate without taking on staffing issues.

    2. An effective, safe diabetic drug with a new mechanism of action, taken into PIII, would add significantly to the valuation of LGND- investing in this would would make financial sense.

    3. Partnering the drug in PIII, or post PIII, would provide more flexibility in terms of structuring the partnering deal: LGND could do either a hefty royalty deal or a split of revenue.

    Sentiment: Strong Buy

  • long_vrts2 by long_vrts2 Jun 2, 2015 1:54 AM Flag

    Next stops of the journey coming up for Rintega: FDA approval and commercialization. I hate to use caps, but I think it's necessary for this to sink in. Dr. Reardon's conclusion on Rintega, with my editorial comments in parenthesis:

    "...We were commenting after reviewing the data here at the meeting, some of those patients who we treated WAY BACK then are CONTINUING TO DO WELL, out OVER10 YEARS now (median OS for vIII+ GBM pts is 15 months, and there is no record of any vIII+ patient living longer than 5.5 year... unless they got Rintega. And 15% of Ritega pts are cancer free long-term...). So there's NO QUESTION (no question means exactly that, ie no more doubt, no more need to question...) I think this -- we're VERY EXCITED (somber neuro-oncologists very rarely express great excitement about anything, unless it's really, really exciting...) about the PROSPECT of this therapeutic GOING FORWARD (the future of Rintega is bright) and its impact right from the beginning of the diagnosis and treatment. Obviously, it's VERY GRATIFYING (somber neuro-oncologists...etc..) to see that even in recurrent patients where the tumor's got a fair amount of momentum, where the relatively immunocompromised, it CAN STILL HAVE AN IMPACT and HAVE A ROLE (Reardon is stealing the thunder of the FDA with this, because the FDA will state the same conclusion when it approves Rintega in recurrent setting...) But I think our biggest expectation and hope is that it will have an EVEN MORE PROFOUND EFFECT when started right from the BEGINNING after diagnosis (without FDA approval in newly diagnosed GBM Rintega could not be started from the "beginning"- speaks for itself IMO).

    Congratulations to CLDX, the investigators who ran the trial and last but not least, CLDX shareholders who sustained CLDX in this endeavor! This is very good news indeed for GBM patients and their families, and their care givers who now have an effective treatment in their arsenal against this dreaded disease.

    Sentiment: Strong Buy

  • 6/7/15: Data to be presented on Phase 1B trial for LGD-6972 in diabetic patients at the ADA conference. Positive results can move LGND valuation 10-15% as this is a major unpartnered asset.

    6/26/15: PDUFA priority review of Kyprolis for second line treatment of multiple myeloma

    10/23/15: PDUFA date for Spectrum's CE-Melphalan (EVOMELA)

    Sentiment: Strong Buy

  • 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

CLDX
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