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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.

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Literature Review

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

  2. 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.

  3. 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.

  4. 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

  5. Study # 2:Ulcerative colitis long-termremission and maintenance with adalimumab (ULTRA 2)

  6. WILLIAM J. SANDBORN,* GERT VAN ASSCHE,‡ WALTER REINISCH,§ JEAN–FREDERIC COLOMBEL,GEERT D’HAENS,¶,# DOUGLAS C. WOLF,** MARTINA KRON,‡‡ MARY BETH TIGHE,§§ ANDREAS LAZAR,‡‡ andROOPAL 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.

  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

  8. 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.

  9. 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.

  10. 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

  11. 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.

  12. 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

  13. Demographics Sandborn WJ, et al. Gastro. 2012;42:257-265

  14. Demographics Sandborn WJ, et al. Gastro. 2012;42:257-265

  15. Demographics Sandborn WJ, et al. Gastro. 2012;42:257-265

  16. Sandborn WJ, et al. Gastro. 2012;42:257-265 Study Design 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

  17. Study Design: Induction Phase ADA 160/80Randomization 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

  18. 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

  19. 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

  20. 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.

  21. Study Evaluations • Evaluations performed 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

  22. 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

  23. “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)

  24. Mayo Endoscopic CriteriaSevere Video Clip Click on image to activate

  25. “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)

  26. Evaluated Efficacy End Points Sandborn WJ, et al. Gastro. 2012;42:257-265

  27. Evaluated Efficacy End Points Sandborn WJ, et al. Gastro. 2012;42:257-265

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

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

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

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

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

  33. Median Trough ADA Concentrations Over Time by Remission Status @ 52 wk Sandborn WJ, et al. Gastro. 2012;42:257-265

  34. 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

  35. 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

  36. 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.

  37. 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

  38. 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

  39. 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

  40. 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

  41. 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

  42. 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!

  43. 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).

  44. 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

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