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

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

3. 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)

4. 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].

5. 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].

6. 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].

7. 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].

8. Zinplava™ - bezlotoxumab Drug Facts
Pharmacokinetics: A
AUC mcg· h/mL; Cmax 185 mcg/mL D
Vd: 7.33L (16%) M
Cl: 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].

9. 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].

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

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

12. 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].

13. 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.

14. 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.

15. 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. .

16. 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. .

17. 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.

18. 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.

19. 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.

20. 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

21. Zinplava™ - bezlotoxumab References
Zinplava [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; October 2016.
Merck & Co., Inc. BLA : 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.

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