Literature Review

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 # 1:Ulcerative colitis long-termremission and maintenance with adalimumab (ULTRA 1)

Walter Reinisch,1 William J Sandborn,2 Daniel W Hommes,3 Geert D’Haens,4 Stephen Hanauer,5 Stefan Schreiber,6 Remo Panaccione,7 Richard N Fedorak,8 Mary Beth Tighe,9 Bidan Huang,9 Wendy Kampman,10 Andreas Lazar,11 Roopal Thakkar9 1Medical University Vienna, Vienna, Austria 2Mayo Clinic, Rochester, Minnesota, USA 3Leiden University Medical Center, Leiden, Netherlands 4Academic Medical Centre, Amsterdam, Netherlands 5University of Chicago Medical Center, Chicago, Illinois, USA 6Christian-Albrechts-University, University-Hospital Schleswig-Holstein, Medical Department I, Kiel, Germany 7University of Calgary, Calgary, AB, Canada 8University of Alberta, Edmonton, AB, Canada 9Abbott, Abbott Park, Illinois, USA 10Abbott, Maidenhead, UK 11Abbott, Ludwigshafen, Germany Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. (ULTRA-1) Gut. 2011;60:780-7

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-termremission and maintenance with adalimumab

Reinisch W, et al. Gut. 2011;60:780-7 Methods • Study Design: 8wk, multicenter, randomized, double-blind trial, placebo controlled study conducted at 94 centers in No. America and Europe • All UC patients were ambulatory, adults with moderate to severe UC, defined by Mayo Score > 6 and endoscopy sub score > 2 despite corticosteroids or immunosuppressant drugs. • Patients were randomly assigned to 3 groups: • Group 1: ADA (160/80/40/40mg) Rx T0, T2wk, T4wk, T6wk • Group 2: ADA ( 80/40/40/40mg) Rx T0, T2wk, T4wk, T6wk • Group 3: PBO (PBO/PBO/PBO) Rx T0, T2wk, T4wk, T6wk • Patients received study medication through week 6 with final study evaluations at week 8 • Patients in the 8 week induction trial were continued in a 52 week Open-Label maintenance extension.

Reinisch W, et al. Gut. 2011;60:780-7 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 (moderate to severe) Schroeder KW, et al. NEJM. 1987;317:1625-9

Reinisch W, et al. Gut. 2011;60:780-7 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.

Reinisch W, et al. Gut. 2011;60:780-7 Methods Study Subjects (exclusion criteria) • Patients with JUST Ulcerative Proctitis. • Any previous treatment with any anti-TNF agent. • IV corticosteroids <14 days from screening. • Any Cyclosporine, Tacrolimus, or Mycophenolate mofetil within 30 days. • Pregnancy, TPN, C difficile infection (< 30 days of baseline), ATBX, Antivirals. • History of Listeria, Histoplasmosis, Chronic HBV, HIV, Immunodeficiency, CNS demyelination, Untreated TB, Malignancy or dysplasia, drug or ETOH abuse <1 yr.

Demographics Reinisch W, et al. Gut. 2011;60:780-7

Reinisch W, et al. Gut. 2011;60:780-7 Study Design Completed – 121 Discontinued – 9 Adverse Event – 5 Lack of Efficacy – 4 Completed – 121 Discontinued – 9 Adverse Event – 4 Withdrew - 1 Lack of Efficacy – 4 Protocol violation – 2 Other - 1 Completed – 118 Discontinued – 12 Adverse Event – 6 Withdrew 2 Lost to Follow-up - 2 Lack of Efficacy – 2

Reinisch W, et al. Gut. 2011;60:780-7 Study Design: Original Protocol Study Evaluations Time 0 2 4 6 8 wks Endoscopy Score + + Mayo Score + + Time 0 Up to -21 days Endoscopy Randomization Time 8 wk Primary End Point (Remission) Time in Weeks 0 2 4 6 8 ADA 160mg 80 40 40 Placebo PBO PBO PBO PBO

Reinisch W, et al. Gut. 2011;60:780-7 Study Design: Amendment 3 Study Evaluations Time 0 2 4 6 8 wks Endoscopy Score + + Mayo Score + + Time 0 Up to -21 days Endoscopy Randomization Time 8 wk Primary End Point (Remission) Time in Weeks 0 2 4 6 8 ADA 80mg 40 40 40 ADA 160mg 80 40 40 Placebo PBO PBO PBO PBO

“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 CriteriaSevere 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)

Definitions: Remission & Response to ADA • Primary Efficacy Endpoint: Clinical Remission • Definition Clinical Remission at 8 wk • Total “Full” Mayo Score < 2 and • No individual sub score > 1 • Definition of Clinical Response at 8 wk • 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. Reinisch W, et al. Gut. 2011;60:780-7

Reinisch W, et al. Gut. 2011;60:780-7 Results: Clinical Remission 8-wk (%) 18.5 * * P = 0.031 9.2 10.0

Reinisch W, et al. Gut. 2011;60:780-7 Study Results: Secondary Efficacy End Points

Reinisch W, et al. Gut. 2011;60:780-7 Clinical Response at 8 wkStratified by Study Region * P < 0.05

Reinisch W, et al. Gut. 2011;60:780-7 Safety Data * P < 0.05

Reinisch W, et al. Gut. 2011;60:780-7 Safety Data

Study Results • Baseline Demographics: • ADA 80/40 group had numerically longer duration of disease, higher mean Mayo Score, higher mean CRP, but the difference was p = NS to other groups. • Primary Outcome • ADA 160/80 group 8 wk remission was 2x greater than Placebo, p = 0.031 (18.5% vs. 9.2%, respectively) Reinisch W, et al. Gut. 2011;60:780-7

Study Results • Sub-Analysis • T-0/Entry Variables Predicting ↓ Remission Rates • Mayo score > 10 • Extensive colitis on IMM or 5-ASA at T0 • High CRP > 10 • Weight > 82 Kg • Placebo 8 wk remission rates were exceptionally high for study participants from the Canada and Eastern Europe Study Regions. Placebo remission rates from those regions exceeded treatment remission rates: 53.8% vs. 50% and 56.5 and 55%, respectively!!!!

Reinisch W, et al. Gut. 2011;60:780-7 Study Conclusions • ADA 160/80 mg is twice as effective as placebo in achieving 8 wk remission rates among patients with moderate to severe UC (18.5% vs. 9.2%, P = 0.031). • ADA 80/40 mg is not an effective induction dose for the treatment of moderate to severe UC compared to placebo (10% vs. 9.2%, p = NS).

Study Conclusions • Secondary Study End Points Placebo vs. ADA 160/80 Mucosal healing: 41.5% vs. 46.9%, p = NS Rectal bleeding : 66.2% vs. 77.7%, p = 0.038 (score < 1) PGA score < 1) 46.9% vs. 60%, p = 0.035 Stool frequency 37.7% vs. 48.5%, p = NS (score < 1) Reinisch W, et al. Gut. 2011;60:780-7

Study Conclusions • Both ADA 160/80 and ADA 80/40 appear to have 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. Reinisch W, et al. Gut. 2011;60:780-7

Reviewer Comments Reinisch, et al, have conducted a much needed prospective, placebo controlled, study on the efficacy of two ADA induction doses for the treatment of patients with moderate-severe UC (non-proctitis) failing conventional corticosteroid &/or immunomodulator Rx. The investigators’ research shows that ADA 160/80 is clearly more effective than ADA 80/40 and Placebo in the induction for 8 wk remission & short term safety. P R McNally, DO, MACG

Reviewer Comments Reinisch, et al, study has several important conflicts in methodology, exclusion of important demographic information and regional variance in study results: • Interim change in study design to include an ADA 80/40 treatment arm (Request of European Regulatory Authorities – Amendment 3) P R McNally, DO, MACG

Reviewer Comments Reinisch, et al, study has several important conflicts in methodology, exclusion of important demographic information and regional variance in study results: • Unexplainable high placebo response rates in Canada and Eastern Europe study groups. The placebo response from these two study regions exceeded ADA treatment response for all 4 regions. • Smoking history (never, active, & discontinued) was not include in the demographic data. This is likely to be an important regional study group variable! P R McNally, DO, MACG

Reviewer Comments Reinisch, et al, fail to answer the following questions? • Would a higher dose of ADA than 160/80 be safe and more effective in the induction dosage for moderate-severe UC? This would seem especially important since the variables: weight > 82 Kg, extensive colitis and high CRP > 10, all predicted non-remitter status. • Why were the placebo response rates of study participants from Canada and Eastern Europe equal to or higher than ADA treatment group from any of the 4 regions patients were recruited from ? P R McNally, DO, MACG

P R McNally, DO, MACG Reviewer Conclusions • Patients with Ulcerative Colitis failing conventional Rx will benefit from the addition of convenient non-hospital/office based subcutaneous ADA therapy. • It is unclear, that ADA160/80 is the optimal induction dosage for moderate to severe UC. Higher doses may be necessary for larger pts (> 82Kg), those with more extensive colitis &/or high CPR > 10. Mucosal healing

P R McNally, DO, MACG Reviewer Conclusions • The future of biologic therapy for UC is NOT one size/one dose fits all. We now need studies to evaluate Anti-TNF dose adjustments for patient size, extent of disease/inflammation (CRP >10) and trough drug levels. Mucosal healing

P R McNally, DO, MACG Reviewer Conclusions • 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

Literature Review