1. 1 Unconventiional Therapies: What to do when all else fails? Scott Plevy, MD Associate Professor of Medicine, Microbiology & Immunology UNC School of Medicine

2. Take Home Point #1 Evaluate the patient and figure out why conventional therapies aren’t working!

3. 6-MP/AZA Non-Response

4. Clinical Scenarios Primary AZA non-response Primary AZA non-response Allopurinol? Allopurinol? Addition of AZA to anti-TNF failure Addition of AZA to anti-TNF failure

5. Xanthine Oxidase Inhibition for Preferential 6-MMP Metabolism 6-thiouric acid 6-MP HPRT 6-TGNs XO TPMT 6-MMP AZA X

6. Preferential 6-MMP Metabolism Allopurinol Therapy Preallopurinol Postallopurinol Sparrow MP et al. Aliment Pharmacol Ther. 2005;22:441. Allopurinol 100 mg added; 6-MP/AZA dose reduced to 25% to 50% of baseline

7. Problems Marrow suppression Marrow suppression Primary AZA non-response Primary AZA non-response Allopurinol? Allopurinol? Not as a anti-TNF sparing strategyNot as a anti-TNF sparing strategy Consider MTX with anti-TNFConsider MTX with anti-TNF Perhaps after anti-TNF failure as monotherapyPerhaps after anti-TNF failure as monotherapy Addition of AZA (or MTX) to anti-TNF failure Addition of AZA (or MTX) to anti-TNF failure No data No data Too little too late? Too little too late?

8. Response to Sequential TNF Inhibitors in Rheumatoid Arthritis Third First Second Analysis time (years) Gomez-Reino et al. Arthritis Research & Therapy. 2006;8:R29 0.00 0.25 0.50 0.75 1.00 00.511.52 P=0.007 Replaced for other causes Replaced for adverse events 0.00 0.25 0.50 0.75 1.00 00.511.52

9. Treatment Algorithm in IBD Patients With Clinical Symptoms (Infliximab and ATI Concentrations) 1 >12 mcg/mL at 4 weeks or detectable trough level; patients should have endoscopic or radiologic imaging Positive ATI Change to another anti-TNF agent Change to non- anti-TNF agent persistent disease Increase infliximab dose or frequency Change to non- anti-TNF agent Change to different anti-TNF agent Change to different anti-TNF agent Subtherapeutic IFX concentration 1 Therapeutic IFX concentration 1 Active disease on endoscopy/radiology? Change to different anti-TNF agent Investigate alternate etiologies yes no Afif W, et al. Am J Gastroenterol 2010;105:1133-9. 9

10. Indications for Surgery: Not So Unconventional  Failure of medical therapy  Recurrent obstruction  Perforation  Fistula or abscess  Hemorrhage  Growth retardation (children)  Carcinoma

11. Unconventinal Immunotherapies

12. Cyclosporine: Limited Efficacy in Crohn’s Disease Therapeutic gain (%) -30-25-20-10-50510203050 Cyclosporine ineffective Cyclosporine effective Byrnskov (7.6 mg/kg) Anglo/Irish (5 mg/kg) CCRPT (4.8 mg/kg) European Multicentre (5 mg/kg) 40 CCRPT, Canadian Crohn’s Relapse Prevention Trial Feagan et al, Inflammatory Bowel Dis 1995; 1: 335

13. Cyclosporine A for IV Steroid Refractory UC: At Least There’s Evidence Lichtiger et al, N Engl J Med 1994; 330: 1841 Steroid-resistant (n=20) Placebo (n=9) Cyclosporine (n=11) Failed (n=9) Colectomy (n=4) Cyclosporine (n=5) Improved (n=5) Improved (n=9) Failed (n=2) Colectomy

14. Tacrolimus in Refractory UC: Clinical Improvement at 2 Weeks Cochrane Database Syst Rev. 2008 16;(3):CD007216.

15. Tacrolimus in Refractory CD: Level III Evidence

16. Problems Adverse events Adverse events Immunosuppression Immunosuppression Nephrotoxicity Nephrotoxicity No efficacy signal in CD No efficacy signal in CD Stil need to think about exit strategies Stil need to think about exit strategies

17. Sargramostim* GM-CSF GM-CSF Hematopoietic factor that stimulates cells of intestinal innate immune system Hematopoietic factor that stimulates cells of intestinal innate immune system Modulation of the initial phase of antigen processing and stimulation Modulation of the initial phase of antigen processing and stimulation Korzenik J et al. N Engl J Med. 2005;352:2193. *GM-CSF=granulocyte-macrophage colony-stimulating factor

18. Sargramostim in moderate to severe CD: n.o.v.e.l 4 286 patients mod-severe disease (CDAI 220–475) 286 patients mod-severe disease (CDAI 220–475) Randomized 2:1 (SS 6 μg/kg:placebo) Randomized 2:1 (SS 6 μg/kg:placebo) Primary endpoint: response ∆ CDAI 100 at Week 8 Primary endpoint: response ∆ CDAI 100 at Week 8 Secondary endpoint: CDAI remission at Wk 8 Secondary endpoint: CDAI remission at Wk 8 25% drop out by Week 8 25% drop out by Week 8 Patients (%) NS Feagan BF, et al. DDW 2007. #737

19. Problems Access/Cost/Copays Access/Cost/Copays Adverse events Adverse events Daily injections Daily injections Bone pain/intolerability Bone pain/intolerability No maintenance strategy No maintenance strategy

20. An FDA approved option for severe refractory CD?

21. Kidney, Skin

22. Month 6 Month 12 P < 0.001 P = 0.005 Placebo Natalizumab ENACT-2: Remission In Anti-TNF Failures (171)(168)(33) (24) (171)(168)(33) (24) Data on File Failed TNF ITT

23. Use limited by risk of PML (total of 232 cases amongst 95,000 pts treated with natalizumab) Risk factors for PML: 1)Longer duration of NAT treatment, >2 yrs 2)Prior Immunosuppressant Use 3)Positive Anti-JC Virus Serology (NEWEST) commercially available ELISA as of 2011 Estimated PML Risk on Natalizumab Bloomgren G et al. New Engl J Med. 2012; 366(20):1870. Estimated PML Risk on NAT (in multiple sclerosis) Natalizumab Exposure Anti-JCV Antibody (+) No Prior Immunosuppresion Prior Immunosuppressant Use 1-24 mo0.35/10002/1000 25-48 mo4/100011/1000

24. Off label therapies in late phase IBD studies

25. Biology of Interleukins 12 and 23 CD4+ TCR Antigen Presenting Cell MHCII Ag Stimulus TLR? IFNg (Th1) p40 p35 IL-12 IL-12R  1 22 IL-23 p40 p19 IL-17 (Th17) IL-23R IL-12R  1 X

26. Sandborn W, et al. N Eng J Med. 2012; 367:1519-1528. Ustekinumab induction and maintenance therapy in refractory Crohn's disease

27. Problems Access/Cost/Copays Doses approved in psoriasis are likely to be far lower with less frequent administration than will be effective in CD

28. Oral Janus Kinase (JK) Inhibitor: Rationale Tofacitinib blocks phosphorylation of STAT and downstream activation JAK α STAT mRNA JAK P P STAT P P P β γ Cytokine Effects on the immune system IL-2 Stimulate the proliferation and differentiation of Th, Tc, B, and natural killer (NK) cells IL-4 Induce the differentiation of Th0 to Th2 Induce immunoglobulin switching IL-7 Promote the development, proliferation and survival of T, B, and NK cells IL-9Stimulate intrathymic T cell development IL-15 Promote the proliferation, cytotoxicity and cytokine production of NK cells IL-21Enhance T and B cell function Sandborn W et al. DDW 2011

29. Sandborn WJ, et al. N Engl J Med. 2012;367:616-624. Tofacitinib in Active Ulcerative Colitis

30. Problems Access/Cost/Copays Adverse events – Immunosuppression – Lipid abnormalities No efficacy signal in CD

31. What our patients want us to tell them works

32. Balance between detrimental and beneficial gut bacteria Injurious Pro-inflammatory Lactobacillus sp. Bifidobacterium sp. Non-pathogenic E. coli Saccharomyces boulardii Bacteroides thetaiotaomicron Protective Probiotic

33. Probiotics in IBD: Systematic Reviews Induction in UC: 5 RCTs Induction in UC: 5 RCTs “Conventional therapy combined with a probiotic does not improve overall remission rates in patients with mild to moderate ulcerative colitis”. “Conventional therapy combined with a probiotic does not improve overall remission rates in patients with mild to moderate ulcerative colitis”. Maintenance in UC: 6 RCTs Maintenance in UC: 6 RCTs “The pooled relative risk was 1.37 (95% CI 0.62- 3.04, p=0.44) showing no significant difference between probiotic and control group”. “The pooled relative risk was 1.37 (95% CI 0.62- 3.04, p=0.44) showing no significant difference between probiotic and control group”. Induction in CD: 1 RCT (n=11) Induction in CD: 1 RCT (n=11) “There is insufficient evidence to make any conclusions”. “There is insufficient evidence to make any conclusions”. Maintenance in CD: 7 small RCTs Maintenance in CD: 7 small RCTs “There is no evidence to suggest that probiotics are beneficial for the maintenance of remission in CD”. “There is no evidence to suggest that probiotics are beneficial for the maintenance of remission in CD”. Zigra PI, et al. Neth J Med. 2007 ;65:411-8 Butterworth AD et al. Cochrane Database Syst Rev. 2008 16:CD006634. Mallon P, et al. Cochrane Database Syst Rev. 2007 17:CD005573. Rolfe VE, et al. Cochrane Database Syst Rev. 2006 18:CD004826.

34. Prospective study of 8 patients with chronic refractory pouchitis Prospective study of 8 patients with chronic refractory pouchitis Nasogastric administration of 30g feces Nasogastric administration of 30g feces Stool samples were also collected from patients for analysis of coliform sensitivities before and 4 weeks after FMT Stool samples were also collected from patients for analysis of coliform sensitivities before and 4 weeks after FMT Pouch Disease Activity Index (PDAI) and Cleveland Global Quality of Life score (CGQoL ) were recorded prior to FMT and four weeks afterwardsPouch Disease Activity Index (PDAI) and Cleveland Global Quality of Life score (CGQoL ) were recorded prior to FMT and four weeks afterwards Results: no change in CGQoL or PDAI Results: no change in CGQoL or PDAI 2 of 3 patients previously resistant to ciprofloxacin became responsive2 of 3 patients previously resistant to ciprofloxacin became responsive Fecal Microbiota Transplant Is Not Effective in Medically Refractory Chronic Pouchitis Landy J, et al. Presented at DDW; May 21, 2013. Abstract 1985.

36. Take Home Point #2 Consider Clinical Trials

37. Current Clinical Trials: Immunologic Interventions in IBD Cytokines –Anti-TNF Certolizumab pegol Infliximab Adalimumab Golimumab –Anti-IL-12/23 CNTO1275 J695 –Anti-IL-17 (AIN457) –Anti-IL-6 receptor –IL-6/STAT3 inhibitor –Jak3 inhibitor Other –Extracorporeal photopheresis –Human mesenchymal stem cells –Bone marrow/stem cell transplatation –Estrogen receptor agonist –More Leukocyte adhesion/recruitment –Anti-  4 Integrin 683699 –Anti-  4  7 (MLN0002) –Anti-  7 –CCR9 antagonist (CCX-282B) –Anti-CXCL10 (MDX-1100) T cell activation –Anti-CD3 NI-0401 –Small molecules AEB071 Innate Immunity –IFN-  1a –TLR3 –TLR9 –TSO

38. Conclusions Evaluate the patient and figure out why “common” therapies aren’t working. Evaluate the patient and figure out why “common” therapies aren’t working. Consider Clinical Trials. Consider Clinical Trials. Forget everything else I told you! Forget everything else I told you!