Transcript No Slide Title

Caspofungin
Breakthrough Treatment in the
Management of Patients with Invasive Candidiasis
Overview: Growing Threat
• Serious fungal infections are on the rise
• Invasive Candida infections
– 4th most common nosocomial bloodstream infection in the
United States*
Pathogen
No. of Isolates
Incidence (%)
3908
1928
1354
934
31.9
15.7
11.1
7.6
Coagulase-negative staphylococci
Staphylococcus aureus
Enterococci
Candida species
* 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;
Edmond MB, Wallace SE, McClish DK, Pfaller MA, Jones RN, Wenzel RP Clin Infect Dis 1999;29:239-244.
In an international surveillance study of bloodstream infections:
Species of Candida Most Commonly Isolated
C. krusei
other Candida
C. tropicalis 2%
spp 5%
8%
C. parapsilosis
15%
C. albicans
54%
C. glabrata
16%
Adapted from Pfaller MA et al and The SENTRY Participant Group Antimicrob Agents Chemother 2000;44:747-751.
Pfaller MA, Jones RN, Doern GV et al and The SENTRY Participant Group Antimicrob Agents Chemother 2000;44:747-751.
In a 3-year surveillance study of nosocomial bloodstream infections in 49 US hospitals:
High Rate of Mortality Associated with
Candidal Bloodstream Infections
45
40%
Percentage of Patients
40
35
30
25%
25
20
15
10
5
0
Patients with candidal
bloodstream infections
Patients with bacterial
(non-candidal)
bloodstream infections
Edmond MB, Wallace SE, McClish DK, Pfaller MA, Jones RN, Wenzel RP Clin Infect Dis 1999;29:239-244.
Patients at High Risk
Potential risk factors include:
Non-Neutropenic
Neutropenic
• Acute renal failure
• Cancer
• Parenteral nutrition
• Transplantation
• Anti-anaerobic agents
• Broad spectrum anti-anaerobic
antibiotic use
• Prior vancomycin use
• Prior vancomycin use
• Intralipid agents
• Immunocompromised state
• Prior surgery
• Surgery
• Indwelling triple-lumen catheters
• Indwelling catheters
Blumberg HM, Jarvis WR, Soucie JM et al and the NEMIS Study Group Clin Infect Dis 2001;33:177-186;
Garber G Drugs 2001;61(suppl 1):1-12.
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 ICUs >48h. Among 4276 patients, 42 CBSIs occurred.
Candidemia in Neutropenic Patients with
Cancer: Clinical Characteristics*
Neutropenic (n=217)
Broad-spectrum antibiotics
in previous 2 weeks
Corticosteroids within
previous 2 weeks
Chemotherapy
within previous 30 days
Abdominal surgery
within previous 2 months
Intravenous hyperalimentation
within previous 30 days
Concomitant infection
within previous week
Central venous catheter (CVC)
in place at time of positive
blood culture
90%
56%
98%
3%
39%
63%
89%
0
* Univariate analyses.
50
% with clinical characteristic
Adapted from Anaissie EJ et al Am J Med 1998;104:238-245.
Anaissie EJ, Rex JH, Uzun O, Vartivarian S Am J Med 1998;104:238-245.
100
Candidemia in Non-Neutropenic Patients
with Cancer: Clinical Characteristics*
Non-Neutropenic (n=257)
Broad-spectrum antibiotics
in previous 2 weeks
Corticosteroids within
previous 2 weeks
Chemotherapy
within previous 30 days
Abdominal surgery
within previous 2 months
Intravenous hyperalimentation
within previous 30 days
Concomitant infection
within previous week
Central venous catheter (CVC)
in place at time of positive
blood culture
80%
23%
49%
29%
52%
61%
88%
0
* Univariate analyses.
50
% with clinical characteristic
Adapted from Anaissie EJ et al Am J Med 1998;104:238-245.
Anaissie EJ, Rex JH, Uzun O, Vartivarian S Am J Med 1998;104:238-245.
100
Caspofungin: New Class of Drug
Breakthrough Mechanism of Action: Targets the Pathogen, Not the Patient
-(1,6)-glucan
Fungal
cell wall
-(1,3)-D-glucan
Phospholipid bilayer
of the fungal cell
membrane
nucleus
-(1,3)-D-glucan synthase
Glucan Synthesis
Inhibitor Nucleoside Analogs
Ergosterol
Polyenes
Azoles
Kartsonis NA. Presented at the 12th European Congress of Clinical Microbiology and Infectious Diseases.
April 24-27, 2002. Milan, Italy.
Caspofungin: Broad Spectrum of Activity
Expanded Spectrum of In Vitro Activity
Data on file, MSD; Bartizal K, Gill CJ, Abruzzo GK et al Antimicrob Agents Chemother 1997;41:2326-2332.
Unique Mechanism of Action (MOA) Offers
Favorable Resistance Profile
• Active in vitro against fluconazole-, amphotericin B-,
or flucytosine-resistant Candida
• Not cross-resistant with azoles or polyenes
• Not intrinsically resistant to Candida isolates
Data on file, MSD; Graybill JR Int J Clin Pract 2001;55(9):633-638; Pfaller MA, Jones RN,
Doern GV et al Diagn Microbiol Infect Dis 1999;35:19-25.
Caspofungin: Indication
• NEW: Invasive candidiasis including candidemia in
neutropenic and non-neutropenic patients
In addition to:
• Invasive aspergillosis in patients who are refractory
to or intolerant of standard therapies
• Esophageal candidiasis
• Oropharyngeal candidiasis
Data on file, MSD.
Caspofungin: Proven Antifungal Efficacy
against Invasive Candidiasis
Clinical Trial: Protocol 014
Caspofungin vs. Amphotericin B Deoxycholate in the
Treatment of Invasive Candidiasis in Neutropenic and
Non-Neutropenic Patients
Data on file, MSD.
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
Data on file, MSD.
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 pts (92 with candidemia)
Amphotericin B:
125 pts (92 with candidemia)
— 50 mg/day
— 0.7–1.0 mg/kg/day
(70 mg loading dose on day 1)
neutropenic patients
— 0.6–0.7 mg/kg/day
non-neutropenic patients
Data on file, MSD.
Protocol 014: Study Design Flow Chart
Positive
culture
collected
Start of
IV study
therapy
< 4 days
Last
positive
culture
End of
2-week
treatment post-therapy
course
follow-up
6- to 8-week
post-therapy
follow-up
14 days
Study treatment course (at least 10 days of IV study therapy;
switch to oral fluconazole possible after day 10)
Primary Efficacy
Time Point
End of IV Study Rx
Secondary Efficacy
Time Points
Day 10 of
IV Rx
End of all
antifungal Rx
2-week
follow-up
Kartsonis NA. Presented at the 12th European Congress of Clinical Microbiology and Infectious Diseases.
April 24-27, 2002. Milan, Italy.
6- to 8-week
follow-up
Protocol 014: Efficacy Evaluation—
Diagnostic Criteria
• 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 (CI) difference
between groups
Data on file, MSD.
Protocol 014: Primary Efficacy Endpoint
• Proportion of patients with favorable overall response
(favorable clinical and microbiological response) at end
of IV therapy
– Modified Intent-To-Treat (MITT): primary assessment
criteria
• Patients received 1 day IV study therapy
– Evaluable Patients (EP): secondary assessment analysis
• Patients met entry criteria, received IV study therapy 5
days, and had full efficacy evaluation at the end of IV
study therapy
Data on file, MSD.
Protocol 014: Caspofungin Demonstrates
Comparable Efficacy Results in MITT Group
Overall Response at End of IV Therapy (test of cure)
100
MITT (n=224)
p=0.0861
90
80
73.4%
Percentage
70
61.7%
60
50
40
30
20
10
0
Caspofungin
80/109
Amphotericin B
71/115
Perfect J. Presented at the 12th European Congress of Clinical Microbiology and Infectious Diseases.
April 24-27, 2002. Milan, Italy; Data on file, MSD.
Protocol 014: Caspofungin Appeared to Have Efficacy
vs. Amphotericin B in Evaluable Patients Analysis*
Overall Response at End of IV Therapy (test of cure)
100
90
80.7%
EP (n=185)
p=0.0346
80
64.9%
Percentage
70
60
50
40
30
20
10
0
Caspofungin
71/88
Amphotericin B
63/97
* Evaluable patients analysis was a secondary analysis.
Perfect J. Presented at the 12th European Congress of Clinical Microbiology and Infectious Diseases.
April 24-27, 2002. Milan, Italy; Data on file, MSD.
Protocol 014: Caspofungin Demonstrates Similar
Efficacy vs. Amphotericin B in Candidemia
100
Percentage of Patients
90
80
70
72.5%
n=92
60
62.5%
n=94
50
40
30
20
10
0
Data on file, MSD.
Caspofungin
Amphotericin B
Protocol 014: Time to First Negative
Blood Culture
100
Caspofungin (n=92)
Amphotericin B (n=94)
90
80
Percentage
70
60
50
Caspofungin
Day 4
Day 7
Day 9
Amphotericin B
19.6%
12.0%
6.5%
19.1%
9.0%
6.4%
40
30
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
Perfect J. Presented at the 12th European Congress of Clinical Microbiology and Infectious Diseases.
April 24-27, 2002. Milan, Italy.
Protocol 014: Failure or Relapse Rates
50
38.2%
40
30
26.6%
20
16.5%
10
6.4% 7.0%
2.7%
0
Failure
(End of IV
study therapy)
Relapse
(6–8 weeks post-Rx)
Toxicity requiring
additional treatment
p=0.0277
Perfect J. Presented at the 12th European Congress of Clinical Microbiology and Infectious Diseases.
April 24-27, 2002. Milan, Italy.
Protocol 014: Mortality Assessment
50
40
34.2%
30.4%
30
20
10
0
4.4%
7.2%
Attributable Mortality*
(p=0.566)
Crude Mortality**
(p=0.528)
* 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.
Data on file, MSD; Perfect J. Presented at the 12th European Congress of Clinical Microbiology and Infectious Diseases.
April 24-27, 2002. Milan, Italy.
Protocol 014: Caspofungin Demonstrates a
Favorable Safety Profile vs. Amphotericin B*
100
Percentage of Patients
90
80
75.2%
70
94/125
60
48.8%
50
42.1%
40
48/114
61/125
30
23.2% 20.2%
20
10
0
AE=adverse event.
Data on file, MSD.
29/125
2.6%
3/114
23/114
11.4%
13/114
26.4%
24.8%
33/125
26/105
8.4%
8/95
* All p values were <0.03; 95% CI for relative risk
of caspofungin vs. amphotericin B was <1.
Other Studies: Amphotericin B Therapy—
Clinical Impact of Acute Renal Failure
• 30% (212) of 707 amphotericin B–treated patients:
acute renal failure (ARF)
• High mortality rate: 27% of 707 amphotericin B patients
Patients with acute
renal failure
Patients without ARF
115/212
54%
79/495 16%
0
10
20
n=707
30
40
50
60
70
80
90
100
Study Design: To assess the mortality and resource utilization resulting from acute renal failure (ARF) associated with
amphotericin B therapy; 707 adult admissions in which parenteral amphotericin B therapy was given were studied at a
tertiary-care hospital.
Bates DW, Su L, Yu DT et al Clin Infec Dis 2001;32:686-693.
Other Studies: Caspofungin Maintains
Favorable Safety/Tolerability Profile
• Overall safety assessed in 876 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 vs. 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 its favorable profile
Data on file, MSD.
Caspofungin: Minimal Drug Interactions
• Not a P450 (CYP) inhibitor
• No antagonistic interaction with amphotericin B
or itraconazole
• Has been used with antirejection drugs tacrolimus
and/or mycophenolate
Data on file, MSD; Bartizal K et al Antimicrob Agents Chemother 1997;41:2326-2332.
Caspofungin: Dosing/Administration
• Once-daily dosing with 50 mg standard dose
• 70 mg loading dose on day 1 for aspergillosis and
invasive candidiasis
• No premedication necessary
• Recommended infusion time: 1 hour
• No dosage adjustment in many cases*
* For patients with moderate hepatic insufficiency (Child-Pugh score 7-9), a dose adjustment to 35 mg daily is recommended.
There is no clinical experience in patients with severe hepatic insufficiency (Child-Pugh score >9).
Data on file, MSD.
Conclusions: Caspofungin—
The New Gold Standard
• Invasive candidiasis:
– Caspofungin is comparable to amphotericin B
(MITT analysis)
– Caspofungin appears to be superior to
amphotericin B (EP analysis)
– Candidemia: Caspofungin is comparable to
amphotericin B
• Overall safety/tolerability profile:
– Caspofungin has a favorable tolerability profile
Data on file, MSD.
References
References