CONVENTIONAL TREATMENT OPTIONS SLIDE RESOURCE SET FDX/13/0068/EUb | August 2013

Snapshot of treatment for initial episodes of Clostridium difficile infection (CDI) Bauer MP, et al. Lancet 2011;377:63–73. Treatments used in an initial episode of CDI in a 2008 European survey FDX/12/0076/EUf | EK206

Rates of clinical cure for metronidazole and vancomycin Zar FA, et al. Clin Infect Dis 2007;45:302–7. p=0.006p=0.36p= / 41 39/ 40 28/ 38 30/ 31 66/ 79 69/ 71 Note: patients were stratified by mild or severe disease based on a severity assessment score developed for this study. Patients received one point each for age >60 years, temperature >38.3°C, albumin level 15,000 cells/mm 3 within 48 hours of enrolment. Two points were given for endoscopic evidence of pseudomembranous colitis or treatment in an intensive care unit. Patients with ≥2 points were considered to have severe CDI FDX/12/0076/EUf  EK205

Rates of clinical success for metronidazole and vancomycin Johnson S, et al. Poster presented at IDWeek 2012; 818. Clinical success was defined as diarrhoea resolution and absence of severe abdominal discomfort due to CDI on Day 10; NS, not significant; qid, four times daily Rates of clinical success in two identical, multicentre, randomised, double-blind, parallel-group trials p<0.05p=NS FDX/12/0076/Euj | OC104

Clinical limitations associated with current treatments for CDI Although metronidazole and vancomycin are effective in a first episode of CDI, therapy remains suboptimal Among the most significant drawbacks of current therapy for CDI are: –Rates of treatment failure with metronidazole of up to 18% 1 –Rates of recurrent infection following treatment with metronidazole and vancomycin of up to 25% within 30 days following treatment 2–4 –Risk of overgrowth of vancomycin-resistant enterococci (VRE) in patients who are already colonised with VRE 5 1.Aslam S, et al. Lancet Infect Dis 2005;5:549–57; 2.Louie TL, et al. N Engl J Med 2011;364:422–31; 3.Lowy I, et al. N Engl J Med 2010;362:197–205; 4.Bouza E, et al. Clin Microbiol Infect 2008;14(Suppl 7):S103–4; 5.Al-Nassir WN, et al. Antimicrob Agents Chemother 2008;52:2403–6. FDX/12/0087/EUu | slide 041

Is there an increasing treatment failure rate with metronidazole? Adapted from Aslam S, et al. Lancet Infect Dis 2005;5:549–57. Average rate of treatment failure in patients receiving metronidazole FDX/12/0076/EUf | EK213 Note: the dates relate to the year of publication not the year of the study

The incidence of recurrent CDI 1.Louie TJ, et al. N Engl J Med 2011;364:422–31; 2.Lowy I, et al. N Engl J Med 2010;362:197–205; 3.Bouza E, et al. Clin Microbiol Infect 2008;4(Suppl 7):S103–4; 4.McFarland LV, et al. Am J Gastroenterol 2002;97:1969–75; 5.McFarland LV, et al. JAMA 1994;271:1913–8. 1 st recurrence of CDI Recurrence(s) of CDI ~45–65% of patients have further recurrences 4,5 Up to 25% of patients have recurrent CDI 1–3 Initial episode of CDI FDX/12/0076/EUb | SJ122

Rates of disease recurrence with metronidazole and vancomycin (1) Adapted from Aslam S, et al. Lancet Infect Dis 2005;5:549–57. Note: the dates relate to the year of publication not the year of the study FDX/12/0076/EUa  MW303

Rates of disease recurrence with metronidazole and vancomycin (2) Johnson S, et al. Poster presented at IDWeek 2012; 818. Rates of recurrence in two identical, multicentre, randomised, double-blind, parallel-group trials p=NS FDX/12/0076/Euj | OC105 NS, not significant

Rates of recurrence for metronidazole and vancomycin grouped by age Johnson S, et al. Poster presented at IDWeek 2012; 818. Recurrence increased with increasing age in metronidazole-treated subjects but remained relatively stable in vancomycin-treated subjects CDI recurrence during 4-week follow-up in patients from two pooled, randomised, double-blind, parallel-group trials p=NS *Subset of subjects aged >65 years; NS, not significant FDX/12/0076/EUq | EB113

Rates of recurrence for metronidazole and vancomycin grouped by sex Johnson S, et al. Poster presented at IDWeek 2012; 818. Male subjects treated with vancomycin had significantly fewer (p<0.05) recurrences vs males treated with metronidazole CDI recurrence during 4-week follow-up in patients from two pooled, randomised, double-blind, parallel-group trials p<0.05p=NS NS, not significant FDX/12/0076/EUq | EB112

Rates of recurrence for metronidazole and vancomycin grouped by C. difficile strain Johnson S, et al. Poster presented at IDWeek 2012; 818. CDI recurrence during 4-week follow-up in patients from two pooled, randomised, double-blind, parallel-group trials p=NS BI, restriction-endonuclease analysis group BI strain of C. difficile (also known as NAP1/027); NS, not significant FDX/12/0076/EUq | EB115

Differences in estimates of CDI recurrence and its definition across Europe Wiegand PN, et al. J Hosp Infect 2012;81:1–14. CountryEstimateDefinition Austria16%A second episode within 60 days of the first Denmark11%Not reported France1%Not reported Germany 3%>40 days after first episode 4%Toxin-positive diarrhoea <30 days post treatment 14%New CDI episode during the next chemotherapy course Ireland 18%Within 8 weeks of the previous episode 36%New CDI episode during 60-day follow-up, ≥48 hours after treatment The Netherlands 3–4%,* 10% † Relapse of CDI >8 weeks after first infection 16%Episode occurring ≤8 weeks after onset of an earlier case 22%Diarrhoea <30 days after initial clinical improvement Poland17%Increased frequency of loose stools with new signs of severe colitis Spain6–18%Not reported Switzerland4%Positive toxin or stool culture up to 3 months from first diagnosis UK 0–2%30-day recurrence 8–11%Toxin-positive diarrhoea up to 4 weeks following treatment 15%Over 12 months 20%Return of diarrhoea ≤30 days after completion of treatment *Ribotypes 001, 014 and 078; † Ribotype 027 FDX/12/0076/EUq | EB107

Vancomycin regimens for recurrent CDI post hoc analysis from two trials (n=163) McFarland LV, et al. Am J Gastroenterol 2002;97:1769–75. * * *p<0.05 compared with vancomycin 1 g/day FDX/12/0076/EUr | SJ230

Rationale for a new treatment CDI remains a disease for which there are significant unmet needs e.g.: –Therapy to provide sustained clinical cure (defined as clinical cure without recurrence) 1 –Therapy to reduce recurrence (relapse and/or reinfection) 1 –Better identification of patients at risk of recurrence or those for whom the impact of recurrence would be most dramatic 2 New approaches under investigation but data from large-scale randomised controlled trials are lacking 3 Management strategies to treat acute episodes of CDI effectively and markedly reduce the risk of recurrence would represent a significant therapeutic advance 4 1.Cornely OA. Clin Microbiol Infect 2012;18(Suppl 6):28­–35; 2.Kelly CP. Clin Microbiol Infect 2012;18(Suppl 6):21­–7; 3.Bauer MP, et al. Clin Microbiol Infect 2009;15:1067–79; 4.Bouza E. Clin Microbiol Infect 2012;18(Suppl 6):5–12. FDX/12/0076/EUk | MB145

Faecal microbiota therapy for CDI StudyIndicationPatientsAdministrationOutcome Eiseman et al Severe PMC4EnemaResolution in all patients MacConnachie et al Recurrent CDI15NG tube86.7% clinical response Arkkila et al Recurrent CDI37Colonoscope92% eradication Khoruts et al Recurrent CDI1ColonoscopeEradication Yoon, Brandt Recurrent CDI/PMC12Colonoscope100% clinical response Rohike et al Recurrent CDI19Colonoscope94.7% clinical response Silverman et al Recurrent CDI7Enema100% asymptomatic Garborg et al Recurrent CDI40Endoscope82.5% eradication Russell et al Recurrent CDI1NG tubeResolution of symptoms Kelly et al Recurrent CDI12Colonoscope100% clinical response Mellow et al Recurrent CDI13Colonoscope92.3% clinical response Kassam et al CDI14Enema100% clinical resolution Kelly et al Recurrent CDI26Colonoscope92% clinical resolution Borody TJ, Khoruts A. Nat Rev Gastroenterol Hepatol 2012;9:88–96. NG, nasogastric; PMC, pseudomembranous colitis FDX/12/0100/EUk | JC129

Faecal microbiota therapy for recurrent CDI: study design 1.van Nood E, et al. N Engl J Med 2013;368:407–15; 2.Protocol to: van Nood E, et al. N Engl J Med 2013;368:407–15. van Nood et al. trial Oral vancomycin 500 mg qid, 14 days Bowel lavage 1× Oral vancomycin 500 mg qid, 4 days Bowel lavage 1× Donor faeces 1× Endpoints 1,2 Diarrhoea (≥3×/day) and C. difficile toxin on Days 35 and 70 Quality of life, days spent in isolation, days admitted to the hospital, attributable costs Psychological analysis of effect of faecal transplant Follow-up 10 weeks, cross-over if failure in antibiotic group qid, four-times daily FDX/12/0100/EUk | JC132

Duodenal faecal microbiota transplantation vs vancomycin plus lavage van Nood E, et al. N Engl J Med 2013;368:407–15. Study stopped after interim analysis No significant differences in adverse events among study groups, except for mild diarrhoea and abdominal cramping in the infusion group on the day of infusion p<0.001 p=0.008 p=0.003 Rates of cure without relapse (%) FDX/12/0076/EUf | EK242

Microbiota diversity in patients before and after faecal infusion versus healthy donors van Nood E, et al. N Engl J Med 2013;368:407–15. van Nood E et al. N Engl J Med 2013;368: Simpson’s reciprocal index DonorsPatients before infusion Patients after infusion FDX/12/0100/EUk | JC135

Faecal bacteriotherapy: limitations No supporting data from prospective, randomised controlled trials 1–3 Very limited data on long-term safety –Administration via colonoscopy, nasogastric tube or retention enema associated with some risk 4 –Potential transmission of infectious agents contained in the donor stool may also carry inherent risks 4 Acceptability of the procedure may be an issue 5 –Patients and physicians reluctant to choose donor-faeces infusion at an early stage 6 1.Gough E, et al. Clin Infect Dis 2011;53:994–1002; 2.Anderson JL, et al. Aliment Pharmacol Ther 2012;36:503–16; 3.Guo B, et al. Aliment Pharmacol Ther 2012;35:865–75; 4.Aas J, et al. Clin Infect Dis 2003;36:580–5; 5.Hedge DD, et al. Ther Clin Risk Manag 2008;4:949–64; 6.van Nood E, et al. N Engl J Med 2013;368:407–15. FDX/12/0076/EUk | MB137

Issues surrounding the clinical application of faecal transplantation Acceptability 1–3 Patient selection –Immunocompromised 3,4 –Concomitant antibiotic therapy 5 –Allergens (e.g. nuts) 4 Donor screening –Epstein–Barr virus, 5 cytomegalovirus, 5 HIV, 4–6 hepatitis A/B/C 4–7 –Syphilis, 7 C. difficile 5–7 –Enteric pathogens including parasites 5–7 –No antibiotics in previous 3 months 4 Cost –Screening 6 –Procedure-related 6 1.Yoon SS, Brandt LJ. J Clin Gastroenterol 2010;44:562–6; 2.Hedge DD, et al. Ther Clin Risk Manag 2008;4:949–64; 3.Borody TJ, Khoruts A. Nat Rev Gastroenterol Hepatol 2012;9:88–96; 4.Bakken JS, et al. Clin Gastroenterol Hepatol 2011;9:1044–9; 5.van Nood E, et al. N Engl J Med 2013;368:407–15; 6.Rohlke F, Stollman N. Therap Adv Gastroenterol 2012;5:403–20; 7.Aas J, et al. Clin Infect Dis 2003;36:580–5. FDX/12/0100/EUk | JC136