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Literature Review

Literature Review. Peter R. McNally, DO, FACP, FACG University Colorado Denver School of Medicine Center for Human Simulation Aurora, Colorado 80045. Introduction. Crohn’s disease is a lifelong, disabling disorder with 2/3 rd of patients requiring surgery in their lifetime.

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Literature Review

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

  2. Introduction • Crohn’s disease is a lifelong, disabling disorder with 2/3rd of patients requiring surgery in their lifetime. • In 1998, introduction of anti-TNF-α agents to treat Crohn’s disease was a tremendous medical advance. Anti-TNF-α treatment promotes complete mucosal healing in ~50% of pts & remission rates of 40-50% are expected in pts with mod-severe disease. Michelassi F, et al. Ann Surg. 1991;214:230-238. Reguelo M, et al. Gastroenterol. 2009;136:441-450. D’Haenes G, et al. Gastroenterol. 1999;116:1029-34.

  3. Introduction • Concerns for ↑ rates of opportunistic infections, lymphoma and splenic T-cell lymphoma have tempered enthusiastic use of anti-TNF-α agents, especially in combination with azathioprine (AZA) and 6-mercaptopurine (6MP). • The study by Colombel and the Sonic Study group reviewed in this edition of www.VHJOE.org scientifically confirms, IFX-AZA combination therapy is more effective and as safe as mono therapy with either IFX or AZA. Kandiel A, et al. Gut. 2005;54:1121-1125. Lichtenstein GR, et al. Gastroenterol Hepatol. 2006;4:2275-2285.

  4. Jean Frederic Colombel, M.D., William J. Sandborn, M.D., Walter Reinisch, M.D., Gerassimos J. Mantzaris, M.D., Ph.D., Asher Kornbluth, M.D., Daniel Rachmilewitz, M.D., Simon Lichtiger, M.D., Geert D’Haens, M.D., Ph.D., Robert H. Diamond, M.D., Delma L. Broussard, M.D., Kezhen L. Tang, Ph.D., C. Janneke van der Woude, M.D., Ph.D., and Paul Rutgeerts, M.D., Ph.D., for the SONIC Study Group* *Members of the Study of Biologic and Immunomodulator Naïve Patients in Crohn’s Disease (SONIC) Study Group Infliximab, Azathioprine, or Combination Therapy for Crohn’s Disease. NEJM. 2010;362:1383-95.

  5. Abbreviations Used • AZA Azathioprine • IFX Infliximab • TNF Tumor necrosis factor • 6MP 6 mercaptopurine • PBO Placebo • CDAI Crohn’s Disease Activity Index • TPMT Thiopurine methyltransferase • 5-ASA 5-aminosalicylic acid or Mesalamine • ATI Antibody to Infliximab • ADA Adalimumab • CTZ Certolizumab pegol

  6. Colombel JF, et al. NEJM. 2010;362:1383-95 Methods • Study Design: randomized, double-blind trial, efficacy evaluation of infliximab (IFX) mono-therapy vs. Azathioprine (AZA) mono-therapy vs. combination therapy (IFX + AZA) in 508 adults with moderate-to-severe Crohn’s disease . • All Crohn’s disease patients were naive to previous immunosuppressive or biologic therapy. • Patients were randomly assigned to 3 groups: • Group 1: intravenous infusion of 5 mg/kg of IFX at weeks 0, 2, and 6 and then every 8 weeks plus daily oral placebo (PBO) capsules • Group 2: 2.5 mg/kg of oral azathioprine plus a placebo (PBO) infusion on the standard schedule • Group 3: IFX plus AZA combination • Patients received study medication through week 30 and then could continue in a blinded study extension through week 50.

  7. Colombel JF, et al. NEJM. 2010;362:1383-95 Methods Study Subjects (inclusion criteria) • All > 21 yrs of age, giving informed written consent • Crohn’s of > 6 weeks duration & mod-severe severity • CDAI (Crohn’s Disease Activity Index) • Remission < 150 points • Mild 150-220 points • Moderate 220-450 points • Severe > 450 points • Failed Rx: 2nd course corticosteroids < 12 mo; or mesalamine (>2.4 g/day); or budesonide (>6 mg/day) • No previous AZA, 6-MP, MTX, anti-TNF-α treatment. Best WR, et al. Development of a Crohn’s disease activity index. Gastroenterol 1976; 70:439-44.

  8. Colombel JF, et al. NEJM. 2010;362:1383-95 Methods Study Subjects (exclusion criteria) • Short bowel syndrome, an ostomy, symptomatic bowel stricture, abscess, recent abdominal surgery (< 6 mo) • History of tuberculosis or other granulomatous infection • (+) chest x-ray or PPD skin test • Recent opportunistic infection (<6 mo) • Active infection Hepatitis B or C • HIV infection or Multiple Sclerosis or Cancer • Homozygous mutant TPMT phenotype

  9. Demographics Colombel JF, et al. NEJM. 2010;362:1383-95

  10. Demographics Colombel JF, et al. NEJM. 2010;362:1383-95

  11. Demographics Colombel JF, et al. NEJM. 2010;362:1383-95

  12. Study Design Colombel JF, et al. NEJM. 2010;362:1383-95

  13. Study Design 508 Pts Randomized 170 pts AZA + PBO 169 pts IFX + PBO 169 pts IFX + AZA 86 pts at 30 wk 111 pts at 30 wk 121 pts at 30 wk 62 pts through 50 wk 85 pts through 50 wk 90 pts through 50 wk Colombel JF, et al. NEJM. 2010;362:1383-95

  14. Study Results Colombel JF, et al. NEJM. 2010;362:1383-95

  15. Study Results Colombel JF, et al. NEJM. 2010;362:1383-95

  16. Study Results Colombel JF, et al. NEJM. 2010;362:1383-95

  17. Study Results Colombel JF, et al. NEJM. 2010;362:1383-95

  18. Study Results Colombel JF, et al. NEJM. 2010;362:1383-95

  19. Study Results: (%) Corticosteroid-free Clinical Remission wk-26 P < 0.001 P < 0.006 P < 0.02 Colombel JF, et al. NEJM. 2010;362:1383-95

  20. Study Results: (%) Mucosal Healing wk-26 P < 0.001 P = 0.02 P = 0.06 Colombel JF, et al. NEJM. 2010;362:1383-95

  21. Study Results: Safety Data Colombel JF, et al. NEJM. 2010;362:1383-95

  22. Study Results: Safety Data Colombel JF, et al. NEJM. 2010;362:1383-95

  23. Study Results: Safety Data Colombel JF, et al. NEJM. 2010;362:1383-95

  24. Study Results: Safety Data Colombel JF, et al. NEJM. 2010;362:1383-95

  25. Safety data • Infusion Reactions • IFX + AZA 5.0% (9/179) • IFX + PBO 16.6% (27/163) • AZA + PBO 5.6% (9/161) P=0.002 P=0.001 Colombel JF, et al. NEJM. 2010;362:1383-95

  26. Study Results: Development of IFX – AB (ATI) % A T I (+) Colombel JF, et al. NEJM. 2010;362:1383-95

  27. Study Results: IFX Trough Levels (μg/ml) P < 0.001 IFX μg/ml Colombel JF, et al. NEJM. 2010;362:1383-95

  28. Colombel JF, et al. NEJM. 2010;362:1383-95 Study Conclusions • IFX + AZA treatment issuperior to IFX & AZA mono-therapy for treatment of mod-severe Crohn’s disease. • 10 End Point – Remission by CDAI @ 26 wk • Combo IFX + AZA = 56.8% • IFX + PBO = 44.4% • AZA + PBO = 30.0% • 20 End Point Healing Pre Rx Post 26wk • Combo IFX + AZA = 65.7%  43.9% • IFX + PBO = 58.6%  30.1% • AZA + PBO = 67.6%  16.5%

  29. Colombel JF, et al. NEJM. 2010;362:1383-95 Study Conclusions • Combo IFX + AZA is as safe as IFX & AZA mono-therapy. • Total Percentage of Serious Infections • Combo IFX + AZA = 3.9 % • IFX + PBO = 4.9 % • AZA + PBO = 5.6 % • Infusion Reactions • Combo IFX + AZA = 5.0 % • IFX + PBO = 16.6% • AZA + PBO = 5.6%

  30. Colombel JF, et al. NEJM. 2010;362:1383-95 Study Conclusions • Comb IFX + AZA appears to decrease the development of ATI and higher trough IFX levels. • Percentage of ATI detected at wk 30 • Combo IFX + AZA = 0.9 % • IFX + PBO = 14.6 % • Trough IFX levels at week 30 • Combo IFX + AZA = 3.5 μg ml • IFX + PBO = 1.6μg ml

  31. Colombel JF, et al. NEJM. 2010;362:1383-95 Reviewer Comments Colombel, and the other members of the SONIC Study Group are praised for conducting a much needed study on the efficacy of IFX + AZA vs. mono therapy with IFX or AZA in patients with mod-severe Crohn’s disease. The investigators’ research shows that IFX +AZA is clearly more effective than mono therapy with IFX or AZA and in the short term (12 mo), just as safe. P R McNally, DO, FACP, FACG

  32. Colombel JF, et al. NEJM. 2010;362:1383-95 Reviewer Comments However, Colombel, et al, fail to answer the following questions? • Are the short term “6-12 mo” improved efficacy and reduced serious infections seen with IFX + AZA durable? • Will > 12 mo of IFX + AZA therapy prove to be the Achille’s heal, with increased development of serious infections and malignancy ? P R McNally, DO, FACP, FACG

  33. Colombel JF, et al. NEJM. 2010;362:1383-95 Reviewer Comments • Greater remission rates for IFX + AZA vs. IFX + PBO may be related to reduced immunogenicity toward the chimeric anti-TNF-α (IFX), as ATI’s are reduced and trough levels of IFX are higher in the combined IFX-AZA group. IFX + AZAIFX + PBO ATI 0.9% 14.6% Trough IFX 3.5 μg/ml 1.6 μg/ml P R McNally, DO, FACP, FACG

  34. Colombel JF, et al. NEJM. 2010;362:1383-95 Reviewer Comments • Many studies of biologic therapy among Crohn’s disease patients have shown that the initiation of therapy earlier in the onset of the disease predicts much higher remission rates. The “Sonic Trial” study evaluated patients with short duration of Crohn’s disease (ave of 2 yrs). The “ high” ~60% remission rate for IFX +AZA seen in the Sonic Trial may be a reflection of the subject enrollment criteria. P R McNally, DO, FACP, FACG

  35. Colombel JF, et al. NEJM. 2010;362:1383-95 Reviewer Comments • Immunogenicity of the 3 FDA approved anti-TNF-α agents (IFX, ADA, CTZ) are different. - Remission rates for ADA + AZA or CTZ + AZA cannot be assumed to be the same as seen with IFX + AZA in the Sonic Trial! - Safety for ADA + AZA or CTZ + AZA cannot be assumed to be the same as seen with IFX + AZA in the Sonic Trial! P R McNally, DO, FACP, FACG

  36. Colombel JF, et al. NEJM. 2010;362:1383-95 Reviewer Comments • Is there an “exit strategy” ? Can combo IFX + AZA treatment “step-down” to just IFX or AZA after 1-2 years of healed mucosa and disease free remission? P R McNally, DO, FACP, FACG

  37. P R McNally, DO, FACP, FACG Reviewer Conclusions • Crohn’s disease is an incredibly devastating and debilitating disorder. More work needs to be done to develop a stratified treatment strategy, that will balance risks of combination IFX + AZA therapy with benefits of disease suppression. • Treatment strategies should be guided by: • Staging Criteria = Montreal Criteria • Genetic Markers = NOD2 (SNP8, SNP12, SNP13) • Antibodies to gut microbiotica (ASCA, OmpC, CBir1, Anti-I2, PANCA) • Serial assessment for mucosal healing • Sonic trial results are specific for IFX + AZA and should not be empirically applied to ADA + AZA or CTZ + AZA. Mucosal healing

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