Efficacy of Bezlotoxumab, the Monoclonal Antibody Targeting C. Difficile Toxin B, for Prevention of C. Difficile Infection

EP0176

European Congress of Clinical Microbiology and Efficacy of Bezlotoxumab, the Monoclonal Antibody Gerding DN1; Kelly CP2; Rahav G3; Lee C4; Dubberke E5; Infectious Diseases Kumar P6; Eves K7; Pedley A7; Tipping R7; Guris D7; Kartsonis N7; Dorr MB7 (ECCMID) 2016 Targeting C. difficile Toxin B, for Prevention of RAI Amsterdam, 1Hines VA Hospital, Hines, IL, USA; 2BIDMC & Harvard Medical School, Boston, MA, USA; Amsterdam, C. difficile Infection (CDI) Recurrence in Patients at High 3Sheba Medical Center, Tel Hashomer, Israel; 4St. Joseph’s Healthcare, Hamilton, ON, Canada; The Netherlands 5Washington University School of Medicine, St Louis, MO, USA; 6Georgetown University School of Medicine, April 09–12, 2016 Risk of Recurrence or CDI-Related Adverse Outcomes Washington, DC, USA; 7Merck & Co., Inc., Kenilworth, NJ, USA

Outcome Measures Figure 2. CDI recurrence rates (A) and difference between bezlotoxumab and •• The 95% Cl for the difference in recurrence rates between bezlotoxumab and Introduction and Purpose •• CDI recurrence: A new episode of diarrhea associated with a positive stool test placebo (B) for subjects in high-risk groups placebo excluded zero for all high-risk groups except subjects infected with the 027 ribotype and subjects infected with any strain associated with poor outcomes for toxigenic C. difficile after clinical cure of baseline episode and within 12 weeks A) •• It has been estimated that Clostridium difficile causes 172,000 infections each following study medication infusion Bezlotoxumab Placebo (027, 078, or 244 ribotypes)  year across the 27 countries of the European Union among individuals 2 years 45  42% •• Among subjects with 1 risk factors, recurrent CDI occurred in 17% (100/588) of of age1,2 However, these data do not take into account a recently documented •• Global cure: Clinical cure of initial episode and no recurrent CDI within 12 weeks 41% 40 bezlotoxumab recipients and 30% (174/582) of placebo recipients 70% increase in incidence of C. difficile infection (CDI) and considerable potential following study infusion 35 34% 3 32% Global Cure for missed diagnoses across Europe Data Analysis 31% 30 29% 28% 27% •• Across the two trials, treatment with bezlotoxumab conferred a 9.7% increase in •• Although antibiotic treatment of primary CDI is often successful, up to 35% of •• Endpoints were estimated from the pooled MODIFY dataset for subjects in the 25% 25 24%  patients experience CDI recurrence after completing initial antibiotic therapy.4,5 bezlotoxumab and placebo groups who had the following risk factors for CDI 22% 22% incidence of global cure versus placebo (P 0.0001) 20 After first recurrence, patients have a 45% probability of a second recurrence, recurrence: age 65 years, 1 CDI episodes in the past 6 months, 2 previous 17% •• Global cure rates for bezlotoxumab were consistently higher than placebo across 15% 15% with the risk increasing with further recurrences6 CDI episodes, immunocompromised, severe CDI (Zar 2), or infected with a 15 all high-risk groups (Figure 3) 11%

strain associated with poor outcomes (027, 078, or 244 ribotype) % subjects, full analysis se t 10 •• Risk factors for CDI recurrence or CDI-related adverse outcomes include: age •• The largest increases in global cure were in subjects 65 years of age (16.2%) 65 years,3,7 history of CDI,4,5 compromised immunity,8,9 clinically severe CDI •• 95% confidence intervals (CIs) for the difference between treatment groups were 5 and those who were immunocompromised at study entry (15.3%) n= 390 405 216 219 100 126 169 145 122 125 102 115 89 100 781 773 (Zar score 2),10 and infection with a strain associated with poor outcomes calculated using Miettinen and Nurminen’s method 0 Age у65 у1 CDI у2 previous Immuno- Severe 027, 078, 027 strain Overall 7,11-13 14 15,16 Safety Outcomes (027, 078, or 244 ) episodes in past CDI compromized CDI (Zar or 244 strain 6 months episodes score у2) •• Bezlotoxumab was generally well tolerated. The types and incidence of •• MODIFY I and MODIFY II were global, randomized, double-blind, placebo-controlled B) adverse events (AEs) and serious AEs were similar across the bezlotoxumab trials of the efficacy and safety of bezlotoxumab (a human monoclonal antibody Results Bezlotoxumab Placebo Difference, %Absolute difference and placebo groups against C. difficile toxin B) alone and in combination with actoxumab (a human % (n/N) % (n/N) Absolute Relative % (95% CI) monoclonal antibody against C. difficile toxin A), for the prevention of CDI Study Population All subjects 16.5 (129/781) 26.6 (206/773) -10.1 -38.0 •• AEs were generally as expected considering the underlying disease severity, Age у65 15.4 (60/390) 31.4 (127/405) -16.0 -50.9 baseline co-morbidities, and age of the population studied recurrence in adults receiving antibiotic treatment (standard of care [SOC]) •• A total of 1554 subjects were included in the full analysis set for the pooled for primary or recurrent CDI17 analysis. Baseline demographics and characteristics were similar in the у1 CDI episodes in past 6 months 25.0 (54/216) 41.1 (90/219) -16.1 -39.2 –– In both studies, bezlotoxumab substantially reduced CDI recurrence and had a bezlotoxumab (n= 781) and placebo (n= 773) pooled analysis groups (Table 1). у2 previous CDI episodes 29.0 (29/100) 42.1 (53/126) -13.1 -31.1 safety profile similar to placebo. The actoxumab arm of MODIFY I was dropped Immunocompromized 15.4 (26/169) 28.3 (41/145) -12.9 -45.6 Conclusions •• The majority of subjects (76%) had at least one risk factor for CDI recurrence or from further study following interim analysis due to lack of efficacy and higher Severe CDI (Zar score у2) 10.7 (13/122) 22.4 (28/125) -11.7 -52.4 CDI-related adverse outcomes rate of serious adverse events and deaths compared with placebo 027, 078, or 244 strain 21.6 (22/102) 32.3 (37/115) -10.6 -33.0 •• Bezlotoxumab, a monoclonal antibody targeting C. difficile toxin B, was efficacious in reducing CDI recurrence rates through 12 weeks when –– Results for the combination of actoxumab and bezlotoxumab were similar to Table 1. Subject baseline characteristics 027 strain 23.6 (21/89) 34.0 (34/100) -10.4 -30.6 17 given to adults receiving SOC antibiotics for CDI (MODIFY I and II) bezlotoxumab alone. Thus, the addition of actoxumab did not improve efficacy. Bezlotoxumab Placebo -30 -20 -10 0 Therefore, only the bezlotoxumab alone versus placebo data are presented here (N=781) (N=773) •• This pooled analysis showed that in key subpopulations at high risk for CDI recurrence and/or CDI-related adverse outcomes, bezlotoxumab Favors bezlotoxumab Favors placebo Number of subjects (%) CDI = C. difficile infection; CI = confidence interval. reduced CDI recurrence and increased rates of global cure compared Objective Subject characteristics with placebo Inpatient 530 (67.9) 520 (67.3) Figure 3. Global cure rates (A) and difference between bezlotoxumab and •• To assess the efficacy of bezlotoxumab in subjects at increased risk for CDI Female 442 (56.6) 449 (58.1) placebo (B) for subjects in high-risk groups References recurrence or CDI-related adverse outcomes using pooled data from the MODIFY 65 years of age 390 (49.9) 405 (52.4) A) 1. Barbut F, et al. Clostridium Difficile infection in Europe: a CDI Europe report. 2013. http://www.multivu.com/assets/60637/ I and MODIFY II studies 1 CDI episodes in past 6 months 216 (27.7) 219 (28.3) Bezlotoxumab Placebo documents/60637-CDI-HCP-Report-original.pdf. 2. Bauer MP, et al. Lancet. 2011;377(9759):63–73. 70 66% 2 previous CDI episodes 100 (12.8) 126 (16.3) 64% 64% 3. Davies KA, et al. Lancet Infect Dis. 2014;14(12):1208-1219. 4. Aslam S, et al. Lancet Infect Dis. 2005;5(9):549–557. Severe CDI (Zar score 2) 122 (15.6) 125 (16.2) 60 57% 56% 54% 55% 54% Methods 52% 5. Kelly CP, LaMont JT. N Engl J Med. 2008;359(18):1932–1940. a 50% 49% Immunocompromized 169 (21.6) 145 (18.8) 50 48% 6. Sheitoyan-Pesant C, et al. Clin Infect Dis. 2016;62(5):574-580. 46% 45% b 42% PCR ribotype (N=490) (N=486) 40% 7. Lessa FC, et al. N Engl J Med. 2015;372(9):825–834. • MODIFY I (MK-3415A-001, NCT01241552) and II (MK-3415A-002, NCT01513239) 40 • 8. Morrison M, et al. Clin Infect Dis. 2011;53(12):1173–1178. Most common strainsc 210 (42.9) 233 (47.9) were randomized, double-blind, placebo-controlled, multicenter, Phase 3 trials 9. See I, et al. Clin Infect Dis. 2014;58(10):1394–1400. 30 conducted from 01-Nov-2011 through 22-May-2015 at 322 sites in 30 countries. 027, 078, or 244 strain 102 (20.8) 115 (23.7) 10. Zar FA, et al. Clin Infect Dis. 2007;45(3):302–307. 027 strain 89 (18.2) 100 (20.6) 20 11. Abou Chakra CN, et al. PLoS One. 2012;7(1):e30258.

•• The design of both studies is summarized in Figure 1 % subjects, full analysis set 12. Inns T, et al. J Hosp Infect. 2013;84(3):235–241. a 10 Figure 1. Trial design flow diagram Defined on the basis of a subject’s medical history or use of immunosuppressive therapy. 13. Rao K, et al. Clin Infect Dis. 2015;61(2):233–241. bDenominator is subjects in the full analysis population with a positive culture. n= 251 195 117 92 100 126 111 73 69 61 102 115 50 45 781 773 14. Walker AS, et al. Clin Infect Dis. 2013;56(11):1589–1600. cMost common strains: ribotypes 027, 014, 002, 001, 106, or 020. 0 Age у65 у1 CDI у2 previous Immuno- Severe 027, 078, 027 strain Overall 15. Lim SK, et al. Clin Infect Dis. 2014;58(12):1723–1730. ALT = alanine aminotransferase; CDI = C. difficile infection; PCR = polymerase chain reaction; ULN = upper limit of normal. episodes in past CDI compromized CDI (Zar or 244 strain 16. De Almeida MN, et al. N Z Med J. 2013;126(1380):9–14. 6 months episodes score у2) 17. Wilcox M, et al. Open Forum Infect Dis. 2015;2 (Suppl 1):S3 Baseline CDI diagnosis B) CDI episode Diarrhea + Toxigenic C. difficile CDI Recurrence Bezlotoxumab Placebo Difference, %Absolute difference Acknowledgments % (n/N) % (n/N) Absolute Relative % (95% CI) •• In both MODIFY I and II, a single 10 mg/kg IV infusion of bezlotoxumab was Medical writing and/or editorial assistance was provided by Edward Rochford, PhD, on behalf of Complete Medical Communications, All subjects 63.5 (496/781) 53.7 (415/773) 9.7 18.1 Macclesfield, UK. This assistance was funded by Merck & Co., Inc., Kenilworth, NJ, USA. • Oral metronidazole superior to placebo in prevention of CDI recurrence over 12 weeks (P=0.0003 for Antibiotic treatment Age у65 64.4 (251/390) 48.1 (195/405) 16.2 33.7 10–14-day regimen • Oral vancomycin ± IV metronidazole MODIFY I and II) Disclosures • Oral fidaxomicin ± IV metronidazole у1 CDI episodes in past 6 months 54.2 (117/216) 42.0 (92/219) 12.2 29.0 –– Recurrence rates with bezlotoxumab were 17.4% and 15.7% in MODIFY I and Funding for this research was provided by Merck & Co., Inc., Kenilworth, NJ, USA. у2 previous CDI episodes 52.0 (52/100) 39.7 (50/126) 12.3 31.0 DNG holds patents for the treatment and prevention of CDI licensed to ViroPharma/Shire, is an advisory board member for Merck, II, respectively, compared with 26.7% and 25.7%, respectively, with placebo Actelion, Rebiotix, and Summit, and is a consultant for Cubist, DaVolterra, Pfizer, Daiichi Sankyo, Sanofi Pasteur and ViroPharma/ Study period Immunocompromized 65.7 (111/169) 50.3 (73/145) 15.3 30.4 Shire. He holds research grants from Seres Therapeutics, CDC and the Department of Veterans Affairs Research Service. •• In the pooled analysis, bezlotoxumab was associated with a 10% absolute Severe CDI (Zar score 2) CPK has acted as a consultant and scientific advisor to Cubist, Merck, Openbiome, Sanofi-Pasteur, Seres Health, Summit and • Actoxumab (MODIFY I only) у 56.6 (69/122) 48.8 (61/125) 7.8 16.0 Day 1: Day 85 reduction in CDI recurrence versus placebo overall Synthetic Biologics and has acted as Principal Investigator for research grants to BIDMC from the NIH, EnteraHealth and Merck. • Bezlotoxumab 027, 078, or 244 strain 54.9 (56/102) 46.1 (53/115) 8.8 19.1 Single IV GR is a consultant and scientific advisor to Merck, Pfizer, and AstraZeneca. • Actoxumab + Bezlotoxumab infusion •• In each of the high-risk groups, the absolute difference in CDI recurrence rate 027 strain 56.2 (50/89) 45.0 (45/100) 11.2 24.9 CL is an advisory board member for Rebiotix and Summit. CL also holds research grants from Rebiotix and Actelion. • Placebo (0.9% normal saline) between bezlotoxumab and placebo was greater than in the overall population ED has conducted research for Merck & Co., Inc., Rebiotix, and Sanofi-Pasteur and is or has been a consultant to Merck & Co., Inc., Rebiotix, Sanofi-Pasteur, Summitt, and Daiichi. -10 010 20 30 PK owns Merck & Co., Inc stocks but has no other conflict of interest. Record loose stools daily; test for toxigenic C. difficile if diarrhea returned •• The largest absolute reductions in CDI recurrence were in subjects 65 years of KE, AP, RT, DG, NK and MBD are current employees of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, age (–16.0%) and those with one or more CDI episodes in the 6 months prior to the Favors bezlotoxumab NJ, USA, and may own stock and/or stock options. CDI = C. difficile infection; CI = confidence interval. baseline episode (–16.1%) (Figure 2)