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Celldex Therapeutics, Inc. (CLDX)

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  • T
    TP
    Two weeks until the first patient in Phase 2 Study of Barzolvolimab in Patients with Chronic Inducible Urticaria hits the 12 week mark.

    "Primary endpoint of the study is the percentage of patients with a negative provocation test at Week 12 (using TempTest® for ColdU and FricTest® for SD)."

    There's a 20 week treatment phase and 24 week follow-up phase.
  • l
    longvrts
    9/9 Dupixent PIII results in Prurigo Nodularis reported. Solid efficacy and safety, with ~60% of patients having clinically meaningful results. CLDX's CDX-0159 is also being tested in PN clinical trial, and since PN is to a large degree driven by mast cells, there is a high probability of successful trial results. BTW, Dupixent revenue projection was increased to $13 Billion/yr by SNY- there is significant potential for CDX-0159 to generate substantial revenue as Dupixent 2.0:

    "Press Release: Dupixent® (dupilumab) late-breaking Phase 3 data at EADV 2022 showed significant improvements in signs and symptoms of prurigo nodularis
    September 08, 2022 11:30 ET | Source: Sanofi - Aventis Groupe

    Dupixent® (dupilumab) late-breaking Phase 3 data at EADV 2022 showed significant improvements in signs and symptoms of prurigo nodularis

    Nearly three times as many Dupixent patients experienced clinically meaningful reductions in itch and skin lesions at 24 weeks compared to placebo
    There are currently no approved medicines specifically indicated to treat prurigo nodularis; regulatory submissions for Dupixent are under Priority Review in the U.S. and under review in the European Union
    22 Dupixent abstracts are being presented at the European Academy of Dermatology and Venereology (EADV) 2022 Congress across four dermatological diseases with underlying type 2 inflammation

    Paris and Tarrytown, N.Y. September 8, 2022. Detailed positive results from the Phase 3 PRIME trial evaluating Dupixent® (dupilumab) in adults with uncontrolled prurigo nodularis were presented today in a late-breaking session at the European Academy of Dermatology and Venereology (EADV) 2022 Congress. These data from one of two pivotal trials in prurigo nodularis show Dupixent significantly reduced itch and skin lesions at 24 weeks.

    In total, 22 scientific abstracts are being presented at the EADV 2022 Congress discussing Dupixent in atopic dermatitis in patients as young as six months, and its investigational use in chronic spontaneous urticaria and bullous pemphigoid, in addition to prurigo nodularis.

    Gil Yosipovitch, M.D.
    Professor of Dermatology, Miller School of Medicine, University of Miami, Director of the Miami Itch Center, and principal investigator of the trial
    “These positive results from the second of two dupilumab Phase 3 trials in prurigo nodularis confirm inhibiting IL-4 and IL-13 can significantly reduce the unrelenting itch and extensive severe skin lesions that often impair patient quality of life. In my practice, relieving itch and clearing skin are often the top priorities for my patients across a range of chronic skin diseases. These data demonstrate dupilumab has the potential to address and manage these debilitating symptoms in another chronic skin disease with underlying type 2 inflammation.”

    The late-breaking data presented at the EADV 2022 Congress are from the randomized, placebo-controlled Phase 3 PRIME trial, which met its primary and key secondary endpoints. At 24 weeks, among patients treated with Dupixent in the trial:

    More than three times as many (60%) experienced a clinically meaningful reduction in itch from baseline, the primary endpoint, compared to placebo patients (18%; p<0.0001).
    Nearly three times as many (48%) achieved clear or almost clear skin, a key secondary endpoint, compared to placebo patients (18%; p=0.0004).
    The safety results of the trial were generally consistent with the known safety profile of Dupixent in its approved dermatological indication. For the 24-week treatment period, overall rates of adverse events (AEs) were 71% for Dupixent and 63% for placebo. AEs most commonly observed with Dupixent (≥5%) included nasopharyngitis (5% Dupixent, 4% placebo) and headache (5% Dupixent, 5% placebo). The rate of treatment discontinuation due to AEs prior to week 24 was 0% for Dupixent compared to 4% for placebo. A numerically lower rate of skin infections was observed with Dupixent (4% Dupixent, 9% placebo).

    Results from this and an earlier Phase 3 trial, PRIME2, will form the basis of regulatory submissions around the world for Dupixent in prurigo nodularis this year. Regulatory submissions are already under review by the European Commission and the U.S. Food and Drug Administration, with the FDA granting Priority Review in May 2022 and a target action date of September 30, 2022.

    The potential uses of Dupilumab in prurigo nodularis, chronic spontaneous urticaria and bullous pemphigoid are currently under clinical development, and the safety and efficacy have not been fully evaluated by any regulatory authority."
  • l
    longvrts
    Report out: conclusive evidence demonstrated regarding mast cells in GI biopsies from pediatric IBS patients. CDX-0159 is first-in-class and best-in-class biologic with clinically proven mast cell inhibitory efficacy. IBS represents a substantial potential indication for 0159:

    "J Pediatr Gastroenterol Nutr. 2022 Aug 17. doi: 10.1097/MPG.0000000000003588. Online ahead of print.

    Identifying Mast Cells in Gastrointestinal Biopsies in Pediatric Irritable Bowel Patients

    Syed Ahsan Rizvi 1, Chukwuemeka Oriala 2, Jessina Thomas 1, Shuan Li 2, Yamen Smadi 1

    Affiliations
    1Center for Digestive Health and Nutrition, Arnold Palmer Hospital for Children.
    2Department of Pathology, Orlando Health, Orlando, Florida.
    PMID: 35976360 DOI: 10.1097/MPG.0000000000003588
    Abstract
    Introduction: Mast cells (MCs) have been proposed to be involved in the pathophysiology of irritable bowel syndrome (IBS). Nonetheless, the quantity and distribution of MCs in the GI tract of pediatric patients with IBS are not well defined. This study aimed to compare the number of MCs in children with and without IBS and to establish histopathological reference values in pediatrics.

    Methods: Forty-nine participants with IBS were prospectively enrolled and classified into IBS with atopy (n=29) and IBS without atopy (n=20). As our retrospective control group, we selected forty-two individuals with a history of polyposis syndrome or GERD with normal histopathology. Retrospective selection of the control cohort was performed in a manner similar to previously published adult and pediatric studies. MCs were prospectively stained immunohistochemically on specimens from the stomach, duodenum, terminal ileum, and descending colon of both groups.

    Results: The IBS group showed significantly more mast cells per high power field (MCs/HPF) in the stomach, duodenum, terminal ileum, and descending colon (p <0.001), irrespective of their atopic status. Optimal MC cut-off values for IBS are ≥20.5 MCs/HPF in the stomach (AUC=0.84); ≥23.0 MCs/HPF in the duodenum (AUC=0.79); ≥33.5 MCs/HPF in the terminal ileum (AUC=0.82); and ≥22.5 MCs/HPF in the descending colon (AUC=0.86).

    Conclusion: Pediatric patients with IBS showed increased numbers of MCs in the stomach, duodenum, terminal ileum, and descending colon when compared with controls. Further trials are needed to explain the role of MCs in pediatric IBS, which might facilitate the development of targeted therapeutic interventions."
  • p
    pnc
    any news I missed A.Hours?
  • l
    longvrts
    8/4 CCXI up $110% today: $3.7 Billion buyout offer by AMGN. CCXI being bought for its autoimmune drug Tavneos. CLDX Barzolvolimab (CDX-1159) is first-in-class and best-in-class anti-inflammatory biologic that inhibits mast cells and has demonstrated outstanding clinical results so far. CLDX market cap will start to reflect the significant value of Barzo;

    "Acquisition Includes TAVNEOS® (avacopan), a First-in-Class Medicine for Patients With Serious Autoimmune Disease

    Tavneos Adds to Amgen's Decades-Long Leadership in Inflammation and Nephrology

    THOUSAND OAKS, Calif. and SAN CARLOS, Calif., Aug. 4, 2022 /PRNewswire/ -- Amgen (NASDAQ: AMGN) and ChemoCentryx, Inc., (NASDAQ: CCXI), a biopharmaceutical company focused on orally administered therapeutics to treat autoimmune diseases, inflammatory disorders and cancer, today announced that the companies have entered into a definitive agreement under which Amgen will acquire ChemoCentryx for $52 per share in cash, representing an enterprise value of approximately $3.7 billion.

    ChemoCentryx Logo
    ChemoCentryx Logo
    "The acquisition of ChemoCentryx represents a compelling opportunity for Amgen to add to our decades-long leadership in inflammation and nephrology with TAVNEOS, a transformative, first-in-class treatment for ANCA-associated vasculitis," said Robert A. Bradway, chairman and chief executive officer at Amgen. "We are excited to join in the TAVNEOS launch and help many more patients with this serious and sometimes life-threatening disease for which there remains significant unmet medical need. We also look forward to welcoming the highly skilled team from ChemoCentryx that shares our passion for serving patients suffering from serious diseases."

    "A fierce commitment to improving human lives is the bond that unites Amgen and ChemoCentryx today," said Thomas J. Schall, Ph.D., president and chief executive officer of ChemoCentryx. "Last year, after 25 years of proud history, we at CCXI delivered on our founding promise with the approval of TAVNEOS for patients with anti-neutrophil cytoplasmic autoantibody-associated vasculitis (ANCA-associated vasculitis). It is an honor to now join Amgen's great mission, and together begin a bright new era bringing landscape-shaping medicines like TAVNEOS to those who will benefit most."

    TAVNEOS is an orally administered selective complement component 5a receptor inhibitor. It was approved by the U.S. Food and Drug Administration in October 2021 as an adjunctive treatment for adult patients with severe active ANCA-associated vasculitis, specifically granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) (the two main forms of ANCA-associated vasculitis), in combination with standard therapy.

    ANCA-associated vasculitis is an umbrella term for a group of multi-system autoimmune diseases with small vessel inflammation. Inflamed vessels may rupture or become occluded giving rise to a broad array of clinical symptoms and signs related to a systemic inflammatory response which may result in profound injury and dysfunction in the kidneys, lungs and other organs.

    Amgen is a leader in inflammation and nephrology. The company's inflammation portfolio includes Otezla®, ENBREL®, TEZSPIRE®, AMGEVITA™ (a biosimilar to HUMIRA®), RIABNI™ (a biosimilar to Rituxan®), and AVSOLA® (a biosimilar to REMICADE®). Amgen's pipeline includes four innovative Phase 2 inflammation medicines – efavaleukin alpha for systemic lupus erythematosus and ulcerative colitis, ordesekimab for celiac disease, rocatinlimab for atopic dermatitis and rozibafusap alfa for systemic lupus erythematosus – as well as ABP 654, a biosimilar to STELARA® that is in Phase 3 development. Amgen's nephrology portfolio includes EPOGEN®, Aranesp®, Parsabiv® and Sensipar®.

    U.S. sales of TAVNEOS in the first quarter of 2022, the first full quarter of sales, were $5.4 million. TAVNEOS is also approved in major markets outside the U.S., including the European Union and Japan. Vifor Fresenius Medical Care Renal Pharma Ltd. will retain exclusive rights to commercialize TAVNEOS outside the U.S., except in Japan where Kissei Pharmaceutical Co., Ltd. holds commercialization rights and Canada where Otsuka Canada Pharmaceutical holds commercialization rights.

    In addition to TAVNEOS, ChemoCentryx has three early-stage drug candidates that target chemoattractant receptors in other inflammatory diseases and an oral checkpoint inhibitor for cancer.

    The transaction has been unanimously approved by each company's board of directors. The transaction is subject to ChemoCentryx stockholder approval, regulatory approvals and other customary closing conditions, and is expected to close in the fourth quarter of 2022.

    Amgen management will comment further on the ChemoCentryx transaction on its Q2 earnings call today.

    PJT Partners acted as financial advisor to Amgen and Wachtell, Lipton, Rosen & Katz is serving as its legal advisor. Goldman Sachs & Co. LLC acted "
  • l
    longvrts
    Report out: Mast cells implicated in osteoporosis and indicated as a target for the treatment of bone diseases. CDX-1159 is first-in-class and best-in-class biologic with potent mast cell inhibitory activity. Clinical trial results so far have reported unprecedented efficacy for 1159 as a mast cell inhibitor:

    "Matrix Biol. 2022 Jul 28;S0945-053X(22)00094-4. doi: 10.1016/j.matbio.2022.07.005. Online ahead of print.

    Mast Cell Chymase Has a Negative Impact on Human Osteoblasts

    Thomas Lind 1, Fabio Rabelo Melo 2, Ann-Marie Gustafson 3, Anders Sundqvist 4, Xinran O Zhao 2, Aristidis Moustakas 2, Håkan Melhus 5, Gunnar Pejler 2

    PMID: 35908613 DOI: 10.1016/j.matbio.2022.07.005
    Cite

    Abstract
    Mast cells have been linked to osteoporosis and bone fractures, and in a previous study we found that mice lacking a major mast cell protease, chymase, develop increased diaphyseal bone mass. These findings introduce the possibility that mast cell chymase can regulate bone formation, but the underlying mechanism(s) has not previously been investigated. Here we hypothesized that chymase might exert such effects through a direct negative impact on osteoblasts, i.e., the main bone-building cells. Indeed, we show that chymase has a distinct impact on human primary osteoblasts. Firstly, chymase was shown to have pronounced effects on the morphological features of osteoblasts, including extensive cell contraction and actin reorganization. Chymase also caused a profound reduction in the output of collagen from the osteoblasts, and was shown to degrade osteoblast-secreted fibronectin and to activate pro-matrix metallopeptidase-2 released by the osteoblasts. Further, chymase was shown to have a preferential impact on the gene expression, protein output and phosphorylation status of TGFβ-associated signaling molecules. A transcriptomic analysis was conducted and revealed a significant effect of chymase on several genes of importance for bone metabolism, including a reduction in the expression of osteoprotegerin, which was confirmed at the protein level. Finally, we show that chymase interacts with human osteoblasts and is taken up by the cells. Altogether, the present findings provide a functional link between mast cell chymase and osteoblast function, and can form the basis for a further evaluation of chymase as a potential target for intervention in metabolic bone diseases."
  • l
    longvrts
    7/26 CDX-1127 news: CLDX publishes report on the efficacy of CDX-1127 to suppress IL-17 production in preclinical model. This makes CDX-1127 a potential drug against inflammatory and auto-immune disorders. Interesting development for CDX-1127 (Varlilumab):

    "Eur J Immunol. 2022 Jul 20. doi: 10.1002/eji.202149698. Online ahead of print.

    Agonistic anti-CD27 antibody ameliorates EAE by suppressing IL-17 production

    Isabel Vogel 1 2 2, Valerie Acolty 1, Tibor Keler 3, Stanislas Goriely 1, Oberdan Leo 1, Muriel Moser 1

    Affiliations
    1Laboratory of Immunobiology, Université Libre de Bruxelles (ULB) - IBMM, Rue des Prof. Jeener et Brachet 12, Gosselies, 6041, Belgium.
    2NeuVasQ Biotechnologies, Rue Auguste Piccard 48, Gosselies, 6041, Belgium.
    3Celldex Therapeutics, Inc., 53 Frontage Road, Suite 220, Hampton, NJ, 08827, USA.
    PMID: 35856659 DOI: 10.1002/eji.202149698

    Abstract
    CD27/CD70 costimulation enhances T-cell survival, memory formation and Th1-cell differentiation and effector function. In addition to promoting Th1 responses, CD27 signalling has been shown to exert a negative regulatory role on IL-17 production, resulting in increased sensitivity of CD27 KO mice to experimental autoimmune encephalomyelitis (EAE). By inducing EAE in full CD27 KO mice, and in a novel, T-cell specific CD27 KO mouse strain (CD4-Cre x CD27flox/flox ), we demonstrate herein that CD27 engagement by its natural ligand (CD70) suppresses IL-17 production in a cell autonomous fashion. We further show that CD27 engagement by an agonistic antibody given after EAE induction or at symptom onset similarly suppresses IL-17 production by activated CD4+ T cells infiltrating the inflamed central nervous system (CNS) while IFNγ production was unaffected, leading to an amelioration of inflammatory-related symptoms. These findings propose CD27 costimulation as a potential candidate for therapeutic manipulation to treat autoimmune and autoinflammatory diseases characterized by excessive IL-17 production. This article is protected by copyright. All rights reserved."
  • F
    Farmer
    @longgvrts I'm curious what's your assessment of IFRX? Thank you!
  • A
    Alex
    Q: What Co. had the only breakthrough therapy des. not to go onto approval?!? If you said CLDX’s Rintega you are correct! The drug extended life by 4months over SOC BUT…the control group matched that. IMO it was unscrupulous doctors tainting the trial w/ cross group dosing & not following trial protocol. I lost over $100k on this company in 2016/17. Glemva was just a pure disappointment & par for the dev. bio investing space but Rintega worked. In the P3 it performed exactly the same as previous trials. The control group was tainted & both patients & investors lost. Tibor Keler is a genius. Marruci is a finance wiz. Conclusion, despite my painful loss in this Co. that absolutely devastated my standard of living (& mental health) I intend on building another position here over the next 12 mos.
  • A
    Ari
    Anyone else notice that CLDX is two days late with reporting their earnings. Makes me begin to wonder....
  • e
    edward
    to the moon Alice, to the Moon, Hopefully
  • p
    pnc
    Panic buyers? thnx
  • A
    Anonymous
    Can anyone explain this in plain English? Thanks!

    Form 8-K Celldex Therapeutics, For: Jul 15
    BY 10K Wizard
    — 4:02 PM ET 07/18/2022
    http://archive.fast-edgar.com/20220718/A3B4822C8Z2289Z222ZS2ZZZ5PQTZ2Y2324G

    Filed on: July 18, 2022
  • A
    Anonymous
    CLDX: SA article

    Celldex: Barzolvolimab Plus Bispecific Antibodies Advancement

    Jul. 14, 2022 3:32 PM ETCelldex Therapeutics, Inc. (CLDX)IBB, XBI, ARKG,
    Terry Chrisomalis

    Marketplace
    Summary

    Proof of concept has been established in using Barzolvolimab in treating Chronic spontaneous urticaria and Chronic inducible urticaria patients in phase 1b studies.

    One phase 2 study with Barzolvolimab treating Chronic spontaneous urticaria patients has been initiated with second phase 2 study in Chronic inducible urticaria expected to start 2nd half of 2022.

    Potential to expand the use of Barzolvolimab in other inflammatory disorders such as Prurigo Nodularis and Eosinophilic esophagitis.

    CDX-1140 and CDX-527 are oncology drugs being advanced in the pipeline; CDX-1140 with CD40 targeting head/neck cancer and lung cancer, CDX-527 bispecific antibody targeting ovarian cancer.

    https://seekingalpha.com/article/4523394-celldex-barzolvolimab-plus-bispecific-antibodies-advancement?mailingid=28386450&messageid=investing_ideas&serial=28386450.66011&source=email_investing_ideas&utm_campaign=Stock+Ideas+Recurring++2022-07-15&utm_content=investing_ideas_control&utm_medium=email&utm_source=seeking_alpha&utm_term=Investing+Ideas
  • A
    Anonymous
    Celldex Therapeutics Presents Positive Data from CDX-0159 Phase 1b Study in Chronic Inducible Urticaria at EAACI 2021
    BY GlobeNewswire
    — 6:01 PM ET 07/09/2021
    - 95% complete response rate after single dose of CDX-0159 -
    - Rapid, profound and durable responses offer patients opportunity for quick, lasting, meaningful relief -
    - Median duration of response 77+ days in Cold Urticaria and 57+ days in Symptomatic Dermographism -
    - Serum tryptase and skin mast cell depletion mirror clinical activity -
    - Favorable safety profile -
    - Company to host webcast conference call on Monday, July 12 at 8:15 a.m. ET -

    HAMPTON, N.J., July 09, 2021 (GLOBE NEWSWIRE) -- Celldex Therapeutics, Inc. ( CLDX
    Loading...
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    ) today announced updated data from the Company’s ongoing, open label Phase 1b clinical trial of CDX-0159 in patients with antihistamine refractory cold urticaria and symptomatic dermographism, the two most common forms of chronic inducible urticaria. These diseases, which are often severe and debilitating, can significantly impact patients’ lives. CDX-0159 is a humanized monoclonal antibody that specifically binds the receptor tyrosine kinase KIT with high specificity and potently inhibits its activity.

    All 19/19 (100%) patients who received a single full dose of CDX-0159 experienced a clinical response to provocation testing. 18/19 (95%) experienced a complete response and 1/19 (5%) experienced a marked partial response. Responses were rapid, profound, and durable and correlated with a depletion of skin mast cells. CDX-0159 was generally well tolerated. These data were presented by Dr. Marcus Maurer, Professor of Dermatology and Allergy at Charité – Universitätsmedizin, in Berlin during a late-breaking poster discussion session (#1046) as part of the European Academy of Allergy and Clinical Immunology (EAACI) Annual Congress 2021.

    “The achievement of a 95% complete response rate, rapid onset and sustained durability after a single dose is unprecedented in this patient population and clearly demonstrates that CDX-0159 has the potential to become an important new treatment option for patients suffering with chronic inducible urticaria,” commented Anthony S. Marucci, President and Chief Executive Officer of Celldex Therapeutics ( CLDX
    Loading...
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    ). “We believe these impressive early data show that CDX-0159 safely depletes mast cells which indicates its potential to impact other diseases with mast cell involvement. We continue to make excellent progress across the CDX-0159 development program in urticaria and expect to expand into prurigo nodularis later this year, and additional indications with mast cell involvement in the future.”

    “These early-stage results are stunning and represent a major breakthrough for patients with inducible urticarias where current treatment options have been unable to provide relief from often severe symptoms,” said Marcus Maurer, M.D., Professor of Dermatology and Allergy at Charité - Universitätsmedizin in Berlin, who is conducting the study. “While individuals with inducible urticaria go to great lengths to avoid disease triggers in their daily lives, many find it impossible to do so and are impacted by severe itching and burning hives that impair all parts of their lives—their work, their concentration, their sleep and their social behavior. CDX-0159 clearly provided a real benefit to these patients and has meaningfully improved their lives. This novel mast cell depleting mechanism is especially exciting because it can provide insights into the involvement of mast cells across many diseases where their role is not yet well understood by the scientific community.”

    Summary of data from ongoing Phase 1b Trial of CDX-0159:

    As of the data cut-off on June 11, 2021, 20 patients had received a single intravenous infusion of CDX-0159 at 3 mg/kg, including 11 patients with cold urticaria and 9 patients with symptomatic dermographism. Patients had high disease activity as assessed by provocation threshold testing. In patients with cold urticaria and symptomatic dermographism baseline critical temperature thresholds were 18.9°C/66°F (range: 5-27°C/41-80.6°F) and FricTest® thresholds were 3.8 (range: 3-4) of 4. Safety results are reported for all 20 patients; activity results are reported for the 19 patients who received a full dose of CDX-0159. 14 of 19 patients completed the 12-week study observation period and five were ongoing (range of 2-8 weeks) as of June 11, 2021.

    All 19/19 (100%) patients experienced a clinical response as assessed by provocation threshold testing; 18/19 (95%) experienced a complete response and 1/19 (5%) experienced a partial response.
    10/10 (100%) patients with cold urticaria experienced a complete response.
    8/9 (89%) patients with symptomatic dermographism experienced a complete response and 1/9 (11%) experienced a partial response.
    Compete responses were observed in all 3 patients (1 cold urticaria; 2 symptomatic dermographism) with prior X
  • l
    longvrts
    Report out: Mast cells implicated in transition from undifferentiated arthritis to psoriatic arthritis. CLDX has the first-in-class and best-in-class mast cell inhibitor in CDX-0159:

    Front Med (Lausanne). 2021 Apr 9;8:656667. doi: 10.3389/fmed.2021.656667. eCollection 2021.

    Synovial Immunohistological Biomarkers of the Classification of Undifferentiated Arthritis Evolving to Rheumatoid or Psoriatic Arthritis

    Andrea Cuervo 1, Raquel Celis 1, Antonio Julià 2, Alicia Usategui 3, Regina Faré 3, Julio Ramírez 1, Ana Belen Azuaga 1, Andrés Lorenzo 1 4, Raimon Sanmartí 1, José L Pablos 3, Juan D Cañete 1
    Affiliations expand
    PMID: 33898490 PMCID: PMC8062857 DOI: 10.3389/fmed.2021.656667

    Abstract
    Background: Undifferentiated arthritis (UA) is defined as an inflammatory arthritis that does not fulfill criteria for a definite diagnosis. Delay in reaching a specific diagnostic and therapy may lead to impaired functional outcomes. Our aim was to identify synovial biomarkers associated with definitive diagnostic classification in patients with UA. Methods: DMARD-naïve UA patients with available initial synovial tissue (ST) and a final diagnosis of rheumatoid arthritis (RA) or psoriatic arthritis (PsA) during follow-up were included and compared with patients with well-defined disease (RA or PsA). Clinical, arthroscopic, and pathological data were compared between groups. Pathology included quantitative immunohistochemical (IHC) analysis of cell types and human interferon-regulated MxA. Principal component analysis (PCA) was performed to extract disease patterns. Results: One hundred and five patients were included: 31 patients with DMARD-naïve UA (19 evolving to RA and 12 to PsA during a median follow up of 7 years), 39 with established RA, and 35 with established PsA. ST from the UA group showed higher macrophage density compared with the established RA and PsA groups. Patients with UA evolving to RA (UA-RA) showed higher MxA expression and CD3+ T-cell density compared with established RA. UA patients evolving to PsA (UA-PsA) showed increased vascularity and lining synovial fibroblast density compared with established PsA. Synovitis of UA-PsA patients showed more mast cells and lining fibroblasts compared with UA-RA. No between-group differences in local or systemic inflammation markers were found. Conclusions: Our results show differences in the cellular composition of UA synovium compared with RA and PsA, with higher density of the cellular infiltrate in the UA groups. Initial expression of the interferon inducible gene MxA could be a biomarker of progression to RA, while higher mast cell and fibroblastic density may be associated with PsA progression.
  • l
    longvrts
    Report out: Combination of CD40 activation plus PD-1/TIGIT blockade eliminates pancreatic cancer in preclinical model. CLDX's CD40 agonist CDX-1140 has demonstrated the highest systemic dosing with an acceptable AE profile. 1140 is currently being tested in a clinical trial against pancreatic cancer in combination with chemo. This report from one of the leading academic cancer research labs suggests that CLDX should test 1140 in combination with PD-1/TIGIT blockers in PC:

    Cancer Cell. 2021 Jul 27;S1535-6108(21)00384-6. doi: 10.1016/j.ccell.2021.07.007. Online ahead of print.

    The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer

    William A Freed-Pastor 1, Laurens J Lambert 2, Zackery A Ely 2, Nimisha B Pattada 3, Arjun Bhutkar 3, George Eng 4, Kim L Mercer 3, Ana P Garcia 3, Lin Lin 3, William M Rideout 3rd 3, William L Hwang 5, Jason M Schenkel 6, Alex M Jaeger 3, Roderick T Bronson 3, Peter M K Westcott 3, Tyler D Hether 7, Prajan Divakar 7, Jason W Reeves 7, Vikram Deshpande 8, Toni Delorey 9, Devan Phillips 9, Omer H Yilmaz 10, Aviv Regev 11, Tyler Jacks 12
    PMID: 34358448 DOI: 10.1016/j.ccell.2021.07.007

    Abstract
    The CD155/TIGIT axis can be co-opted during immune evasion in chronic viral infections and cancer. Pancreatic adenocarcinoma (PDAC) is a highly lethal malignancy, and immune-based strategies to combat this disease have been largely unsuccessful to date. We corroborate prior reports that a substantial portion of PDAC harbors predicted high-affinity MHC class I-restricted neoepitopes and extend these findings to advanced/metastatic disease. Using multiple preclinical models of neoantigen-expressing PDAC, we demonstrate that intratumoral neoantigen-specific CD8+ T cells adopt multiple states of dysfunction, resembling those in tumor-infiltrating lymphocytes of PDAC patients. Mechanistically, genetic and/or pharmacologic modulation of the CD155/TIGIT axis was sufficient to promote immune evasion in autochthonous neoantigen-expressing PDAC. Finally, we demonstrate that the CD155/TIGIT axis is critical in maintaining immune evasion in PDAC and uncover a combination immunotherapy (TIGIT/PD-1 co-blockade plus CD40 agonism) that elicits profound anti-tumor responses in preclinical models, now poised for clinical evaluation.
  • l
    longvrts
    7/9/21 CDX-0159 late-breaking abstract at EAACI 2021: robust efficacy/safety, prolonged duration of treatment and molecular mechanism of action defined.

    In a nutshell: CDX-0150 is an innovative, revolutionary drug that will transform the treatment landscape for mast cell caused disease.

    My take: CDX-0159 is a mega blockbuster in the making. CLDX valuation will at least triple from current levels in the short to mid-term. Long term:....?
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    longvrts
    4/28 Dupixent news shines a positive light on the significant potential of CDX-0159: Dupixent performance boosts prospects for 0159 which has better mechanism of action and clinical efficacy in overlapping indications. 0159 on track to become a high impact drug in the auto-immune segment:"PHARMASanofi's Dupixent puts on another stellar show, and it's still 'at the beginning' of its journey: execBy Angus LiuApr 28, 2022 08:37amSanofi recently raised Dupixent?s peak sales target to more than 13 billion euros and looks to add at least 1.5 million additional eligible patients worldwide by 2025. (sanofi)Five years after its first FDA approval in eczema, Sanofi?s Dupixent is still blazing a trail in inflammatory diseases.That?s the evaluation of Bill Sibold, Sanofi?s global head of specialty care, after the Regeneron-partnered drug posted a 46% revenue increase in the first quarter to 1.61 billion euros ($1.79 billion), ahead of industry watchers? expectations.?We?re still only at the beginning of our journey, with approximately 8% [Dupixent] market penetration in adults? in atopic dermatitis, Sibold said during an investor call Thursday.The relocation provides added laboratory technology, automation. and sample storage capacity to address increasing demand for molecular and immuno- assay development and testing services; supporting growth in vaccine, and immuno-oncology development.Dupixent?s 46% revenue growth at constant currencies marks the largest of a first quarter for the med so far. Sales outside of the U.S. jumped 69%. And the drug?s 38% U.S. increase is ?even more impressive,? Sibold said, because less than 90% of physicians? offices have reopened since the beginning of the pandemic.Amid competition, there may be some ?downward pressure? on Dupixent?s net price in the U.S., but Sibold said, ?there is nothing out of the ordinary here.?Sanofi recently raised Dupixent?s peak sales target to at least 13 billion euros. More than 430,000 patients are now on the IL-4/13 inhibitor across inflammatory disease indications, Sibold said, and the French pharma is planning to add at least 1.5 million eligible patients worldwide by 2025 with new label expansions.On a roll, Sanofi raises Dupixent's peak sales target to #$%$13B-plusOn that front, the FDA recently put Dupixent?s application for eosinophilic esophagitis under priority review, potentially making it the first approved drug for the disorder. Sanofi and Regeneron have also filed the drug for the itch condition prurigo nodularis with U.S. and European regulators.Meanwhile, competitors are piling into the market. Leo Pharma in December won an FDA go-ahead for IL-13-specific injection Adbry in moderate to severe atopic dermatitis. Eli Lilly just posted what Jefferies analysts called ?compelling? phase 3 data for its own IL-13 antibody lebrikizumab, with skin clearance at least on par with Dupixent or better by absolute numbers. In less direct threats to Dupixent, oral JAK inhibitors such as AbbVie?s Rinvoq and Pfizer?s Cibinqo are also entering the ring. But Sanofi is undeterred.?We believe that the additional treatment options for patients contribute to unlocking significant incremental growth potential for Dupixent through market expansion as well as improved physician and patient awareness,? Sibold said.?We?ve seen it around the world where competitors have come into the market, it helps to accelerate growth,? he added. ?As the product with the best profile, guess who wins??Sanofi, Regeneron score fast FDA review for Dupixent in eosinophilic esophagitisIn addition to Dupixent as ?the foundation and the cornerstone? in type 2 inflammatory diseases, CEO Paul Hudson noted Sanofi currently has 10 molecules in development in the area, including injectables, oral drugs and a topical candidate. Those programs could start to enter the market as early as 2025.Outside of immunology, Sanofi is trying to catch up in oncology under Hudson?s leadership. The company?s CD38 drug Sarclisa reeled in 65 million euros. In its head-to-head competition against Johnson & Johnson?s Darzalex, Sarclisa expects a delayed key readout in the second half of the year in newly diagnosed multiple myeloma.Under generic pressure to its top-selling cancer drug Jevtana in Europe, Sanofi?s entire oncology portfolio brought in 244 million euros sales in the first quarter, up 6.8% at unchanged exchange rates.Overall, Sanofi?s first-quarter haul came in at 9.67 million euros, representing an 8.6% increase at constant currencies."