Transcript Invasive Candidiasis (Protocol 014)

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A Comprehensive Review of
the Problem of Fungal Infections
and the Latest Clinical and
In Vitro Data with
CANCIDAS™† (caspofungin, MSD)
†Trademark
of Merck & Co., Inc., Whitehouse Station, NJ, USA
Slide 1
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Invasive Fungal Infections
Slide 2
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Clinical Findings in Aspergillus and Candida
An Introduction
Slide 3
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Invasive Fungal Infections Are a Growing Problem:
Focus on Aspergillosis
• Incidence of fungal infections has risen dramatically
– Increase in immunocompromised patients
– Increased invasive procedures
• Aspergillus is the second most common fungal
pathogen after Candida
• Up to 90% mortality in immunocompromised patients
despite treatment
Adapted from Andriole VT J Antimicrob Chemother 1999;44:151–162; Groll AH et al Adv Pharmacol 1998;44:343–500; Denning DW Clin
Infect Dis 1998;26:781–805; Andriole VT Curr Clin Top Infect Dis 1998;18:19–36; Lin S-J et al Clin Infect Dis 2001;32:358–366; Paterson DL,
Singh N Medicine (Baltimore) 1999;78:123–138.
Slide 4
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Invasive Fungal Infections Are a Growing Problem:
Focus on Candidiasis
• Serious fungal infections are on the rise
• Invasive Candida infections
– 4th most common nosocomial bloodstream
infection in the United States*
Pathogen
Coagulase-negative staphylococci
Staphylococcus aureus
Enterococci
Candida species
No. of Isolates
Incidence (%)
3908
1928
1354
934
31.9
15.7
11.1
7.6
*In a 3-year (1995–1998) surveillance study of 49 hospitals in the United States.
Adapted from Edmond MB et al Clin Infect Dis 1999;29:239–244; Andriole VT J Antimicrob Chemother 1999;44:151–162;
Uzun O, Anaissie EJ Ann Oncol 2000;11:1517–1521.
Slide 5
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Invasive Fungal Infections:
Patients at High Risk
Potential risk factors include:
Non-Neutropenic
• Acute renal failure
• Parenteral nutrition
• Anti-anaerobic agents
• Prior vancomycin use
• Intralipid agents
• Prior surgery
• Indwelling triple-lumen catheters
Neutropenic
• Cancer
• Transplantation
• Broad-spectrum anti-anaerobic
antibiotic use
• Prior vancomycin use
• Immunocompromised state
• Surgery
• Indwelling catheters
National Epidemiology of Mycosis Survey (NEMIS) was a prospective, multicenter study conducted at 6 US sites from 1993–1995
to examine rates of risk factors for the development of candidal bloodstream infections (CBSIs) among patients in surgical and
neonatal intensive care units >48 hours. Among 4276 patients, 42 CBSIs occurred.
Adapted from Blumberg HM et al, and the NEMIS Study Group Clin Infect Dis 2001;33:177–186; Garber G Drugs 2001;
61(suppl 1):1–12.
Slide 6
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Invasive Fungal Infections:
Current Treatment Options
• Amphotericin B
– The “gold standard” for efficacy
– Wide variety of acute and chronic side effects
 Including nephrotoxicity, even with lipid formulations
• Azoles
– Older agents: Inconsistent clinical efficacy in Aspergillus
infections
– Newer triazoles: clinical efficacy against Aspergillus infections
– Increasing resistance in candidal infections caused by nonalbicans species
– Numerous drug interactions associated with cytochrome P450
Adapted from Deray G J Antimicrob Chemother 2002;49(suppl S1):37–41; Cannon JP, Garey KW, Danziger LH Pharmacotherapy
2001;21(9):1107–1114; White MH et al Clin Infect Dis 1998;27(2):296–302; Walsh TJ et al Antimicrob Agents Chemother
2001;45(12):3487–3496; Andriole VT J Antimicrob Chemother 1999;44:151–162; Groll AH et al Adv Pharmacol 1998;44:343–500;
Denning DW et al Clin Infect Dis 2002;34:563–571; Bates DW et al Clin Infect Dis 2001;32:686–693; Graybill JR Int J Clin Pract
2001;55:633–638; Groll AH, Walsh TJ Swiss Med Wkly 2002;132:303–311.
Slide 7
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Mechanism of Action
of Current Antifungal Agents
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Mechanism of Action:
Amphotericin B
• Binds to ergosterol in fungal cell membranes, resulting
in a change in membrane permeability that allows leakage
of intracellular components
• Mammalian cell membranes also contain sterols
• It has been suggested that the damage to human cells and
fungal cells may be caused by common mechanisms
Adapted from Fungizone® Intravenous Package Insert. Apothecon® (A Bristol-Myers Squibb Company), April 1998; Stevens DA,
Bennett JE. In: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill
Livingstone, 2000:448–459; Andriole VT J Antimicrob Chemother 1999;44:151–162.
Slide 9
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Mechanism of Action:
Azoles
• Inhibit fungal CYP450 3A–dependent
C14-alpha-demethylase, resulting in
– Depletion of ergosterol
– Accumulation of toxic sterols
– Damage to cytoplasmic membrane
CYP450=cytochrome P-450
Adapted from Harari S Drugs 1999;58:621–631; Stevens DA, Bennett JE. In: Mandell, Douglas, and Bennett’s Principles and
Practice of Infectious Diseases. 5th ed. Philadelphia: Churchill Livingstone, 2000:448–459; Andriole VT J Antimicrob Chemother
1999;44:151–162; Andriole VT Curr Clin Top Infect Dis 1998;18:19–36.
Slide 10
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New Mechanism of Action:
Caspofungin
• Caspofungin is the first of a new class of antifungals,
the glucan synthesis inhibitors, also called the
echinocandins
• The glucan synthesis inhibitors have a unique mechanism
of action that may provide efficacy and tolerability
Adapted from Marco F et al Diagn Microbiol Infect Dis 1998;31:33–37; Groll AH et al Adv Pharmacol 1998;44:343–500; Graybill JR et al
Antimicrob Agents Chemother 1997;41:1775–1777; Groll AH, Walsh TJ Curr Opin Infect Dis 1997;10:449–458.
Slide 11
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New Mechanism of Action:
Caspofungin (cont’d)
• Beta (1,3)-D-glucan is essential to the cell-wall integrity
of many fungi, including Aspergillus and Candida spp.
• Caspofungin specifically inhibits beta (1-3)-D-glucan synthesis,
thereby compromising the integrity of the fungal cell wall
• As a result, the fungal cell wall becomes permeable, and cell lysis
occurs in the absence of osmotic support
• Beta (1-3)-D-glucan synthesis does not occur in human cells
Adapted from Groll AH, Walsh TJ Curr Opin Infect Dis 1997;10:449–458; Tkacz JS. In: Emerging Targets in Antibacterial and
Antifungal Chemotherapy. New York: Routledge, Chapman & Hall, 1992:495–523.
Slide 12
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Site of Action of Selected Antifungal Agents
Cell membrane
Polyenes
Azoles
Cell wall
Glucan synthesis
inhibitors
(echinocandins)
Adapted from Andriole VT J Antimicrob Chemother 1999;44:151–162; Graybill JR et al Antimicrob Agents Chemother
1997;41:1775–1777; Groll AH, Walsh TJ Expert Opin Invest Drugs 2001;10(8):1545–1558.
Slide 13
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Mechanisms of Action of Current Therapies
and Implications for Efficacy
Agent
Fungal Cell
Target
Activity
Clinical Implications
Amphotericin B
Membrane
Binds to ergosterol; causes
cell death
Potent, broad-spectrum
activity
Azoles
Membrane
Inhibits CYP450
enzyme responsible
for ergosterol synthesis;
damages cytoplasmic
membrane
Activity of variable
potency and spectrum
Caspofungin
Wall
Inhibits glucan synthesis;
disrupts cell-wall structure
Broad-spectrum antifungal
activity; potential for
additive effects in
combination therapy
Adapted from Andriole VT J Antimicrob Chemother 1999;44:151–162; Stevens DA, Bennett JE. In: Mandell, Douglas, and Bennett’s
Principles and Practice of Infectious Diseases. 5th ed. New York: Churchill Livingstone, 2000:448–459; Graybill JR et al Antimicrob
Agents Chemother 1997;41:1775–1777; Franzot SP, Casadevall A Antimicrob Agents Chemother 1997;41(2):331–336.
Slide 14
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Mechanisms of Action of Current Therapies
and Implications for Tolerability
• The activity of amphotericin B in human and
fungal cells may underlie its serious toxicities,
including nephrotoxicity
• Weaker effects in human than in fungal cells contribute
to the favorable tolerability of the triazole antifungals
• The unique, specific mechanism of action of caspofungin
results in a low potential for mechanism-based toxicities
Adapted from Groll AH et al Adv Pharmacol 1998;44:343–500; Sawaya BP et al J Am Soc Nephrol 1995;6:154–164; Tkacz JS
In: Emerging Targets in Antibacterial and Antifungal Chemotherapy. New York: Routledge, Chapman & Hall, 1992:495–523;
Marco F et al Diagn Microbiol Infect Dis 1998;31:33–37.
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In Vitro Activity of Caspofungin
Slide 16
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Caspofungin: Spectrum of in vitro Activity
Against Aspergillus spp.
• Potent in vitro activity seen against many filamentous
fungi and yeast, including Aspergillus spp.
– Aspergillus fumigatus
– Aspergillus flavus
– Aspergillus niger
– Aspergillus nidulans
– Aspergillus terreus
– Aspergillus candidus
Adapted from Groll AH, Walsh TJ Curr Opin Infect Dis 1997;10:449–458.
Slide 17
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Caspofungin: Spectrum of in vitro Activity
Against Candida spp.
Candida albicans
Candida dubliniensis
Candida glabrata
Candida guilliermondii
Candida kefyr
Candida krusei
Candida lipolytica
Candida lusitaniae
Candida parapsilosis
Candida rugosa
Candida tropicalis
• Caspofungin is active against strains of Candida with intrinsic
or acquired resistance to fluconazole, amphotericin B, or flucytosine
consistent with their different mechanisms of action
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Clinical Trials of Caspofungin
Slide 19
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Empirical Therapy (Protocol 026)
Objective
• To compare the proportions of patients with persistent
fever and neutropenia who achieve a favorable overall
response to treatment with caspofungin versus liposomal
amphotericin B.
Slide 20
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Empirical Therapy (Protocol 026)
Study Design
• Double-blind, randomized, multicenter study
• Caspofungin 50 mg daily (after 70 mg day 1) versus
L-AMB 3 mg/kg daily
• Data Safety and Monitoring Board monitored accumulating data
• Blinded Adjudication Committee assessed baseline and
breakthrough fungal infections
L-AMB=liposomal amphotericin B
Slide 21
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Empirical Therapy (Protocol 026)
Patient Population
• Inclusion criteria included the following:
– Age >16 years old
– Chemotherapy for leukemia, lymphoma, or other cancers OR
bone marrow or peripheral-blood stem-cell transplantation
– Neutropenia (ANC <500 µl) of 4 days’ duration
– >4 days of prior systemic antibacterial therapy
– Fever (>38.0ºC)
• Exclusion criteria included the following:
– Inadequately treated bacterial infection
– Abnormal laboratory values
– Parenteral amphotericin B within 10 days prior to study treatment
– Expected survival of <5 days or Karnofsky score <30
– Concomitant rifampin, cyclosporin A, or systemic antifungal therapy
Slide 22
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Empirical Therapy (Protocol 026)
Primary Endpoint
• Fulfillment of the following 5 criteria
– Successful outcome of the baseline infection
– No breakthrough infection during treatment or within
7 days post-therapy
– Survival up to 7 days post-therapy
– No premature discontinuation due to toxicity or lack
of efficacy
– Fever resolution for 48 hours during the period
of neutropenia
Slide 23
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Empirical Therapy (Protocol 026)
Efficacy and Safety Hypotheses
• Primary Hypothesis: Caspofungin would be non-inferior
to L-AMB for the primary composite endpoint
• Safety Hypothesis: Caspofungin will be non-inferior to L-AMB
with respect to frequency of
– Nephrotoxicity (doubling in serum creatinine or increase by
1.0 mg/dl if serum creatinine elevated at entry – primary
safety endpoint)
– Infusion-related events
– Drug-related AEs
– Discontinuations due to drug-related AEs
AE=adverse event
Slide 24
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Empirical Therapy (Protocol 026)
Baseline Characteristics of Patients
Percent
Caspofungin
L-AMB
(n=564)
(n=547)
Male, %
Median age, years (range)
Primary diagnosis
Acute myelogenous leukemia (%)
Acute lymphocytic leukemia (%)
Non-Hodgkin’s lymphoma (%)
High risk (%)
Allogeneic HSCT (%)
Relapsed acute leukemia (%)
Antifungal prophylaxis (%)
ANC <100/µl (%)
Duration of therapy (days)
Mean/median (range)
57.6
51 (17–83)
54.3
49 (16–83)
65.2
10.5
10.5
26.6
6.6
20.0
56.2
72.0
62.7
9.3
11.3
22.9
7.5
15.4
56.3
75.0
13/11 (1–90)
12.5/10 (1–90)
Slide 25
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Empirical Therapy (Protocol 026)
Response Rates vs. Liposomal Amphotericin B (MITT)
Favorable Overall Response
Success in Baseline Infection
No Breakthrough Infection
Survival to 7-Day Follow-Up
No Endpoint Discontinuation
Resolution of Fever
–10
–5
0
5
10
15
25
60
Difference in %
 Favors AmBisome
Favors Caspofungin 
Slide 26
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Empirical Therapy (Protocol 026)
Successful Outcome of Baseline Infections—
Overall (MITT)
Caspofungin (n=27)
52
26
L-AMB (n=27)
0
10
20
30
40
50
60
% of patients
Slide 27
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Empirical Therapy (Protocol 026)
Successful Outcome of Baseline Infections—
Aspergillus and Candida Infections (MITT)
Aspergillus infections
42
Caspofungin (n=12)
L-AMB (n=12)
8
0
5
10
15
20
25
30
35
40
45
Candida infections
Caspofungin (n=12)
67
L-AMB (n=12)
42
0
10
20
30
40
50
60
70
80
% of patients
Slide 28
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Empirical Therapy (Protocol 026)
Breakthrough Infections (MITT)
Caspofungin
(n=556)
L-AMB
(n=539)
29
23
Aspergillus spp.
10
9
Candida spp.
16
14
4
0
Total patients with breakthrough infections
Other*
* Other included: Basidomycetes, Fusarium, Zygomycetes
Slide 29
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Empirical Therapy (Protocol 026)
Survival (MITT)
100
90
Percent survival
80
p=0.044
70
60
50
40
30
20
Caspofungin (n=556)
L-AMB (n=539)
10
0
7
14
21
28
35
42
49
56
63
8
8
6
6
Study day
Caspofungin n= 556
L-AMB
n= 539
547
523
412
362
192
185
82
80
37
38
18
20
13
10
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Empirical Therapy (Protocol 026)
Discontinuations Due to Lack of Efficacy
or Toxicity (MITT)
Caspofungin (n=556)
10.3
14.5
L-AMB (n=539)
0
2
4
6
8
10
12
14
16
% of patients
Slide 31
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Empirical Therapy (Protocol 026)
Mortality
No. (%) of deaths
in patients with
Caspofungin
(n=556)
L-AMB
(n=539)
Baseline infections
3/27
(11.1%)
12/27
(44.4%)
Breakthrough infections
10/29
(34.5%)
9/23
(39.1%)
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Empirical Therapy (Protocol 026)
Adverse Events
Favors Favors
Caspofungin L-AMB
Nephrotoxicity
Infusion-related AEs
Drug-related* AEs
Discontinuation due to
drug-related* AEs
–30
–20
–10
0
10
Difference in %
*Considered possibly, probably, or definitely drug related by the investigator
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Empirical Therapy (Protocol 026)
Drug-Related AEs
• Caspofungin had significantly fewer
– Drug-related clinical AEs
p value
<0.001
– Discontinuations due to serious drug-related
clinical AEs
0.015
– Drug-related laboratory AEs
<0.001
– Discontinuations due to drug-related lab AEs
0.010
Slide 34
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Empirical Therapy (Protocol 026)
Summary and Conclusions
• Caspofungin was as effective as L-AMB as empirical therapy of suspected
fungal infection in febrile neutropenic patients
• Caspofungin provided benefits vs. L-AMB in
– Response of baseline fungal infections
– No premature discontinuations
• Caspofungin beneficially influenced survival
– Survival to 7 days
– Survival by Kaplan-Meier (p=0.044)
– Survival from baseline fungal infection (p<0.01)
• Caspofungin and L-AMB were similar for
– Breakthrough infection
– Resolution of fever
• Caspofungin was better tolerated than L-AMB with respect to
– Nephrotoxicity
– Infusion-related events
– Drug-related AEs
– Discontinuation due to drug-related AEs
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Invasive Aspergillosis (Protocol 019)
Study Design
• Multicenter, open-label, noncomparative study
– Caspofungin 70 mg on day 1, followed by 50 mg
once daily
• Patients must have
– Documented invasive aspergillosis
– Met criteria as refractory to or intolerant of standard
therapies, including
 Amphotericin B
 Amphotericin B lipid formulations
 Itraconazole
 Investigational azoles
Adapted from Maertens J et al. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy; San Diego, Calif,
September 2002. Poster M-868.
Slide 36
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Invasive Aspergillosis (Protocol 019)
Study Design (cont’d)
• Using modified Mycoses Study Group criteria, invasive aspergillosis
was identified as
– Definite: positive tissue histopathology or positive tissue culture
obtained by invasive procedure (transbronchial biopsy or percutaneous
needle aspiration)
– Probable: positive radiographic or computed tomographic evidence
with supporting culture from bronchoalveolar lavage or sputum,
galactomannan enzyme-linked immunosorbent assay, and/or at least
two positive polymerase chain reactions
• Treatment duration: 28 to 90 days*
– Duration of therapy was based on the severity of the patient’s underlying
disease, recovery from immunosuppression, and rapidity of clinical
response
*Longer durations of therapy were allowed for individual patients after discussion with the clinical monitor.
Adapted from Maertens J et al. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy; San Diego, Calif,
September 2002. Poster M-868.
Slide 37
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Invasive Aspergillosis (Protocol 019)
Endpoints
• Clinical efficacy was assessed at the end of intravenous therapy
– Favorable clinical response: complete or partial response
• Safety and tolerability profiles were monitored
and assessed
• Cases were reviewed by an independent expert panel
• All patients with the appropriate diagnosis who received
at least one dose of caspofungin were included in the analysis
of efficacy
Adapted from Maertens J et al. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy; San Diego, Calif,
September 2002. Poster M-868.
Slide 38
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Invasive Aspergillosis (Protocol 019)
Baseline Characteristics of Patients
Patient Characteristics (N=83 evaluable patients)
• Majority (86%) were refractory to standard therapy
• 77% had pulmonary aspergillosis
• Underlying conditions
– 72% hematologic malignancy*
– 11% organ transplant
– 4% solid tumor
– 13% corticosteroids and other risk factors**
• 23% of patients were neutropenic***
*Includes 25 patients with a bone-marrow transplant/peripheral stem-cell transplant; 21 with allogeneic transplantation
**Corticosteroid use in four patients, and skull trauma, methotrexate, mycobacterial lung infection, and chronic graft-versus-host
disease in one patient each. Three patients with no discernible risk factor
***Neutropenia was defined as an absolute neutrophil count <500 cells/µl
Adapted from Maertens J et al. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy; San Diego, Calif,
September 2002. Poster M-868.
Slide 39
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Invasive Aspergillosis (Protocol 019)
Favorable Clinical Response at the End
of Therapy
Percent of Patients
60
Overall (Patients
receiving >1 dose)
Patients treated
>7 days
50
40
30
20
45%
56%
(37/66)
(37/83)
(26/63)
10
0
Caspofungin
(n=83)
Caspofungin
(n=66)
Adapted from Maertens J et al. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy; San Diego, Calif,
September 2002. Poster M-868.
Slide 40
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Invasive Aspergillosis (Protocol 019)
Favorable Clinical Response 4 Weeks
Post-Therapy
Percent of Patients
Overall
4-Week Follow-Up*
50
40
30
20
41%
(26/63)
10
29%
(16/55)
0
Caspofungin
(n=63)
Caspofungin
(n=55)
* Four-week follow-up data in the clinical study of caspofungin were based on investigator assessments; the expert panel did not
*Four-week
review these
follow-up
data. data based on investigator assessments
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Invasive Aspergillosis (Protocol 019):
Safety Profile (Clinical AEs)
Incidence for any one drug-related* clinical AE
in patients with invasive aspergillosis was 2%
• Drug-related clinical AEs occurred in 12.2% of the patients
• Drug-related clinical AEs reported in >1% patients included
fatigue (2.2%), fever (2.2%), flushing (2.2%), nausea (2.2%),
infused-vein complications (2.2%), and vomiting (2.2%)
• Only one patient discontinued therapy because of a drug-related
clinical AE
AE(s)=adverse experience(s)
*Determined by investigator to be possibly, probably, or definitely drug related
Adapted from Maertens J et al. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy; San Diego, Calif,
September 2002. Poster M-868.
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Invasive Aspergillosis (Protocol 019)
Safety Profile (Systemic Infusion-Related AEs*)
• 89% of the 90 patients received an overall rating of
“no systemic infusion-related events”
• Systemic infusion-related events were captured daily,
and an overall assessment was performed on the last day
of caspofungin therapy
*Including fever, rigors, hypotension, anaphylaxis
Adapted from Maertens J et al. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy; San Diego, Calif,
September 2002. Poster M-868.
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Invasive Aspergillosis (Protocol 019)
Safety Profile (Laboratory AE)
• 13% of patients experienced a drug-related*
laboratory AE
• Only one patient discontinued therapy due to a drugrelated* laboratory AE: an increased serum creatinine
that occurred in one patient who had previously been
intolerant of amphotericin B
*Determined by the investigator to be possibly, probably, or definitely drug related
Adapted from Maertens J et al. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy; San Diego, Calif,
September 2002. Poster M-868.
Slide 44
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Invasive Aspergillosis (Protocol 019)
Summary and Conclusions
• 45% favorable response rate in patients refractory
to or intolerant of standard therapy
– Amphotericin B
– Lipid amphotericin B
– Itraconazole
– Investigational azoles
• Favorable tolerability profile
– Drug-related* clinical AEs occurred in 12% of the patients
– 2% incidence for any one drug-related* clinical AE
*Determined by the investigator to be possibly, probably, or definitely drug related
Adapted from Maertens J et al. 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy; San Diego, Calif,
September 2002. Poster M-868.
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Invasive Aspergillosis (Protocol 028/029)
Study Design
Comparison with historical controls
• A retrospective analysis based on medical chart review
of patients with documented invasive aspergillosis (N=206)
• Inclusion criteria, diagnosis, and outcomes were similar
to those of Protocol 019
• Using modified Mycoses Study Group criteria, invasive aspergillosis
was identified as
– Definite: positive tissue histopathology or positive tissue culture
obtained by invasive procedure
– Probable: positive radiographic or computed tomographic
evidence with supporting culture from bronchoalveolar
lavage or sputum and/or galactomannan enzyme-linked
immunosorbent assay
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Invasive Aspergillosis (Protocol 028/029)
Patient Characteristics (N=214)
• 1313 cases were initially reviewed; after screening for patients matched to
Protocol 019 criteria, 229 cases were evaluated and 214 cases were
considered to be refractory and/or intolerant
• Of these remaining 214, 8 patients had an indeterminate end-of-treatment
outcome and were excluded in the secondary analysis
• Of the 214 patients included in the final analysis, 193 were refractory,
5 were intolerant, and 16 had an indeterminate clinical assessment at
the end of week 1
• Underlying conditions (n=229)
– 70% hematologic malignancy
– 15% organ transplant
– 5% solid tumor
– 10% other
• 26% of patients were neutropenic
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Invasive Aspergillosis (Protocol 028/029)
Favorable Overall Clinical Response
Percent of Patients
Protocol 019
Protocol 028/029
50
40
30
20
41%
(26/63)
17%
10
(35/206)
0
Caspofungin patients
(clinical trials)
(n=63)
Patients treated with
standard therapies
(retrospective study)
(n=206)
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Invasive Aspergillosis (Protocol 028/029)
Favorable Clinical Response After 7 Days
of Therapy
Percent of Patients
Protocol 019
Protocol 028/029
50
40
30
20
50%
(26/52)
17%
10
(35/206)
0
Caspofungin patients
(clinical trials)
(n=52)
Patients treated with
standard therapies
(retrospective study)
(n=206)
Slide 49
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Invasive Candidiasis
Species of Candida Most Commonly Isolated
in Bloodstream Infections
In an international surveillance study:
C. krusei
2%
C. tropicalis
8%
other Candida spp
5%
C. albicans
54%
C. parapsilosis
15%
C. glabrata
16%
Adapted from Pfaller MA et al and The SENTRY Participant Group Antimicrob Agents Chemother 2000;44:747–751.
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Invasive Candidiasis
Mortality Associated with Candidemia
45
Percent of Patients
40
35
40%
30
25
25%
20
15
10
5
0
Patients with CBSIs
Patients with bacterial
(non-candidal)
bloodstream infections
Adapted from Edmond MB et al Clin Infect Dis 1999;29:239–244.
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Invasive Candidiasis
Candidemia in Neutropenic Patients with
Cancer: Clinical Characteristics
Neutropenic (n=217)
Broad-spectrum antibiotics
in previous 2 weeks
90%
Corticosteroids within
previous 2 weeks
56%
Chemotherapy within
previous 30 days
98%
Abdominal surgery within
previous 2 months
3%
Intravenous hyperalimentation
within previous 30 days
39%
Concomitant infection
within previous week
CVC in place at time
of positive blood culture
63%
89%
0
50
100
% with clinical characteristic*
CVC=central venous catheter
*In univariate analysis
Adapted from Anaissie EJ et al Am J Med 1998;104:238–245.
Slide 52
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Invasive Candidiasis
Candidemia in Non-Neutropenic Patients
with Cancer: Clinical Characteristics
Non-neutropenic (n=257)
Broad-spectrum antibiotics
in previous 2 weeks
80%
Corticosteroids within
previous 2 weeks
23%
Chemotherapy within
previous 30 days
49%
Abdominal surgery within
previous 2 months
29%
Intravenous hyperalimentation
within previous 30 days
52%
Concomitant infection
within previous week
CVC in place at time
of positive blood culture
61%
88%
0
50
100
% with clinical characteristic*
*In univariate analysis
Adapted from Anaissie EJ et al Am J Med 1998;104:238–245.
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Invasive Candidiasis (Protocol 014)
Objective
• To compare the proportion of caspofungin acetate patients
with both a favorable clinical response and a favorable
microbiological assessment at the time of discontinuing IV
antifungal therapy with that of amphotericin B patients
IV=intravenous
Slide 54
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Invasive Candidiasis (Protocol 014)
Design
• Multicenter, randomized, double-blind, comparative study
• To compare the proportion of caspofungin patients with
a favorable clinical response and a favorable microbiological
assessment at the time of discontinuing IV antifungal therapy
with that of amphotericin B patients
• Patients (>18 years old) stratified by neutropenic status
Caspofungin:
114 patients (90 with candidemia)
Amphotericin B:
125 patients (91 with candidemia)
– 50 mg/day
(70 mg loading dose on day 1)
– 0.7–1.0 mg/kg/day
neutropenic patients
– 0.6–0.7 mg/kg/day
non-neutropenic patients
Adapted from Mora-Duarte J et al N Engl J Med 2002;347(25):2020–2029.
Slide 55
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Invasive Candidiasis (Protocol 014)
Design (cont’d)
Positive
culture
collected
Start of
IV study
therapy
4 days
Last
positive
culture
End of
2-week
treatment post-therapy
course
follow-up
14 days
6- to 8-week
post-therapy
follow-up
Ref 1, p 21
Study treatment course (at least 10 days of IV study therapy;
switch to oral fluconazole possible after day 10)
Primary efficacy
time point
Secondary efficacy
time points
End of IV Study Rx
Day 10 of
IV Rx
End of all
antifungal Rx
2-week
follow-up
6- to 8-week
follow-up
Adapted from Kartsonis NA. Presented at the 12th European Congress of Clinical Microbiology and Infectious Diseases,
Milan, Italy, April 24–27, 2002.
Slide 56
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Invasive Candidiasis (Protocol 014)
Efficacy Evaluation: Study Definitions
• Favorable clinical response
– Complete resolution of signs/symptoms of Candida
• Favorable microbiological response or presumptive eradication
– Candida eradication from follow-up cultures
• Definition of comparability
– 95.6% confidence interval difference between groups
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Invasive Candidiasis (Protocol 014)
Efficacy Endpoints
• Proportion of patients with favorable overall response
(favorable clinical and microbiological response) at end
of IV therapy
– MITT analysis: primary assessment
 Patients received 1 day IV study therapy
– EP analysis: secondary assessment
 Patients met MITT criteria, received IV study therapy
5 days, received no concomitant antifungal therapy,
and had no protocol violations
MITT=modified intention-to-treat analysis; EP=evaluable patients
Adapted from Mora-Duarte J et al N Engl J Med 2002;347(25):2020–2029.
Slide 58
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Invasive Candidiasis (Protocol 014)
Efficacy vs. Amphotericin B
(MITT Analysis)
Percent of Patients
Favorable Overall Response at End of IV Therapy (test of cure)
100
90
80
70
60
50
40
30
20
10
0
MITT (n=224)
p=0.09
73.4%
61.7%
Caspofungin
80/109
Adapted from Mora-Duarte J et al N Engl J Med 2002;347(25):2020–2029.
Amphotericin B
71/115
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Invasive Candidiasis (Protocol 014)
Efficacy vs. Amphotericin B
(Evaluable Patients Analysis)
Percent of Patients
Favorable Overall Response at End of IV Therapy (test of cure)
100
90
80
70
60
50
40
30
20
10
0
Evaluable patients (n=185)
p=0.03
80.7%
64.9%
Caspofungin
71/88
Amphotericin B
63/97
*Evaluable patients analysis was a secondary analysis.
Adapted from Mora-Duarte J et al N Engl J Med 2002;347(25):2020–2029.
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Invasive Candidiasis (Protocol 014)
Efficacy vs. Amphotericin B in Patients
with Candidemia (MITT)
Favorable Overall Response at End of IV Therapy (test of cure)
100
Percent of Patients
90
80
70
60
71.7%
62.8%
50
40
30
20
10
0
Caspofungin
(n=90)
Adapted from Mora-Duarte J et al N Engl J Med 2002;347(25):2020–2029.
Amphotericin B
(n=91)
Slide 61
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Invasive Candidiasis (Protocol 014)
Time to First Negative Blood Culture
100
Caspofungin (n=92)
Amphotericin B (n=94)
Percent of Patients
90
80
70
Caspofungin
60
50
40
30
Day 4
Day 7
Day 9
19.6%
12.0%
6.5%
Amphotericin B
19.1%
8.5%
6.4%
20
10
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Study Day
Adapted from Perfect J. Presented at the 12th European Congress of Clinical Microbiology and Infectious Diseases,
Milan, Italy, April 24–27, 2002; Mora-Duarte J et al N Engl J Med 2002;347(25):2020–2029.
Slide 62
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Invasive Candidiasis (Protocol 014)
Failure or Relapse Rates (MITT Analysis)
Percent of Patients
50
40
38.3%
30
26.6%
20
16.5%
10
6.4%
0
Failure
(End of IV
study therapy)
7.0%
Relapse
(6–8 weeks post-Rx)
Adapted from Mora-Duarte J et al N Engl J Med 2002;347(25):2020–2029.
2.8%
Toxicity requiring
additional treatment
p=0.03
Slide 63
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Invasive Candidiasis (Protocol 014)
Mortality Assessment
Percent of Patients
50
40
34.2%
30
30.4%
20
10
0
4.4%
7.2%
Attributable Mortality*
(p=0.57)
Crude Mortality**
(p=0.53)
*Attributable mortality was defined as meeting any one of the following criteria:
– Positive Candida culture within 48 hours of death
– Histopathological or microbiological evidence of Candida on autopsy
– Candida infection identified as an investigator-determined cause of death
**Crude mortality was defined as the mortality rate from all causes of death
Adapted from Mora-Duarte J et al N Engl J Med 2002;347(25):2020–2029.
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Invasive Candidiasis (Protocol 014)
Percent of Patients
Safety Profile of Caspofungin vs.
Amphotericin B
100
90
80
70
60
50
40
30
20
10
0
75.2%
(94/125)
48.8%
(61/125)
42.1%
(48/114)
23.2%
(3/114) (29/125)
2.6%
20.2%
(23/114)
26.4%
(33/125)
11.4%
(13/114)
8.4%
(8/95)
24.8%
(26/105)
All p values were <0.03; 95% CI for relative risk of caspofungin versus amphotericin B was <1
CI=confidence interval
Adapted from Mora-Duarte J et al N Engl J Med 2002;347(25):2020–2029; Perfect J. Presented at the 12th European Congress of
Clinical Microbiology and Infectious Diseases, Milan, Italy, April 24–27, 2002.
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Invasive Candidiasis (Protocol 014)
Summary and Conclusions
• Invasive candidiasis
– Caspofungin was comparable to amphotericin B
(primary MITT analysis)
– Caspofungin appeared to be superior to
amphotericin B (secondary EP analysis)
– Candidemia: caspofungin was comparable to
amphotericin B
• Overall safety/tolerability profile
– Caspofungin had a favorable tolerability profile
Adapted from Mora-Duarte J et al N Engl J Med 2002;347(25):2020–2029.
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Esophageal/Oropharyngeal Candidiasis (Protocols 003, 004, and 020)
Objectives
• Primary Objective—Protocol 003
– To evaluate the efficacy, safety profile, and tolerability of caspofungin
(50 or 70 mg daily) versus amphotericin B (0.5 mg/kg daily) in patients
with esophageal candidiasis
• Primary Objective—Protocol 004
– To determine the efficacy, safety profile, and tolerability of two doses of
amphotericin B (0.5 mg/kg daily) caspofungin (50 or 70 mg daily) and to
compare these profiles to that of amphotericin B in patients with symptomatic
esophageal and/or oropharyngeal candidiasis in a Phase II dose-ranging study
• Primary Objective—Protocol 020
– To determine the efficacy, safety profile, and tolerability of caspofungin
compared with that of fluconazole in the treatment of Candida esophagitis
in a Phase III study
Adapted from Villanueva A et al Clin Infect Dis 2001;33:1529–1535; Arathoon EG et al Antimicrob Agents Chemother 2002;46:
451–457; Villanueva A et al Am J Med 2002;113:294–299.
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Esophageal/Oropharyngeal Candidiasis (Protocols 003 and 004)
Study Design
Phase IIa: Protocol 003
Phase IIb: Protocol 004
• Design
– Multicenter, double-blind, randomized,
comparative trial
• Patients
– 128 adults (21 to 66 years of age) with
documented esophageal candidiasis
– 80% HIV positive
• Analysis
– Modified intent to treat: patients
who received at least one dose of therapy
and had microbiologically documented disease
• Treatments
– Caspofungin 50 mg/day*
– Caspofungin 70 mg/day*
– Amphotericin B deoxycholate 0.5 mg/kg/day**
• Duration of Treatment
– 14 days
• Clinical endpoints
– Response at 14 days after completion
of treatment
• Design
– Multicenter, double-blind, randomized,
comparative trial
• Patients
– 138 adults (18 to 65 years of age) with
documented oropharyngeal or esophageal
candidiasis
– 98% HIV positive
• Analysis
– Modified intent to treat: patients who received at
least one dose of therapy and had microbiologically
documented disease
• Treatments
– Caspofungin 35 mg/day*
– Caspofungin 50 mg/day*
– Caspofungin 70 mg/day*
– Amphotericin B deoxycholate 0.5 mg/kg/day**
• Duration of Treatment
– Oropharyngeal candidiasis: 7 days
– Esophageal candidiasis: 10 days
• Clinical endpoints
– Favorable response at 3- to 4-day follow-up
HIV=human immunodeficiency virus
*Administered as a single daily dose infused over 1 hour; **Administered as a single daily dose infused over at least 2 hours
Adapted from Villanueva A et al Clin Infect Dis 2001;33:1529–1535; Arathoon EG et al Antimicrob Agents Chemother 2002;46:
451–457.
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Esophageal/Oropharyngeal Candidiasis (Protocol 020)
Study Design
Phase III: Protocol 020
• Design
– Multicenter, double-blind, randomized trial
• Patients
– 177 adults with endoscopically and microbiologically documented Candida esophagitis
– 87% HIV positive
• Analysis
– Modified intent to treat: patients who received at least one dose of study drug and
had a confirmed diagnosis
– Secondary evaluable patients per protocol: patients who received 5 days of study drug,
did not take concomitant antifungal drugs from baseline through the 5- to 7-day post-therapy
visit, completed their follow-up evaluation, and had no serious protocol violations
• Treatment
– Caspofungin 50 mg once daily by IV infusion over 1-hour period
– Fluconazole 200 mg once daily by IV infusion over 1-hour period
• Duration of Treatment
– 7 to 21 days
• Clinical Endpoints
– Therapeutic response at 5 to 7 days after discontinuation of study drug
Adapted from Villanueva A et al Am J Med 2002;113:294–299.
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Esophageal/Oropharyngeal Candidiasis (Protocols 003, 004, and 020)
Clinical Tolerability Compared to Fluconazole
Comparison of the Most Common Drug-Related Clinical AEs in Clinical Studies*
(Incidence ≥5% for at least one treatment dose [per comparison] by body system)
Study 1 Phase III (percent)
Caspofungin
50 mg (n=83)
Fluconazole
200 mg (n=94)
Studies 2 and 3 Phase II (percent)
Caspofungin
50 mg (n=80)
Caspofungin
70 mg (n=65)
Amphotericin B
0.5 mg/kg (n=89)
Body as a Whole
Asthenia/fatigue
Chills
Edema/swelling
Fever
Malaise
Pain
Pain, abdominal
0.0
0.0
0.0
3.6
0.0
0.0
3.6
0.0
0.0
0.0
1.1
0.0
0.0
2.1
0.0
2.5
0.0
21.3
0.0
1.3
2.5
0.0
1.5
0.0
26.2
0.0
4.6
0.0
6.7
75.3
5.6
69.7
5.6
5.6
9.0
12.0
15.7
8.5
8.5
2.5
11.3
1.5
13.8
0.0
22.5
3.6
6.0
1.2
2.1
6.4
3.2
1.3
2.5
1.3
3.1
3.1
3.1
11.2
21.3
13.5
6.0
0.0
1.1
0.0
11.3
0.0
7.7
0.0
19.1
7.9
Peripheral Vascular
Infused vein complication
Phlebitis/thrombophlebitis
Digestive System
Diarrhea
Nausea
Vomiting
Nervous System & Psychiatric
Headache
Tremor
Skin & Skin Appendage
Erythema
1.2
0.0
1.3
1.5
7.9
Induration
0.0
0.0
0.0
3.1
6.7
Rash
0.0
0.0
1.3
4.6
3.4
*Relationship to drug was determined by the investigator to be possibly, probably, or definitely drug related. Patients who received
caspofungin 35 mg daily in these studies are not included in this table.
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Esophageal/Oropharyngeal Candidiasis (Protocols 003, 004, and 020)
Drug-Related Laboratory AE Profile
Compared to Fluconazole
Comparison of the Most Common Drug-Related Laboratory Abnormalities*,**
Incidence >5% (for at least one treatment dose) by Laboratory Test Category
Caspofungin
50 mg (n=163)
(percent)
Caspofungin
70 mg (n=65)
(percent)
Fluconazole
200 mg (n=94)
(percent)
Amphotericin B
0.5 mg/kg (n=89)
(percent)
Blood Chemistry
Alanine transaminase (ALT) increased
Aspartate transaminase (AST) increased
Blood urea increased
Serum albumin decreased
Serum alkaline phosphatase increased
Serum bicarbonate decreased
Serum creatinine increased
Serum potassium decreased
10.6
13.0
0.0
8.6
10.5
0.9
0.0
3.7
10.8
10.8
0.0
4.6
7.7
0.0
1.5
10.8
11.8
12.9
1.2
5.4
11.8
0.0
2.2
4.3
22.7
22.7
10.3
14.9
19.3
6.6
28.1
31.5
11.1
12.3
6.2
1.5
3.1
4.6
5.4
5.4
8.6
32.6
37.1
7.9
0.0
1.1
0.0
0.0
3.8
7.7
0.0
5.1
0.0
8.0
12.0
24.0
Hematology
Hematocrit decreased
Hemoglobin decreased
White blood cell count decreased
Urinalysis
Urine casts increased
Urine red blood cell count increased
Urine white blood cell count increased
*Three comparative studies were conducted to evaluate the efficacy of caspofungin for the treatment of esophageal candidiasis.
One study compared caspofungin to IV fluconazole. In addition, two dose-ranging studies compared different doses of
caspofungin to amphotericin B. In all 3 studies, patients were required to have symptoms and microbiological documentation of
esophageal candidiasis; and most patients had advanced AIDS (with CD4 counts < 50/mm3).
**Relationship to drug was determined by the investigator to be possibly, probably, or definitely drug related. Patients who
received caspofungin 35 mg daily in these studies are not included in this table.
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Esophageal/Oropharyngeal Candidiasis (Protocols 003 and 004)
Increase in Serum Creatinine Compared
to Amphotericin B
Rare Elevations in Serum Creatinine Levels
Percent of Patients
40
Serum Creatinine Increases
30
28%
(25/89)
20
10
0
1.5%
0%
Caspofungin
50 mg
(n=80)
(1/65)
Caspofungin
70 mg
(n=65)
Amphotericin B
0.5 mg/kg
(n=89)
Adapted from Villanueva A et al Clin Infect Dis 2001;33:1529–1535; Arathoon EG et al Antimicrob Agents Chemother 2002;46:
451–457.
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Esophageal/Oropharyngeal Candidiasis (Protocols 003, 004, and 020)
Summary and Conclusions
• Caspofungin was generally well tolerated.
• The incidence of clinical and laboratory side effects
characteristic of amphotericin B (e.g., fever and chills,
 hemoglobin concentration, hypokalemia,  serum
creatinine levels) occurred less often with caspofungin.
Adapted from Villanueva A et al Clin Infect Dis 2001;33:1529–1535; Arathoon EG et al Antimicrob Agents Chemother
2002;46:451–457; Villanueva A et al Am J Med 2002;113:294–299.
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Other Information on Caspofungin
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Safety Profile Across Multiple
Clinical Studies
• Overall safety assessed in 1440 patients
• 394 patients enrolled in Phase I studies
• Most patients with Candida infections had serious underlying
medical conditions, including hematologic or other malignancy,
recent major surgery, or HIV
• In a clinical study among patients with oropharyngeal or esophageal
candidiasis, caspofungin (n=83) demonstrated a comparable tolerability
profile versus fluconazole (n=94)
• In a clinical study among patients with invasive candidiasis, caspofungin
(n=114) demonstrated a superior tolerability profile to amphotericin B
(n=125)
• In an open-label, noncomparative aspergillosis (n=69) study, caspofungin
maintained a favorable profile
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Caspofungin vs. Amphotericin B
Label-to-Label Comparison of Dosing
Caspofungin
Amphotericin B
Dosing
Dosing
Day 1
70 mg/day*
After Day 1
50 mg/day
1-hour infusion
0.25 mg/kg to
1.5 mg/kg***
2- to 6-hour infusion
No premedication is necessary
No Dosage Adjustment Is Necessary
In patients with renal insufficiency
In patients with mild hepatic insufficiency
(Child-Pugh score 5 to 6)**
In the elderly
Dosage Adjustment Is Required
Based on disease state and
underlying condition
*For patients with invasive aspergillosis and febrile neutropenia; for patients with esophageal and/or oropharyngeal candidiasis,
50 mg/day
**For patients with invasive aspergillosis and moderate hepatic insufficiency (Child-Pugh score 7 to 9), an adjustment of the daily
dose to 35 mg is recommended after the initial 70 mg loading dose. For patients with esophageal and/or oropharyngeal
candidiasis and moderate hepatic insufficiency, a daily dose of 35 mg is recommended with no loading dose. There is no clinical
experience in patients with severe hepatic insufficiency (Child-Pugh score >9).
***Optimal dose is unknown
Adapted from Fungizone® Intravenous Package Insert.
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Dosing and Administration
• Caspofungin has been tolerated for up to 162 days
of therapy in a clinical study*
• Duration of treatment is based on
– Severity of patient’s underlying disease
– Recovery from immunosuppression
– Clinical response
*69 patients received from 1 to 162 days of therapy
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Indications
• Empirical therapy for presumed fungal infections in febrile
neutropenic patients
• Invasive candidiasis including candidemia in neutropenic
and non-neutropenic patients
• Invasive aspergillosis in patients who are refractory to or
intolerant of standard therapies
• Esophageal candidiasis
• Oropharyngeal candidiasis
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Contraindications
• Caspofungin is contraindicated in patients with
hypersensitivity to any component of this product
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Precautions
• Caspofungin should be used with caution in the following patient groups
– Pregnant women
 Caspofungin should not be used in pregnancy unless clearly
necessary
– Nursing mothers
 Women receiving caspofungin should not breast-feed
– Patients with hepatic insufficiency
 For patients with mild hepatic insufficiency (Child-Pugh score 5 to 6),
no dosage adjustment is needed
 For patients with moderate hepatic insufficiency (Child-Pugh score 7 to
9), after the initial 70 mg loading dose, caspofungin 35 mg daily is
recommended
 There is no clinical experience in patients with severe
hepatic insufficiency (Child-Pugh score >9)
– Children
 Tolerability and effectiveness in pediatric patients have not been
established
 Use in patients under 18 years of age is not recommended
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Drug-Drug Interactions
• Caspofungin is not an inhibitor of any enzymes in
the CYP450 system
• Caspofungin does not interact with the following agents
– Antirejection drugs: mycophenolate
– Antifungal agents: amphotericin B, itraconazole
• Concomitant use with cyclosporine is not recommended
until multiple-dose use in patients is studied
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Summary
• Specific mechanism of action
– First in a new class of beta (1-3)-D-glucan
synthesis inhibitors
• A new option that offers both efficacy and tolerability
• Now available for invasive aspergillosis*
*In patients refractory to or intolerant of other antifungal therapies
Adapted from Graybill JR et al Antimicrob Agents Chemother 1997;41:1775–1777; Groll AH, Walsh TJ Curr Opin Infect Dis 1997;
10:449–458; Onishi J et al Antimicrob Agents Chemother 2000;44:368–377.
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Cannon JP, Garey KW, Danziger LH. A prospective and retrospective analysis of the nephrotoxicity and efficacy
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A Comprehensive Review of the Problem of Fungal
Infections and the Latest Clinical and In Vitro Data
with CANCIDAS™† (caspofungin, MSD)
Before prescribing, please consult
the manufacturers’ prescribing information.
Merck does not recommend the use of any product
in any different manner than as described
in the prescribing information.
Copyright © 2004 Merck & Co., Inc., Whitehouse Station, NJ, USA.
All rights reserved.
6-05 CAN 2004-W-6281-SS
Printed in USA
VISIT US ON THE WORLD WIDE WEB AT http://www.merck.com
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