Ulcerative Colitis: Applying Guidelines in Practice

This presentation developed was by David Rubin, MD, Millie Long, MD, MPH, and Anita Afzali, MD, MPH, for a CME activity titled, Ulcerative Colitis: Applying Guidelines in Practice

1. Jointly Provided by Ulcerative Colitis: Applying Guidelines in Practice David T. Rubin, MD, AGAF Joseph B. Kirsner Professor of Medicine UChicago Medicine Millie D. Long, MD, MPH, AGAF Associate Professor of Medicine UNC School of Medicine Anita Afzali , MD, MPH, AGAF, FACG Professor of Medicine OSU Wexner Medical Center |

2. Disclosures: David T. Rubin, MD Dr. Rubin discloses the following commercial relationships: Consultant: AbbVie, Altrubio , Allergan, Arena Pharmaceuticals, Athos, Bellatrix, Boehringer Ingelheim, Bristol Myers Squibb, Celgene/ Syneos , Connect BioPharma, GalenPharma / Atlantica , Genentech/Roche, Gilead, InDex , Ironwood, Iterative Scopes, Janssen, Lilly, Materia Prima, Pfizer, Prometheus Biosciences, Reistone , Takeda, and Techlab Research: Takeda

3. Disclosures: Millie D. Long, MD, MPH Dr. Long discloses the following commercial relationships: Consultant: AbbVie, Bristol Myers Squibb, Calibr , Genentech, Janssen, Lilly, Pfizer, Prometheus, Roche, Salix, Takeda, Target Pharmasolutions , Theravance , and Valeant Research: Pfizer and Takeda

4. Disclosures: Anita Afzali , MD, MPH Dr. Afzali discloses the following commercial relationships: Consultant: AbbVie, Area Pharmaceuticals, Bristol Myers Squibb, DiaSorin , Janssen, Lilly, Pfizer, Takeda, and TLL Pharma Advisory Board: AbbVie, Bristol Myers Squibb, Gilead, Janssen, Lilly, Pfizer, and Takeda Research: AbbVie, Bristol Myers Squibb, Janssen, Pfizer, and Takeda

5. IBD Today More than 3.1 million cases estimated in the United States Ulcerative colitis (UC): 50% Crohn’s disease (CD): 50% Frequently young at diagnosis (ages 15-30) Most IBD patients do not have a family history Affects all ethnicities Most IBD patients are not Jewish Intriguing group of first generation Americans affected CDC, 2018; Kornbluth et al, 2010; Lichtenstein et al, 2009; Cosnes et al, 2011; Loftus et al, 2002.

6. Incidence: Ulcerative Colitis Overall incidence: 6-14 per 100K Peak age of onset: 2nd to 4th decades In US, 30,000 new cases each year Herrinton et al, 2008; Loftus et al, 2007; Bernstein et al, 1999; Shivananda et al, 1996; Loftus et al, 2014.

7. Burden of Inflammatory Bowel Disease Is Accelerating in the US and Around the World Kaplan & Windsor, 2021.

8. How do we treat ulcerative colitis?

9. Goals of Management of UC Diagnosis including extent of disease and biopsy Movement to separate activity and severity Induction of clinical response/remission and mucosal healing Maintenance therapy identified based on induction therapy and prognosis Screen and treat for anxiety/depressive disorders Prevention of complications (cancer, hospitalization, infections, other drug-related) ACTIVITY : How sick the patient is NOW SEVERITY : Includes elements of PROGNOSIS Rubin et al, 2019.

10. ACG UC Activity Index   Remission Mild Moderate-Severe Fulminant Stools (#/day) Formed stools <4 >6 >10 Blood in stools None Intermittent Frequent Continuous Urgency None Mild, occasional Often Continuous                     Hemoglobin Normal Normal <75% of normal Transfusion required ESR <30 <30 >30 >30 CRP (mg/L) Normal Elevated Elevated Elevated Fecal calprotectin (µg/g) <150-200 >150-200 >150-200 >150-200 Endoscopy (Mayo subscore ) 0-1 1 2-3 3 UCEIS 0-1 2-4 5-8 7-8 Truelove & Witts, 1955; Rubin et al, 2019.

11. Polling Question 1/5

12. Polling Question 1/5 Answer In addition to number of stools, the new modified ACG UC Activity Index also includes which symptom? Mucus discharge Fecal urgency Rectal pain Abdomen pain

13. Assessment of Disease Risk Standard assessment of UC activity (mild, moderate, severe) insufficient in guiding selection of therapy Need to assess risk of colectomy Low Risk for Colectomy Limited anatomic extent Mild endoscopic disease High Risk for Colectomy Extensive colitis Deep ulcers Age <40 High CRP and ESR Low albumin Steroid-requiring disease History of hospitalization C. difficile infection CMV infection Dassopoulos et al, 2015; Rubin et al, 2019.

14. Polling Question 2/5

15. Polling Question 2/5 Answer Which factor is associated with a high risk for colectomy? Age 45 Normal CRP and ESR Left-sided colitis History of C. difficile infection

16. Mucosal Healing Is a Preferred Outcome Treat to achieve MH (increases sustained steroid-free remission, prevents hospitalizations/ surgery) 1,2 Fecal calprotectin as surrogate for endoscopy when endoscopy not feasible to assess for mucosal healing and disease activity 1,2 Histological healing is distinct from endoscopic mucosal healing 3  and is not yet a target “Histological remission”=absence of neutrophils 1 Rubin et al, 2019; 2 Wei et al, 2017; 3 Magro et al, 2017.

17. STRIDE 2 Treatment Targets in Both Crohn’s Disease and Ulcerative Colitis Active disease Therapy according to risk Symptomatic response Consider, but not formal targets: Crohn’s disease: Transmural healing Ulcerative colitis: Histological healing   Symptomatic remission and normalization of CRP Short – term targets Long – term targets Intermediate targets Targets not reached Endoscopic healing, normalized QOL and absence of disability Turner et al, 2021.

18. Polling Question 3/5

19. Polling Question 3/5 Answer Based on the updated STRIDE 2 recommendations, histologic healing is now a treatment target in UC. True False

20. For Mild-Moderate UC Induction: Mild proctitis  r ectal 5-ASA recommended (1 g/day) 1,2,3,4,5 Left-sided mild UC  rectal 5-ASA (≥ 1 g/day) in combination with oral 5-ASA ( ≥ 2.0 g/day) 1,2,3,4,5,6 Mild extensive UC  oral 5-ASA ( ≥ 2.0 g daily) 1,5 Mild UC (any extent)  use a low dose (2.0-2.4 g/day) of 5-ASA 2 , in comparison with a higher dose (4.8 g) 1 Mild-moderate UC not responding to oral 5-ASA  + budesonide MMX 9 mg/day 1,2,3,5 Maintenance: Mildly active proctitis  rectal 5-ASA (1 g daily) 1,2,6 Mildly active left-sided or extensive UC  oral 5-ASA therapy (≥2 g/day) 1,2,3,4 Recommend against systemic steroids 1,3,6 1 Rubin et al, 2019; 2 Harbord et al, 2017; 3 Bressler et al, 2015; 4 Choi et al, 2017; 5 Ko et al, 2019; 6 Wei et al, 2017.

21. General Principles of Aminosalicylates Effective for induction of mild to moderate UC (15-40%) Effective for maintenance of mild to moderate UC (58%-78%) Delivery-response relationship: Get the drug to the location of the disease Very safe, but not completely safe (renal) 1,2 1 Van Staa et al, 2004; 2 Gisbert et al, 2007; 3 Rubin et al, 2019.

22. Treatment Options for the High-Risk UC Outpatient Treatment Induction Maintenance Dosing Comments Steroids ✓ X Prednisone 40 mg PO QD Thiopurines X ✓ TPMT first (possibly NUDT15 too) Anti-integrin (vedolizumab) ✓ ✓ 0, 2, 6 week then q8 week IV (SC coming) Anti-p40 (ustekinumab) ✓ ✓ IV load, then SC q8 week Anti-TNF (adalimumab, golimumab, infliximab) ✓ ✓ Variable based on drug, best evidence for TDM JAK inhibitor (tofacitinib) ✓ ✓ Fail TNF inhibitor first (required) S1P receptor modulator (ozanimod) ✓ ✓ Dose titration in first week Rubin et al, 2019; Dassopoulos et al, 2015; Feuerstein et al, 2017.

23. Polling Question 4/5

24. Polling Question 4/5 Answer Which treatment option is not used as induction therapy in UC? Azathioprine TNF antagonists JAK inhibitor Sphingosine 1 receptor modulator

25. Induction of Remission: Moderate-Severe UC UC failing to respond to 5-ASA therapy  oral systemic corticosteroids 1,2,3,4 ; early use of biologics 6 Moderate UC  oral budesonide MMX 1 Moderate-severe UC of any extent  oral systemic corticosteroids 1,3,4 Anti-TNF therapy using adalimumab , golimumab or infliximab 1,3,6 Infliximab in combination with a thiopurine 1,2,3,4,6 Vedolizumab 1,2,3,6 Ustekinumab 5,6 If failed anti-TNF  vedolizumab 1,2,3,4 or tofacitinib 1,6 (or ustekinumab ) 5,6 Recommend against monotherapy with thiopurines or methotrexate 1,3,6 1 Rubin et al, 2019; 2 Harbord et al, 2017; 3 Bressler et al, 2015; 4 Choi et al, 2017; 5 Sands, Peyrin-Biroulet et al, 2019; 6 Feuerstein et al, 2020 .

26. Maintenance of Remission: Moderate-Severe UC Recommend against systemic steroids 1,3,5 Thiopurines 1,2,3,4,5,7 Against using methotrexate 1,2,3,7 Anti-TNF therapy using adalimumab , golimumab or infliximab 1,2,3,4,5,7 Vedolizumab 1,4 ,7 Ustekinumab 6,7 Tofacitinib 1,7 5 mg PO BID or 10 mg PO BID Rubin et al, 2019; Harbord et al, 2017; Bressler et al, 2015; Choi et al, 2017; Wei et al, 2017; Sands, Sandborn et al, 2019; Feuerstein et al, 2020 .

27. Comparative Effectiveness Study in UC Favors Anti-TNF (mostly infliximab) Combined with IMMs… UC SUCCESS Trial 1 Panaccione et al, 2014.

28. Tofacitinib for Induction and Maintenance of Moderately-to-Severely Active UC Clinical Remission Mucosal Healing Sandborn et al, 2017.

29. Management of Patients on Tofacitinib Lab At initiation 4-8 weeks Every 3 months Lymphocytes ✔ ✔ ✔ Neutrophils ✔ ✔ ✔ Hemoglobin ✔ ✔ ✔ Lipids ✔ Liver enzymes ✔ ✔ ✔ P2P3LTE Screen for VTE risk Herpes zoster risk is stable over time Sandborn et al, 2017; Winthrop et al, 2018 . Vaccinate for zoster (use attenuated vaccine)

30. Ustekinumab for Induction and Maintenance in Moderate-Severe UC Induction Maintenance Sands, Sandborn et al, 2019.

31. Randomized, Controlled Trial of Vedolizumab vs Adalimumab in Patients with Active UC (VARSITY) N=769, VDZ (n=383) or ADA (n=386) Clinical Remission at Week 52 (Primary Endpoint) Sands, Peyrin-Biroulet et al, 2019.

32. Polling Question 5/5

33. Polling Question 5/5 Answer In VARSITY UC trial, vedolizumab and adalimumab were comparable in achieving the primary endpoint of clinical remission at week 52. True False

34. Use of 5-ASA in UC Patients Escalated to Biologics Does Not Modify Outcomes Analysis of patient level data for participants in clinical trials of infliximab and golimumab in moderate-severe UC 1 Data regarding UC patients on a 5-ASA regimen and started on a biologic therapy per health claims database 2   5-ASA vs. no concomitant 5-ASA in TNFi -treated patients Risk of major adverse outcomes according to 5-ASA use Singh et al, 2018; Ungaro et al, 2019. Outcome Adjusted OR (95% CI) p-value Clinical Remission 0.67 (0.45-1.01) 0.06 Clinical Response 0.89 (0.60-1.33) 0.58 Endoscopic Remission 1.12 (0.82-1.51) 0.48 Biochemical Remission 0.94 (0.61-1.46) 0.79

35. Management of the Hospitalized Patient with Acute Severe Colitis DVT prophylaxis 1,4 Test for C. diff 1,4,7 ; treat with vancomycin 1 Avoid opiods 1,4 Methylprednisolone 40-60 mg/day 8 , 60 mg/day 1 or hydrocortisone 100 mg 3-4x/day 1,2,3,7 If inadequate response to IVCS in 3-5 days  infliximab or cyclosporine 1,2,3,4,6,8 Surgery if fail to respond to medical therapy 4,5,6,7 If remission with cyclosporine , maintain remission with thiopurines 1 or vedolizumab 1 See also IDSA Guidelines 2018 1 Rubin et al, 2019; 2 Harbord et al, 2017; 3 Choi et al, 2017; 4 Bitton et al, 2012; 5 Ross et al, 2014; 6 Brown et al, 2018; 7 Wei et al, 2017; 8 Feuerstein et al, 2020 .

36. Sphingosine-1 Phosphate Receptors S1P1, 2 and 3 receptors expressed ubiquitously S1P4 is confined to lymphoid and hematopoietic tissues S1P5 primarily white matter of the CNS and spleen Jozefczuk et al, 2020.

37. Efficacy of Ozanimod in Moderate to Severe UC at Week 10 (Induction, ITT) 12.4 P < .0001 21.9 P < .0001 15.7 P < .0001 8.9 P < .001 Sandborn et al, 2020.

38. Efficacy of Ozanimod in Moderate to Severe UC at Week 52 (Maintenance, ITT) Danese et al, 2020. *

39. Safety of Ozanimod in Moderate to Severe UC Sandborn et al, 2020. Number of Patients (%) Induction Period (Week 10) Maintenance Period (Week 52) Placebo (n = 216) Ozanimod (n = 429) Placebo (n = 227) Ozanimod (n = 230) Any TEAE 82 (38.0) 172 (40.1) 83 (36.6) 113 (49.1) Common TEAEs (≥ 3% in any group) Anemia 12 (5.6) 18 (4.2) 4 (1.8) 3 (1.3) Nasopharyngitis 3 (1.4) 15 (3.5) 4 (1.8) 7 (3.0) Headache 4 (1.9) 14 (3.3) 1 (0.4) 8 (3.5) ALT increased 11 (2.6) 1 (0.4) 11 (4.8) Arthralgia 3 (1.4) 10 (2.3) 6 (2.6) 7 (3.0) Gamma- glutamyltransferase increased 5 (1.2) 1 (0.4) 7 (3.0) Serious TEAEs 7 (3.2) 17 (4.0) 18 (7.9) 12 (5.2) UC exacerbation * 4 (1.9) 6 (1.4) 9 (4.0) 1 (0.4) Anemia * 4 (0.9) 1 (0.4) Appendicitis/Complicated appendicitis * 1 (0.2) 3 (1.2) Severe TEAEs 4 (1.9) 14 (3.3) 9 (4.0) 9 (3.9) TEAEs leading to treatment discontinuation 7 (3.2) 14 (3.3) 6 (2.6) 3 (1.3)

40. Ozanimod Users’ Guide (Oral S1PR 1&5 Modulator) Zeposia ® prescribing information, 2021.

41. What Are the Unmet Needs in UC? Danese et al, 2019.

42. Despite best efforts, differences in disease management goals may exist between patients and clinicians 1 DEFINITION OF REMISSION †1 TREATMENT DURATION EXPECTATIONS 2 In a 2019 survey that included UC patients* (n=1030) and clinicians (N=654), clinicians and patients differed in 1,2 : 1 Rubin et al, 2020; 2 Afzali et al, 2020.

43. The Complexity of Shared Decision Making PATIENT DOCTOR/IBD NURSE DISEASE PAYER

44. The Complexity of Shared Decision Making DOCTOR/IBD NURSE DISEASE PAYER Desire for treatment Faith in doctor/IBD nurse Fear of unknown PATIENT

45. The Complexity of Shared Decision Making DOCTOR/IBD NURSE DISEASE PAYER Desire for treatment Faith in doctor/IBD nurse Fear of unknown PATIENT Therapeutic recommendation Cost of drugs Fear of doing harm Fear of treatment failure Adequacy of database Strength of training Ready solution offered by drugs Urgency for decision Clinical judgment Desire to solve problem

46. Factors in Treatment Decisions in IBD Efficacy - Available evidence - Clinical trial vs. real world Safety - Drug-related AEs - Disease-related AEs Access - Insurance coverage - Cost and time to patient Convenience - Mode of delivery - Frequency of dose

47. Breakout Rooms Interactive Case Discussions

48. Case Study Takeaways

49. Q&A Session

50. Summary: Ulcerative Colitis Applying Guidelines in Practice Separate activity and severity to assess acuity and prognosis Combine symptom improvement with objective markers of disease control Do not maintain with steroids- embrace steroid-sparing options (including surgery) Schedule healthy visits and plan prevention for your patients