University Colorado Denver Center for Human Simulation Literature Review Peter R. McNally, DO, MACG University Colorado Denver School of Medicine Center for Human Simulation Aurora, Colorado 80045

Introduction Ulcerative Colitis is a lifelong, disabling disorder with 20-30% of patients requiring surgery in their lifetime. Steroid refractory UC ranges from 25-57%, of which only 40-60% are responsive to immunomodulator Rx with AZA or 6-MP. This leaves a substantial number of UC patients with medically refractory disease and need for surgical solution or new effective medical Rx. Langholz E, et al. Gastroenterol. 1992;103:1444-51.

Introduction The Active Ulcerative Colitis Trials (ACT-1 and Act-2) were the first large, randomized, placebo controlled trials that firmly established the efficacy of Infliximab (IFX, Anti-TNF-α) in the treatment of moderate to severe UC. Development of neutralizing antibodies to IFX (ATI), primary lack of response, need for intravenous administration, has lead to the evaluation of other less antigenic Anti-TNF agents that can be administered subcutaneously. Rutgeerts P,et al.Infliximab for induction & maintenance therapy for UC.NEJM.2005;353:2462-76. Oussalah A,et al. Aliment Pharm Ther. 2008;28:966-972. Peyrin-Biroulet L, et al. World J Gastro. 2007;13:2328-2332.

Introduction This VHJOE Literature Review will examine the results of two Clinical Drug Trails evaluating Adalimumab (ADA) for the induction and maintenance treatment of Moderate-Severe UC failing conventional therapy. Study # 1 by Reinisch W, et al, examined the efficacy of ADA for the induction of clinical remission of moderate-severe UC (ULTRA-1). Study # 2 by, Sandborn WJ, et al, examined the efficacy of ADA to induce and maintain clinical remission of moderate-severe UC (ULTRA-2). Reinisch W, et al. Gut. 2011;60:780-7. Sandborn WJ, et al. Gastroenterology. 2012;42:257-265

Study # 2: Ulcerative colitis long-term remission and maintenance with adalimumab (ULTRA 2)

WILLIAM J. SANDBORN,* GERT VAN ASSCHE,‡ WALTER REINISCH,§ JEAN–FREDERIC COLOMBEL, GEERT D’HAENS,¶,# DOUGLAS C. WOLF,** MARTINA KRON,‡‡ MARY BETH TIGHE,§§ ANDREAS LAZAR,‡‡ and ROOPAL B. THAKKAR§§ Adalimumab Induces and Maintains Clinical Remission in Patients With Moderate-to-Severe Ulcerative Colitis GASTROENTEROLOGY 2012;142:257–265 *University of California San Diego, La Jolla, California; ‡University Hospital of Gasthuisberg, Leuven, Belgium; §Medical University Vienna, Vienna, Austria; Centre Hospitalier Universitaire de Lille, Lille, France; ¶Academic Medical Center, Amsterdam, The Netherlands; #Imelda GI Clinical Research Center, Bonheiden, Belgium; **Atlanta Gastroenterology Associates, Atlanta, Georgia; ‡‡Abbott GmbH & Co. KG, Ludwigshafen, Germany; §§Abbott, Abbott Park, Illinois.

Abbreviations Used ADA Adalimumab 5-ASA 5-aminosalicylic acid or Mesalamine Anti-TNF α Anti-TNF Antibody ATI Antibody to Infliximab AZA Azathioprine IFX Infliximab 6MP 6 mercaptopurine PBO Placebo TNF Tumor necrosis factor ULTRA Ulcerative colitis long-term remission and maintenance with adalimumab

Sandborn WJ, et al. Gastro. 2012;42:257-265 Methods Study Design: Phase 3, multicenter randomized, double-blind, placebo-controlled trial conducted at 103 centers North America, Europe, New Zealand, and Israel. All UC patients were adults with moderate to severe UC ( > 3 mo. duration), defined by Mayo Score > 6 and endoscopy sub score > 2 despite concurrent corticosteroids or immunosuppressant drugs. Patients were randomly assigned to 2 groups: Group 1: ADA (160/80/40 mg) Rx T0, T2wk, T4wk, T6wk,…EOW...T52wk Group 2: PBO (PBO/PBO/PBO) Rx T0, T2wk, T4wk, T6wk,....EOW…T52wk Patients received study medication through week 52 with final study evaluations at week 52. After 12 wks non-responders were allowed into Open label ADA 40 mg EOW, non-responders at that dose were allowed to escalate to ADA 40 mg EW.

Methods: Concurrent Therapy Sandborn WJ, et al. Gastro. 2012;42:257-265 Methods: Concurrent Therapy Concurrent Therapy Corticosteroid stable dose oral prednisone (> 20 mg / day for at least 2 wk or < 20 mg/day for at least 40 days) before baseline. Pts on immunomodulators were to receive at least a 3-mo consecutive course of azathioprine (AZA, at least 1.5 mg/kg/day, or highest dose tolerated) or 6-mercaptopurine (6-MP, at least 1 mg/kg/day). Both drugs had to be given at a stable dose for at least 4 weeks. Concurrent therapy was not required for those patients intolerant to Rx Prior Anti-TNF other than ADA was allowed, if the pt. was intolerant to or had loss of response to the agent for > 8 wks.

Methods Study Subjects (inclusion criteria) Sandborn WJ, et al. Gastro. 2012;42:257-265 Methods Study Subjects (inclusion criteria) All adults, giving informed written consent. UC confirmed by colonoscopy or sigmoidoscopy with biopsy performed within 21 days of study initiation. Moderate Severe UC despite stable treatment with corticosteroids &/or immunomodulators (concurrent Rx not required for those intolerant to these Rx). UC Disease Severity defined by “Full” Mayo Score. maximum score = 12 Total score = 6-12 (Moderate to Severe) Endoscopy sub score = 2-3 Schroeder KW, et al. NEJM. 1987;317:1625-9

Methods Study Subjects (inclusion criteria) Sandborn WJ, et al. Gastro. 2012;42:257-265 Methods Study Subjects (inclusion criteria) Definition of Stable Treatments Prednisone > 20 mg for > 14 days or < 20 mg/day for > 40 days And/or Immunomodulator for > 90 days and stable dose for > 28 days. (AZA dose > 1.5 mg/kg/day or 6-MP dose > 1 mg/kg/day) . Female patients were post menopausal or using accepted birth control methods.

Methods Study Subjects (exclusion criteria) Sandborn WJ, et al. Gastro. 2012;42:257-265 Methods Study Subjects (exclusion criteria) Patients with JUST Ulcerative Proctitis. IV corticosteroids <14 days from screening Any Cyclosporine, Tacrolimus, or Mycophenolate mofetil within 30 days. Enema therapy within 2 wk of study entry. Pregnancy, TPN, C difficile infection (< 30 days of baseline), ATBX (IV < 1 mo. or oral < 2 wk), Antivirals. History of Listeria, Histoplasmosis, Chronic HBV, HIV, Immunodeficiency, CNS demyelination, Untreated TB, Malignancy or dysplasia, drug or ETOH abuse last year

Demographics Characteristic Placebo N=246 ADA N=248 Total N=494 Gender ♂ (%) 152 (62%) 142 (57%) 294 (59%) Age, years (mean) 41 yr 40 yr Weight, kg (mean) 77 kg 75 kg 76 kg Disease Location (%) Pan-colitis 49% 48% Left-sided 39% Other 9% 8% Sandborn WJ, et al. Gastro. 2012;42:257-265

Demographics Characteristic Placebo N=246 ADA N=248 Total N=494 Disease Duration, yrs (mean) 8.5 yr 8.1 yr 8.3 yr Mayo Score, mean 8.9 Endoscopy sub score 2.5 Rectal bleeding, sub score 1.7 PGA sub score 2.2 Stool Frequency, sub score 2.6 CRP, mg/l: median 4.2 4.1 Sandborn WJ, et al. Gastro. 2012;42:257-265

Demographics Characteristic Placebo N=246 ADA N=248 Total N=494 Concomitant Rx, (%) Corticosteroid (without IMM) 57% 61% 59% IMM (without corticosteroid) 33% 38% 35% Corticosteroid + IMM 18% 20% 19% Prior Anti-TNF Therapy Sandborn WJ, et al. Gastro. 2012;42:257-265

Study Design pts randomized (1 : 1) N = 494 248 pts ADA 246 pts Sandborn WJ, et al. Gastro. 2012;42:257-265 Study Design pts randomized (1 : 1) N = 494 248 pts ADA 246 pts Placebo Completed – n=154 Discontinued – n= 94 Withdrew n=8 Lost f/u n=1 Protocol violation n=1 Other n=9 Completed – n=131 Discontinued – n=115 Adverse Event – 4 Withdrew Protocol violation n=5 Other - n=11

Study Design: Induction Phase ADA 160/80 Randomization 1:1 Study Evaluations Time 0 2 4 8 wks Endoscopy Score + + Mayo Score + + Time 0 Up to -21 days Endoscopy Randomization 1:1 Time 52 wk Primary End Point (Remission) Treatment Interval (Time in Weeks) 0 2 4 6 8 12,… ADA 160mg 80 40 40 40 40 Placebo PBO PBO PBO PBO PBO PBO Sandborn WJ, et al. Gastro. 2012;42:257-265

Sandborn WJ, et al. Gastro. 2012;42:257-265 Study Design: ADA Maintenance for Responders & Open Label ADA for Non-Responders at 12 wk Study Evaluations: 0,2,4,8,12,16,20,26,32, 38, 44, 52 wk Full Mayo : 0, 8, 32, 52wk Partial Mayo : 0, 4,8, 20, 32, 52wk IBD Questionnaire:0, 4,8, 20, 32, 52wk After 12 wk able to switch to open label ADA 40 mg EOW Time 52 wk Primary End Point (Remission) Time in Weeks 0 8 12 14 … 50 52wk Maintenance ADA 40mg EOW,… 40 40 Open label ADA 40mg EOW,… 40 40 Definition: Inadequate or Non-Responder Mayo Score > baseline on 2 consecutive visits Partial Mayo Score > 7 on 2 consecutive visits While on Open label ADA 40 mg EOW, non-remitters permitted to escalate to ADA 40 mg weekly

Definitions: Remission & Response to ADA Primary Efficacy Endpoint: Clinical Remission Definition Clinical Remission Total “Full” Mayo Score < 2 and No individual sub score > 1 Definition of Clinical Response A ↓ in “Full” Mayo Score by > 3 points (or > 30% drop) from baseline with a rectal bleeding score ↓ by > 1 or absolute rectal bleeding score of 0-1. Sandborn WJ, et al. Gastro. 2012;42:257-265

Study Design Intra-Study Management of Concomitant Rx Open Label ADA Sandborn WJ, et al. Gastro. 2012;42:257-265 Study Design Intra-Study Management of Concomitant Rx Immunomodulator Rx remained at constant dosage 5-ASA Rx remained at constant dosage Prednisone could be tapered after 8 weeks at the discretion of the investigator, that pt. had a satisfactory clinical response. Taper 5 mg/wk until a dosage of 10 mg reached, thereafter taper at 2.5 mg/wk until “0” Open Label ADA Allowed to escalate dosage to 40 mg every week, if demonstrated inadequate response at two consecutive visits.

Study Evaluations Evaluations performed at: Mayo Score at: Weeks: 0,2,4,8,12,16,20,26,32,38,44,52/early termination Mayo Score at: Weeks: 0,8,32,52/early termination Partial Mayo Score determined at all visits IBD Questionnaire: Weeks: 0,4,8,20,32,52/early termination Sandborn WJ, et al. Gastro. 2012;42:257-265

Study Definitions Definition Clinical Remission Mayo Score < 2, no individual score > 1 Definition Clinical Response Mayo Score ↓ > 3 pts and at least 30% with ↓ bleeding sub score of at least 1 pt. or absolute rectal bleeding sub score of 0 or 1. Sandborn WJ, et al. Gastro. 2012;42:257-265

“Full” Mayo Score Scores range from 0 to 3 pts for each variable Bowel movement (BM) frequency Normal (0 pts); 1-2 BM > nl (1 pts); 3-4 BM > nl (2 pts); > 5 BM > nl (3 pts). Rectal bleeding None (0 pts); Streaks on stool < 50% BM’s (1 pts); Obvious blood with most BM’s (2 pts); Blood alone (3 pts). Endoscopy Normal (0 pts); Mild: erythema, ↓ vascularity,Mild friability (1 pts); Moderate: marked erythema, lack vascular pattern, friability (2 pts); Severe: spontaneous bleeding, ulceration (3 pts). Physician Global Assessment (PGA) Normal (0 pts); Mild (1 pts); Moderate (2 pts); Severe (3 pts)

Mayo Endoscopic Criteria Severe Video Clip Click on image to activate

“Partial” Mayo Score Scores range from 0 to 3 pts for each variable Bowel movement (BM) frequency Normal (0 pts); 1-2 BM > nl (1 pts); 3-4 BM > nl (2 pts); > 5 BM > nl (3 pts) Rectal bleeding None (0 pts); Streaks on stool < 50% BM’s (1 pts); Obvious blood with most BM’s (2 pts); Blood alone (3 pts) No Endoscopy Physician Global Assessment (PGA) Normal (0 pts); Mild (1 pts); Moderate (2 pts); Severe (3 pts)

Evaluated Efficacy End Points Placebo N=246 ADA N=248 P value Sustained Remission per Mayo Score @ 8 & 52 wk 4.1 8.5 .047 Sustained Response per Mayo Score @ 8 & 52 wk 12.2 23.8 <.001 Sustained mucosal healing per Mayo Score @ 8 & 52 wk 10.6 18.5 .013 PGA < 1 at 8 wk 37.4 46 .058 SFS < 1 at 8 wk 28.5 37.9 .028 RBS < 1 at 8 wk 58.1 70.2 .006 Sandborn WJ, et al. Gastro. 2012;42:257-265

Evaluated Efficacy End Points Placebo N=246 ADA N=248 P value Discontinued corticosteroid before 52 wk and 52wk remission 5.7 13.3 .035 Discontinued corticosteroid and achieved sustained remission at 32 wk and 52wk remission 1.4 10 .002 IBDQ responder at 52 wk 16.3 26.2 .007 IBDQ responder at 8 wk 45.5 58.1 .006 Sandborn WJ, et al. Gastro. 2012;42:257-265

Results: Remission Rates (%) * * * P < 0.05 Sandborn WJ, et al. Gastro. 2012;42:257-265

Results: Response Rates (%) * * * P < 0.05 Sandborn WJ, et al. Gastro. 2012;42:257-265

Results: Mucosal Healing (%) * * * P < 0.05 Sandborn WJ, et al. Gastro. 2012;42:257-265

Results: Patients with Remission per Partial Mayo Score (%) * * P < 0.05 Sandborn WJ, et al. Gastro. 2012;42:257-265

Results: Patients Who Discontinued Steroids (%) * * P < 0.05 Sandborn WJ, et al. Gastro. 2012;42:257-265

Median Trough ADA Concentrations Over Time by Remission Status @ 52 wk Mean + SD (Nnmiss) Treatment Group Week 8 Week 32 Week 52 40 mg EOW pts who were remitters (n=42) 11.4 + 5.15 (41) 10.6 + 5.64 (39) 10.8 + 7.45 (39) 40 mg EOW pts who were non-remitters N=153 8.49 + 4.35 (110) 6.95 + 3.98 (70) 6.18 + 4.22 (62) Sandborn WJ, et al. Gastro. 2012;42:257-265

Summary of Treatment-Emergent Adverse Events Only one AE to reached statistical significance: “Any injection site related AE” Placebo 10 (3.8%) vs. ADA 31 (12.1%), p < 0.001 Malignancy was seen only in the ADA group Squamous cell carcinoma (1) and Gastric cancer (1) Sandborn WJ, et al. Gastro. 2012;42:257-265

Development of ADA-Antibodies 2.9% (7 of 245 pts) developed antibodies to ADA. All patients developing ADA-AB were on ADA-mono therapy Sandborn WJ, et al. Gastro. 2012;42:257-265

Sandborn WJ, et al. Gastro. 2012;42:257-265 Study Conclusions ADA is effective and safe for induction and maintenance of remission of moderate to severe UC failing conventional therapy. ADA appears to be less effective in patients that have already failed Anti-TNF therapy. ADA trough levels of > 10 appear to be predictive of remission. Development of ADA – Ab is more common among patients on ADA-mono therapy.

Sandborn WJ, et al. Gastro. 2012;42:257-265 Study Conclusions ADA was more effective than Placebo in both 8 and 52 wk mucosal healing. Placebo vs.. ADA Mucosal healing 8 week: 31.7% vs. 41.1% p < 0.05 52 week: 15.4% vs. 25.0% p < 0.05

Study Conclusions ADA 160/80/40 EOW appears to be safe in the treatment of moderate-severe UC. No significant difference between ADA vs.. Placebo for any AE: malignancy, injection reaction, opportunistic infection, CHF, demyelination or Lupus-like reactions. Sandborn WJ, et al. Gastro. 2012;42:257-265

Reviewer Comments Sandborn, et al, have conducted a much needed prospective placebo controlled study on the efficacy of ADA 160/80 induction followed by 40 mg EOW for the induction and maintenance treatment of patients with moderate-severe UC (non-proctitis) failing conventional corticosteroid &/or immunomodulator Rx. The investigators’ research shows that ADA 160/80 induction followed by 40 mg EOW is clearly more effective than and Placebo for induction and maintenance of remission for 52 wk. P R McNally, DO, MACG

Reviewer Comments Sandborn, et al, ULTRA-2 study has several important differences from previous Anti-TNF (IFX ACT 1 and ACT 2) treatment of patients with moderate to severe UC failing conventional therapy: The ULTRA-2 ADA-UC Trial was conducted 8-10 yrs after the ACT 1 & ACT 2 IFX-UC Trials. None of the pts in the ACT trial had received prior biologic Rx, while 40% of the pts in the ULTRA-2 ADA-UC trial had intolerance or failure of prior Anti-TNF. P R McNally, DO, MACG

Reviewer Comments ACT 1 & ACT 2 IFX trials did not permit pts with inadequate response to leave the blinded trial and receive open label drug. The ULTRA-2 ADA-UC Trial used different methodology to calculate the Mayo Score: worst score from the last 3 days, versus the average score for the last 3 days for the ACT 1 & ACT IFX-UC Trials. P R McNally, DO, MACG

P R McNally, DO, MACG Reviewer Conclusions The ULTRA-2 ADA-UC Trial clearly demonstrates that ADA 160/80 then 40 mg EOW is effective acute and maintenance treatment for UC patients failing conventional treatment with corticosteroids and/or AZA/6-MP. There appears to be a definable ADA trough of 10 for remitters, suggesting that dose adjustment to ADA trough drug levels may improve remission rates. This needs to be evaluated prospectively!

P R McNally, DO, MACG Reviewer Conclusions There is much is to be further learned by the ULTRA-2 Sub analysis. The opportunity for both ADA and PBO patients to switch into open label ADA 40mg EOW and then escalate into ADA 40 mg EW will further our understanding of ADA dose response in UC. ADA group had 116 switch to open label (ADA 40 mg EOW) at 12 wk and 68 of these pts later dose escalated (ADA 40 mg EW). PBO group had 135 switch to open label (ADA 40 mg EOW) at 12 wk and 84 pts later dose escalated (40 mg EW).

P R McNally, DO, MACG Reviewer Conclusions The future of biologic therapy for UC is NOT one size/one dose fits all. Anti-TNF dose adjustment by weight, disease severity/inflammation (CRP > 10) and ADA trough > 10. The key primary end point for future IBD treatment trials will be complete mucosal healing. Achievement of that end point will lead to complete disease free remission. Mucosal healing