1. Monotherapy using 6-MP or azathioprine for IBD is not dead yet: long live the tried and true Jean-Frederic Colombel Icahn School of Medicine at Mount Sinai New York, NY

2. Conflicts of interest J-F Colombel has served as consultant, advisory board member or speaker for Abbvie, ABScience, Amgen, Bristol Meyers Squibb, Celltrion, Danone, Ferring, Genentech, Giuliani SPA, Given Imaging, Janssen, Immune Pharmaceuticals, Medimmune, Merck & Co., Millenium Pharmaceuticals Inc., Neovacs, Nutrition Science Partners Ltd., Pfizer Inc. Prometheus Laboratories, Protagonist, Receptos, Sanofi, Schering Plough Corporation, Second Genome, Shire, Takeda, Teva Pharmaceuticals, Tigenix, UCB Pharma, Vertex, Dr. August Wolff GmbH & Co.

3. Maximal prescription during the 4-yr calendar period Crohn’s disease (n=3852) Ulcerative Colitis (n=1880) Are we still using azathioprine monotherapy ? Evolution of prescription of drugs in IBD during the last 20 years Hôpital St-Antoine, Paris Courtesy J.Cosnes

4. What should we consider ? Efficacy Safety Practicality and cost For the sake of time let’s concentrate on Crohn’s disease

5. Efficacy of AZA/6MP vs placebo at inducing remission in Crohn’s disease NNT = 5 Prefontaine E et al. Cochrane database of systematic reviews 2010

6. Efficacy of AZA/6MP vs placebo for steroid sparing effect Prefontaine E et al. Cochrane database of systematic reviews 2010

7. Efficacy of AZA/6MP vs placebo for fistula improvement or healing Prefontaine E et al. Cochrane database of systematic reviews 2010

8. Efficacy of AZA/6MP vs placebo at maintaining remission in Crohn’s disease NNT = 5 Prefontaine E et al. Cochrane database of systematic reviews 2010 NNT = 6

9. Endpoint Mean difference (CI 95%) with control arms (%)pNNT Clinical recurrence (1 year) 8 (1–15)0.02113 Clinical recurrence (2 years) 13 (2–24)0.0188 Endoscopic recurrence (1 year)23 (9–37) 0.00164 Severe endoscopic recurrence (i2–i4)15 (1.8–29)0.0267 Peyrin-Biroulet L et al. Am J Gastroenterol 2009 NNT = number needed to treat AZA for the prevention of post-operative recurrence of Crohn’s disease

10. Why should we abandon a drug that works ? Gastroenterology 2013

11. p=0.022p=0.009 31 44 57 p<0.001 52/17075/16996/169 AZA + placebo IFX + placebo IFX + AZA 100 80 60 40 20 0 Steroid-free remission = CDAI <150 points Primary endpoint Proportion of patients (%) Colombel JF et al. NEJM 2010 Sonic: steroid-free remission at week 26

12. p=0.055p=0.023 17 30 44 p<0.001 18/10928/9347/107 AZA + placebo IFX + placebo IFX + AZA 100 80 60 40 20 0 Colombel JF et al. NEJM 2010 Mucosal healing: complete absence of mucosal ulcerations in the colon and terminal ileum as assessed by video endoscopy Proportion of patients (%) Sonic : complete mucosal healing at week 26

13. Diagnosis of CD Age <40 years Perineal disease Need for steroids During first 3 months ≤6 months Randomisation AZA early 2.5mg/kg (n=60) ≥2/3 criteria AZA if needed (n=60) Primary endpoint: Number of trimesters without – activity – steroids – IFX – surgery – hospitalisation 36 months The Rapid study The RAPID study Cosnes J et al. Gastroenterology 2013;145: 758-65

14. RAPID AZTEC Cosnes J et al. Gastroenterology 2013;145: 758-65Panes J et al. Gastroenterology 2013;145: 766-74 Cosnes J et al. Gastroenterology 2013;145: 758-65 Early “top-down” therapy with azathioprine is not more effective than placebo or conventional therapy

15. Jean Dela Fontaine 1625 The tortoise and the hare Rien ne sert de courir, il faut partir a point !

16. Progression of digestive damage and inflammatory activity in a theoretical patient with Crohn’s disease Pariente B, et al. Inflamm Bowel Dis 2011 Inflammatory activity (CDAI, CDEIS, CRP) Surgery Stricture Fistula/abscess Disease onset Diagnosis Early disease Crohn’s disease as a progressive disease years

17. Short duration…. 12 months Limitations of current clinical trials in evaluating long-term impact of therapies

18. Use of azathioprine delays phenotype progression in Crohn’s disease No treatment before change N = 344 AZA Before change N = 349 AntiTNF + AZA before change N = 100 P<0.01 ns Magro F, et al. Am J Gastroenterol 2014

19. Thiopurine use is associated with a 40% lowered risk of surgical resection in Crohn’s disease Chatu S, et al. Am J Gastroenterol 2014

20. What should we consider ? Efficacy Safety Practicality and cost

21. TREAT Lichtenstein G et al. DDW 2010 Infections and azathioprine

22. Lymphomas and azathioprine Beaugerie L et al. Gastroenterology 2013

23. Avoid azathioprine Young males –HSTLs (1/5000) EBV-negative young males –Fatal Epstein Barr virus-associated hemophagocytic syndrome (1/500) Patients >65 yrs –Lymphoma –Infections Beaugerie L et al. Lancet 2009 How to reduce the risk of lymphomas associated with azathioprine ?

24. Continuing Discontinued Never received <50 years 50-65 years >65 years Thiopurine therapy Cases of NMSC (n) 039336 233 6 3 4 5 1 2 0 Peyrin-Biroulet L et al. Gastroenterology 2011 Yearly incidence rate (per 1,000 patient-years) Azathioprine and non-melanoma skin cancers

25. How to reduce the risk of skin cancers associated with azathioprine ? Low-risk patients Dark skin No pre-malignant lesions No history of BCC/SCC No outdoor occupation Young age Moderate-high risk patients Sunburns/exposure to ionizing radiation Light skin, freckling or facial telangiectasia Outdoor occupations Living in high sun exposure countries High exposure to sun as a child Psoriasis treatment with oral psoralen and PUVA High cumulative exposure to thiopurines Combination therapy Increasing age New medical skin exam in 3-5 years Surveillance based on risk stratification Skin examination every other year Very high-risk patients History of cutaneous malignancies Manage on individual basis Torres J et al. Inflam Bowel Dis 2013

26. More about thiopurines safety… Beaugerie L et al. Gut 2014 Azathioprine does not increase the risk of new or recurrent cancers in patients with past history of cancer Azathioprine is safe during pregnancy Jharap B et al. Gut 2014

27. First exposure Drug development Phase I-IIIa trials healthy volunteers selected patients Number of side-effects reported Launch First renewal rare ADRs (< 1/1.000) different population, risk groups long-term use co-medication & interactions medication errors, misuse The learning curve of side-effects

28. What should we consider ? Efficacy Safety Practicality and cost

29. Healthcare costs of IBD have shifted from hospitalisation and surgery towards anti-TNF  therapy Anti-TNF use accounts for 64% and 31% of total costs in CD and UC Van der Valke ME et al. Gut 2012

30. We cannot exclude cost considerations… With the same 1-year budget one can treat efficiently 1 patient with anti-TNF And 100 with AZA ! Bourrier A, Seksik P, Cosnes J. Current Drug Targets 2013

31. When should we use thiopurine monotherapy ?

32. Prediction: profiling in order to take the best therapeutic decision Courtesy Tine Jess

33. Crohn’s disease evaluation and treatment: clinical decision tool Sandborn WJ. Gastroenterology 2014

34. Crohn’s disease evaluation and treatment: clinical decision tool Sandborn WJ. Gastroenterology 2014

35. Crohn’s disease evaluation and treatment: clinical decision tool Sandborn WJ. Gastroenterology 2014

36. Crohn’s disease evaluation and treatment: clinical decision tool Sandborn WJ. Gastroenterology 2014

37. Clinical case Daperno M et al. Gastrointestinal Endosc 2004 1 1 1 1 1 1 3 33 yr old. Non smoker. CD of ileum since 2004. CDAI = 200. No perianal disease. Some bloating and nausea TPMT : 37; EBV serology +.

38. Clinical case

39. Backup slides

40. Early “top-down” therapy with azathioprine decreases the need for perianal surgery Cosnes J et al. Gastroenterology 2013;145: 758-65

41. Algorithm for post-operative CD Ileocolonic resection High risk* Low risk*** Moderate risk** Anti-TNF agent Azathioprine No treatment Endoscopy 6mo-1year Anti-TNF agent Anti-TNF agent + IS Azathioprine Anti-TNF agent No treatment Aza or anti-TNF : penetrating disease, prior surgery, smokers, failure to IS; ** : short duration of disease (<10yrs), >10 cm resection; ***: long disease duration (>10 yrs) short fibrostenotic stricture Swoger JM, Regueiro M. Expert Rev Clin Immunol 2010 Algorithm for the prevention of post-operative recurrence of Crohn’s disease

42. Azathioprine versus aminosalicylates for steroid-dependent active UC p=0.006 Patients treated successfully at 6 months (%) Treatment success defined as clinical remission (Powell-Tuck Index score of 0) and endoscopic remission (Baron Index score ≤1), plus steroid discontinuation Ardizzone S, et al. Gut 2006;55:47–53 72 patients treated with concurrent tapering doses of steroids *0.8g at breakfast and lunch, and 1.6g at dinner 5-ASA 3.2 g/d (in 3 divided doses) * AZA 2 mg/kg/day 5-ASA, 5-aminosalicylic acid ; AZA, azathioprine

43. Azathioprine, infliximab and combination in early ulcerative colitis: UC SUCCESS trial Panaccione R, et al. Gastroenterology 2014 Patients were biologic-naive with moderate-severe UC (Mayo score 6) who were failing corticosteroids and either naive to AZA, or had stopped AZA 3 months before entry. AZA, azathioprine; IFX, infliximab. Steroid-free remission at Week 16 0 AZA (N=76) 20 40 60 80 100 n=18 24% IFX (N=77) n=17 22% IFX + AZA (N=78) n=31 40% p=0.813 p=0.032 p=0.017 Proportion of patients (%)

44. Azathioprine, infliximab and combination in early ulcerative colitis: UC SUCCESS trial Mucosal healing at Week 16 0 AZA (N=76) 20 40 60 80 100 n=28 37% IFX (N=77) n=42 55% IFX + AZA (N=78) n=78 63% p=0.028 p=0.001 p=0.295 Proportion of patients (%) Patients were biologic-naive with moderate-severe UC (Mayo score 6) who were failing corticosteroids and either naive to AZA, or had stopped AZA 3 months before entry. AZA, azathioprine; IFX, infliximab. Panaccione R, et al. Gastroenterology 2014

45. Proposed moderate UC algorithm Respond and taper Maintenance 5-ASA Respond and taper Maintenance 5-ASA Fail Prednisone 10–12 weeks Steroid dependent AZA x 10–12 weeks AZA x 10–12 weeks 2‒4 weeks Steroid refractory Anti-TNF +/- Immunomodulators Anti-TNF +/- Immunomodulators Adapted from: Panaccione R et al. Aliment Pharmacol Ther 2008;28:674–88. Moderate