DOCSLIB.ORG

Safety and Toxicity of Combined Oclacitinib and Carboplatin Or Doxorubicin in Dogs with Solid Tumors: a Pilot Study Laura E

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Safety and Toxicity of Combined Oclacitinib and Carboplatin Or Doxorubicin in Dogs with Solid Tumors: a Pilot Study Laura E Barrett et al. BMC Veterinary Research (2019) 15:291 https://doi.org/10.1186/s12917-019-2032-4 RESEARCH ARTICLE Open Access Safety and toxicity of combined oclacitinib and carboplatin or doxorubicin in dogs with solid tumors: a pilot study Laura E. Barrett1, Heather L. Gardner2, Lisa G. Barber1, Abbey Sadowski1 and Cheryl A. London1* Abstract Background: Oclacitinib is an orally bioavailable Janus Kinase (JAK) inhibitor approved for the treatment of canine atopic dermatitis. Aberrant JAK/ Signal Transducer and Activator of Transcription (STAT) signaling within hematologic and solid tumors has been implicated as a driver of tumor growth through effects on the local microenvironment, enhancing angiogenesis, immune suppression, among others. A combination of JAK/STAT inhibition with cytotoxic chemotherapy may therefore result in synergistic anti-cancer activity, however there is concern for enhanced toxicities. The purpose of this study was to evaluate the safety profile of oclacitinib given in combination with either carboplatin or doxorubicin in tumor-bearing dogs. Result: Oclacitinib was administered at the label dose of 0.4–0.6 mg/kg PO q12h in combination with either carboplatin at 250-300 mg/m2 or doxorubicin at 30 mg/m2 IV q21d. Nine dogs were enrolled in this pilot study (n =4 carboplatin; n = 5 doxorubicin). No unexpected toxicities occurred, and the incidence of adverse events with combination therapy was not increased beyond that expected in dogs treated with single agent chemotherapy. Serious adverse events included one Grade 4 thrombocytopenia and one Grade 4 neutropenia. No objective responses were noted. Conclusions: Oclacitinib is well tolerated when given in combination with carboplatin or doxorubicin. Future work is needed to explore whether efficacy is enhanced in this setting. Keywords: Oclacitinib, Carboplatin, Doxorubicin, Chemotherapy Background [1]. Along with the role of JAK/STAT in driving normal The Janus Kinase (JAK) and Signal Transducer and Acti- cellular processes, STAT3, and to a lesser extent STAT5, vator of Transcription (STAT) protein families are import- are well defined contributors to tumor cell growth, while ant mediators of signal transduction for both cytokine and also promoting inflammation within the tumor micro- growth factor receptors involved in hematopoiesis and environment that supports disease progression [2–5]. inflammation. Upon ligand binding to cytokine receptors Given its crucial role in promotion of angiogenesis, inva- and subsequent transphosphorylation, JAKs activate intra- sion and metastasis, immune evasion, and cell prolifera- cellular signaling cascades through phosphorylation of tion and survival, the JAK/STAT3 pathway is an attractive STATs, which then act as transcription factors for a variety target for anti-neoplastic therapeutics. Several different of downstream targets. Specificity is determined by com- STAT3 inhibitors have been evaluated in vitro and mouse binations of particular JAK (JAK1, JAK2, JAK3, TYK2) models in vivo with variable success. Despite this progress, and STAT family members (STAT1, STAT2, STAT3, significant barriers to clinical translation remain including STAT4, STAT5a, STAT5b, STAT6), in addition to the development of a STAT3 specific inhibitor with limited cytokine or growth factor that initiated pathway activation off-target effects, a good pharmacokinetic profile and low clinical toxicity [2, 6, 7]. Given that much of STAT activa- * Correspondence: [email protected] tion is driven through JAKs, it is possible to manipulate 1Cummings School, Tufts University, Foster Hospital for Small Animals, 200 Westboro Rd, N., Grafton, MA 01536, USA the status of STAT phosphorylation through targeted Full list of author information is available at the end of the article inhibition of specific JAK family members. One JAK3 © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Barrett et al. BMC Veterinary Research (2019) 15:291 Page 2 of 7 inhibitor, tofacitinib, (Xeljanz®, Pfizer), has received ap- Methods proval from the Food and Drug Administration (FDA) for Eligibility the treatment of rheumatoid arthritis, psoriatic arthritis, This clinical trial was approved by the Institutional Animal and ulcerative colitis, and other JAK inhibitors are being Care and Use Committee at Tufts University and the Clin- investigated in a variety of immune-mediated inflamma- ical Studies Review Committee at the Cummings School of tory diseases in people [8, 9]. Ruxolitinib (Jakafi®, Incyte Veterinary Medicine. Written informed consent was ob- Corp.), a JAK1/JAK2 inhibitor, has been important in man- tained from owners prior to clinical trial enrollment. Client agement of myeloproliferative neoplasms, such as myelofi- owned dogs with cytologically and/or histologically con- brosis and polycythemia vera, in which gain-of-function firmed carcinoma, sarcoma, or melanoma with measurable mutationsinJAK2arefoundin50–95% of patients [7]. local or metastatic disease were eligible for enrollment. And while constitutive STAT3 phosphorylation is common Prior chemotherapy, radiation therapy, or other investiga- in many cancers, JAK inhibitors have had limited clinical tional drug was allowable with a one-week washout period efficacy as single agents for the treatment of advanced stage before enrollment. Inclusion criteria included age of at solid tumors in people thus far [7, 10, 11]. It is therefore least one year, modified ECOG performance score of 0–1, likely that biologic activity of JAK/STAT inhibition in the absolute neutrophil count > 1000, platelet count > 80,000, setting of solid tumors will require combination with other total bilirubin < 1.5x the upper limit of normal, alanine therapeutic modalities, such as chemotherapy. transaminase <3x the upper limit of normal, serum creatin- With respect to canine cancers, activation of JAK/STAT ine < 1.5x the upper limit of normal, and no other serious pathways have been documented in diffuse large B cell systemic disorder considered incompatible with the study. lymphoma, osteosarcoma, metastatic mammary carcin- Initial screening included physical examination, complete oma, and hemangiosarcoma [12–15]suggestingthatas blood count, serum biochemistry profile, urinalysis and with some human cancers, blockade of this pathway may thoracic radiographs and/or abdominal ultrasound for have biologic activity in dogs. Oclacitinib, a JAK inhibitor evaluation of metastatic disease. with significant structural similarities to tofacitinib, is FDA approved for the control of pruritus associated with allergic Drug product and concomitant medications dermatitis and the control of atopic dermatitis in dogs over Oclacitinib was provided by Zoetis (Parsippany, New 12 months of age. Oclacitinib has preference for JAK1 in- Jersey) in 3.6 mg, 5.4 mg, and 16 mg tablets. The target hibition over JAK2 at the recommended doses, causing dose of oclacitinib was 0.4–0.6 mg/kg orally every 12 h downregulation of JAK1/JAK3 dependent cytokines (IL-2, throughout the 42 day duration of the study. Concomitant IL-4, IL-6, IL-13, and IL-31), with minimal effects on medications acceptable for use included: metoclopramide, JAK2-dependent cytokines (erythropoietin (EPO) and ondansetron, maropitant, famotidine, ranitidine, omepra- granulocyte/monocyte-colony stimulating factor (GM- zole, metronidazole, bismuth subsalicylate, loperamide, CSF)) [16]. Oclacitinib has a favorable safety profile, butorphanol, tramadol, fentanyl, diphenhydramine, and S- though mild decreases in white blood cell and platelet adenosylmethionine/silybin. counts have been documented [17–20]. Similarly, ruxoliti- nib is associated with dose-dependent thrombocytopenia Study design and anemia in people with myelofibrosis [21, 22]. These The purpose of this study was to determine the safety and are expected adverse events, as the JAK/STAT pathway is tolerability of oclacitinib in combination with chemother- widely utilized by cytokines important in hematopoiesis, apy. This was a pilot study with the intent to assess ad- including GM-CSF, EPO and thrombopoietin (TPO) [23]. verse events associated with drug combination, so no Given the emerging role of STAT3 in canine cancers such power calculation was made. Patients were prospectively as osteosarcoma, there is interest in combining JAK/STAT enrolled into this trial and received either carboplatin inhibition (oclacitinib) with conventional chemotherapy. (Group 1) or doxorubicin (Group 2), based upon clini- However, there was concern that inhibition of cytokine sig- cian’s preference, tumor histology and prior chemotherapy naling critical for hematopoiesis would impair hematologic treatment (carboplatin versus doxorubicin). Because recovery from cytotoxic chemotherapy, particularly those several dogs has received prior chemotherapy, it was not known to cause myelosuppression, such as carboplatin possible to randomize dogs to the study groups. Dogs in and doxorubicin. Therefore, the purpose of this
Load more

Recommended publications
  • CVMP Assessment Report for APOQUEL (EMEA/V/C/002688/0000) International Non-Proprietary Name: Oclacitinib Maleate
    18 July 2013 EMA/481054/2013 Veterinary Medicines and Product Data Management Committee for Medicinal Products for Veterinary Use CVMP assessment report for APOQUEL (EMEA/V/C/002688/0000) International non-proprietary name: oclacitinib maleate Assessment report as adopted by the CVMP with all information of a commercially confidential nature deleted. 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8447 E -mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2013. Reproduction is authorised provided the source is acknowledged. Introduction The applicant Pfizer Animal Health S.A. submitted on 26 July 2012 an application for marketing authorisation to the European Medicines Agency (The Agency) for APOQUEL, through the centralised procedure falling within Article 3(2)(a) of Regulation (EC) No 726/2004 (new active substance). During the procedure the applicant changed to Zoetis Belgium S.A. The eligibility to the centralised procedure was confirmed by the CVMP on 12 January 2012 falling under Article 3(2)(a) of Regulation (EC) No 726/2004 as APOQUEL contains a new active substance which was not authorised in the Community on the date of entry into force of the Regulation. APOQUEL film-coated tablets contain oclacitinib (as oclacitinib maleate) as the active substance. There are three different strengths of the (film-coated) tablets, containing 3.6 mg, 5.4 mg and 16 mg oclacitinib (as the maleate salt), and each is contained in blister packs (polychlorotrifluoroethylene (PCTFE)/polyvinylchloride (PVC)/aluminium) which are supplied in outer cartons containing 20 or 100 tablets.
    [Show full text]
  • 5.10.20 Final Part 1 No Prelimeary Pages
    IDENTIFICATION OF NOVEL TREATMENT APPROACHES FOR HUMAN AND CANINE OSTEOSARCOMA By Ya-Ting Yang A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Comparative Medicine and Integrative Biology- Doctor of Philosophy 2020 ABSTRACT IDENTIFICATION OF NOVEL TREATMENT APPROACHES FOR HUMAN AND CANINE OSTEOSARCOMA By Ya-Ting Yang Osteosarcoma (OSA) is an aggressive neoplasm, characterized with high level of heterogeneity, high metastatic potential and poor prognosis in both humans and dogs. In this study, I used drug screening studies including existing therapeutic agents and novel compounds to identify more effective approaches to treat human and canine osteosarcoma. One of the challenges in the field of OSA is to identify optimal tools for study. A limited number of human and canine OSA cell lines are available. In this study, I established and characterized a new cell line, BZ, derived from a German shepherd dog with OSA and studied key oncogenic pathways in BZ. Our findings revealed activation of STAT3 and ERK pathways in BZ, as well as in a number of other cell lines, indicating that these two pathways are critical for cell survival and proliferation in OSA and the potential of using STAT3 and ERK inhibitors. Furthermore, I screened ten tyrosine kinase inhibitors (TKIs) on two dog and one human OSA cell lines. Among the selected TKIs, sorafenib showed promising results in effectively inhibited cell growth and migration in vitro studies. In addition, the effects of combing sorafenib with current chemotherapeutics (cisplatin, carboplatin, and doxorubicin) for OSA were investigated. Data from the combination index pointed to synergistic effects of sorafenib combined with doxorubicin and resulted in profound cell arrest at G2/M phase.
    [Show full text]
  • Successful Treatment of Atopic Dermatitis with the JAK1 Inhibitor Oclacitinib
    PROC (BAYL UNIV MED CENT) 2018;31(4):524–525 Copyright # 2018 Baylor University Medical Center https://doi.org/10.1080/08998280.2018.1480246 Successful treatment of atopic dermatitis with the JAK1 inhibitor oclacitinib Isabel M. Haugh, MB, BAO, BCha, Ian T. Watson,b and M. Alan Menter, MDa aDepartment of Dermatology, Baylor University Medical Center, Dallas, Texas; bTexas A&M College of Medicine, Bryan, Texas ABSTRACT We report the first case of atopic dermatitis successfully treated with the oral Janus kinase-1 (JAK1) inhibitor oclacitinib. A man in his 70s, with a 6-year history of skin disease refractory to topical and biologic therapies, self-prescribed this veterinary medication with rapid remission of symptoms. He has remained in remission for 7 months with no reported adverse side effects or infections. JAK1 plays a central role in expression of proinflammatory cytokines IL-4, IL-5, and IL-13, which play an important role in the pathogenesis of atopic dermatitis. Ruxolitinib and tofacitinib are JAK inhibitors currently approved by the Food and Drug Administration for the treat- ment of myelofibrosis, rheumatoid arthritis, and psoriatic arthritis in humans. Oclacitinib is not currently indicated for use in humans. KEYWORDS Atopic dermatitis; eczema; JAK1; oclacitinib clacitinib is a Janus kinase-1 (JAK1) inhibitor DISCUSSION approved for the treatment of pruritus secondary Oclacitinib selectively inhibits JAK1 of the JAK signal O to allergic dermatitis and atopic dermatitis in transducer and activator of transcription (JAK-STAT) path- canines. JAK1 plays a role in the expression of way, which plays a central role in cytokine signaling of pro- interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 inflammatory cytokines in atopic dermatitis, both in dogs (IL-13) in proinflammatory signaling pathways known to and in humans.
    [Show full text]
  • TITLE PAGE PASS Information
    TITLE PAGE PASS information Title Project Sc(y)lla: SARS-Cov-2 Large-scale Longitudinal Analyses on the comparative safety and effectiveness of treatments under evaluation for COVID-19 across an international observational data network Protocol version 1.1 identifier Date of last version of 28August2020 protocol EU PAS register number To be completed after protocol finalization Active substance Medicinal product Research question and The overarching objective is to evaluate the objectives comparative effects of COVID-19 treatments Country(-ies) of study France, Germany, Netherlands, South Korea, Spain, UK, and the USA. Others might join in the future. Authors Patrick Ryan Daniel Prieto-Alhambra on behalf of the OHDSI COVID consortium 1. TABLE OF CONTENTS 1. Table of contents ............................................................................................................................................. 2 2. List of abbreviations......................................................................................................................................... 3 3. Responsible parties .......................................................................................................................................... 3 5. Amendments and updates .............................................................................................................................. 4 7 Rationale and background...............................................................................................................................
    [Show full text]
  • APOQUEL® (Oclacitinib Tablet): Fast-Acting and Safe Itch Relief For
    APOQUEL® (oclacitinib tablet): Fast-Acting and Safe Itch Relief for Dogs Your veterinarian has recommended APOQUEL to help control your dog’s itch due to allergic skin disease. APOQUEL provides fast, effective relief from itch and inflammation without many of the side effects associated with steroids.1-3* *Common side effects of steroids include polyuria, polydipsia and polyphagia. Side effects of APOQUEL reported most often are vomiting and diarrhea. WHAT IS ALLERGIC SKIN DISEASE? Itching in dogs can be caused by fleas, food or environmental allergens such as pollens, molds or house-dust mites. The 4 most common allergies are: CONTACT ALLERGY ENVIRONMENTAL INDOOR FLEA FOOD (carpet, shampoo, AND OUTDOOR ALLERGENS ALLERGY ALLERGY environmental chemicals— (pollen, dust mites, or mold) insecticides, fertilizers) WHAT IS APOQUEL USED FOR? APOQUEL is used for the control of itch associated with allergic skin disease and for control of atopic skin disease in dogs at least 12 months of age. APOQUEL significantly reduces itching, and also decreases the associated inflammation, redness or swelling of the skin. WHAT CAN I EXPECT WHEN MY DOG RECEIVES APOQUEL? Fast Relief Unique Treatment APOQUEL starts to relieve itch within 4 hours, Unlike other treatments, APOQUEL targets a key itch signal in which is comparable to steroids. 3 the nervous system and has minimal impact on the immune system. APOQUEL effectively controls itch within 24 hours.1 APOQUEL also allows your veterinarian to continue to diagnose the underlying cause of itch while providing your dog with relief. 3,4 Safety APOQUEL is safe to use in dogs 12 months of age and older.
    [Show full text]
  • Development and Progression of Proteinuria in Dogs Treated with Masitinib for Neoplasia: 28 Cases (2010-2019)
    / PAPER Development and progression of proteinuria in dogs treated with masitinib for neoplasia: 28 cases (2010-2019) M. Kuijlaars1,*, J. Helm* and A. McBrearty* a.com *Small Animal Hospital, University of Glasgow, Glasgow, Scotland, G611QH, UK 1Corresponding author email: [email protected] v OBJECTIVES: To describe the incidence, severity and progression of proteinuria over the first 6 months of masitinib treatment in tumour-bearing dogs without pre-existing proteinuria. To describe the effect of treatment on urine protein:creatinine and renal parameters in patients with pre-existing proteinuria. MATERIALS AND METHODS: Records were reviewed from patients receiving masitinib for neoplasms between June 1, 2010, and May 5, 2019. Patients without pre-treatment and at least one urine protein:creatinine after ≥7 days treatment were excluded. Signalment, tumours and concurrent diseas- es, treatments, haematology, biochemistry and urinalysis results before, during and after treatment for up to 202 days were collected. Patient visits were grouped into six timepoints for analysis. .bsa RESULTS: Twenty-eight dogs were included. Eighteen percent of dogs non-proteinuric at baseline (four of 22) developed proteinuria during treatment, all within 1 month of treatment initiation. One dog developed hypoalbuminaemia, none developed oedema or ascites, azotaemia or were euthana- sed/died due to proteinuria. Masitinib was immediately discontinued in both dogs in which urine protein:creatinine greater than 2.0 was detected and in both, proteinuria improved. Six dogs with pre-treatment proteinuria were treated with masitinib, significant worsening of protein- uria did not occur. Neither azotaemia nor severe hypoalbuminaemia occurred. CLINICAL SIGNIFICANCE: Proteinuria, when it occurs, tends to develop within 1 month of masitinib com- mencement and may progress rapidly.
    [Show full text]
  • Recombinant Human Interferon-Alpha 14 for the Treatment of Canine
    Received: 8 June 2020 Revised: 15 January 2021 Accepted: 3 February 2021 DOI: 10.1002/vro2.6 RESEARCH ARTICLE Recombinant human interferon-α for the treatment of canine allergic pruritic disease in eight dogs Breno C. B. Beirão, Aline C. Taraciuk Carolina Trentin Max Ingberman Luiz F. Caron Chris McKenzie William H. Stimson, 1 Imunova Análises Biológicas LTDA, Curitiba, Abstract Brazil Background: Allergic pruritic diseases are increasingly common in dogs. This group 2 Departamento de Patologia Básica, Universidade of conditions hampers life quality as pruritus progressively interferes with normal Federal do Paraná, Curitiba, Brazil behaviours. Therefore, new treatment modalities for canine allergic pruritic diseases are 3 Veterinary Consultant, Avenida Nossa Senhora necessary. While novel drugs have recently reached the market, there is still the need for de Lourdes,63, Curitiba, Brazil other therapeutic approaches. Some dogs are refractory even to the newer compounds, 4 ILC Therapeutics Ltd. Biocity, Scotland, and cost is also an important issue for these. Older therapeutic modalities are only mod- Lanarkshire, UK erately successful or have considerable secondary efects, as is the case with glucocorti- 5 Immunology Department, Strathclyde University, Glasgow, Scotland, UK coids. Objectives: Report on the use of recombinant human interferon-α14 (rhIFN-α14) for Correspondence the treatment of canine allergic pruritus. Following the experience with a similar com- BrenoC.B.Beirão,ImunovaAnálisesBiológicas pound in the Japanese market, it was expected that rhIFN-α14couldaltertheTh1/Th2 LTDA,R.ImaculadaConceição,1430,Curitiba, disbalance that drives these diseases. 80215-182, Brazil. Email: [email protected] Methods: Here, we present an uncontrolled trial in which eight dogs with clinical diag- nosis of allergic pruritus were treated with rhIFN-α14,eitherorallyorviasubcutaneous Funding information: Imunova Análises Biológi- injections.
    [Show full text]
  • Supplementary Materials
    1 Supplementary Materials Figure S1. Flowchart of the Material and Methods: PRISMA flow diagram of the study. RCT, randomized controlled trial. 2 Table S1. Search strategies modified in MEDLINE (a), Embase (b), Cochrane CENTRAL (c), and Web of Science (d) a. Search strategy in MEDLINE (via Ovid MEDLINE(R), 1946–present; search date: 2021/01/29) # Search syntax Citations found 1 ("atopic dermatitis" OR eczema*).mp 2 exp "Dermatitis, Atopic"/ OR exp "Eczema"/ 3 ((Janus ADJ3 kinase* ADJ3 inhibit*) OR (JAK* ADJ3 inhibit*) OR Abrocitinib OR "PF-04965842" OR Baricitinib OR LY3009104 OR Olumiant OR INCB028050 OR Delgocitinib OR "JTE-052" OR Gusacitinib OR ASN002 OR Ruxolitinib OR INCB018424 OR INCA24 OR Tofacitinib OR Tasocitinib OR "Tofacitinib citrate" OR Xeljanz OR CP690550 OR Upadacitinib OR "ABT-494" OR RINVOQ OR Cerdulatinib OR "RVT-502" OR PRT062070 OR Peficitinib OR ASP015K OR Filgotinib OR GLPG0634 OR Solcitinib OR "1206163-45-2" OR GLPG0778 OR GSK2586184 OR SHR0302 OR "ATI-502" OR "ATI 50002" OR "A 301" OR "PF- 06700841" OR "RVT-501" OR Decernotinib OR "VX-509" OR Pacritinib OR SB1518 OR Oclacitinib OR Apoquel OR "PF-03394197" OR Fedratinib OR TG101348 OR SAR302503 OR "Fedratinib hydrochloride" OR Inrebic).mp 4 exp "Janus Kinase Inhibitors"/ 5 (1 OR 2) AND (3 OR 4) 195 b. Search strategy in Embase (via Ovid, 1974–present; search date: 2021/01/29) # Search syntax Citations found 1 ("atopic dermatitis" OR eczema*).mp 2 exp "atopic dermatitis"/ OR exp "eczema"/ 3 ((Janus ADJ3 kinase* ADJ3 inhibit*) OR (JAK* ADJ3 inhibit*) OR Abrocitinib
    [Show full text]
  • Veterinary Dermatology and the Human Counterpart
    “PARALLELS AND DIVERGENCE”: VETERINARY DERMATOLOGY AND THE HUMAN COUNTERPART Jackie Campbell, DVM, Diplomate ACVD Disclosure I have no actual or potential conflict of interest in relation to this program/presentation. Dermatology for Animals? Common diseases we treat and parallels Atopic Dermatitis and Cutaneous Adverse Food Reactions Immune mediated diseases: Pemphigus Complex, Uveodermatologic Syndrome, Vasculitis Neoplasia: Squamous cell carcinoma, Cutaneous T cell Lymphoma Miscellaneous “fun” stuff Zoonotic Aspect What can our patients give your patients? Methicillin resistant staphylococcus Dermatophyte Sarcoptes Allergen dander contribution Canine Atopic Dermatitis The most common dermatologic disease we treat in all species Canine atopic dermatitis increasingly common disease Pruritus Secondary pyoderma Secondary Malassezia Otitis Pododermatitis Clinical Signs Palmar aspect of carpi Periocular and Perioral Canine Atopic Dermatitis Comparable counterpart to human AD Pruritus, erythema Conjunctivitis, rhinitis not typical Pruritus frustrating for pet owners Secondary skin infections Secondary pyoderma Resistant Staph Pseudintermedius increasingly common Malassezia dermatitis Typically progressively worsens with age Classic Collarettes Hypothesis of Canine AD Genetic mutations associated with impaired epidermal barrier Filaggrin, ceramides Alterations in microbiome Breed predisposition Development of allergen specific IgE Th2 mediated response in acute phase IL4, IL6, IL13, IL31 Th1 shift in more
    [Show full text]
  • Leveraging Comparative Oncology to Maximize Translational Outcomes
    Leveraging Comparative Oncology to Maximize Translational Outcomes Cheryl London, DVM, PhD Research Professor, Tufts University Associated Faculty Professor, Ohio State University Consortium for Canine Comparative Oncology (C3O) Symposium Thomas Executive Conference Center, JB Duke Hotel February 17, 2017 High failure rate in oncology drug development Failure rate is not financially sustainable Amid flurry of new cancer drugs, how many offer real benefits? By Liz Szabo, Kaiser Health News Updated 4:01 AM ET Story highlights •Pushed by those who want earlier access to medications, FDA has approved a flurry of oncology drugs in recent years •A few have been home runs, allowing patients with limited life expectancies to live for years •But many more offer only marginal benefits, a researcher says Overall cancer survival has barely changed over the past decade. The 72 cancer therapies approved from 2002 to 2014 gave patients only 2.1 more months of life than older drugs, according to a study in JAMA Otolaryngology-Head & Neck Surgery. And those are the successes. Two-thirds of cancer drugs approved in the past two years have no evidence showing that they extend survival at all. The result: For every cancer patient who wins the lottery, there are many others who get little to no benefit from the latest drugs. Reasons for Failure Other 6% Financial 7% Safety 21% Efficacy 66% Most rodent models lack critical features of spontaneous neoplasia Many models use immunodeficient mice that lack key microenvironment components Cancer typically develops
    [Show full text]
  • Apoquel (Oclacitinib)
    Oclacitinib (ok-la-sit-ti-nib) Category: Anti-Itch & Anti-Inflammatory Agent Other Names for this Medication: Apoquel® Common Dosage Forms: Veterinary: 3.6 mg, 5.4 mg, & 16 mg tablets. Human: None. This information sheet does not contain all available information for this medication. It is to help answer commonly asked questions and help you give the medication safely and effectively to your pet. If you have other questions or need more information, contact your veterinarian or pharmacist. This drug SHOULD NOT be used in patients: Key Information XXThat are allergic to it. XXBecause oclacitinib is a new medication, be sure to report XXWith serious infections. any unexpected side effects to your veterinarian. XXThat are less than 12 months old. XXOclacitinib works quickly. Many dogs show improvement within the first few days of treatment. XXThat are used for breeding or are pregnant or lactating. XXThe most commonly reported side effects are vomiting, This drug should be used WITH CAUTION in patients: diarrhea, lack of appetite, increased thirst, and lethargy. XXWith ongoing infections. XXSerious side effects, including increased risk of infections If your pet has any of these conditions, talk to your veterinarian and skin disorders, are possible. about the potential risks versus benefits. XXThis medication is usually given twice a day for the first 2 weeks then decreased to once a day. What are the side effects of this medication? Due to its recent approval and limited clinical use, oclacitinib’s XXWash hands immediately after handling tablets. adverse effect profile is not fully known. Side effects commonly reported that usually are not serious include: How is this medication useful? XXVomiting, diarrhea, lack of appetite.
    [Show full text]
  • N141345 Apoquel Untitled Letter
    Dawn M. Cleaver, DVM Associate Director, Regulatory Affairs Zoetis, Inc. 333 Portage Street Kalamazoo, MI 49007 RE: NADA 141-345 APOQUEL® (oclacitinib tablet) Dear Dr. Cleaver, The U.S. Food and Drug Administration (FDA), Center for Veterinary Medicine (CVM), Division of Surveillance has reviewed the website for APOQUEL (oclacitinib tablet), https://www.zoetisus.com/products/dogs/apoquel/index.aspx. This website makes false or misleading representations about the risks associated with APOQUEL. The website therefore misbrands APOQUEL within the meaning of the Federal Food, Drug, and Cosmetic Act (FD&C Act), and makes its distribution violative. 21 U.S.C. 352(a), (n); 321(n); 331(a). Background Below are the indication and summary of the most serious and most common risks associated with the use of APOQUEL. According to the FDA-approved package insert (PI), APOQUEL is indicated for the control of pruritus associated with allergic dermatitis and control of atopic dermatitis in dogs at least 12 months of age. The PI contains warnings and precautions including the following: (1) should not be used in dogs with serious infections; (2) may increase susceptibility to infection, including demodicosis, and exacerbate neoplastic conditions; (3) is not for use in breeding dogs, or pregnant or lactating bitches; (4) has not been evaluated in combination with glucocorticoids, cyclosporine, or other systemic immunosuppressive agents; and (5) dogs receiving APOQUEL should be monitored for the development of infections, including demodicosis, and neoplasia. U.S. Food and Drug Administration Center for Veterinary Medicine 7500 Standish Place Rockville, MD 20855 www.fda.gov False or Misleading Risk Presentation Promotional materials misbrand a drug if they are false or misleading with respect to risk or benefits.
    [Show full text]