Inflammatory Bowel Disease: A Panel Discussion on Clinical and Operational Strategies for Biologic Usage

© 2020. All rights reserved. No part of this report may be reproduced or distributed without the expressed written permission of PTCE. This activity is supported by an educational grant from Takeda Pharmaceuticals U.S.A., Inc. Moderator

Rolf Benirschke CEO Legacy Health Strategies San Diego, California Panelists

Patrick Nichols, PharmD Christopher Owens, PharmD, MPH Clinical Pharmacist Associate VP for Health Sciences Vanderbilt University Medical Center Associate Professor Nashville, Tennessee Idaho State University College of Pharmacy Pocatello, Idaho Faculty Disclosures

Rolf Benirschke; Patrick Nichols, PharmD; and Christopher Owens, PharmD, MPH, have no relevant financial relationships with commercial interests to disclose. Pharmacy Times Continuing Education™ Planning Staff: Jim Palatine, RPh, MBA; Maryjo Dixon, RPh, MBA; Rose Namissa, PharmD, BCPS; Brianna Schauer, MBA; Susan Pordon; and Brianna Winters have no financial relationships with commercial interests to disclose. An anonymous peer reviewer has been used as part of content validation and conflict resolution. The peer reviewer has no relevant financial relationships with commercial interests to disclose. The content of this activity may include information regarding the use of products that may be inconsistent with, or outside the approved labeling for, these products in the United States. Pharmacists should note that the use of these products outside current approved labeling is considered experimental and are advised to consult the prescribing information for these products. Educational Objectives

After completion of this activity, participants will be able to: • Explain the effect that uncontrolled inflammatory bowel disease (IBD) has on patient quality of life • Examine relevant safety and efficacy data associated with current and emerging agents for treating IBD • Identify specialty pharmacy operational practices that have the greatest effect on improving patient outcomes Part I: Introduction Inflammatory Bowel Disease (IBD)

IBD includes 2 major types of chronic, idiopathic, autoimmune conditions of the gastrointestinal tract that result in significant morbidity, impairments in function and quality of life, and health care costs

Crohn disease (CD) Ulcerative colitis (UC) • May occur • Confined to the anywhere along the rectum and colon GI tract (sometimes • Affects all layers— “backwash ileitis”) “transmural” and • Affects colonic characterized by epithelium, “skip lesions” mucosa, and submucosal layers

While seemingly discrete conditions, both are increasingly recognized as “segmented” or heterogenous in nature – wide variation in presentations, complications, prognosis Crohn’s Disease & Ulcerative Colitis, Comparison. Image supplied by Monica Schroeder/SCIENCESOURCE. Hemstreet BA. Inflammatory Bowel Disease. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e. McGraw-Hill. accesspharmacy.mhmedical.com. Etiology of IBD • Increased permeability • Mucosal Complex interaction of inflammation genetic, Intestinal barrier microbial/intestinal, Environment immunologic, and • Smoking • Diet environmental factors • Medications Genetics • NSAIDS • Isotretinoin • Stress • Increased susceptibility • Alteration of gut microbiota • Genetic polymorphisms Immune response

• Impaired barrier function • Immune system dysregulation

Adapted from Ramos GP, Papadakis KA. Mayo Clin Proc. 2019; 94(1):155-165. Burden of IBD Medical Economic Quality of Life Issues Opportunities for Specialty Pharmacists to Improve or Enhance the Care of Patients With IBD Initial and follow-up counseling

Ensure access to prescribed specialty medications

Explain importance of adherence in achieving treatment goals

Provide information about therapeutic drug monitoring (TDM)

Discuss importance of smoking cessation and other nonpharmacologic options Question & Answer Session 1 Part II: Treatment Paradigm Pathophysiology

JAK Inhibitors: Tofacitinib Upadacitinib Filgotinib

TNF Antagonists: Certolizumab

Phosphodiestrase-4 inhibitor: Apremilast

Anti--12/23: Anti-interleukin-23: Risakizumab Sphingosine 1-Phospate Guselkimab Receptor S1PR: Anti-Leukocyte Trafficking, Anti-Adhesion: Ozanimod Anti-MAdCAM Reprinted from Lancet, 389/10080, Ungaro R, et al, “Ulcerative colitis,” 1756-1770 Copyright 2017, with permission from Elsevier. Reprinted from The Lancet, 389, Ungaro R, et al, “Ulcerative colitis,” 7156-7770 Copyright 2017, with permission from Elsevier. Medications for IBD Crohn disease Ulcerative colitis

Sulfasalazine 5-Aminosalicylates Sulfasalazine, mesalamine, olsalazine, balsalazide Prednisone Prednisone Budesonide EC Corticosteroids Budesonide MMX Foam/Enema/Suppository Foam/Enema/Suppository Azathioprine/6-MP Azathioprine/6-MP Methotrexate Immunomodulators Cyclosporine Tacrolimus Tacrolimus Infliximab Infliximab Adalimumab Adalimumab Biologics Golimumab Vedolizumab Vedolizumab Ustekinumab Ustekinumab

Small molecule Tofacitinib

Lichtenstein GR, et al. Am J Gastroenterol. 2018;113(4):481-517; Rubin DT, et al. Am J Gastroenterol. 2019:114:1. Biologics: TNFα Inhibitors Infliximab Adalimumab Certolizumab pegol Golimumab (Remicade) (Humira) (Cimzia) (Simponi) Pharmacology Human (75%)-murine Human antibody (Ab) PEGylated Fab’ fragment, Human Ab (25%) antibody human Ab FDA indications CD and UC (+ pediatric): CD (+ pediatric): induction CD: maintenance UC: induction induction, maintenance UC: induction, Mod-severe, with maintenance inadequate response/intolerant to prior tx Route IV (vial) SC (Pen, PFS, vial) SC (PFS, vial) SC (Smartject, PFS) Administration I: 5 mg/kg at weeks 0, 2, I: 160 mg, then 80 mg at I: 400 mg at weeks 0, 2, and I: 200 mg, then 100 mg at and 6 week 2 4 week 2 M: 5 mg/kg Q8 weeks M: 40 mg Q2 weeks M: 400 mg Q4 weeks M: 100 mg Q4 weeks Adverse effects Infusion reaction, serum Injection-site reaction, Injection-site reaction, Injection-site reaction, sickness, malignancy, malignancy, malignancy, malignancy, serious infection, serious infection serious infection serious infection increased mortality III/IV heart failure Love BL. Am J Manag Care. 2016;22(suppl 3):s39-s50. Other Biologics Natalizumab* Vedolizumab Ustekinumab (Tysabri) (Entyvio) (Stelara) Pharmacology Human antibody (Ab) directed at Human Ab directed at α4 subunit Human IL-12/23 antagonist, α4 subunit of α4β1 and α4β7 of α4β7 integrin; inhibits decreases IL-12/23–mediated integrins; inhibits lymphocyte lymphocyte migration signaling responsible for chronic migration inflammation FDA indications CD: induction, maintenance CD: induction, maintenance CD: induction, maintenance UC: induction, maintenance UC: induction, maintenance

Route IV (vial) IV (vial) IV (induction, vial) SC (maintenance, PFS) Administration I: 300 mg x 1 I: 300 mg at 0, 2, and 6 weeks I: 260–520 mg (based on ABW) IV x M: 300 mg Q4 weeks M: 300 mg Q8 weeks 1, then 8 weeks M: 90 mg SC Q8 weeks Adverse effects Injection-site reactions Injection-site reactions, serious Injection-site reactions, serious Progressive multifocal infection, nasopharyngitis infection, malignancy, RPLS leukoencephalopathy (PML) No reported cases of PML <0.1%; limited availability* *Restricted distribution program (TOUCH) to minimize PML. Love BL. Am J Manag Care. 2016;22(suppl 3):s39-s50; Scherl EJ, et al. Therap Adv Gastroenterol. 2010;3(5):321-328. Small Molecule Tofacitinib (Xeljanz)

Pharmacology Janus kinase (JAK) inhibitor

FDA indications UC: induction, maintenance

Route Oral Administration 10 mg PO BID (or 22 mg daily for XR) for 8-16 weeks; if responsive, maintain

Adverse effects/ • Not recommended to combine with biologics or immunosuppressants monitoring • Dose-dependent herpes zoster risk; consider recombinant shingles vaccine • Monitoring • Lipid profile at week 4-8 • CBC/diff baseline, weeks 4 and 8, and every 3 months • Skin exam annually (increased nonmelanoma risk) • Liver enzymes every 3 months

Xeljanz. Prescribing information. Pfizer Inc; 2020; Sandborn WJ, et al. N Engl J Med. 2017;376:1723-1736. Updated IBD Treatment Guidelines

• Paradigm shift in management • Separate disease activity from disease severity • Include prognosis when deciding on induction and maintenance therapy • Focus on mucosal healing and objective evidence of disease control, including fecal calprotectin • Consider provider and patient treatment goals • All biologics are appropriate first-line for patients whose disease severity warrants it

Lichtenstein GR, et al. Am J Gastroenterol. 2018;113(4):481-517; Rubin DT, et al. Am J Gastroenterol. 2019:114:1. AGA Clinical Care Pathways: Risk Factors for More Severe Disease Course • Crohn Disease • Ulcerative Colitis • Early age at diagnosis (<30) • Age <40 • Extensive anatomic involvement • Extensive colitis • Perianal and/or severe rectal • Steroid-requiring disease disease • Deep ulcers • Deep ulcers • History of hospitalization • Prior surgical resection • High CPR and ESR • Strictures and/or penetrating • C diff infection behavior • Cytomegalovirus (CMV) infection

American Gastroenterological Association. Guidelines for the identification, assessment, and initial medical treatment in CD and UC. Accessed March 3, 2020. gastro.org/guidelines Clinical Management vs Treat-to-Target: The CALM Study

Colombel JF, et al. Lancet. 2018;390(10114):2779-2789. Goals of Therapy

Biologic: Prevent complications normalization of biomarkers • Therapy adverse effects/toxicity Levels of Remission • Hospitalizations Histologic: • ED visits mucosal healing • Surgery Steroid-free: • Cancer risk avoid repeated courses of OCS Enhance quality of life Clinical: • Pain and discomfort absence of • Weight and nutrition symptoms • Sleep quality and energy • Social and physical activities • Occupational productivity

Reenaers C, et al. World J Gastroenterol. 2012;18(29):3823-3827; Hommes D, et al. J Crohns Colitis. 2012;6(suppl 2):S224-S234; Kim AH, et al. J Crohns Colitis. 2018;12(4):408-418. Window of Opportunity for Improved IBD Outcomes

Another intervention point

Republished from Colombel JF, et al. 13th Congress of the European Crohn’s and Colitis Organisation. February 16, 2018. emjreviews.com/gastroenterology/symposium/individualised-care-for-crohns-disease-evolving-approaches-for-a-progressive-disease/ Available under the terms of a Creative Commons Attribution Non-Commercial 4.0 License (creativecommons.org/licenses/by-nc/4.0/). Treatment Goals Treatment Considerations

Dosage Form Route Coverage

• PO, IV, SC • Convenience • Insurance • Patient formulary/prior preference authorization Biosimilars Biosimilars • FDA-approved agents (as of December 2019) include: • Infliximab-dyyb • Adalimumab-atto • Infliximab-abda • Adalimumab-adbm • Infliximab-qbtx • Adalimumab-adaz • Infliximab-axxq • Adalimumab-bwwd • Adalimumab-afzb • Reference: Purple Book • Optimal place in therapy has not been established • Expected to have significant cost savings; potentially a 30% reduction in cost • Many providers may not be confident with equivalence in efficacy and safety

Deiana S, et al. World J Gastroenterol. 2017;23(2):197-203; Danese S, et al. Nat Rev Gastroenterol Hepatol. 2017;14(1):22-31; FDA. Biosimilar product information. Accessed April 25, 2020. www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm580432.htm. fda.gov/drugs/biosimilar-product-information What’s New? VARSITY Study

Figures from N Engl J Med, Sands BE, et al, “Vendolizumab versus adalimumab for moderate-to-severe ulcerative colitis,” 381, 1215-1225 © 2020 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. New Approvals/Indications

• Ustekinumab • Now approved to treat adult patients with moderately to severely active ulcerative colitis • Dosing schedule is identical to Crohn disease • Patient will receive a weight-based IV induction dose • Maintenance dosing is 90 mg SC every 8 weeks beginning 8 weeks after IV dose • Tofacitinib • Extended release (XR) now approved for the treatment of moderately to severely active ulcerative colitis in patients who have had an inadequate response or intolerance to TNF-blockers • XR 22 mg should be used once daily for 8 weeks, then evaluated for transition to maintenance therapy • XR 22 mg should be discontinued after 16 weeks if adequate therapeutic response is not achieved • XR 11 mg once daily is used for maintenance dosing • XR 22 mg once daily may be considered for short duration if patient loses response to maintenance dosing

Stelara. Prescribing information. Janssen Biotech; 2020; Xeljanz/Xeljanz XR. Prescribing information. Pfizer Inc; 2019. Question & Answer Session 2 Pipeline Therapies IBD Treatment Pipeline

• SC vedolizumab (VDZ) • Being developed as alternative to IV formulation • VISIBLE 1 • Phase 3 trial demonstrated SC VDZ is as effective as IV VDZ maintenance therapy in patients with moderately to severely active UC who had a clinical response to IV VDZ induction • If approved, will require IV induction followed by SC injections • Presents teaching and other opportunities for specialty pharmacists

• IL-23 inhibitors • , , , , brazikumab • Being studied for treatment of CD and/or UC

Jairath V, et al. Am J Gastroenterol. 2019;114:S10; Sandborn WJ, et al. Gastroenterology. 2020;158(3):537-549; Clinicaltrials.gov IBD Treatment Pipeline

• Etrolizumab • Anti-ß7 integrin antibody • HICKORY trial is phase 3 study evaluating etrolizumab for induction and maintenance of remission in patients with moderately to severely active UC who were previously exposed to anti-TNFs • Ontamalimab • Anti-MAdCAM-1 antibody • TURANDOT and TURANDOT II demonstrate ability of ontamalimab to induce remission in moderately to severely active UC • Etrasimod • Oral, selective sphingosine 1-phosphate receptor (S1P) modulator • Promising results in early studies in UC

Danese S, et al. Am J Gastroenterol. 2019;114: S21-S22; Danese S. Gastroenterology. 2020;158(3):467-470; Sandborn WJ, et al. Gastroenterology. 2020;158(3):550-561; ClinicalTrials.gov. Accessed May 7, 2020. clinicaltrials.gov/ct2/show/NCT02100696 IBD Treatment Pipeline

• Janus kinase (JAK) inhibitors • Oral “small molecules” • Current • Tofacitinib is currently only JAK inhibitor approved for use in IBD (UC) • Investigational • Upadacitinib is approved for treatment of rheumatoid arthritis • Being studied for treatment of CD and UC • Filgotinib • New drug application submitted for rheumatoid arthritis treatment • Being studied for treatment of CD and UC

Danese S. Gastroenterology. 2020;158(3):467-470; Clinicaltrials.gov Specialty Pharmacists Optimizing Outcomes Monitoring Parameters

Screening for Vaccinations Heart Failure Adverse Effects Hep B and TB

Injection site, Therapeutic FDA Black Box Behavioral infusion, and Drug Monitoring Warnings Health others (TDM)

Garcia-Doval I, et al. Br J Dermatol. 2017;176(3):643; Mocci G, et al. J Crohns Colitis. 2013;7(10):769-79; Cheifetz A, et al. Am J Gastroenterol. 2003;98(6):1315. Gabriel SE. Arthritis Rheum. 2008;58(3):637. Feuerstein JD, et al. Gastroenterology. 2017;153(3):827-834. Farraye FA, et al. Am J Gastroenterol. 2017;112(2):241-258. CCF Checklist. https://www.crohnscolitisfoundation.org/science-and-professionals/programs-materials/health-maintenance-checklist.pdf. Accessed February 16, 2020. Rubin DT, et al. Am J Gastroenterol. 2019;114(3):384-413. Lichtenstein GR, et al. Am J Gastroenterol. 2018;113(4):481-517. Health Maintenance Checklist

Health Maintenance Checklist. Crohn’s & Colitis Foundation. Accessed May 7, 2020. crohnscolitisfoundation.org /sites/default/files/2019- 09/Health%20Maintenance %20Checklist%202019- 3.pdf Quality Measures Specialty Pharmacists and Adherence

Ensure Proper Adherence Tracking Perform Interventions Technology Utilization Administration • Medication possession • Utilize adherence • Patients identified as • May be as simple as ratio (MPR) and other measures to identify nonadherent should be using a calendar adherence measures patients who may counseled on the reminder on a phone or often can track require a pharmacist importance of other electronic device fill/claims history with intervention adherence to alert patient when limitations • Maintenance refill • Barriers to adherence dose is due • In-person teaching questionnaires should be addressed • Recommend that • May require change patients visit in medication or manufacturer websites referral to the provider

Shah NB, et al. Am J Health Syst Pharm. 2019;76:1296-1304; Shah NB, et al. Inflamm Bowel Dis. 2020;26(2):314-320. Challenges for Specialty Pharmacy

Obtaining coverage for certain biologics and biosimilars

Dose optimization

Gaps in treatment/changes in preferred medications due to changes in job or insurance Treatment failures Question & Answer Session 3 Final Remarks/Conclusions Additional Resources • Clinical Practice Guidelines • American Gastroenterological Association gastro.org/guidelines • Management of Crohn’s Disease in Adults https://acgcdn.gi.org/wp-content/uploads/2018/04/ACG-Crohns- Guideline-Summary.pdf • Ulcerative Colitis in Adults s3.gi.org/physicians/guidelines/UlcerativeColitis.pdf • Support Groups/Patient Education and Advocacy • Crohn’s & Colitis Foundation crohnscolitisfoundation.org • IBD Support Foundation ibdsf.org THANK YOU! Jim Palatine, RPhTHANK, MBA YOU! President Pharmacy Times Continuing Education™

© 2020. All rights reserved. No part of this report may be reproduced or distributed without the expressed written permission of PTCE.