Unconventiional Therapies: What to do when all else fails?

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 • Allopurinol? • Addition of AZA to anti-TNF failure

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

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

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

8. 1.00 0.75 0.50 0.25 0.00 0 0.5 1 1.5 2 Response to Sequential TNF Inhibitors in Rheumatoid Arthritis 1.00 First Replaced for adverse events Second 0.75 Replaced for other causes Third 0.50 P=0.007 0.25 0.00 Analysis time (years) 0 0.5 1 1.5 2 Gomez-Reino et al. Arthritis Research & Therapy. 2006;8:R29

9. Treatment Algorithm in IBD Patients With Clinical Symptoms (Infliximab and ATI Concentrations) Therapeutic IFX concentration1 Subtherapeutic IFX concentration1 Positive ATI Increase infliximab dose or frequency Change to different anti-TNF agent Active disease on endoscopy/radiology? Change to another anti-TNF agent no yes persistent disease Change to different anti-TNF agent Investigate alternate etiologies Change to different anti-TNF agent Change to non- anti-TNF agent Change to non-anti-TNF agent 1 >12 mcg/mL at 4 weeks or detectable trough level; patients should have endoscopic or radiologic imaging Afif W, et al. Am J Gastroenterol 2010;105:1133-9.

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 -5 0 5 10 20 30 40 50 Byrnskov (7.6 mg/kg) Anglo/Irish (5 mg/kg) CCRPT (4.8 mg/kg) European Multicentre (5 mg/kg) Cyclosporineineffective Cyclosporineeffective 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 Steroid-resistant (n=20) Placebo(n=9) Cyclosporine(n=11) Failed(n=9) Failed(n=2) Colectomy(n=4) Cyclosporine(n=5) Colectomy Improved(n=5) Improved(n=9) Lichtiger et al, N Engl J Med 1994; 330: 1841

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 • Immunosuppression • Nephrotoxicity • No efficacy signal in CD • Stil need to think about exit strategies

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

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

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

20. An FDA approved option for severe refractory CD?

21. Kidney, Skin

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

23. Estimated PML Risk on Natalizumab • Use limited by risk of PML (total of 232 cases amongst 95,000 pts treated with natalizumab) • Risk factors for PML: • Longer duration of NAT treatment, >2 yrs • Prior Immunosuppressant Use • Positive Anti-JC Virus Serology (NEWEST) commercially available ELISA as of 2011 Bloomgren G et al. New Engl J Med. 2012; 366(20):1870.

24. Off label therapies in late phase IBD studies

25. IL-12 Stimulus TLR? p35 p40 IL-12Rb1 X IFNg (Th1) b2 CD4+ Ag Antigen Presenting Cell TCR MHCII IL-17 (Th17) IL-23R IL-12Rb1 p19 p40 IL-23 Biology of Interleukins 12 and 23

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

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. STAT STAT STAT STAT JAK JAK mRNA Oral Janus Kinase (JK) Inhibitor:Rationale Cytokine Tofacitinib blocks phosphorylation of STAT and downstream activation γ β α P P P P P Sandborn W et al. DDW 2011

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

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 Protective Probiotic Injurious Pro-inflammatory Lactobacillus sp. Bifidobacterium sp. Non-pathogenic E. coli Saccharomyces boulardii Bacteroides thetaiotaomicron

33. Probiotics in IBD: Systematic Reviews • 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”. • 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”. • Induction in CD: 1 RCT (n=11) • “There is insufficient evidence to make any conclusions”. • Maintenance in CD: 7 small RCTs • “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. Fecal Microbiota Transplant Is Not Effective in Medically Refractory Chronic Pouchitis • Prospective study of 8 patients with chronic refractory pouchitis • Nasogastric administration of 30g feces • 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 afterwards • Results: no change in CGQoL or PDAI • 2 of 3 patients previously resistant to ciprofloxacin became responsive Landy J, et al. Presented at DDW; May 21, 2013. Abstract 1985.

36. Take Home Point #2 Consider Clinical Trials

37. 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-a4 Integrin 683699 Anti-a4b7 (MLN0002) Anti-b7 CCR9 antagonist (CCX-282B) Anti-CXCL10 (MDX-1100) T cell activation Anti-CD3 NI-0401 Small molecules AEB071 Innate Immunity IFN-b1a TLR3 TLR9 TSO Current Clinical Trials: Immunologic Interventions in IBD

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