Optimizing Management of IBD: Beyond Anti-TNFs Remo Panaccione, MD, FRCPC Director, Inflammatory Bowel Disease Clinic Professor of Medicine University of Calgary 1 Disclosures: R. Panaccione Consultant for: AbbVie, ActoGeniX, AGI Therapeutics, Alba Therapeutics Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore, Aptalis, Astellas, Athersys, Atlantic Healthcare, BioBalance, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Celek, Cellerix, Cerimon, ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle, Eisai Medical Research, Elan, EnGene, Eli Lilly, Enteromedics, Exagen Diagnostics, Ferring, Flexion Therapeutics, Funxional Therapeutics, Genentech, Genzyme, Gilead, Given Imaging, GlaxoSmithKline, Human Genome Sciences, Ironwood, Janssen, KaloBios, Lexicon, Lycera, Meda, Merck & Co., Merck Research Laboratories, MerckSerono, Millennium, Nisshin Kyorin, Novo Nordisk, NPS Pharmaceuticals, Optimer, Orexigen, PDL Biopharma, Pfizer, Procter and Gamble, Prometheus Laboratories, ProtAb, Purgenesis Technologies, Receptos, Relypsa, Salient, Salix, Santarus, Shire Pharmaceuticals, Sigmoid Pharma, Sirtris (a GSK company), S.L.A. Pharma (UK), Targacept, Teva, Therakos, Tillotts, TxCell SA, UCB Pharma, Vascular Biogenics, Viamet and Warner Chilcott UK. Speaker’s fees for: Abbvie, Aptalis, AstraZeneca, Ferring, Janssen, Merck, Prometheus, Shire, Takeda Advisory Board for: Abbvie, Abbott, Amgen, Aptalis, AstraZeneca, Baxter, Biogen Idec, Eisai, Ferring, Genentech, Janssen, Merck, Shire, Elan, Glaxo-Smith Kline, Hospira, Pfizer, Bristol-Myers Squibb, Takeda, Cubist, Celgene, Salix Research/Educational Support from: Abbvie, Ferring, Janssen, Shire Takeda 2 Objectives 1. Discuss new treatment targets in IBD – Where we were – Where we are – Where we are going 2. Review the latest data that will impact your clinical practice in 2016 and beyond 3. Discuss positioning of new therapies in IBD 3 Managing IBD in 2016: An evolution in IBD care Crohn’s disease (CD) 5-ASA Steroids Anti-TNFs for CD Vedolizumab for UC5 Azathioprine1 Initial report Anti-TNFs for CD Biosimilars 1995 2000 2005 2010 2015/16 5-ASA Steroids Azathioprine, Anti-TNFs for UC Vedolizumab for CD5 Cyclosporin1,2 Ulcerative Colitis (UC) Surgery 1. Mulder DJ, et.al. A tale of two diseases: The history of inflammatory bowel disease. J Crohn Colitis 2013; 8:341–348 2. Botoman AV, et al. Management of Inflammatory Bowel Disease. Am Fam Physician 1998;57:57–68 3. National Institute for Health and Care Excellence technology appraisal guidance [TA40]: The clinical effectiveness and cost effectiveness of infliximab for Crohn's Disease https://www.nice.org.uk/guidance/ta40. 4. National Institute for Health and Care Excellence technology appraisal guidance [TA329]: Infliximab, adalimumab and golimumab for treating moderately to severely active ulcerative colitis after the failure of conventional therapy (including a review of TA140 and TA262): http://www.nice.org.uk/guidance/ta329/chapter/about-this-guidance. 5. National Institute for Health and Care Excellence technology appraisal guidance [TA342] - Vedolizumab for treating moderately to severely active ulcerative colitis. June 2015. http://www.nice.org.uk/guidance/ta342. Last accessed June 2015. 4 Introducing Biological Therapy: Where we were The biologic revolution began over 15 years ago with the approval of infliximab for the treatment of moderate to severe CD1. Despite the development and approval of “newer” anti TNFs, the overall induction of remission in RCTs was ~30-50%2-5 and maintenance of remission was ~20-40%.6-10 Therefore there is a need to develop new agents for the treatment of IBD. 1. Schreiber S, et al. Gastroenterology 2005;129:807–18. 1. Schreiber S, et al. N Engl J Med 2007;357:239–50. 2. Sandborn WJ, et al. N Engl J Med 2007;357:228–38. 2. Hanauer SB, et al. Lancet 2002;359:1541–9. 3. Hanauer SB, et al. Gastroenterology 2006;130:323–33. 3. Colombel JF, et al. Gastroenterology 2007;132:52–65. 4. Targan SR, et al. N Engl J Med 1997;337:1029–35. 4. Sandborn WJ, et al. N Engl J Med 2007;357:228–38. 5 Where we are: Lessons learned during the anti-TNF era Anti-TNFs are safe Antibodies are bad; adequate drug levels are good There is value in combination therapy Treating early is better We can treat beyond symptoms We can decrease surgical /hospitalization rates We do better in real life than in clinical trials 6 Phenotypic features of Crohn's disease associated with anti-TNF treatment failure Retrospective study using the Alberta Inflammatory Bowel Disease Consortium registry. Probability of surgery over time after anti-TNF prescription depending on phenotype at prescription (B1=inflammatory, B2=stricturing, B2L1=ileal stricturing , B3=penetrating) 0.5 B2 0.4 B2L1 0.3 B3 0.2 B1 0.1 Cumulative probability ofprobability Cumulative 0 major abdominal surgery major abdominal surgery (%) 0 1 2 3 4 5 Follow-up in years 7 Moran, Panaccione et al. Clin Gastroenterol Hepatol 2014 Mar;12(3):434-42 Randomised Evaluation of an Algorithm for Crohn’s Treatment (REACT 1) 20 practices 20 practices 60 patients per practice Symptomatic remission (HBI≤4 and no corticosteroids) Usual care Accelerated care treatment algorithm Conventional management 100 Early combined immunosuppression Time to first hospitalisation, surgery or complication 80 p=0.790 p=0.498 p=0.389 p=0.250 40 HR (95% CI) = 0.73 (0.62, 0.86), p<0.001 (%) (%) 60 34.7% 30 CM 27.4% ECI 40 20 Patients Patients 20 10 0 or complications 0 Baseline Month 6 Month 12 Month 18 Month 24 Hospitalisation, surgery 0 3 6 9 12 15 18 21 24 Time (months) REACT cluster randomisation: 898 CD in conventional management vs 1094 CD in early combined immunosuppression 8 Khanna R, et al. Lancet 2015 8 Temporal trend analysis of colectomy rates: stratified by emergent vs. elective colectomy Colectomy rates in adults hospitalised for a flare of UC 6 Total 5 Elective Emergent 4 3 2 1 0 Incidence per 100,000 population population 100,000per Incidence 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 UC, ulcerative colitis. Temporal changes were evaluated using linear regression models to estimate the average annual percent change (AAPC) in surgical rates. 9 Kaplan GG, et al. Am J Gastro 2012; 107:1879–87. Real Life vs. Clinical Trials: The example of ADA and IFX in UC 10 Sandborn et al. Curr Med Res Opin. 2016 Mar 30:1-9 Many biologic agents have failed in IBD Anti-IL-2 receptor – Basiliximab1 – Daclizumab2 Anti-CTLA-4 – Abatacept3 Anti-CD3 receptor – Visilizumab4 1. Sands BE, et al. Gastroenterology 2012 Aug;143:356–64. 2. Van Assche G, et al. Gut 2006;55:1568–74. 3. Sandborn WJ, et al. Gastroenterology 2012;143:62–69. 4. Sandborn WJ, et al. Gut 2010;59:1485–92. 11 The IBD therapeutic pipeline TNFK-005 Neovacs IL inhibitors Phase I Chemokine receptors C326 QPharm SCH-900222 Merck & Co Phase II Centocor CCX282-B GSK Ustekinumab Vidofludimus 4SC CCX-025 GSK Phase III PF-04236921 Pfizer Immunomodulators PF 05230900 Pfizer ZP1848 Zealand Registration QAX576 Novartis AMG 827 Amgen RDP 58 Genzyme GSK Launched GSK 1070806 AIN 457 Novartis Rifaximin EIR Natalizumab laquinimod Teva / Active Biotech AlphaWessermann ELND-004 Elan/Biogen Idec Elan/Biogen Idec PF-547659 Pfizer Novo Nordisk NN8555 CAM inhibitors Pfizer Vedolizumab Tofacitinib Adalimumab AbbVie Millenium / Takeda AJM-300 Ajinomoto Certolizumab pegol UCB Infliximab HMPL-004 Hutchinson JAK3 inhibitors Centocor Remestemcel-L Osiris Ozoralizumab Pfizer PDA-001 Celgene Cellular Cellerix Debiaerse OvaSave TXCell Neovacs Stem cell therapies TNF-α inhibitors Adapted from Danese S. Gut 2012;61:918–32. 12 Emerging therapies in IBD Leukocyte Trafficking inhibitors Anti S1 P1 – Vedolizumab – Ozanimod – Etrolizumab – Anti-MAdCAM Anti-SMAD 7 Anti IL-12/23 – Mongersen – Ustekinumab – Briakinumab – Rizankinumab Jak inhibitors – Tofacitinib 13 Lymphocytes Preferentially Migrate to Particular Tissues Throughout the Body • As part of the body’s adaptive immune response, lymphocytes are imprinted for migration to areas of inflammation in certain tissues • Lymphocytes become imprinted in certain lymphoid tissues in which they first encounter antigen • After this initial activating encounter, lymphocytes preferentially leave the blood in the same type of tissue in which they became activated 14 Salmi M, Jalkanen S. Immunol Rev. 2005;206:100-113. Agace W. Nat Rev Immunol. 2006;6:682-692. α4β7 Integrin–MAdCAM-1 is One of the Interactions That Contributes to Chronic Inflammation in UC and CD MAdCAM-1 MAdCAM-1 Accumulation of excess infiltrating lymphocytes in the gastrointestinal tissue Memory T lymphocyte α4β7 α4 β7 integrin subunit subunit α4β7−MAdCAM-1 interaction has been implicated as an important contributor to the chronic inflammation that is a hallmark of UC MAdCAM-1=mucosal addressin cell adhesion molecule-1 and CD 15 Briskin M, et al. Am J Pathol. 1997;151:97-110. Vedolizumab is a novel gut-selective anti-inflammatory biologic Humanized mAb that binds exclusively to the α4β7 integrin heterodimer – Does not bind to α4β1 or αEβ7 integrin1 Selective antagonist of α4β7 integrin – Inhibits adhesion to MAdCAM-1 and fibronectin, but not VCAM-11 Contains a mutated Fc region, preventing elicitation of2 – Complement-mediated cytotoxicity – Antibody-dependent cellular cytotoxicity – Cytokine release Fc, fragment crystallisable; mAb, monoclonal antibody ; VCAM-1, vascular cell adhesion molecule-1 . 16 1. Soler D, et al. J Pharmacol Exp Ther 2009;330:864–75;. GEMINI I: vedolizumab induction therapy for UC Phase 3, multicentre, prospective, RCT (N=374) – Randomised 3:2, patients received VDZ 300mg (IV) or PBO on days 1 & 15 Mod-to-severe active UC (Mayo 8.6, mean), despite conventional therapy – UC diagnosis ~6.4 yrs, CS (~54%), IS (~31%) and anti-TNF failures (~39%) Rates of AEs and serious AEs were similar between VDZ and PBO groups Week 6 outcomes after 2-dose induction All p<0.0001 VDZ vs. PBO Primary endpoint 100 PBO (n=149) VDZ 300 mg (n=225) 80 60 47 41 40 25 17 25 20 5 0 Patients (%) Patients Response Remission Mucosal healing AE, adverse event; CS, corticosteroid; IS, immunosuppressant; RCT, randomised controlled trial 17 Feagan et al, N Engl J Med.