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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:
1. Appropriately recommend Zinplava™ -
(bezlotoxumab)
2. 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
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%)
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
5%
3%
Nausea
4%
3%
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
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
MODIFY II
BEZLO
ACTO+BEZLO
Placebo
Hospitalization status
Inpatient
Outpatient
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
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%)
Merck & Co.; Inc. AC Briefing Document. 2016:1-110.
Zinplava™ - bezlotoxumab
Literature Review
• Efficacy Results:
Endpoint
BEZLO
(n=810)
ACTO+
BEZLO
(n=800)
C. difficile
17.4%
15.9%
infection
p=0.0003 p<0.0001
recurrence
through
15.7%
14.9%
week 12
p=0.0003 p<0.0001
Placebo
(n-803)
27.6%
25.7%
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
% (n/m)
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)
15.4%
(26/100)
31.4%
(127/405)
28.3%
(41/145)
Immunocompromised
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
1.
www.zinplava.com
2.
Zinplava [package insert]. Whitehouse Station, NJ:
Merck & Co., Inc.; October 2016.
3.
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.
4.
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