Optimizing Advanced Therapies in Ulcerative Colitis by Integritas Communications

Faculty Maria T. Abreu, MD Director, Crohn's & Colitis Center Professor of Medicine Professor of Microbiology and Immunology Vice Chair for Research, Department of Medicine Chair, International Organization for the Study of In ammatory Bowel Disease University of Miami Miller School of Medicine Miami, Florida Dr. Maria T. Abreu is a gastroenterologist who specializes in in ammatory bowel disease (IBD). She completed her medical degree at the University of Miami, Miller School of Medicine. Her postdoctoral training included an internship and residency in medicine at the Brigham and Women’s Hospital in Boston, Massachusetts, and a clinical and research fellowship in gastroenterology at the University of California, Los Angeles (UCLA). She was an Associate Professor of Medicine at Mount Sinai School of Medicine, New York, NY, and head of their In ammatory Bowel Disease (IBD) Center. She is currently the Director of the Crohn’s and Colitis Center, Professor of Medicine and Professor of Microbiology and Immunology at the University of Miami Miller School of Medicine. Dr. Abreu was honored in April 2018 with the Provost’s Award for Scholarly Activity. She was appointed in June 2018 to serve as the Vice Chair of Research for the Department of Medicine. Dr. Abreu has more than 20 years of leadership experience in basic, translational, and clinical research and mentoring. Dr. Abreu was elected to the American Society for Clinical Investigation in 2010 and in 2018 to the Association of American Physicians (AAP). She holds key positions with several professional societies. She is past Council Chair of the American Gastroenterological Association (AGA) Institute Council. Her most recent appointment is as Chair of the International Organization for the Study of In ammatory Bowel Disease (IOIBD). Also, in 2019, she was elected Councillor-at-Large of the American Gastroenterological Association (AGA) Governing Board for a term of 3 years. Dr. Abreu is a recipient of the 2019 Sherman Prize by The Bruce and Cynthia Sherman Charitable Foundation that recognizes outstanding achievements in IBD. In 2020, she received the Mentoring Award from the IMIBD (Immunology, Microbiology, and IBD) section of the AGA. In Fall of 2020, she received the Healio’s Lifetime Disruptor Award. This award goes to a gastroenterologist or hepatologist who consistently pushed the gastroenterology eld forward through innovative treatments, practice management, patient care or research. Dr. Abreu is frequently invited as a speaker (in English and Spanish) at symposia on basic science and clinical topics all over the world. She has authored more than 100 peer-reviewed articles, books, chapters, and reviews.

Jean-Frédéric Colombel, MD Professor of Medicine, Gastroenterology Director, In ammatory Bowel Disease Center Icahn School of Medicine at Mount Sinai New York, New York

Over the past 20 years, Dr. Jean-Frédéric Colombel and his colleagues in Lille, France, have established a successful comprehensive research and health care network fully dedicated to IBD, Crohn’s disease (CD), and ulcerative colitis (UC). Their research center is composed of 3 complementary groups: a medical and surgical department which has performed many multi-center studies at the national and international level, an epidemiological group based upon the IBD North-Western Registry, and a physiopathological group devoted to the study of immunological mechanisms and the development of new therapeutic targets in regulation of digestive in ammation. Thanks to the development of multiple local, national, and international collaborations, they have been able to make some important contributions to the pathophysiology of IBD. The most remarkable are the collection and sampling of IBD families that eventually led to the identi cation of nucleotide-binding oligomerization domain containing 2 (NOD2) as a susceptibility gene for CD, and the development of the anti-Saccharomyces cerevisiae antibodies (ASCA) test, which is still the most sensitive and speci c serologic marker for CD and elucidation of the potential role of Candida albicans in CD, and the identi cation of a new pathovar of Escherichia coli known as adherent-invasive E coli (AIEC) associated with ileal CD. At the national level, Dr. Colombel has been one of the leaders of the Groupe d'Etude Thérapeutique des Affections In ammatoires du Tube Digestif (GETAID), initiating and participating in many clinical trials that have helped to improve therapeutic strategies in IBD, especially regarding the use of immunomodulators and biologics. Apart from international recognition, one of the biggest achievements of the GETAID has been the emergence of a new generation of young and bright European gastroenterologists with an interest in IBD. At the international level, Dr. Colombel has been involved as a participant or primary investigator in most recent therapeutic trials with biologics. The main concretization of this work has been the publication of more than 500 peer-reviewed papers and 30 chapters of books, most of them in the domain of IBD, as primary author or co-author. Dr. Colombel has been invited to give talks in many countries either during IBD meetings or national and international meetings including United European Gastroenterology Week (UEGW) and Digestive Disease Week (DDW). He has been and is still on the editorial board of several gastroenterology journals including Clinical Gastroenterology and Hepatology, Nature Reviews in Gastroenterology & Hepatology, In ammatory Bowel Disease, and Journal of Crohn’s and Colitis. He was associate editor of Gut from 2005 to 2009 and is currently associate editor of Alimentary Pharmacology and Therapeutics, in charge of IBD papers. This leadership in IBD has been recognized by his colleagues who elected him as the president of European Crohn´s and Colitis Organisation (ECCO) from 2008 to 2010, and chair of the International Organization for the Study of In ammatory Bowel Diseases (IOIBD) from 2021 to present. He has been the director of the IBD Center at Mount Sinai since January 1, 2013.

Preamble Target Audience The educational design of this activity addresses the needs of clinical gastroenterologists and specialist nurse practitioners and physician assistants involved in the treatment of patients with ulcerative colitis (UC).

Statement of Need/Program Overview The introduction of biologic therapies that target underlying disease processes has dramatically changed the treatment of ulcerative colitis (UC). However, agents of the tumor necrosis factor (TNF) inhibitor class are limited by primary nonresponse and loss of response in a substantial proportion of patients, disease relapse after cessation of therapy, immunogenicity, and adverse effects such as risk for infection and malignancy.1 As the treatment of UC is complex and variable, there is a greater need to better understand the mechanistic pro les, clinical evidence, and placement of advanced, non-TNF inhibitor therapies within the management of moderate to severe disease.1 This IBD eHealth Source™, comprised of 4 chapters, will provide published clinical evidence and guideline recommendations surrounding the strati cation of high-risk UC patients, available treatment options for moderate to severe disease, the translation of evidence to best practice when deciding among induction and maintenance therapies, and longitudinal patient assessment and objective monitoring strategies to help achieve treat-to-target (T2T) goals. Clinical data will be augmented with pertinent qualitative-research–derived insights from expert faculty to provide actionable recommendations for practicing clinicians.

Reference 1. Coskun M, Vermeire S, Nielsen OH. Trends Pharmacol Sci. 2017;38(2):127-142.

Educational Objectives After completing this activity, the participant should be better able to: • Appropriately assess disease severity and activity to identify high-risk patients with UC who may be candidates for advanced treatment with biologics or small molecule inhibitor agents • Describe guideline recommendations and clinical trial evidence surrounding induction and maintenance therapies for moderate-to-severe UC • Implement treat-to-target strategies that utilize objective measures of remission as well as patient reported outcomes (PROs) to reach patient-centered treatment goals • Translate evidence to informed therapeutic selection when evaluating the positioning of biologics and small molecule inhibitors for rst-line induction, maintenance, or next-line therapy

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group (Global) and Integritas Communications. Global is accredited by the ACCME to provide continuing medical education for physicians.

Physician Credit Designation Global designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Term of Offering This activity was released on October 15, 2021, and is valid for 1 year. Requests for credit must be made no later than October 15, 2022.

Global Contact Information For information about the accreditation of this program, please contact Global at 303-395-1782 or cme@globaleducationgroup.com.

Instructions to Receive Credit In order to receive credit for this activity, the participant must complete the preactivity questionnaire, score 75% or better on the posttest, and complete the program evaluation.

Fee Information & Refund/Cancellation Policy There is no fee for this educational activity.

Disclosure of Con icts of Interest Global adheres to the policies and guidelines, including the Standards for Integrity and Independence in Accredited CE, set forth to providers by the Accreditation Council for Continuing Medical Education (ACCME) and all other professional organizations, as applicable, stating those activities where continuing education credits are awarded must be balanced, independent, objective, and scienti cally rigorous. All persons in a position to control the content of an accredited continuing education program provided by Global are required to disclose all nancial relationships with any ineligible company within the past 24 months to Global. All nancial relationships reported are identi ed as relevant and mitigated by Global in accordance with the Standards for Integrity and Independence in Accredited CE in advance of delivery of the activity to learners. The content of this activity was vetted by Global to assure objectivity and that the activity is free of commercial bias. All relevant nancial relationships have been mitigated. The faculty have the following relevant nancial relationships with ineligible companies:

Maria T. Abreu, MD Consultant/Independent Contractor: AbbVie Inc., Alimentiv Inc., Arena Pharmaceuticals, Inc., Bellatrix Pharmaceuticals, Inc., Bristol Myers Squibb, Cosmo Bio USA, Eli Lilly and Company, Gilead Sciences, Inc.,

Physician Accreditation Statement

Imedex, LLC, Janssen Pharmaceuticals, Inc., Prometheus Biosciences, Takeda Pharmaceuticals U.S.A., Inc.; Grant/Research Support: P zer Inc., Prometheus Biosciences, Takeda Pharmaceuticals U.S.A., Inc.; Honoraria (general): AbbVie Inc., Bellatrix Pharmaceuticals, Inc., Bristol Myers Squibb, Eli Lilly and Company, Gilead Sciences, Inc., Janssen Ortho, LLC, Prometheus Biosciences; Honoraria (teaching, lecturing, or speaking): Alimentiv Inc., Arena Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Microba Life Sciences, PRIME Education, LLC, Takeda Pharmaceuticals U.S.A., Inc., UCB S.A.

Jean-Frédéric Colombel, MD Consultant/Independent Contractor: AbbVie Inc., Amgen Inc., Arena Pharmaceuticals, Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol Myers Squibb, Celgene Corporation, Eli Lilly and Company, Ferring Pharmaceuticals, Galmed Research and Development Ltd, Genentech, Inc., GlaxoSmithKline plc, Janssen Pharmaceuticals, Inc., Kaleido Biosciences, Imedex Inc., Immunic Therapeutics, Iterative Scopes, Inc., Merck & Co., Inc., Microba Life Sciences, Novartis International AG, PBM Capital Group, P zer Inc., Sano S.A., Takeda Pharmaceuticals U.S.A., Inc., TiGenix NV, Vifor Pharma Group; Grant/Research Support: AbbVie Inc., Janssen Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc.; Stock Shareholder: Intestinal Biotech Development; Other/Royalty (lectures): AbbVie Inc., Amgen Inc., Allergan, Inc., Ferring Pharmaceuticals, Shire plc, Takeda Pharmaceuticals U.S.A., Inc. The following planners and managers have no relevant nancial relationships with ineligible companies: Lindsay Borvansky, Andrea Funk, Liddy Knight, Ashley Cann, Kim Rodriguez, Celeste Collazo, MD, Rose O’Connor, PhD, CHCP, Jim Kappler, PhD

Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. Global and Integritas Communications do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the of cial prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Introduction

This eHealth Source™ for moderate-to-severe ulcerative colitis (UC) will focus on topics related to the comprehensive evaluation of patients, management goals, clinical evidence for the use of non–tumor necrosis factor (TNF) inhibitor therapies, and the placement of advanced therapies within the treatment algorithm for moderately to severely active UC. Clinical data will be augmented with pertinent qualitative, research-derived insights—via video commentary—to provide actionable recommendations from experts to practicing clinicians.

VIDEO 1: Introduction Maria T. Abreu, MD

Evidence for Advanced Therapies in UC—

From Patient Assessment to Guideline Recommendations Evaluating Disease Activity and Disease Severity In UC, the nature of disease progression is variable and characterized by symptoms that wax and wane; however, UC is strongly associated with a high level of morbidity that is underscored by a colectomy rate of 10% to 15%.1 Several poor prognostic factors have been shown to correlate with increased colectomy risk (Table 1).2

The utilization of such indicators to appropriately risk-stratify patients is critical to the early implementation and initiation of effective therapy as well as the mitigation of long-term complications.3,4 Identifying high-risk patients and developing personalized management strategies, however, includes assessing both disease activity and severity, and applying both of these measures to informed treatment and monitoring decisions.2

Unlike disease activity—which de nes the burden of in ammation at a single point in time and is important to the choice of induction therapy, the need for hospital admission, and assessment of drug ef cacy —disease severity takes into account disease course (ie, failure to respond to therapies, need for hospitalization, need for steroids), phenotype, disability/functionality, and the cumulative complications caused by UC, which can be used to predict complications and determine prognosis (Figure 1).4,5

VIDEO 2: Patient Assessment Jean-Frédéric Colombel, MD

To grade disease activity, the 2019 American College of Gastroenterology (ACG) Clinical Guideline for Adult UC has proposed new de nitions based on patient-reported outcomes (PROs) [bleeding and normalization of

bowel habits] as well as laboratory- and endoscopy-based values [in ammatory burden] (Table 2).2 PROs correlate well with established indexes of disease severity and may contribute to an improved ability to predict patient-de ned remission—an important measure of decreased symptom severity, symptom frequency, and increased quality of life.2 Laboratory biomarkers include C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and fecal calprotectin (FC).6,7 Serum in ammatory markers CRP (an acute phase reactant) and ESR (a measure of the acute phase response) are relatively nonspeci c for UC but frequently correlate with endoscopic severity of disease.8 CRP and ESR may also have prognostic implications, predicting risk of colectomy or response to therapy.9-12 FC, a neutrophil-derived protein present in stools, is a more selective marker of intestinal in ammation than CRP or ESR, and has a high negative predictive value. Because FC correlates with numerous endoscopic activity indices, it can also be used as a surrogate noninvasive biomarker in the monitoring of disease activity as well as assessment of therapeutic response.2 Endoscopic features included within ACG’s proposed UC Index include the Mayo endoscopic subscore and the UC Endoscopic Index of Severity (UCEIS).13,14 Both incorporate vascular pattern, bleeding, ulcers, and erosions.13,14 The UCEIS has demonstrated a high correlation with disease severity, with preliminary data suggesting that improvement in UCEIS score upon treatment is predictive of medium- and long-term outcomes.13,14 Other available indexes for determining quantitative disease activity include the full Mayo Clinic Score, Pediatric UC Activity Index (PUCAI), PRO2, Rachmilewitz Index, Seo Index, and Simple Clinical Colitis Activity Index (SCCAI).14-21 Among these, the best validity and responsiveness have been achieved with the PUCAI, SCCAI, and partial Mayo score.

Lastly, although histology has not yet been implemented as a marker of disease activity in real-world practice, it has been used in clinical trials along with the aforementioned validated indices. Several studies have demonstrated the presence of mucosal neutrophils as predictive of clinical relapse, hospitalization, and steroid use; with an increased degree of histological in ammation associated with dysplasia and colorectal cancer.2 However, a speci c index for its use has yet to be identi ed, and more research is needed to discern its value as a target for management and prognosis. These factors are general guides for disease activity. With the exception of remission, a patient does not need to have all factors to be considered in a speci c category.

Once severity of disease and patients’ prognosis has been determined, appropriate treatment should be selected.2 Induction therapy for moderate-to-severe UC may include 5-aminosalicylate (5-ASA) agents, corticosteroids (ie, systemic and budesonide multi-matrix [MMX] system), immunosuppressive agents (ie, thiopurines), tumor necrosis factor (TNF)-α antagonists, anti-integrin agents (ie, vedolizumab), Janus kinase inhibitors (ie, tofacitinib), interleukin (IL)-12/23 antagonists (ie, ustekinumab), and sphingosine 1-phosphate (S1P) receptor modulators (ie, ozanimod), the class of agents most recently approved by the US Food and Drug Administration (FDA).2,5

The American Gastroenterological Association (AGA) 2020 guideline panel suggests the early use of TNF-α inhibitors or advanced therapies such as vedolizumab and ustekinumab, rather than gradual step-up therapy—as delaying effective treatment for the induction of remission can lead to harm in high-risk patients. The American Gastroenterological Association (AGA) 2020 guideline panel suggests the early use of TNF-α inhibitors or advanced therapies such as vedolizumab and ustekinumab, rather than gradual step-up therapy—as delaying effective treatment for the induction of remission can lead to harm in high-risk patients.5,22 To date, there are 4 advanced therapies approved for use in the treatment of UC. These include vedolizumab, a humanized monoclonal antibody that selectively targets α4β7 integrin on lymphocytes in the gut,23,24 ustekinumab, an inhibitor of interleukins (IL)-12 and -23, tofacitinib, a member of the small molecule inhibitor class of oral Janus kinase (JAK) inhibitors, and ozanimod, a selective regulator (agonist) of S1P receptor subtype 1 and 5. Vedolizumab was approved by the FDA in 2014 for the treatment of adult patients with moderately to severely active UC.25 Results from its phase 3, GEMINI 1 study, whose population cohorts consisted of approximately 40% of patients who had experienced failure of previous TNF-α inhibitor therapies, demonstrated that treatment with vedolizumab led to signi cantly higher response rates at week 6 (47.1% vs placebo, 25.5%; P<0.001) and a higher proportion of patients with UC in clinical remission at week 52 (41.8%, Q8W dosage, and 44.8%, Q4W dosage vs placebo, 15.9%; P<0.001).25 Further, a post hoc analysis of GEMINI 1 found that a larger proportion of patients treated with vedolizumab achieved sustained corticosteroid-free clinical remission compared with the placebo group. Vedolizumab treatment, no prior anti-TNF exposure, and shorter disease duration were found to be associated with sustained corticosteroidfree clinical remission.26 The increased speci city of this agent has translated into an improved safety pro le —including the absence of progressive multifocal leukoencephalopathy (PML) reporting—compared with the rst-in-class agent, natalizumab.27 Furthermore, an investigation of safety data from 6 clinical trials accounting for more than 4800 patient-years of vedolizumab exposure concluded that vedolizumab has a favorable safety pro le with low incidence of serious infections, infusion-related reactions, and malignancies.28 Ustekinumab received FDA approval in late 2019, based on results from the placebo-controlled UNIFI study that investigated its ef cacy in inducing and maintaining remission in patients with moderately to severely active UC, approximately half of whom had experienced previous treatment failure with biologic agents.29 Signi cantly more patients achieved clinical remission at week 8 following treatment with ustekinumab

Clinical Evidence Surrounding the Ef cacy and Safety of Advanced Therapies

compared with placebo. Furthermore, among those who responded to ustekinumab induction therapy and underwent a second randomization, signi cantly more patients achieved clinical remission at week 44 with ustekinumab treatment every 8 (43.8%, P<0.001) or 12 (38.4%, P=0.002) weeks compared with placebo (24.0%).29 Its durability of response was also shown in a long-term extension study up to 92 weeks.30 With respect to safety, pooled-data analysis across 6 phase 2/3 in ammatory bowel disease (IBD) studies reported a favorable bene t-risk pro le with safety events that were generally comparable to placebo, including rates of serious infection and malignancies.31 Tofacitinib was FDA approved for moderately to severely active UC in 2019 for patients who either have had an inadequate response or intolerance to TNF-α inhibitors. Tofacitinib received its approval based on the phase 3, placebo-controlled OCTAVE studies—composed of cohorts in which approximately 50% of patients previously experienced treatment failure with TNF inhibitors—which demonstrated its ef cacy in inducing and maintaining remission in this patient population.32 In the OCTAVE Induction 1 trial signi cantly more patients treated with tofacitinib 10 mg twice daily (BID) achieved remission at 8 weeks compared with placebo-treated patients (18.5% vs 8.2%, P=0.007).32 Similarly, in the OCTAVE Induction 2 trial, remission at 8 weeks occurred in 16.6% of patients in the tofacitinib 10 mg BID group compared with placebo, 3.6% (P<0.001). In the OCTAVE Sustain trial, treatment with 5 mg or 10 mg tofacitinib BID led to a signi cantly larger proportion of patients achieving remission at 52 weeks compared with placebo (34.3% and 40.6%, respectively, vs 11.1%, P<0.001).32 With respect to safety, tofacitinib has been studied most extensively for the treatment of rheumatoid arthritis (RA), with almost 20,000 patient years of exposure collected.33 In its clinical trial program, tofacitinib treatment was associated with increased incidence of herpes zoster infection.34 Additionally, preliminary outcomes from a postmarketing study, which included RA patients with at least 1 cardiovascular risk factor, found a dose-dependent increased risk of pulmonary embolism, thrombosis, and death associated with tofacitinib; this prompted an updated FDA label boxed warning.35 However, more recently, the FDA completed their review of the postmarketing safety study’s nal outcomes and concluded that there is an increased risk of serious heart-related events and death, even with the lower tofacitinib dose.36 Therefore, the FDA is requiring revisions to the boxed warnings of all agents within the JAK inhibitor class that have an indication for the treatment of arthritis and other in ammatory conditions. Lastly, the most recent agent to join the UC treatment armamentarium is the selective S1P receptor modulator ozanimod. Ozanimod received its FDA approval for the treatment of moderately to severely active UC in May 2021 based on ndings from its phase 3, placebo-controlled studies, True North. Trial cohorts consisted of patients who had refractory disease or intolerance to aminosalicylates, corticosteroids, immunomodulators, or biologics, 30% of whom had previously received TNF inhibitor therapy.37 During the induction part of study, treatment with ozanimod 0.92 mg once daily led to a signi cantly greater proportion of patients achieving the primary endpoint of clinical remission at week 10 compared with those in the placebo group (18% vs 6%; P<0.0001).37 Patients who achieved a clinical response with ozanimod during the induction trial or in an open-label arm were included in the maintenance part of the study. At week 52, 37% of patients in the ozanimod group and 19% of patients in the placebo group met the ef cacy endpoint of clinical remission (P<0.0001).37 The most common treatment-emergent adverse events reported include increases in hepatic enzymes, upper respiratory infection, and headache. With respect to long-term safety, no new safety signals were identi ed during ≥4 years of follow-up in its phase 2 open-label extension study.38 Ozanimod is contraindicated in patients who have experienced cardiovascular events within the 6 months preceding treatment.39

Guideline Recommendations for the Use of Advanced, Non-TNF Inhibitor Therapies While the hierarchical placement of these advanced, non-TNF inhibitor agents for UC has yet to be elucidated with controlled, head-to-head clinical trials, the ACG and AGA do provide limited guidance on their use.2,5 For example, the latest available 2020 AGA guidelines recommend that vedolizumab or in iximab, rather than adalimumab, be used for induction therapy in the outpatient management of those who are naïve to biologic therapy (conditional recommendation, moderate quality evidence).5 This recommendation is supported by results from the head-to-head, randomized controlled, VARSITY trial conducted by Sands and colleagues, which compared vedolizumab to adalimumab, a TNF inhibitor, in patients with moderately to severely active UC, who were either naïve to biologic therapy or who had discontinued treatment with a TNF inhibitor other than adalimumab (biologic-exposed enrollment capping at 25%).40 Study results found vedolizumab to be superior to adalimumab with respect to clinical remission and endoscopic improvement (Figure 2).40

Additionally, signi cantly more patients treated with vedolizumab versus adalimumab achieved clinical remission (31.3% vs 22.5%) and endoscopic improvement (39.7% vs 27.7%) at week 52. Vedolizumab, however, did not demonstrate superiority in corticosteroid-free remission outcomes versus adalimumab (12.6% vs 21.8%).40 When comparing the ef cacy of vedolizumab with that of in iximab in biologic-naïve patients, 1 post hoc analysis of 3 UC clinical trial programs found that comparable proportions of patients had achieved clinical response (in iximab, 60.5% vs vedolizumab, 60.0%, P=0.884) and clinical remission (in iximab, 39.9% vs vedolizumab, 38.6%, P=0.736) at week 6.41 Similarly, the proportion of patients achieving clinical remission at 1 year was also comparable (in iximab, 39.9%; vedolizumab, 38.6%). In iximab, however, was found to result in higher rates of endoscopic remission (in iximab, 36.0% vs vedolizumab, 25.6%; P=0.003) in biologic-naïve patients with UC.41

Alternatively, in outpatients who have been previously exposed to biologic agents, speci cally in iximab, the AGA recommends the use of ustekinumab or tofacitinib as induction therapy (conditional recommendation, low quality evidence).5 Again, because controlled comparative studies are limited, these recommendations are primarily based on indirect evidence. One such study providing the basis for these 2 aforementioned recommendations is a network meta-analysis conducted by Singh and colleagues. Results from their systematic review and ranking of agents using surface under the cumulative ranking (SUCRA) probabilities model ranked ustekinumab and tofacitinib the highest for induction of remission in patients with prior exposure to TNF antagonists.42 The positioning of ozanimod still needs to be determined.

VIDEO 3: Guidelines and Placement of Advanced Therapies Jean-Frédéric Colombel, MD

Beyond the Guidelines:

Using Real-World Data and Clinical Experience to Drive Management Decisions in Moderate to Severe UC Treatment Selection for Initiation & Sequencing Many patients do not achieve remission with or lose responsiveness to TNF-α inhibitor therapy.43-46 In fact, primary nonresponse to TNF-α inhibitor therapy has been noted in up to 30% of patients with IBD, whereas secondary nonresponse occurs in approximately half of patients.45,46 In addition to nonresponse, TNF-α inhibitor therapy is associated with a number of adverse events, including risk of serious infection as well as malignancy.47 These safety concerns have arisen from clinical studies and real-world experience.47,48 Consequently, non–TNF-α inhibitor treatment options are needed for a substantial number of patients with UC. Thus, to better elucidate initial induction therapy and bridge some of the data gaps surrounding treatment sequencing following failure in patient populations experiencing primary or secondary nonresponse, real-world experience and comparison studies are greatly needed. One such retrospective, real-world study by Patel and colleagues, designed to compare the treatment effectiveness of vedolizumab and in iximab, found that biologic-naive patients who received vedolizumab had better long-term real-world effectiveness measures than those who received in iximab, including higher treatment persistence at 24 months after initiation of maintenance phase (vedolizumab, 77.6% vs in iximab, 64.6%; P=0.0005).49 EVOLVE, a more recent real-world study, also investigated the comparative clinical effectiveness and safety of vedolizumab versus TNF-α inhibitors in biologic-naïve patients with IBD. In addition to demonstrating a clear advantage with use of vedolizumab in terms of safety—exhibiting signi cantly lower rates of serious adverse events in patients with UC compared to those who received TNFα inhibitors (hazard ratio [HR]=0.37 [con dence interval, CI, 0.21-0.63])—the EVOLVE study revealed lower incidence of disease exacerbations in vedolizumab-treated patients (HR=0.58 [CI, 0.45-0.76]).50 Although no controlled, head-to-head clinical trials have yet compared ustekinumab with TNF-α inhibitors as rst-line induction therapy, real-world studies are available to support its effectiveness and safety in treatment-refractory moderate to severe UC. One retrospective real-world study conducted by Amiot and colleagues found that among a cohort of 103 patients with disease that was highly refractory to therapy, with 70% of patients previously exposed to ≥2 TNF-α inhibitors and 85% to vedolizumab, treatment with

ustekinumab resulted in over a third (35.0%, P<0.001) of patients achieving the primary endpoint of steroidfree clinical remission at weeks 12-16.51 Additionally, treatment with ustekinumab resulted in the absence of rectal bleeding and normal stool frequency (subscores of 0) in nearly a fth (19.4%) of patients (P<0.001). Ustekinumab failure was associated with patients’ clinical severity as well as previous use of biologic therapy. In another real-world study, conducted by Hong and colleagues in a similar cohort of patients, 92% of whom had prior exposure to biologics or tofacitinib, nearly half (45%) achieved clinical remission by month 12.52 With respect to real-world evidence for tofacitinib in the management of treatment-refractory, moderate to severe UC (patient with a history of immunomodulator, anti-TNFα, or vedolizumab treatment), a small, multicenter, observational study conducted in Germany by Hoffmann and colleagues found that 28.9% achieved steroid-free clinical remission at week 8, whereas 53%, experienced primary nonresponse to tofacitnib.53 A larger, multicenter observational study of biologic treatment-refractory UC, conducted in the UK by Honap and colleagues, demonstrated better outcomes associated with tofacitinib therapy. Overall, 74% of patients responded to tofacitinib at week 8 and 44% achieved steroid-free remission at week 26.54

VIDEO 4: Real-world Use of Advanced Therapies Jean-Frédéric Colombel, MD

Finally, while UC treatment with a TNF antagonist, such as in iximab, is frequently combined with an immunomodulator to mitigate immunogenicity and improve treatment outcomes;55 there is no evidence that supports the bene cial use of other therapies as combination therapy—underscoring the importance of individualizing regimens based on safety and the best available evidence.5,56

Physician Clinical Decision-making Tools and Prediction Models Clinical decision-making tools and predictors of response may be used to inform treatment in UC. One such instrument is the clinical decision support tool (CDST) developed by Dulai and colleagues. From logistic regression analyses of data from the GEMINI 1 clinical trial of vedolizumab, the CDST was validated in patient sample populations within real-world practice.57 Utilizing independent variables—including previous TNF exposure, disease duration, baseline endoscopy, and baseline albumin—the CDST can identify patients most likely to enter corticosteroid-free remission during vedolizumab therapy. Other studies that have attempted to identify predictors of response to treatment in moderate to severe UC include those by Ghoshal and colleagues and Popa and colleagues, each utilizing a machine learning model.58,59 With data collected from 263 patients, Ghoshal and colleagues were able to determine that the following list of factors were predictive of nonresponse to initial medical treatment, including oral prednisolone, intravenous hydrocortisone, intravenous cyclosporin, and in iximab: • presence of complications • use of cyclosporin • lower hemoglobin • lower platelets

• lower albumin • lower serum potassium • higher CRP Their accuracy rate was 73% in correctly classifying response to medical treatment in patients with UC.58 Similarly, Popa and colleagues developed a machine learning model to predict disease activity among patients with UC. However, they sought to identify factors associated with treatment response to TNF inhibitors.59 In the test and validation sets, the classi er had an accuracy of 90% and 100%, respectively, for predicting disease activity, which may help in deciding whether to increase doses or switch to another biologic agent. Neither of these models has yet been validated. Lastly, when considering predictors of response, one must take into account extraintestinal manifestations (EIM) of disease. Collaboration across specialties may be necessary to select appropriate therapies that may more broadly target EIM symptoms.4

Let’s Not Stop There. . . Treat-to-Target Strategies to Reach Shared Decision-making Goals Objective Measures of Disease and Therapeutic Response The ACG recommends treating UC to achieve mucosal healing (de ned as resolution of in ammatory changes by absence of friability, blood, erosions, and ulcers in all visualized segments of gut mucosa—Mayo endoscopic subscore of 0 or 1),2,60 thereby, improving the likelihood of sustained steroid-free remission and preventing hospitalizations and surgery. Clinical remission (absence of symptoms; no rectal bleeding and no urgency) is another measure of remission that relates to improvement in PROs. Many studies, however, have underscored the discordance between PROs and mucosal healing. Thus, clinical remission should not be used as the sole treatment target, as a signi cant number of patients will continue to have mucosal in ammation without symptoms.2 Histologic quiescence and normalization have also been shown to be predictive of relapse-free survival; however, few patients reach these more stringent endpoints and they have yet to be validated as treatment targets.61 The growing recognition of endoscopic remission and deep remission (a combination of clinical remission and mucosal healing) as treatment targets as well as their prognostic signi cance for relapse, hospitalization needs, and surgery highlight the need for them to be included both in the monitoring and long-term management of UC.62,63 To support the longitudinal management of UC, treat-to-target (T2T) strategies that incorporate both clinical and objective therapeutic targets, as described above, as well as shared decision-making approaches have been de ned by the Selecting Therapeutic Targets in In ammatory Bowel Disease (STRIDE) committee and recently updated by the Initiative of the International Organization for the Study of IBD (IOIBD).64,65 The goal of the STRIDE T2T approach is to achieve disease remission—and to prevent long-term complications of disease —by adjusting therapy according to prede ned treatment response targets. While endoscopy is the gold standard for diagnosing mucosal healing, less invasive biomarkers can also be used for the detection of mucosal healing as well as to assess subclinical disease relapse, response to therapy, or distinguish between in ammatory and nonin ammatory causes of symptoms.2,66 One such marker of in ammation that has become a part of routine use for many clinicians treating patients with UC is FC. FC levels have been shown to correlate with endoscopic and histologic in ammation and therefore may be used as a surrogate, noninvasive marker to guide treatment, monitor response to therapy, or assess subclinical relapse.67-72

Studies have demonstrated that fecal calprotectin levels ≤60 μg/g can predict deep remission and those <187 mg/kg may predict mucosal healing. FC levels ≥321 mg/kg in settings of clinical remission were associated with an elevated relapse risk at 6 and 12 months.73,75 FC levels have a sensitivity of 87.3% for endoscopic in ammation and a speci city of 77.1%, with the best sensitivity achieved at a cutoff level of 50 μg/g and the best speci city achieved at cutoff levels greater than 100 μg/g.76 Other noninvasive fecal biomarkers of mucosal healing that have been intensely investigated include lactoferrin, a neutrophil-derived protein responsible for limiting bacterial growth by decreasing iron availability, and matrix metalloproteinase-9 (MMP-9), an endopeptidase that directly degrades extracellular matrix proteins and activates cytokines/chemokines to regulate tissue remodeling. The potential utility of these latter fecal markers in clinical practice, however, have yet to be determined. CRP, a serum-based marker has also been found to positively correlate with endoscopic activity of the disease, however, its accuracies, sensitivities, and speci cities ought to be interpreted with caution.66 Generally, it is best to identify the right noninvasive marker for individual patients and its relationship to degree of endoscopic in ammation.

Symptom Monitoring and PROs Proactive disease and symptom monitoring—as recommended by guidelines and supported by T2T strategies —has the potential to offset risks of disease-related complications in UC.77 However, numerous publications have reported failure to reassess mucosal in ammation following the initiation of biologic therapy, with less than 50% of cases undergoing some form of objective disease monitoring within 12 months.77 Compounding this lack of adherence to T2T management is the recognition that STRIDE PRO targets (rectal bleeding and diarrhea/altered bowel habits) may fail to completely capture major quality of life issues that are relevant to patients’ treatment goals.47,78 Patient surveys and other studies have further elucidated concerns of patients living with IBD—including fecal incontinence, fatigue, and bowel urgency.79 Similarly, Abreu and colleagues recently conducted an online survey to ascertain the patient’s perspective on symptom impact and disease severity.80 Results of the survey revealed that most patients with UC rated their disease as moderate or severe, which correlated with the respective number of symptom days. Additionally, irrespective of the number of disease ares reported by patients, fatigue/low energy was the most commonly reported symptom. This information is especially important given that it is not currently considered in PROs nor adequately addressed with current medical therapy. As a result, major developments in optimizing PRO targets have emerged. One such tool is the Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms (UC-PRO/SS) diary, which scores 9 characteristics grouped into 2 symptom domains—bowel and functional.81 Work is underway to fully validate the UCPRO/SS score, but initial evidence suggests that the scores are reliable, valid, and ready for further use in clinical studies.81 Finally, the relationship between objective measurements of disease and factors that are important to patients need not be proportionate. Thus, when de ning treatment success—which will vary from patient to patient—all domains need to be considered within the holistic approach to IBD management.80,82 This includes dedicating the necessary time to discuss with patients the clinical pro les of available treatment options, including

VIDEO 5: T2T Strategies and Shared Decision-Making Goals Maria T. Abreu, MD

associated risks and bene ts (Table 3), as preference-sensitive decisions may impact therapeutic selection. To help translate evidence-based data into patient-friendly consumable information, decision aids may be useful.83 One example of a shared decision-making tool is the novel, web-based decision aid called my Actively Informed Decision (myAID). While still in its pilot phase, patients and clinicians who vetted the aid have conveyed its acceptability and feasibility for facilitating communication and shared decisions within the management of their disease.84

What’s Next? . . . Options for Nonresponders and Longterm Maintenance Switching Treatment in UC – Reactive Therapeutic Drug Monitoring Often the natural course of UC requires patients to switch treatments, undergo dose escalation, or consider surgery—required in 3% to 17% of adults.85 The need for switching is also relevant for the considerable proportion of patients with UC that does not respond to induction therapy, known as primary failure, or that loses response over time, known as secondary failure.86 Up to 50% of patients with UC require dose escalation during their treatment course.87 Therefore, therapeutic drug monitoring (TDM)—a means of measuring drug levels and assessing for the presence of antidrug antibodies—can be used to better optimize drug concentrations, determine the underlying cause of drug failure, and ultimately improve clinical outcomes.88 However, it is important to note that trough concentrations can vary with disease severity, degree of in ammation, use of immunomodulators, patient sex, body-mass index, and mechanisms of drug clearance.88 The AGA has provided guidelines for TDM in IBD, particularly with respect to anti-TNF therapy. They suggest that reactive TDM be utilized for guiding treatment changes in patients with active IBD who are receiving maintenance anti-TNF therapy.88,89 Target trough concentrations are different for each anti-TNF agent and are shown below in Table 4.88

A general guide has been provided by the AGA to help assist in treatment decisions based on results of reactive TDM testing in anti-TNF treated patients (Table 5). Trough concentrations should be assessed initially.88 If the trough level is at or above the target, patients may consider switching to a drug in a different class. For trough concentrations below the suggested threshold in patients with active disease who have no antidrug antibodies, initial treatment should be optimized by reducing the dosing interval and/or increasing the dose, and/or adding an immunomodulatory drug.88 If the drug trough concentration is not detectable and high-titer antidrug antibodies are present, patients should consider switching to a different drug in the same class or to a drug in a different class. If the drug trough concentration is not detectable and low-titer antidrug antibodies are present, patients may consider optimizing initial treatment by reducing the dosing interval, increasing the dose, and/or adding an immunomodulatory drug.

Several questions remain, however, regarding TDM. First, evidence does not address the optimal timing for measuring trough concentrations; the AGA currently recommends trough levels be drawn as close to the next dose as possible. Second, if antidrug antibodies are detected, it is unclear which cutoff level is clinically signi cant. Third, the bene t of reactive TDM during the induction phase of therapy is unknown, including its usefulness in directing treatment changes versus the standard empiric approach to dose escalation.88 Finally, there is a paucity of data relevant to TDM for advanced therapies, such as vedolizumab and ustekinumab.88 One systematic review and meta-analysis of 5 cohort studies evaluating TDM for vedolizumab found that in patients with UC, trough concentrations ≥18.5–20.8 μg/mL at week 6 of induction and ≥9.0–12.6 μg/mL at maintenance were associated with favorable clinical outcomes. It was also noted that vedolizumab trough concentrations were signi cantly higher among patients experiencing clinical and/or endoscopic remission versus those not in remission.91 Similarly, other clinical trials and realworld data suggest that an exposure–ef cacy relationship may exist for vedolizumab. However, results are not as clear as they are for TNF-α inhibitor therapy.92 The AGA guideline panel does not have any recommendations for the use of routine proactive TDM for adult patients with quiescent IBD.88 Some

VIDEO 6: Therapeutic Drug Monitoring Maria T. Abreu, MD

prospective studies in children with Crohn’s disease have demonstrated improved outcomes with proactive TDM measurements in adalimumab-treated patients.93 Target trough concentrations for asymptomatic patients and the importance of low-titer antidrug antibodies are unclear, which may contribute to confusion and inappropriate therapeutic changes in patients who have achieved remission.88

Achieving Corticosteroid-Free Maintenance of Remission in UC The AGA guideline panel recommends that if an agent is found effective in inducing remission or response, it should be continued for maintenance of remission.5 However, this standard-of-care practice excludes corticosteroids. In fact, the ACG strong recommends against the use of systemic corticosteroids for maintenance of remission in UC.2 Although corticosteroids have been shown to be highly ef cacious within the induction treatment of UC, they are associated with both short-term and long-term side effects; including a higher risk for colectomy and relapse.94,95 In fact, following initial corticosteroid exposure, approximately two-thirds of patients will need reintroduction of corticosteroids, and another one-third of patients will become dependent on steroids over time.96 Therefore, a treatment goal is the achievement and maintenance of corticosteroid-free remission.97 Some individuals, however, experience corticosteroid-dependent UC. The ACG recommends that those who meet this criterion who have not responded to available medical therapy be considered for surgery and offered referral to an experienced colorectal surgeon.2

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Report of the ECCO pathogenesis workshop on anti-TNF therapy failures in in ammatory bowel diseases: de nitions, frequency and pharmacological aspects. J Crohns Colitis. 2010;4(4):355-366.

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Clinical Resource Center™ Guidelines ACG Clinical Guideline: Ulcerative Colitis in Adults. Rubin DT, et al. Am J Gastroenterol. 2019;114(3):384-413. https://pubmed.ncbi.nlm.nih.gov/30840605/

AGA Clinical Practice Guideline on the Management of Moderate to Severe Ulcerative Colitis. Feuerstein JD, et al. Gastroenterology. 2020;158(5):1450-1461. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175923/

ACG Clinical Guideline: Preventive Care in In ammatory Bowel Disease. Farraye F, et al. Am J Gastroenterol. 2017;112(2):241-258. https://journals.lww.com/ajg/fulltext/2017/02000/acg_clinical_guideline__preventive_care_in.15.aspx

American Gastroenterological Association Institute Guideline on Therapeutic Drug Monitoring in In ammatory Bowel Disease. Feuerstein JD, et al. Gastroenterology. 2017;153(3):827-834. https://pubmed.ncbi.nlm.nih.gov/28780013/

Suggested Reading Approach to the management of recently diagnosed in ammatory bowel disease patients: a user's guide for adult and pediatric gastroenterologists. Agrawal M, et al. Gastroenterology. 2021;161(1):47-65. https://pubmed.ncbi.nlm.nih.gov/33940007/

STRIDE-II: An update on the Selecting Therapeutic Targets in In ammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD. Turner D, et al. Gastroenterology. 2021;160(5):1570-1583. https://pubmed.ncbi.nlm.nih.gov/33359090/

A treat-to-target update in ulcerative colitis: a systematic review. Ungaro R, et al. Am J Gastroenterol. 2019;114(6):874-883. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553548/

From bench to bedside: fecal calprotectin in in ammatory bowel diseases clinical setting. Mumolo MG, et al. World J Gastroenterol. 2018;24(33):3681-3694. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127662/

Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis. Sands BE, et al. N Engl J Med. 2019; 381(13):1215-1226. https://www.nejm.org/doi/full/10.1056/NEJMoa1905725

Comparison of real-world treatment outcomes with vedolizumab versus in iximab in biologicnaive patients with in ammatory bowel disease. Patel H, et al. Crohn's Colitis 360. 2019;1(2):otz022. https://academic.oup.com/crohnscolitis360/article/1/2/otz022/5545355

Prediction of outcome of treatment of acute severe ulcerative colitis using principal component analysis and arti cial intelligence. Ghoshal UC, et al. JGH Open. 2020;4(5):889-897. https://pubmed.ncbi.nlm.nih.gov/33102760/

P025 Ozanimod ef cacy, safety, and histology in patients with moderate-to-severe ulcerative colitis during induction in the phase 3 True North study. Sandborn W, et al. Am J Gastroenterol. 2020;115(suppl 1):S6-S7. https://pubmed.ncbi.nlm.nih.gov/33566499/

FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic in ammatory conditions. US Food and Drug Administration. 2021. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-relatedevents-cancer-blood-clots-and-death

The safety of vedolizumab for ulcerative colitis and Crohn's disease. Colombel JF, et al. Gut. 2017;66(5):839-851. https://pubmed.ncbi.nlm.nih.gov/26893500/

Safety of ustekinumab in in ammatory bowel disease: pooled safety analysis of results from phase 2/3 studies. Sandborn WJ, et al. In amm Bowel Dis. 2021;27(7):994-1007. https://academic.oup.com/ibdjournal/article/27/7/994/5910238

De ning success in treating patients with in ammatory bowel disease. Theede K, Burisch J. Expert Rev Clin Immunol. 2017;13(7):645-647. https://pubmed.ncbi.nlm.nih.gov/28395558/

Patient Resources American College of Gastroenterology https://gi.org/topics/in ammatory-bowel-disease/

American Gastroenterological Association https://gastro.org/practice-guidance/gi-patient-center/

Crohn’s and Colitis Foundation http://www.crohnscolitisfoundation.org/

European Crohn’s and Colitis Organisation https://www.ecco-ibd.eu/

National Institute of Diabetes and Digestive and Kidney Diseases https://www.niddk.nih.gov/health-information/digestive-diseases/ulcerative-colitis

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