INNOVATION AND TECHNOLOGY

Transcription

1 INNOVATION AND TECHNOLOGY NEW THERAPIES FOR COMMON SKIN DISEASES 2017 NAVC PROCEEDINGS 1

2 TABLE OF CONTENTS ANTIMICROBIAL RESPONSIBILITY AND RESISTANCE 3 Improving Clinical Outcomes Mark Papich, DVM, MS, DACVCP John Angus, DVM, DACVD NOT JUST SKIN DEEP 7 The Game-Changing Science of Allergic Itch Andrea Gonzales, PhD SWITCH OFF THE ITCH 11 Practical Application of New Therapies Natalie Marks, DVM Lindsay McKay, DVM, DACVD 2

3 ANTIMICROBIAL RESPONSIBILITY AND RESISTANCE IMPROVING CLINICAL OUTCOMES Mark Papich DVM, MS, DACVCP Professor of Clinical Pharmacology North Carolina State University Affiliations: Chairholder of the Clinical and Laboratory Standards Institute (CLSI) Veterinary Antimicrobial Susceptibility Testing Subcommittee, member of the US Pharmacopeial Convention (USP) Expert Panel on Veterinary Drug Formulations Research: Define and improve rational drug therapy in animals; disposition of antibiotics and other drugs in a variety of animal species John Angus DVM, DACVD Veterinary Dermatologist Animal Dermatology Clinic Affiliations: Journal of the American Animal Hospital Association, Veterinary Dermatology ANTIMICROBIAL RESPONSIBILITY AND RESISTANCE: IMPROVING CLINICAL OUTCOMES 3

4 ANTIMICROBIAL RESPONSIBILITY AND RESISTANCE IMPROVING CLINICAL OUTCOMES TREATING CANINE SUPERFICIAL PYODERMA What Is the Organism Involved? Staphylococcus pseudintermedius is the most common bacterium isolated from superficial canine pyoderma 1 ANTIMICROBIAL STEWARDSHIP Choose an antibiotic with the best chance for RAPID and COMPLETE RESOLUTION of the infection What Is Your Job as the Veterinarian? First priority is to resolve the current infection EMPIRICAL TREATMENT WITH A SYSTEMIC ANTIMICROBIAL SAFETY Minimize risk to the patient EFFICACY Highest probability of success Spectrum of activity Distribution to target organ EASE OF USE Greater client compliance WHAT ARE THE ISCAID GUIDELINES? ISCAID = International Society for Companion Animal Infectious Diseases ISCAID guidelines available at Developed by a working group of clinical microbiologists, pharmacologists, and internal medicine specialists with expertise in infectious diseases and antimicrobial use Objectives To provide guidelines on: Antimicrobial drug choice Antimicrobial drug dosing Reducing inappropriate use 4 ANTIMICROBIAL RESPONSIBILITY AND RESISTANCE: IMPROVING CLINICAL OUTCOMES

5 WHAT DO THE GUIDELINES SAY? Understanding Antimicrobial Tiers: ISCAID Guidelines for Selecting a Systemic Antimicrobial Drug (AMD) for Superficial Bacterial Folliculitis (SBF) 1st Tier 1st or 2nd Tier 2nd Tier Primary choice empirical therapy of known or possible SBF Clindamycin or lincomycin 1st-generation cephalosporins (e.g., cephalexin, cefadroxil) Amoxicillin-clavulanate Trimethoprim- and ormetoprim-potentiated sulfonamides Clinical efficacy would support the inclusion of all of these drugs as 1st-tier AMDs 3rd-generation cephalosporins (i.e., cefovecin, cefpodoxime) Reserved primarily for infections caused by resistant strains Tetracyclines (i.e., doxycycline, minocycline) Chloramphenicol Fluoroquinolones Rifampin Aminoglycosides (e.g., gentamicin, amikacin) Why Are 3rd-Generation Cephalosporins Listed as Both 1st and 2nd Tier? According to Dr. Mark Papich: When these drugs were placed as either 1st or 2nd tier, it had nothing to do with inducing resistance for Staphylococcus. The concern was about the gram-negative organisms, particularly about the selection of the highly resistant, extended-spectrum beta-lactamase (ESBL)-producing organisms. This is a concern all over the world in food animals, companion animals, and human medicine. These are bacteria, primarily Escherichia coli, that produce an ESBL that renders the organisms resistant to the extended-spectrum drugs, particularly the 3rd-generation cephalosporins. OTHER TREATMENT FACTORS Duration of Treatment: Do All Patients Need 3-4 Weeks of Antibiotics? NO! 14 days of systemic cephalosporin resolves 86% of canine superficial pyoderma cases. 2 A recheck examination should be conducted to confirm the outcome. Topical Therapy: How and Why Should I Incorporate Topical Therapy? Topical drug therapy can deliver higher concentrations at the infection site Topical antibiotic therapy options for antimicrobial-resistant infections: Topical mupirocin ointment Topical fusidic acid Antibacterial shampoos, mousses, and sprays Remember: Skin is on THE OUTSIDE. ANTIMICROBIAL RESPONSIBILITY AND RESISTANCE: IMPROVING CLINICAL OUTCOMES 5

6 ANTIMICROBIAL RESISTANCE Why Might Empirical Treatment Fail? Key organism of interest in cases of antibiotic-resistant canine dermatologic infections: Methicillin-resistant Staphylococcus pseudintermedius (MRSP) The number one factor for the selection of antibiotic resistance is THE USE OF ANY AND ALL ANTIBIOTICS. What Should I Do If I Suspect an MRSP Infection? STEP 1. Get a reliable culture and susceptibility test. To determine which of the following drugs will be effective in a specific case Long-term: Can help track resistance trends in own practice area STEP 2. Select an appropriate antibiotic based on results of the culture and susceptibility test. 2nd-Tier Antimicrobial Options Rifampin Clindamycin Chloramphenicol Fluoroquinolones Tetracyclines Aminoglycosides (gentamicin, amikacin) Other Options Rarely used in animals and expensive Vancomycin Linezolid KEY TAKEAWAYS 1. Antimicrobial stewardship Clinically relevant resistance occurs when antibiotics are used at therapeutic doses Use antibiotics only when needed Use the BEST antibiotic for the SHORTEST period of time to achieve RAPID and COMPLETE resolution 2. Include topical therapy Don t worry about overbathing dogs 3. If antibiotic therapy fails, conduct a culture and susceptibility test REFERENCES 1. Bacterial skin diseases. In: Medleau L, Hnilica KA, eds. Small Animal Dermatology: A Color Atlas and Therapeutic Guide. 2nd ed. Philadelphia, PA: Elsevier; 2006: Six R, Cherni J, Chesebrough R, et al. Efficacy and safety of cefovecin in treating bacterial folliculitis, abscesses, or infected wounds in dogs. JAVMA. 2008;233: ANTIMICROBIAL RESPONSIBILITY AND RESISTANCE: IMPROVING CLINICAL OUTCOMES

7 NOT JUST SKIN DEEP THE GAME-CHANGING SCIENCE OF ALLERGIC ITCH Andrea Gonzales PhD Senior Research Director, Global Therapeutics Research Zoetis LLC PhD, University of North Carolina at Chapel Hill, 1997 Research: Understanding mechanisms involved in the pathobiology of canine atopic dermatitis and identifying new targets for therapeutic intervention in allergic conditions in companion animals NOT JUST SKIN DEEP: THE GAME-CHANGING SCIENCE OF ALLERGIC ITCH 7

8 NOT JUST SKIN DEEP THE GAME-CHANGING SCIENCE OF ALLERGIC ITCH THE SCIENCE OF ITCH What Is PRURITUS? Itching an unpleasant sensation that triggers the desire to scratch. 1 Acute = Essential defense mechanism to warn host against potentially harmful substances on the skin Chronic = Not advantageous to host; impacts quality of life Allergy and Itch: A CHANGING PERSPECTIVE CURRENT VIEW OF ALLERGIC ITCH Crosstalk between: The skin The immune system The nervous system Defective skin barrier Immune dysregulation Itch signals are mediated by the nervous system Numerous chemical mediators including cytokines act on itch receptors on nerve endings What Are CYTOKINES? A type of cell mediator; messenger proteins secreted by cells to communicate with other cells. Functions: Initiate or control immune and inflammatory responses Communicate with non-immune cells such as neurons Cytokine dysregulation can contribute to disease conditions Drive clinical signs associated with allergic skin disease Neuronal Itch Stimulation Scratching Inflammatory Processes Proallergic cytokine receptor Extracellular Intracellular JAK enzyme Cytokine The Janus kinase (JAK) signaling pathway is implicated in allergic itch. Proallergic cytokines bind to receptors that activate JAK signaling pathways When activated, the result is a vicious cycle of neuroimmunological interaction and pruritus A large body of evidence implicates the cytokine IL-31 in pruritic skin conditions in dogs, 2 humans, and other mammalian species Downstream signal cascade THEREFORE: Proallergic and pruritogenic cytokines that activate JAK signaling pathways are primary targets for therapeutic modulation of allergic itch. 8 NOT JUST SKIN DEEP: THE GAME-CHANGING SCIENCE OF ALLERGIC ITCH

9 TARGETED SOLUTIONS FOR ALLERGIC ITCH OCLACITINIB An Intracellular Solution Oclacitinib (APOQUEL, Zoetis) binds to JAK enzymes associated with the intracellular component of the receptor for proallergic and pruritogenic cytokines Inactivation of the enzyme prevents initiation of the subsequent signaling cascade Oclacitinib blocks the JAK signaling pathway, resulting in interruption of the function of proallergic and pruritogenic cytokines Oclacitinib decreases pruritus associated with allergic dermatitis 3 Proallergic cytokine receptor Extracellular Intracellular Oclacitinib (APOQUEL ) JAK enzyme Proallergic cytokines IL-2 IL-13 IL-4 IL-31 IL-6 Downstream signaling is blocked IMPORTANT SAFETY INFORMATION Do not use APOQUEL in dogs less than 12 months of age or those with serious infections. APOQUEL may increase the chances of developing serious infections, and may cause existing parasitic skin infestations or pre-existing cancers to get worse. APOQUEL has not been tested in dogs receiving some medications including some commonly used to treat skin conditions such as corticosteroids and cyclosporines. Do not use in breeding, pregnant, or lactating dogs. Most common side effects are vomiting and diarrhea. APOQUEL has been used safely with many common medications including parasiticides, antibiotics and vaccines. ANTI-IL-31 MONOCLONAL ANTIBODY THERAPY An Extracellular Solution MONOCLONAL ANTIBODIES Lab-produced antibodies that bind to a single epitope (binding site) on a specific antigen Anti-IL-31 monoclonal antibody (mab) therapy (CYTOPOINT, Zoetis) prevents IL-31 from binding to its receptor When IL-31 cannot bind to its receptor, the itch signal cannot be transmitted IL-31 cytokine Proallergic cytokine receptor Extracellular Anti-IL-31 mab (CYTOPOINT ) cytok Extrac The anti-il-31 mab resulted in a significant reduction and inhibition of pruritus in an IL-31-induced pruritus model 4 Intracellular JAK enzyme Receptor remains inactive; downstream signaling is not triggered Intrace JAK The Ins and Outs of Monoclonal Antibody Therapy Administration Distribution Catabolism Subcutaneous, intramuscular, or intravenous 50%-100% bioavailability Through interstitial fluid, lymphatics, and blood system Does not passively penetrate cell membranes or cross the blood-brain barrier Broken down by cells into peptides and amino acids Extended half-life NOT metabolized by kidney or liver enzymes Drug-drug interactions are rare No conversion to reactive or toxic metabolites NOT JUST SKIN DEEP: THE GAME-CHANGING SCIENCE OF ALLERGIC ITCH 9

10 CYTOPOINT : EFFICACY & SAFETY EFFICACY Mean Pet Owner Assessed Pruritus Visual Analog Scale (VAS) Pruritus Severity Descriptions (Owner VAS) Extremely Severe Severe Moderate Mild Very Mild Normal Dose Administered Day of Study CYTOPOINT 2.0 mg/kg Placebo Least Squares Mean Owner VAS Score (mm) CYTOPOINT is an injectable caninized anti-il-31 monoclonal antibody that aids in the reduction of clinical signs of atopic dermatitis in dogs. Mean pruritus scores were significantly different from placebo-treated dogs after 24 hours. 5 Mean pruritus scores were in the mild to very mild range from Day 2 and continued for 6 weeks. 5 SAFETY Field Safety Study Adverse health events associated with CYTOPOINT were comparable to placebo-treated client-owned dogs with atopic dermatitis 5 Laboratory Safety Study No adverse treatment-related effects were observed in a laboratory safety study in which 7 consecutive monthly subcutaneous injections of CYTOPOINT were administered to laboratory beagles at doses of 3.3 mg/kg or 10 mg/kg (12 dogs per group) 6 KEY TAKEAWAYS The cytokine IL-31 is a key molecule in allergic itch. Therefore, blocking the action of IL-31 has therapeutic benefits in the control of allergic itch. INTRACELLULAR: Oclacitinib (APOQUEL, Zoetis) binds and inhibits JAK enzymes within a cell that associate with proallergic cytokine receptors JAK enzymes are activated AFTER a cytokine, including IL-31, binds to the receptor Oclacitinib inactivates subsequent JAK-dependent signaling cascades, reducing pruritus and clinical signs of allergic dermatitis EXTRACELLULAR: Anti-IL-31 mab therapy (CYTOPOINT, Zoetis) prevents IL-31 from binding to IL-31 receptors on cutaneous sensory nerves The receptor remains inactive, thus aiding in the reduction of clinical signs of atopic dermatitis REFERENCES 1. Rothman S. Physiology of itching. Physiol Rev. 1941;21(2): Gonzales A, Humphrey W, McCall R, et al. Interleukin-31: its role in canine pruritus and naturally occurring canine atopic dermatitis. Vet Derm. 2013;24(1):48-53.e Data on file, Study Report No. 7B61W , Zoetis Inc. 4. Data on file, Study Report No. C660Z-US , Zoetis Inc. 5. Data on file, Study Report No. C961R-US , Zoetis Inc. 6. Data on file, Study Report No. C863R-US , Zoetis Inc. 10 NOT JUST SKIN DEEP: THE GAME-CHANGING SCIENCE OF ALLERGIC ITCH

11 SWITCH OFF THE ITCH PRACTICAL APPLICATION OF NEW THERAPIES Natalie Marks DVM Veterinarian/Co-Owner Blum Animal Hospital American Veterinary Medical Foundation (AVMF) award for America s Favorite Veterinarian Affiliations: American Animal Hospital Association (AAHA), American Veterinary Medical Association (AVMA), Illinois State Veterinary Medical Association (ISVMA), Chicago Veterinary Medical Association (CVMA) Lindsay McKay DVM, DACVD Veterinary Dermatologist VCA Arboretum View Animal Hospital Affiliations: American College of Veterinary Dermatology (ACVD), American Academy of Veterinary Dermatology (AAVD), Chicagoland Veterinary Dermatology Group (CVDG) SWITCH OFF THE ITCH: PRACTICAL APPLICATION OF NEW THERAPIES 11

12 SWITCH OFF THE ITCH PRACTICAL APPLICATION OF NEW THERAPIES MANAGEMENT OF PRURITUS ASSOCIATED WITH ALLERGIC AND ATOPIC DERMATITIS Important Principles for Management of Allergic Patients Client Communication Set client expectations for prognosis and management Client Education Allergies may not be curable, but there are new options for customized therapy Follow-Up and Recheck Examinations A structured workup is necessary to make a specific diagnosis Re-evaluation during this process is critical for optimization of results MECHANISMS OF ITCH Proallergic cytokine receptor Cytokine Scratching Extracellular Intracellular JAK enzyme Neuronal Itch Stimulation Inflammatory Processes Downstream signal cascade The Janus kinase (JAK) signaling pathway is implicated in allergic itch. When activated, the result is a vicious cycle of neuroimmunological interaction and pruritus. A number of proallergic cytokines (cell-to-cell messenger proteins) bind to receptors of the JAK signaling pathway. Factors to Manage in Allergic/Atopic Dermatitis Pruritus (itch) Inflammation Secondary infections Skin barrier 12 SWITCH OFF THE ITCH: PRACTICAL APPLICATION OF NEW THERAPIES

13 TARGETED SOLUTIONS FOR ALLERGIC ITCH WHICH SOLUTION Is Right for My Patient? Oclacitinib (APOQUEL, Zoetis) Indications For the relief of pruritus within 4 hours, without the negative side effects associated with steroids For any allergic dermatitis Suitable for dogs at least 12 months of age Rapid itch relief during workup of allergic cases Anti-IL-31 monoclonal antibody (mab) therapy (CYTOPOINT, Zoetis) For sustained relief within hours of pruritus associated with canine atopic dermatitis Suitable for ANY dog, including cases where other treatments may be problematic (see page 14 for examples) Administration and Dosing Daily oral administration May be used on long-term basis Flexible dosing allows start/stop quickly and avoids tapering Subcutaneous injection Duration lasting 4-6 weeks Nonpharmaceutical; no known drug-to-drug interaction OCLACITINIB: A JANUS KINASE INHIBITOR Proallergic cytokine receptor Extracellular Intracellular Oclacitinib (APOQUEL ) JAK enzyme Proallergic cytokines IL-2 IL-13 IL-4 IL-31 Downstream signaling is blocked Flea allergy dermatitis flares (with appropriate flea control) Food allergy trial Contact allergy flare Atopic flare Hot spots (with appropriate antimicrobial therapy) Sarcoptic mange (with appropriate miticidal therapy) IL-6 Oclacitinib (APOQUEL, Zoetis) provides rapid, effective itch relief for dogs 1 without the side effects commonly experienced with steroids, while diagnosing underlying allergy, including: Parasites Infections Food or contact allergy Atopic dermatitis APOQUEL can be used for acute, subacute, and as needed pruritus relief. Probable allergy dermatitis Itch relief during allergy testing Itch relief during treatment of otitis externa Itch relief while waiting for antibiotics to have effect IMPORTANT SAFETY INFORMATION Do not use APOQUEL in dogs less than 12 months of age or those with serious infections. APOQUEL may increase the chances of developing serious infections, and may cause existing parasitic skin infestations or pre-existing cancers to get worse. APOQUEL has not been tested in dogs receiving some medications including some commonly used to treat skin conditions such as corticosteroids and cyclosporines. Do not use in breeding, pregnant, or lactating dogs. Most common side effects are vomiting and diarrhea. APOQUEL has been used safely with many common medications including parasiticides, antibiotics and vaccines. SWITCH OFF THE ITCH: PRACTICAL APPLICATION OF NEW THERAPIES 13

14 CYTOPOINT : ANTI-IL-31 MONOCLONAL ANTIBODY THERAPY A Case-Based Review of Key Benefits CYTOPOINT (Zoetis) neutralizes IL-31, the neuronal itch initiator. Provides long-lasting relief from atopic dermatitis with a single in-clinic injection 2 IL-31 cytokine Proallergic cytokine receptor Anti-IL-31 mab (CYTOPOINT ) cytok Extracellular Extra CYTOPOINT can be used in ANY DOG with atopic dermatitis. Consider also cases of canine atopic dermatitis where other treatments may be problematic, such as in the examples below. Intracellular JAK enzyme Receptor remains inactive; downstream signaling is not triggered Intrac JAK Rapid Onset The SHORT SEASON atopic RAPID ONSET OF EFFECT and LONG DURATION for as-needed therapy. Appropriate for patients with clinical signs lasting only a few months per year Long Duration The YOUNG or TINY atopic SAFE for small or young patients. Alternative to pharmaceutical options that may be difficult to dose in small patients or not indicated for young patients Safe The SENSITIVE or HARD-TO-MEDICATE atopic EASE OF ADMINISTRATION and improved compliance for patients that are difficult to dose orally. SAFE for patients that have GI sensitivities or experience adverse effects from other treatments. Ease of Administration No Drug Interaction Targeted The atopic with CONCURRENT DISEASE The REFRACTORY atopic NO DRUG INTERACTIONS for patients being treated with other pharmaceuticals. SAFE for patients with comorbidities. Including those with infections or undergoing chemotherapy TARGETED therapy neutralizes IL-31. May be effective in patients unresponsive to other therapies REFERENCES 1. Data on file, Study Report No. 7B61W , Zoetis Inc. 2. Data on file, Study Report No. C660Z-US , Zoetis Inc. 14 SWITCH OFF THE ITCH: PRACTICAL APPLICATION OF NEW THERAPIES

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