1. Division of GASTROENTEROLOGY & HEPATOLOGY Use and Efficacy of Fecal Transplant for Refractory Clostridium difficile in IBD Patients Edward V. Loftus, Jr., MD Professor of Medicine Division of Gastroenterology and Hepatology Mayo Clinic Rochester, Minnesota ©2011 MFMER | slide-1

2. Loftus Disclosures (last 12 months) Consultant AbbVie UCB Janssen Takeda Immune Pharmaceuticals MedImmune Celgene Research support AbbVie UCB Bristol-Myers Squibb Shire Genentech Janssen Amgen Pfizer Takeda GlaxoSmithKline Robarts Clinical Trials

3. History of Fecal Transplant 4 th century Chinese Medicine Human fecal suspension by mouth for diarrhea related to food poisoning 17 th century Veterinary Medicine Transfauntation (transfer of cecal contents or fresh feces) from healthy horses to treat horses with diarrhea WWII: “consumption of fresh warm camel feces has been recommended by Bedouins as remedy for bacterial dysentery; efficacy confirmed by German soldiers in North Africa” 1958: Fecal enema for pseudomembranous colitis Micrococcus pyogenes 1983: Fecal enema for C. difficile infection 1991 – 2014: Multiple reports of fecal transplant for C. difficile ©2011 MFMER | slide-3 Brandt L Gastrointest Endosc 2013 Aug;78(2):240-9. Smits LP et al, Gastroenterology 2013;145:946-53.

4. FMT for Recurrent Clostridium difficile Infection: Systematic Review and Meta-Analysis 11 studies, 273 patients Pooled resolution rate, 89% Trend that lower GI administration had higher resolution rate (91%) than UGI route (81%) ©2011 MFMER | slide-4 Kassam Z et al, Am J Gastroenterol 2013;108:500-8.

5. Randomized Trial of FMT vs Vancomycin vs Vancomycin Plus Bowel Lavage for Recurrent Clostridium difficile Infection 43 patients with recurrent C. difficile infection Initially planned 40 patients in each of 3 arms Primary endpoint: cure of CDI without relapse within 10 wks C diff tests at weeks 2, 3, 5, 10 Interim analysis: study terminated early because efficacy already demonstrated No serious adverse events ©2011 MFMER | slide-5 Van Nood E et al, N Engl J Med 2013;368:407-15.

6. Cost-Effectiveness of FMT for Recurrent Clostridium difficile Infection Cost-utility analysis of 4 strategies Metronidazole Oral vancomycin Fidaxomicin FMT via colonoscopy Modeled 2 additional recurrences Most cost-effective approach was FMT via colonoscopy Incremental cost-effectiveness ratio was $17,016 per QALY relative to oral vancomycin FMT dominated metronidazole and fidaxomicin In order for fidaxomicin to be cost-effective, cost would need to be less than $1359 ©2011 MFMER | slide-6 Konijeti GG et al, Clin Infect Dis 2014;58:1507-14.

7. Oral Capsulized Frozen FMT for Relapsing Clostridium difficile Infection 20 patients with recurrent CDI received capsulized frozen FMT from healthy volunteer donors 70% resolution of diarrhea after single capsule-based FMT; after retreatment of non-responders overall response rate 90% ©2011 MFMER | slide-7 Youngster I et al, JAMA 2014;312:1772-8.

8. FMT in IBD: An Historical Perspective The year 1989: Kansas City A physician (J.D.B.) 7 years: Steroid refractory, active & severe UC Controlled with α-tocopherylquinone Large volume retention enemas with donor flora Symptom free for 6 months, off medications, normal endoscopy and no acute inflammation The year 1989: Australia 45/M with UC for 18 mo (pancolitis) and elevated LFTs Refractory to sulfasalazine Received FMT and asymptomatic in days No recurrence at 3 months ©2011 MFMER | slide-8 Bennet D, Lancet 1989, Jan 21: 164. Borody T, Med J Austr 1989; 150: 604.

9. FMT in IBD: The Data Case series of 6 patients with UC 3 males, 3 females Age 25 – 53 years 2 had left sided colitis, 2 with pancolitis Disease duration < 5 years FMT administered as retention enemas every 5 days Symptoms improved in 1 week Complete reversal achieved in all patients by 4 months ©2011 MFMER | slide-9 Borody T, J Clin Gastroenterol 2003;37(1):42–47.

10. 2012 Systematic Review of FMT in IBD ©2011 MFMER | slide-10 Anderson JL et al, Aliment Pharmacol Ther 2012; 36: 503-516.

11. FMT in IBD: The Data 41 patients (20 males, 18 females, 3 unknown) Age range: 11 - 78 years 27 with UC 12 with Crohn’s 2 with indeterminate Duration of follow-up: 2 weeks - 13 years Disease duration: 18 months - >20 years Variable extent of disease Variable prior treatment for IBD Most reports had donor screening protocols ©2011 MFMER | slide-11 Anderson JL et al, Aliment Pharmacol Ther 2012; 36: 503-516.

12. FMT in IBD: The Data 26 patients: FMT for treatment of IBD Among 17 patients: 13/17 ceased IBD medications within 6 weeks 16 patients experienced symptom reduction / resolution within 4 months 15 experienced complete resolution within a year Among 24 patients: 15 (63%) had no evidence of active disease 3–36 months after FMT ©2011 MFMER | slide-12 Anderson JL et al, Aliment Pharmacol Ther 2012; 36: 503-516.

13. FMT in IBD and C. difficile infection 15 patients received FMT for CDI In 12 patients 12/12: resolution of CDI 11/12: marked reduction / complete resolution of diarrhea FMT resulted in improved response to IBD medications in 6 patients ©2011 MFMER | slide-13 Anderson JL, Aliment Pharmacol Ther 2012; 36: 503-516

14. FMT for UC: Variable Clinical, Serological, and Microbiological Response 5 pts with moderate to severe UC refractory to standard therapy, 3 days of FMT via NJT and enema 1 pt had clinical response by wk 12, 2 pts had no change, and 2 worsened All developed fever and elevated CRP immediately after FMT ©2011 MFMER | slide-14 Angelberger S et al, Am J Gastroenterol 2013;108:1620-30.

15. FMT for UC: The Backlash Continues 6 patients with UC refractory to standard therapy received FMT via colonoscopy All 6 had short-term improvement in 1 st 2 weeks 4 of 6 had increased stool frequency by day 30 No change in fecal calprotectin or CRP No patients achieved remission ©2011 MFMER | slide-15 Kump PK et al, Inflamm Bowel Dis 2013;19:2155-65. Total Mayo Score Over the Course of the Study

16. FMT for IBD: Systematic Review & Meta-Analysis 2014 18 studies (9 cohort, 8 case reports, 1 RCT), 122 patients (79 UC, 39 Crohn’s, 4 IBDU) Overall response rate, 45% 22% UC 61% Crohn’s Conclusion: safe, but effectiveness highly variable ©2011 MFMER | slide-16 Colman RJ & Rubin DT, J Crohns Colitis 2014 online early. Overall response in cohort studies, 36.2%

17. FMT in IBD: Systematic Review 31 studies, 133 IBD patients 43% had recurrent C. difficile infection Resolution or reduction of symptoms in 80 patients (71%) When an objective score was used, 62% partial or complete response In those without C. difficile, 69% Endoscopic improvement in 57%, but only in 20% when objective score was used Fever and increased CRP not uncommon ©2011 MFMER | slide-17 Ianiro G et al, Medicine (Baltimore) 2014;93(19):e97.

18. Prospective, double blind RCT 53 active UC patients (Mayo score ≥ 4 with endoscopic Mayo subscore ≥ 1) Negative for C. difficile 42% on steroids, 19% on immunomodulators, and 9% on biologics 6 weeks of once-weekly fecal microbiota therapy delivered by retention enemas (n = 27) vs placebo delivered by water enemas (n=26) Results No difference in remission between groups at week 6 (assessed by Mayo score, IBDQ and EQ-5D) No adverse events related to FMT Limitations Short duration (6 weeks) Small sample size 18 UC Patients Failed to Show Significant Improvement After FMT: Placebo-Controlled RCT Moayeddi P, et al. Gastroenterology 2014;146(5):S-159. Mayo Score at Week 6 IBDQ at Week 6

19. FMT in IBD: Lessons from C. difficile studies ©2011 MFMER | slide-19 Hamilton MJ, Am J Gastroenterol 2012; 107:761–767 IBD included Microscopic colitis N=4 Complete remission of diarrhea No mention of IBD remission from FMT

20. FMT for Recurrent Clostridium difficile Infection in Immunocompromised Patients Multicenter retrospective analysis of 80 pts with recurrent CDI who were immunosuppressed Included 36 pts with IBD on immunosuppressants or biologics Efficacy in IBD population: 86% had resolution of CDI with first FMT Overall cure rate (including 2 nd FMT), 94% Safety: SAE in 15% within 12 wks post-FMT 2 deaths, including one witnessed aspiration while sedated for scope to administer FMT SAE rate for IBD patients similar (11%) 5 IBD pts (14%) had disease flare post-FMT, and 3 UC pts underwent colectomy ©2011 MFMER | slide-20 Kelly CR et al, Am J Gastroenterol 2014;109:1065-71.

21. FMT in IBD Patients with Recurrent Clostridium difficile infection: Mayo Rochester Experience (n=13) 7 Crohn’s, 6 UC Median age, 27 years (range, 21-48) Median IBD duration, 3 years (0.2-15) Median 4 C diff infection episodes (1-12) Median 5 failed treatment regimens (2-13) 77% failed at least 2 drugs 77% failed a prolonged vancomycin taper IBD drugs included 5-ASA (6), biologics (6), IMM (3), steroids (5) ©2011 MFMER | slide-21 Khanna S et al, Am J Gastroenterol 2013;108(Suppl 1):S508

22. FMT in IBD Patients with Recurrent Clostridium difficile Infection: Mayo (cont) After FMT, 92% noted clinical improvement in symptoms and overall well-being 1 patient saw no improvement, was C diff positive 6 patients had complete resolution 6 patients had partial resolution Median time to resolution was 2 days (1-14) No patients stopped IBD therapies In fact, 46% required escalation of IBD therapy at some point after FMT despite being C diff negative Conclusion: Safe and effective for recurrent C. diff, but doesn’t appear to improve the course of IBD ©2011 MFMER | slide-22 Khanna S et al, Am J Gastroenterol 2013;108(Suppl 1):S508

23. Conclusions Fecal microbial transplantation appears to be highly effective in eradicating recurrent Clostridium difficile infection In the subset of IBD patients with recurrent CDI, FMT also appears to be highly effective and reasonably safe including in patients on immunomodulators and biologics It is far from certain that FMT will be effective for the treatment of IBD itself in the absence of recurrent CDI Placebo-controlled RCT of fecal enemas in UC was negative ©2011 MFMER | slide-23