Michael Chiorean MD IBD Lead Physician Enterprise Puget Sound CoDirector IBD Center Swedish Medical Group mchiorean4 Francis A Farraye MD MSc Director Inflammatory Bowel Disease Center ID: 1044299
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1. State of the Art Management of Ulcerative ColitisMichael Chiorean, MDIBD Lead – Physician Enterprise Puget SoundCo-Director, IBD Center - Swedish Medical Group@mchiorean4Francis A. Farraye, MD, MScDirector, Inflammatory Bowel Disease CenterProfessor of MedicineMayo Clinic, Jacksonville, FLfarraye.francis@mayo.edu@FarrayeIBD
2. Chiorean DisclosuresPfizerBMSAbbVieJanssenTakedaLillyArena Pharmaceuticals (Pfizer)Medtronic
3. Farraye DisclosuresConsulting Fee: Arena, BMS, Braintree Labs, GI Reviewers, GSK, Iterative Scopes, Janssen, Pfizer, SebelaOwnership Interest: Innovation PharmaceuticalsDSMB: Bacainn Pharmaceuticals, Lilly, Theravance
4. Evolving Therapeutic Targets in IBDIn 1988 when Dr. Farraye Started to Practice, We had the Following Medications to Treat IBDSulfasalazinePrednisone6MP or Azathioprine
5. Evolving Therapeutic Targets in IBDIBD Treatment in 2022 is Getting Very ComplicatedCorticosteroidsPrednisone, budesonide MMXMesalamine (oral and topical)Mesalamine, sulfasalazine, balsalazideMethotrexateThiopurines (6MP, azathioprine)Biologic TherapiesAnti-TNFs (infliximab including biosimilars), adalimumab and golimumab as monotherapy or with concomitant immunomodulatorAnti Integrins (vedolizumab)Anti IL 12/23 (ustekinumab)Small moleculesJAK inhibitors (Tofacitinib and upadacitinib)S1P modulators (Ozanimod)
6. Targeted Therapies for UC (2022)Anti-TNFAnti-integrinAnti-IL-12/23Anti-IL-23*JAK inhibitorsS1-PR modulatorsInfliximabVedolizumabUstekinumabMirikizumabTofacitinibOzanimodAdalimumabRisankizumabUpadacitinibEtrasimodGolimumabGulsekumabFilgotinibDrugs in Development in Red
7. The Old and the New: Definitions of UC severityOld classificationMild<4 stools/dayOccasional blood, mild painModerate4-6 BM/day, freq bleedingAnemia, painSevere7-10 BM/day, all bloodyAnemia, feverFulminant>10 BMs, blood alone, painPeritoneal signs(New) Risk stratification:High risk predictorsExtensive diseaseAge < 40Severe symptomsDeep ulcersHigh CRPLow AlbuminSteroid-refractoryHospitalizationCo-infection (C Diff, CMV)Kornbluth A, et al. Am J Gastroenterol 2010; Dassopoulos T, et al. Gastro 2015. Rubin DT, et al. Am J Gastroenterol. 2019 Mar;114(3):384-413. acuity
8. Emerging Treatment Strategies in IBDTreat based on severity/risk/prognosisTreat more effectively – deep remissionUse objective markers (treat to target)Focus on QOLConsider extraintestinal manifestations (EIM)
9. Treatment of Mild to Moderate Ulcerative ColitisSulfasalazine5-ASA linked to a sulfa carrier that is active in the colon5-ASA agentsMesalamine and balsalazideTopical mesalamine (suppository, enema, foam) Budesonide MMX (corticosteroid with an extensive first pass metabolism and targeted colon delivery) Safe and effective in mild to moderate Ulcerative Colitis
10. Steroid-free Remission in Moderate to Severe UC with anti-TNF-alpha Drugs (Normalized)Rutgeerts et al. – NEJM ’05; Sandborn et al. – Gastro ‘12; Sandborn et al. – Gastro ‘14 *normalized by placebo response rates
11. Vedolizumab in Moderate to Severe UC: Gemini IOutcomes Through Week 52n=149* p<0.001† p=0.008‡ p=0.01*Feagan et al. – NEJM ‘13*******†‡
12. Ustekinumab for Moderate to Severe UCResults at week 44Sands et al. – NEJM 2019;381(13):1201-1214
13. Tofacitinib for Induction and Maintenance of Remission in Moderate to Severe UCRemission = Total Mayo score ≤ 2, no score >1 and bleeding =0p<0.001p<0.001OCTAVE Induction 1OCTAVE Induction 2p<0.001p<0.001OCTAVE SustainSandborn et al. – NEJM ‘17
14. Sandborn WJ et al. N Engl J Med 2021;385:1280-1291Ozanimod in Moderate to Severe UC – True North
15. Upadacitinib250 patients randomized to variable doses of upadacitinib vs placebo73.2% previously exposed to anti-TNFAdverse events of special interest were low (<5%) except anemia, abnormal LFTs and CPK elevationsIn the maintenance study, 30 mg dose had approximately 10% better efficacy in most endpoints compared to 15 mg doseSandborn WJ, et al. Gastroenterology. 2020 Jun;158(8):2139-2149; Panaccione R, et al. UEG 2021.Induction StudyMaintenance Study
16. VDZ vs. ADA in Moderate to Severe UC (VARSITY)p=0.0061p=0.0005Sands et al. – NEJM ‘19
17. Relative Efficacy of Biologics and Small Molecules in Moderate Severe UC (New Network Meta-Analysis)Induction of clinical remissionBio-NaïveBurr et al. – Gut ‘21Ranking based on probability of being the best drugInconsistency “hot spot”Upadacitinib had the highest probability to be the best drug for induction of clinical remission
18. Head to Head Comparative Trials in UCProtagonistsPopulationWinnerEndpointVARSITYVDZ vs. ADAMixedVDZ*Wk 52 remission31% v 22%Sands et al – NEJM ’17HIBISCUS I & IIETRO vs. ADA vs. PboBionaïveWk 10 remission19% v 24% v 9%Rubin et al. – Lancet GH ’22GARDENIAETRO vs. IFXBionaïveWk 10 resp + w 54 rem19% v 20%Danese et al. – Lancet GH ‘22Patients not treated per SOC: no dose optimization, no combo aTNF therapy
19. Breaking the Ceiling of UC TherapyOne year efficacy of current therapeuticsRemission – 20%Response – 50%Pathways to improve outcomes:Predict ideal drug – ideal patient (personalized medicine)Combo therapy
20. Golimumab-Guselkumab (a-IL-23) Combo in UC: VEGASands et al. – ECCO 2022;OP36
21. Approach to Disease Monitoring in IBDPeyrin-Biroulet et al., STRIDE I – Am J Gastro ‘15
22. How Long Should We Wait to See a Response5-ASASteroidsThiopurineMTXAnti-TNFanti-Integrina-IL-12/23TOFA and UpaOzanimodMax 4.8 g PO1 g PR4 weeksBudesonide 9 mg QD – 4 wksPrednisone 40-60 mg QD – 2 weeksIV solumedrol 60 mg QD – 3 daysWeight-based or 6TGN-based dosing for TP – 10 weeksMtx 25 mg/kg weekly – 8 weeksAfter loading doses and 1st maintenance dose (8-10 wks)May include accelerated induction/dose escalationMay be difference IV vs. SQAfter loading and 1-2 maintenance doses (12-16 weeks)10 mg BID – 8-16 weeksMay be longer for bio-experienced 0.92 mg QD x 10 weeks
23. Positioning Therapeutics in Ulcerative ColitisDisease SeverityMildModerateSevereAct QuicklyAct SafelyAct Wisely(cost-utility, QOL)VDZ, USTK, OZANaTNF, JAKinib5-ASA, BudesonideThink Disease Severity and Risk First!
24. SummaryCurrent treatment strategies in UC emphasize disease severity and riskDespite expanding Rx choices with different MOA, there remains a major unmet need in UCMedications with superior safety profiles should be used first for patients with moderate diseaseIFX and JAKinibs are favorites for patients with severe UCNear-future strategies may be dominated by combination regimens rather than “personalized therapy”
25. Thank You!
26. Approach to UC Treatment 2022-Bio-naive PatientsBionaïveSevere UCModerate UCIFX TOFA*USTKVDZOZANCys AClinical TrialSurgeryFirst Line2nd Line3rd LineVDZUSTKOZANIFX TOFA**consider using first line in pts w ASUC
27. Approach to UC Treatment 2022- Treatment Experienced PatientsPrior effective therapy2nd Line3rd LineRx ExperiencedaTNFVDZUSTKOZANJAKinibS1PRMSwitch to other aTNF or alternative MOASwitch outside of classSwitch w/in groupaTNF, TOFAOther JAKAlternative MOAVDZUSTKOZANClinical TrialSurgery