Inflammatory Bowel Disease: Current Treatment Strategies Edward V. Loftus, Jr., M.D. Professor of Medicine Division of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota, U.S.A. ©2010 MFMER | slide-1 Loftus Disclosures (last 12 months) • Research support • Consultant • AbbVie •AbbVie • UCB •UCB • Genentech •Janssen • Janssen •Takeda • Amgen •Bristol-Myers Squibb • Pfizer •Amgen • Takeda •Salix • Robarts Clinical Trials •CVS Caremark • Gilead •Eli Lilly • Receptos •Pfizer • Celgene • Seres Therapeutics • MedImmune Overview • Existing treatment paradigms for Crohn’s • Evolving paradigms • Risk stratification • Treating earlier in disease course • Measuring objective inflammation to base treatment • Objective treatment endpoints • Therapeutic drug monitoring • New therapies ©2010 MFMER | slide-3 Management of Crohn’s Disease Prednisone, Budesonide AZA/6MP/MTX Anti-TNF (Infliximab, Adalimumab, Certolizumab Induction pegol) Vedolizumab or Natalizumab AZA/MTX, Anti-TNF, Anti-Integrin Maint Lichtenstein GR, Hanauer SB, Sandborn WJ. Am J Gastroenterol 2009;104:465-83. Baumgart DC, Sandborn WJ. Lancet 2012;380:1590-1605. Evolving Treatment Paradigm Using Available Data for Risk Prognostication ©2010 MFMER | slide-5 Risk Factors Associated With Intestinal Complications: Crohn’s, Olmsted County Characteristic Hazard 95% CI Ratio Terminal ileum 7.8 3.5 – 17.4 Ileocolonic 5.6 2.3 – 13.9 Upper GI 9.5 3.0 – 30.1 Perianal fistula 1.7 0.99 – 2.86 Thia KT et al. Gastroenterology 2010;139:1147-55. AGA Clinical Pathway for Crohn’s Disease: Characterizing Risk Low Risk High Risk >30 years Age at diagnosis <30 years Anatomic Limited Extensive involvement Perianal and/or No severe Yes rectal disease Superficial Ulcers Deep Prior surgical No Yes resection Stricturing and/or No penetrating Yes Sandborn WJ. 7 Gastroenterology. 2014;147:702-705. behavior AGA Clinical Pathway for Crohn’s Disease: Initial Treatment Low-risk patient Moderate/high-risk patient Ileum and/or proximal colon, none to minimal symptoms Options Options • Anti-TNF monotherapy over no therapy • Budesonide 9 mg/day with or without AZA or thiopurine monotherapy • Tapering course of prednisone with or • Anti-TNF + thiopurine over thiopurine without AZA monotherapy or anti-TNF monotherapy • Methotrexate for patients who do not tolerate purine analog in combination with anti-TNF Diffuse or left colon, none to minimal symptoms Options • Tapering course of prednisone with or without AZA Sandborn WJ. Gastroenterology. 2014;147:702-705. 8 Efficacy of biologics in CROHN’S DISEASE 80 74.5 Clinical remission with induction therapy – only biologic-naïve patients 70 60 50 39.7 40 37.5 35.7 32.5 31.6 29.8 29.2 30 26.5 20 20 12.2 10 4 Clinical Remission with with InductionClinical therapy Remission (%) 0 Targan Lemann CLASSIC-1 Watanabe PRECISE-1 Sandborn Infliximab Adalimumab Certolizumab pegol ©2011 MFMER | slide-9 Crohn’s “Net Remission” at Six Months: Certolizumab, Adalimumab, Infliximab 1 Certolizumab Pegol – PRECISE 2 Infliximab – ACCENT I2 100 100 Pbo CzP Pbo IFX 80 80 64.1 58.5 60 47.9 60 39.0 40 40 28.6 30.7 22.8 18.3 21.0 20 20 12.3 % % of Patients % % of Patients 0 0 Open-label Week 26 Net Open-label Week 30 Net Induction remission remission Induction remission remission Week 6 week 26 Week 2 week 30 Certolizumab Pegol – PRECISE 14 Adalimumab - CHARM3 100.0 Pbo ADA 100 Pbo CzP 80.0 80 58.0 60.0 60 40.0 40.0 40 29.5 23.2 18.3 17.0 20 20.0 9.9 % % of Patients % % of Patients 0 0.0 Net Open Label Week 26 Net remission Induction remission remission week 26 Week 4 week 26 1. Schreiber et al. New Engl J Med 2007;357:239-250 2. Hanauer et al. Lancet 2002;359:1541-49 3. Colombel et al. Gastroenterology 2007;132:52-65 4. Sandborn et al. New Engl J Med 2007;357:228-38 Mucosal Healing With Adalimumab in CD (EXTEND) 50 ADA induction (160/80 mg)/placebo ADA QOW (40 mg) 40 P=0.056, NS P<0.001 30 27.4% 24.2% 20 13.1% Patients (%) Patients 10 0 8/61 17/62 0/61 15/62 0 Week 12 ITT Week 52 ITT ITT, intent-to-treat; NS, not significant Primary End Point Rutgeerts P et al. Gastroenterology. 2012;142:1102. Infliximab Effect on Hospitalizations and Surgeries – ACCENT I Crohn’s-related Hospitalizations Intra-abdominal Surgeries 40 38 7.4 35 8 7 30 24 6 25 23 23.5 5 20 4 3.1 2.9 15 3 2.6 10 2 5 1 Hospitalizations Per 100 Pts Hospitalizations 0 with (%) Surgeries Patients 0 Episodic 5 mg/kg 10 mg/kg Combined Episodic 5 mg/kg 10 mg/kgCombined Rutgeerts P, et al. Gastroenterology. 2004;126:402-13. Infliximab Prevents Endoscopic Recurrence in Post-Operative Crohn’s disease (PREVENT) Compare the efficacy of IFX with PBO in the prevention of clinical and endoscopic recurrence of CD following ileocolonic resection (randomized ≤45 days from surgery) Clinical recurrence=composite of CDAI>200, >70 pt increase, and endoscopic recurrence (Rutgeerts ≥i2) Regueiro M et al, Gastroenterology 2016;150:1568-78. Infliximab Prevents Endoscopic Recurrence in Post-Operative Crohn’s disease (PREVENT) Technically a negative study since primary endpoint not met, but infliximab reduced endoscopic recurrence by ≥50% Risk factors for clinical recurrence: Prior anti-TNF exposure >1 resection Regueiro M et al, Gastroenterology 2016;150:1568-78. SONIC: Corticosteroid-Free Clinical Remission at Week 26 Primary Endpoint 100 p<0.001 80 p=0.009 p=0.022 60 56.8 44.4 40 30.6 20 Proportion of Patients (%) 52/170 75/169 96/169 0 AZA + placebo IFX + placebo IFX+ AZA Colombel JF, et al. N Engl J Med. 2010;362:1383-1395. Infliximab vs Infliximab/MTX for Crohn’s-COMMIT Trial • Crohn’s patients in flare on steroids • Fixed steroid taper • All pts IFX 5 mg/kg usual induction/maintenance • Randomized to MTX or placebo (10 mg increased to 25 mg weekly • Primary endpoint: time to treatment failure (failure to • Negative study achieve steroid-free remission at week 14 or • Because all pts failure to maintain this thru week 50 received steroids? Feagan BG et al, Gastroenterology 2014; 146:681-8. Indirect Treatment Comparison Network Meta-analysis of Biologics in Biologic-Naïve Crohn’s Disease Patients • Infliximab (IFX) may be superior to certolizumab pegol (CZP), but is comparable to adalimumab (ADA) for induction of remission • All agents are comparable for maintenance of remission Singh et al. Mayo Clin Proc 2014;89:1621 ©2011 MFMER | slide-17 Limitations of Network Meta-analysis • Differences in trial design – no trial of standard IFX induction therapy • Differences in co-interventions • Indirect comparisons with no head-to-head trials – decreases quality of evidence • All short-term trials of induction and 1-year maintenance therapy • No data on long-term patient-relevant outcomes (hospitalization, surgery, etc.) • Registration trials, with restrictive inclusion criteria – not real-world experience ©2011 MFMER | slide-18 Infliximab vs. Adalimumab for Crohn’s disease U.S. Medicare Database • Retrospective cohort, 2006-2010 • Biologic-naïve adults with CD, treated with IFX (n=1459) vs. ADA (n=871) Outcome of Interest Adjusted HR (95% CI) IFX vs. ADA Hospitalization 0.88 (0.72-1.07) Surgery 0.79 (0.60-1.05) • Limitations • Older cohort – 44.2% >60y old • In patients younger than 65y, IBD-related surgery IFX vs. ADA – OR, 0.66 (0.47-0.93) Osterman et al. Clin Gastroenterol Hepatol 2014;12:811 ©2011 MFMER | slide-19 Infliximab vs. Adalimumab-Crohn’s Risk of IBD-RELATED HOSPITALIZATION Adjusted HR (IFX vs. ADA): 0.80 (0.66-0.98) % of patients free of event date after index of patients free of event % Singh et al. Presented at DDW; May 19, 2015; Abstract 922 ©2011 MFMER | slide-20 Infliximab vs. Adalimumab-Crohn’s Risk of ABDOMINAL SURGERY Adjusted HR (IFX vs. ADA): 0.76 (0.58-0.99) % of patients free of event date after index % of patients free of event Singh et al. Presented at DDW; May 19, 2015; Abstract 922 ©2011 MFMER | slide-21 Infliximab for UC: ACT 1 and ACT 2 Clinical Remission ACT 1 ACT 2 Placebo IFX 5 mg/kg IFX 10 mg/kg Placebo IFX 5 mg/kg IFX 10 mg/kg ‡ 45 § † ‡ † § 40 39 † § 36 40 ‡ 37 34 ‡ 34 35 34 35 35 32 30 28 30 26 25 25 20 20 16 17 15 15 15 11 10 10 6 Percent of Patients Percent 5 of Patients Percent 5 0 0 8 Weeks 30 Weeks 54 Weeks 8 Weeks 30 Weeks † P 0.002 vs placebo ‡ P 0.003 vs placebo § P = 0.001 vs placebo Rutgeerts P et al. N Engl J Med 2005;353:2462-76 ACT1/2 Trials: Survival Free of Colectomy Sandborn WJ et al, Gastroenterology 2009;137:1250-60. UC SUCCESS Trial: Combination IFX/AZA Vs. Monotherapy in Moderate to Severe UC – Week 16 90% * * P < 0.05 vs AZA * ** P<0.05 vs AZA and vs IFX 80% 77% 69% * 70% * 63% 60% 55% 50% 50% ** AZA 40% 40% 37% IFX AZA + IFX 30% 24%22% 20% 10% 0% Steroid-free Response Mucosal healing remission Conclusion: IFX+AZA superior to both AZA and IFX monotherapy in inducing steroid-free remission Panaccione R et al, Gastroenterology 2014;146:392-400. Adalimumab for Moderate to Severe UC: Induction/Maintenance Trial (n=494) Week 8 Endpoints Week 52 Endpoints 60% ** 60% 50.4% * 50% 50% 41.1% 40% 34.6% 40% * 31.7% * Placebo 30.2% Placebo 30% * 30% ** 25.0% ADA 18.3% ADA 20% 16.5% 20% 17.3% 15.4% 9.3% 8.5% 10% 10% 0% 0% * p<0.05 Mucosal healing ** p<0.005 Clinical remissionClinical response Mucosal healing Clinical remissionClinical response Sandborn WJ et al, Gastroenterology 2012;142:257-65.