Zinplava™ - bezlotoxumab Manufacturer: Merck & Co., Inc. FDA Approval Date: October 21st, 2016 Amanda D’Ostroph, PharmD Candidate

Zinplava™ - bezlotoxumab Manufacturer: Merck & Co., Inc. FDA Approval Date: October 21st, 2016

Zinplava™ - bezlotoxumab Objectives At the end of this presentation participants will be able to: Appropriately recommend Zinplava™ - (bezlotoxumab) Effectively educate patients on the purpose, proper use and potential adverse effects of Zinplava™ - (bezlotoxumab)

Zinplava™ - bezlotoxumab Clinical Application Indication: To reduce the recurrence of Clostridium difficile infection (CDI) in patients 18 years of age or older who are receiving antibacterial drug treatment of CDI and who are at high risk for CDI recurrence Place in therapy: A novel adjunctive option to help reduce the recurrence of CDI and the associated morbidity and mortality Zinplava [package insert].

Zinplava™ - bezlotoxumab Clinical Application Contraindications: None Warnings and Precautions: Use in patients with a history of congestive heart failure is reserved for when the benefit outweighs the risk Zinplava [package insert].

Zinplava™ - bezlotoxumab Clinical Application Pregnancy: Category C No human data available Monoclonal antibodies are know to cross the placenta with increasing amounts during the second and third trimesters Lactation: No data available Category C - Animal reproduction studies have not been conducted Lactation – according to the manufacturer, the decision to continue or discontinue breast-feeding during therapy should take into account the risk of infant exposure, the benefits of breast-feeding to the infant, and the benefits of treatment to the mother. Zinplava [package insert].

Zinplava™ - bezlotoxumab Drug Facts Pharmacology: Selective, fully-human monoclonal antibody that binds to Clostridium difficile toxin B and neutralizes its effects IgG1 immunoglobulin Zinplava [package insert].

Zinplava™ - bezlotoxumab Drug Facts Pharmacokinetics: A AUC 53000 mcg· h/mL; Cmax 185 mcg/mL D Vd: 7.33L (16%) M Cl: 0.317 L/day (41%) E t1/2 :approximately 19 days (28%) Long half life of bezlotoxumab allows sustained toxin neutralization throughout the at-risk recurrence period Zinplava [package insert].

Zinplava™ - bezlotoxumab Drug Interactions Drug Interactions – Object Drug / Precipitant Drug: Bezlotoxumab is eliminated by catabolism No metabolic drug-drug interactions are expected Zinplava [package insert].

Zinplava™ - bezlotoxumab Adverse Effects Common Adverse Effects: Adverse Effect Zinplava™ % Placebo % Headache 7% 5% Pyrexia 3% Nausea 4% Clearance of Zinplava [package insert].

Zinplava™ - bezlotoxumab Monitoring Parameters Efficacy Monitoring: CDI recurrence (confirmed diagnosis) Toxicity Monitoring: No findings of toxicity observed in studies Zinplava [package insert].

Zinplava™ - bezlotoxumab Prescription Information Dosing: Single dose of 10 mg/kg administered as an IV infusion over 60 minutes Infuse diluted solution via a central line or peripheral line Cost: Expected to be available first quarter 2017 Zinplava [package insert].

Zinplava™ - bezlotoxumab Literature Review Purpose: Investigate if monoclonal antibodies to C. difficile toxin A and toxin B in addition to standard of care antibiotic therapy will decrease CDI recurrence Assess safety and tolerability Design: International randomized, double-blind, placebo-controlled, Phase 3 trials Compared with placebo Merck & Co.; Inc. AC Briefing Document. 2016:1-110.

Zinplava™ - bezlotoxumab Literature Review Phase 3 Trial Treatment Arms Stratification MODIFY I ACTO BEZLO ACTO+BEZLO Placebo Oral SoC Metronidazole Vancomycin Fidaxomicin Hospitalization status Inpatient Outpatient MODIFY II Compared with placebo The median time for the bezlotoxumab infusion was three days after the start of SoC (range -1 to 14). ACTO – actoxumab, BEZLO - bezlotoxumab SoC – standard of care Merck & Co.; Inc. AC Briefing Document. 2016:1-110.

Zinplava™ - bezlotoxumab Literature Review Inclusion Criteria: Confirmed CDI diagnosis Diarrhea (3 or more loose stools of Type 5, 6, and/or 7 on the Bristol stool chart in a 24-hour period) Positive stool test for toxigenic C. difficile Standard of care antibiotic 10-14 day regimen protocols allowed for enrollment of subjects with diverse ages, underlying comorbidities (including immunocompromising conditions), ongoing systemic antibiotic use, history of multiple CDI recurrences, severe CDI, in multiple healthcare settings (nursing homes, and intensive care units) Merck & Co.; Inc. AC Briefing Document. 2016:1-110. .

Zinplava™ - bezlotoxumab Literature Review Patient Characteristics: North American/European (87.5%) Female (56%) White (80%) Metronidazole (46%); Vancomycin (48%) ≥ 65 years old (51%) ≥ 1 episode of CDI in past 6 months (27%) Hospitalized at study entry (67%) Mean age 64.3 Merck & Co.; Inc. AC Briefing Document. 2016:1-110. .

Zinplava™ - bezlotoxumab Literature Review Efficacy Results: Endpoint BEZLO (n=810) ACTO+ BEZLO (n=800) Placebo (n-803) C. difficile infection recurrence through week 12 17.4% p=0.0003 15.9% p<0.0001 27.6% 15.7% 14.9% 25.7% The actoxumab arm was stopped for efficacy and safety reasons after an interim analysis. Patients were assessed for clinical cure of the presenting CDI episode, defined as no diarrhea for 2 consecutive days following the completion of a ≤14 day SoC regimen. Patients who achieved clinical cure were then assessed for recurrence of CDI through 12 weeks following administration of the infusion of ZINPLAVA or placebo. CDI recurrence was defined as the development of a new episode of diarrhea associated with a positive stool test for toxigenic C. difficile following clinical cure of the presenting CDI episode. Merck & Co.; Inc. AC Briefing Document. 2016:1-110.

Zinplava™ - bezlotoxumab Literature Review Efficacy Results: High Risk Subgroups - Recurrence at week 12 BEZLO % (n/m) Placebo Any prior episode(s) within the previous 6 months 25.0% (54/216) 41.1% (90/219) Clinically severe C. difficile infection 10.7% (13/122) 22.4% (28/125) ≥65 years old 15.4% (60/390) 31.4% (127/405) Immunocompromised (26/100) 28.3% (41/145) The actoxumab arm was stopped for efficacy and safety reasons after an interim analysis. Merck & Co.; Inc. AC Briefing Document. 2016:1-110.

Zinplava™ - bezlotoxumab Literature Review Conclusions: Bezlotoxumab given with SoC antibiotic treatment significantly reduced the recurrence of CDI compare to SoC alone Benefit was demonstrated over 12 weeks Treatment with combination actoxumab/ bezlotoxumab did not provide added efficacy over bezlotoxumab alone. Merck & Co.; Inc. AC Briefing Document. 2016:1-110.

Zinplava™ - bezlotoxumab Summary Zinplava™ (bezlotoxumab) is a novel, non- antibiotic, monoclonal antibody that neutralizes the effect of C. difficile toxin B Zinplava™ fulfils a significant unmet medical need for therapies to prevent CDI recurrence It is dosed as a single weight-based dose of 10 mg/kg, administered by IV infusion over 60 minutes Adverse effects of bezlotoxumab include: nausea, pyrexia, and headache Cautious risk/benefit use is suggested in patients with a history of CHF

Zinplava™ - bezlotoxumab References www.zinplava.com Zinplava [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; October 2016. Merck & Co., Inc. BLA 761046: Bezlotoxumab injection for the prevention of Clostridium difficile Infection (CDI) Recurrence. Antimicrobial Drugs Advisory Committee Briefing Document. June 2016; 1(1):1-110. Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis 2007;45(3):302-7.

Zinplava™ - bezlotoxumab Manufacturer: Merck & Co., Inc. FDA Approval Date: October 21st, 2016 Amanda D’Ostroph, PharmD Candidate