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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*.

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Caspofungin

Caspofungin

Breakthrough Treatment in the Management of Patients with Invasive Candidiasis


Overview growing threat

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 (%)

Coagulase-negative staphylococci390831.9

Staphylococcus aureus192815.7

Enterococci135411.1

Candida species9347.6

*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 JAntimicrob 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.


Caspofungin

In an international surveillance study of bloodstream infections:Species of Candida Most Commonly Isolated

C. krusei

2%

other Candida

spp 5%

C.tropicalis

8%

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.

Pfaller MA, Jones RN, Doern GV et al and The SENTRY Participant Group Antimicrob Agents Chemother 2000;44:747-751.


High rate of mortality associated with candidal bloodstream infections

In a 3-year surveillance study of nosocomial bloodstream infections in 49 US hospitals:

High Rate of Mortality Associated with Candidal Bloodstream Infections

45

Patients with candidal bloodstream infections

40%

40

35

30

25%

25

Percentage of Patients

20

15

10

5

0

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

Patients at High Risk

Neutropenic

  • Cancer

  • Transplantation

  • Broad spectrum anti-anaerobic antibiotic use

  • Prior vancomycin use

  • Immunocompromised state

  • Surgery

  • Indwelling catheters

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

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

Candidemia in Neutropenic Patients with Cancer: Clinical Characteristics*

Neutropenic (n=217)

Broad-spectrum antibiotics in previous 2 weeks

Corticosteroids within previous 2 weeks

Chemotherapywithin previous 30 days

Abdominal surgerywithin previous 2 months

Intravenous hyperalimentationwithin 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

50

100

% with clinical characteristic

*Univariate analyses.

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.


Candidemia in non neutropenic patients with cancer clinical characteristics

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

Chemotherapywithin previous 30 days

Abdominal surgerywithin previous 2 months

Intravenous hyperalimentationwithin 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

50

100

% with clinical characteristic

*Univariate analyses.

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.


Caspofungin new class of drug

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 bilayerof the fungal cell

membrane

nucleus

Ergosterol

Polyenes

Azoles

-(1,3)-D-glucan synthase

Glucan Synthesis

Inhibitor

Nucleoside Analogs

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

Caspofungin: Broad Spectrum of Activity

Expanded Spectrum of In Vitro Activity

C. albicans

C. glabrata

C. parapsilosis

C. tropicalis

C. krusei

C. guilliermondii

C. lipolytica

C. dubliniensis

C. kefyr

C. lusitaniae

C. rugosa

C. pseudotropicalis

A. flavus

A. fumigatus

A. terreus

A. niger

A. nidulans

CANDIDA ALBICANS

CANDIDA NON-ALBICANS

ASPERGILLUS

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

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

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

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

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

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: Amphotericin B:114 pts (92 with candidemia)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/daynon-neutropenic patients

Data on file, MSD.


Protocol 014 study design flow chart

Protocol 014: Study Design Flow Chart

Positive culture collected

Start of IV study therapy

Last positive culture

End of treatment course

2-week post-therapy follow-up

6- to 8-week post-therapy follow-up

Study treatment course (at least 10 days of IV study therapy; switch to oral fluconazole possible after day 10)

14 days

< 4 days

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

6- to 8-week follow-up

Kartsonis NA. Presented at the 12th European Congress of Clinical Microbiology and Infectious Diseases. April 24-27, 2002. Milan, Italy.


Protocol 014 efficacy evaluation diagnostic criteria

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

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

Protocol 014: Caspofungin Demonstrates Comparable Efficacy Results in MITT Group

Overall Response at End of IV Therapy (test of cure)

Caspofungin

80/109

100

MITT (n=224)

p=0.0861

90

73.4%

80

70

61.7%

60

Percentage

50

40

30

20

10

0

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

100

EP (n=185)

p=0.0346

80.7%

90

80

64.9%

70

60

Percentage

50

40

30

20

10

0

Caspofungin

71/88

Amphotericin B

63/97

Protocol 014: Caspofungin Appeared to Have Efficacy vs. Amphotericin B in Evaluable Patients Analysis*

Overall Response at End of IV Therapy (test of cure)

*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

Protocol 014: Caspofungin Demonstrates Similar Efficacy vs. Amphotericin B in Candidemia

Caspofungin

100

90

72.5%

80

62.5%

70

n=92

60

n=94

Percentage of Patients

50

40

30

20

10

0

Amphotericin B

Data on file, MSD.


Protocol 014 time to first negative blood culture

Protocol 014: Time to First Negative Blood Culture

100

Percentage

Caspofungin (n=92)

90

Amphotericin B (n=94)

80

70

Caspofungin Amphotericin B

Day 4 19.6%19.1%

Day 712.0%9.0%

Day 96.5%6.4%

60

50

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

Protocol 014: Failure or Relapse Rates

50

Failure

(End of IV study therapy)

Caspofungin (n=109)70/50 mg

Amphotericin B (n=115)0.6–1.0 mg/kg

38.2%

40

26.6%

30

16.5%

20

7.0%

6.4%

10

2.7%

0

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

Protocol 014: Mortality Assessment

50

Caspofungin 70/50 mg

Amphotericin B 0.6–1.0 mg/kg

34.2%

40

30.4%

30

20

7.2%

4.4%

10

0

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

Protocol 014: Caspofungin Demonstrates a Favorable Safety Profile vs. Amphotericin B*

100

Caspofungin 70/50 mg

Amphotericin B 0.6–1.0 mg/kg

90

75.2%

80

94/125

70

60

48.8%

Percentage of Patients

42.1%

50

61/125

48/114

40

26.4%

24.8%

23.2%

30

20.2%

33/125

26/105

29/125

20

23/114

11.4%

8.4%

2.6%

13/114

10

8/95

3/114

0

All drug-related AEs

Drug-relateddiscontinuationsdue to AEs

Infusion-related systemic AEs

Hypokalemiarequiring potassium treatment

Nephrotoxicity

AE=adverse event.

Data on file, MSD.

*All p values were <0.03; 95% CI for relative riskof caspofungin vs. amphotericin B was <1.


Other studies amphotericin b therapy clinical impact of acute renal failure

0

10

20

30

40

50

60

70

80

90

100

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

115/212

54%

79/495

16%

n=707

Patients without ARF

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

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

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

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

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


References1

References


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