1. Download from www.cancidas.aewww.cancidas.ae Caspofungin Breakthrough Treatment in the Management of Patients with Invasive Candidiasis

2. Download from www.cancidas.aewww.cancidas.ae Overview: Growing Threat Serious fungal infections are on the rise Invasive Candida infections –4th most common nosocomial bloodstream infection in the United States* Serious fungal infections are on the rise Invasive Candida infections –4th most common nosocomial bloodstream infection in the United States* *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 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. Coagulase-negative staphylococci390831.9 Staphylococcus aureus192815.7 Enterococci135411.1 Candida species9347.6 Coagulase-negative staphylococci390831.9 Staphylococcus aureus192815.7 Enterococci135411.1 Candida species9347.6 Pathogen No. of Isolates Incidence (%)

3. Download from www.cancidas.aewww.cancidas.ae In an international surveillance study of bloodstream infections: Species of Candida Most Commonly Isolated Pfaller MA, Jones RN, Doern GV et al and The SENTRY Participant Group Antimicrob Agents Chemother 2000;44:747-751. C. glabrata 16% C. glabrata 16% C. albicans 54% C. albicans 54% C. parapsilosis 15% C. parapsilosis 15% C. tropicalis 8% C. tropicalis 8% C. krusei 2% C. krusei 2% other Candida spp 5% other Candida spp 5% Adapted from Pfaller MA et al and The SENTRY Participant Group Antimicrob Agents Chemother 2000;44:747-751.

4. Download from www.cancidas.aewww.cancidas.ae High Rate of Mortality Associated with Candidal Bloodstream Infections Patients with candidal bloodstream infections Edmond MB, Wallace SE, McClish DK, Pfaller MA, Jones RN, Wenzel RP Clin Infect Dis 1999;29:239-244. 0 0 5 5 10 15 20 25 30 35 40 45 40% 25% Percentage of Patients Patients with bacterial (non-candidal) bloodstream infections In a 3-year surveillance study of nosocomial bloodstream infections in 49 US hospitals:

5. Download from www.cancidas.aewww.cancidas.ae 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. 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. 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 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 Neutropenic Cancer Transplantation Broad spectrum anti-anaerobic antibiotic use Prior vancomycin use Immunocompromised state Surgery Indwelling catheters

6. Download from www.cancidas.aewww.cancidas.ae Candidemia in Neutropenic Patients with Cancer: Clinical Characteristics* 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 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 % 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. *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. Neutropenic (n=217) 0 0 100 50 56% 3% 39% 63% 98% 90% 89%

7. Download from www.cancidas.aewww.cancidas.ae Candidemia in Non-Neutropenic Patients with Cancer: Clinical Characteristics* *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. *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. 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 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 % with clinical characteristic Non-Neutropenic (n=257) 0 0 100 50 23% 29% 52% 61% 49% 80% 88%

8. Download from www.cancidas.aewww.cancidas.ae Kartsonis NA. Presented at the 12 th European Congress of Clinical Microbiology and Infectious Diseases. April 24-27, 2002. Milan, Italy. Caspofungin: New Class of Drug Nucleoside Analogs  -(1,3)-D-glucan Ergosterol Polyenes Azoles Ergosterol Polyenes Azoles Phospholipid bilayer of the fungal cell membrane Phospholipid bilayer of the fungal cell membrane Fungal cell wall  -(1,6)-glucan  -(1,3)-D-glucan synthase Glucan Synthesis Inhibitor  -(1,3)-D-glucan synthase Glucan Synthesis Inhibitor nucleus Breakthrough Mechanism of Action: Targets the Pathogen, Not the Patient

9. Download from www.cancidas.aewww.cancidas.ae Caspofungin: Broad Spectrum of Activity Data on file, MSD; Bartizal K, Gill CJ, Abruzzo GK et al Antimicrob Agents Chemother 1997;41:2326-2332. C. albicans C. glabrata CANDIDA ALBICANS C. parapsilosis C. tropicalis C. krusei C. guilliermondii C. lipolytica C. dubliniensis C. kefyr C. lusitaniae C. rugosa A. flavus A. fumigatus A. terreus A. niger A. nidulans CANDIDA NON-ALBICANS ASPERGILLUS Expanded Spectrum of In Vitro Activity C. pseudotropicalis

10. Download from www.cancidas.aewww.cancidas.ae 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 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.

11. Download from www.cancidas.aewww.cancidas.ae 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 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.

12. Download from www.cancidas.aewww.cancidas.ae 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 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.

13. Download from www.cancidas.aewww.cancidas.ae 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.

14. Download from www.cancidas.aewww.cancidas.ae 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 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/day non-neutropenic patients 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/day non-neutropenic patients Data on file, MSD.

15. Download from www.cancidas.aewww.cancidas.ae Study treatment course (at least 10 days of IV study therapy; switch to oral fluconazole possible after day 10) Protocol 014: Study Design Flow Chart Kartsonis NA. Presented at the 12 th European Congress of Clinical Microbiology and Infectious Diseases. April 24-27, 2002. Milan, Italy. Start of IV study therapy Positive culture collected < 4 days Last positive culture End of treatment course 2-week post-therapy follow-up 6- to 8-week post-therapy follow-up 14 days Day 10 of IV Rx End of all antifungal Rx End of IV Study Rx 2-week follow-up 6- to 8-week follow-up Primary Efficacy Time Point Secondary Efficacy Time Points

16. Download from www.cancidas.aewww.cancidas.ae 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 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.

17. Download from www.cancidas.aewww.cancidas.ae 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 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.

18. Download from www.cancidas.aewww.cancidas.ae Protocol 014: Caspofungin Demonstrates Comparable Efficacy Results in MITT Group Caspofungin 80/109 Caspofungin 80/109 Perfect J. Presented at the 12 th European Congress of Clinical Microbiology and Infectious Diseases. April 24-27, 2002. Milan, Italy; Data on file, MSD. 0 0 10 20 30 40 50 60 70 80 90 73.4% 61.7% Amphotericin B 71/115 Amphotericin B 71/115 100 MITT (n=224) p=0.0861 MITT (n=224) p=0.0861 Percentage Overall Response at End of IV Therapy (test of cure)

19. Download from www.cancidas.aewww.cancidas.ae Protocol 014: Caspofungin Appeared to Have Efficacy vs. Amphotericin B in Evaluable Patients Analysis* *Evaluable patients analysis was a secondary analysis. Perfect J. Presented at the 12 th European Congress of Clinical Microbiology and Infectious Diseases. April 24-27, 2002. Milan, Italy; Data on file, MSD. *Evaluable patients analysis was a secondary analysis. Perfect J. Presented at the 12 th European Congress of Clinical Microbiology and Infectious Diseases. April 24-27, 2002. Milan, Italy; Data on file, MSD. Caspofungin 71/88 Caspofungin 71/88 0 0 10 20 30 40 50 60 70 80 90 80.7% 64.9% Amphotericin B 63/97 Amphotericin B 63/97 100 Percentage EP (n=185) p=0.0346 EP (n=185) p=0.0346 Overall Response at End of IV Therapy (test of cure)

20. Download from www.cancidas.aewww.cancidas.ae Protocol 014: Caspofungin Demonstrates Similar Efficacy vs. Amphotericin B in Candidemia Caspofungin Data on file, MSD. 0 0 10 20 30 40 50 60 70 80 90 72.5% 62.5% Amphotericin B 100 Percentage of Patients n=92 n=94

21. Download from www.cancidas.aewww.cancidas.ae Protocol 014: Time to First Negative Blood Culture Percentage Perfect J. Presented at the 12 th European Congress of Clinical Microbiology and Infectious Diseases. April 24-27, 2002. Milan, Italy. 0123456789101112131415161718192021222324 0 10 20 30 40 50 60 70 80 90 100 Study Day Caspofungin Amphotericin B Day 4 19.6%19.1% Day 712.0%9.0% Day 96.5%6.4% Caspofungin Amphotericin B Day 4 19.6%19.1% Day 712.0%9.0% Day 96.5%6.4% Caspofungin (n=92) Amphotericin B (n=94)

22. Download from www.cancidas.aewww.cancidas.ae Protocol 014: Failure or Relapse Rates Perfect J. Presented at the 12 th European Congress of Clinical Microbiology and Infectious Diseases. April 24-27, 2002. Milan, Italy. 0 0 10 20 30 40 26.6% 6.4% 50 Failure (End of IV study therapy) Failure (End of IV study therapy) 38.2% 7.0% 2.7% 16.5% Relapse (6–8 weeks post-Rx) Relapse (6–8 weeks post-Rx) Toxicity requiring additional treatment p=0.0277 Toxicity requiring additional treatment p=0.0277 Caspofungin (n=109) 70/50 mg Amphotericin B (n=115) 0.6–1.0 mg/kg Caspofungin (n=109) 70/50 mg Amphotericin B (n=115) 0.6–1.0 mg/kg

23. Download from www.cancidas.aewww.cancidas.ae Protocol 014: Mortality Assessment * 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 12 th European Congress of Clinical Microbiology and Infectious Diseases. April 24-27, 2002. Milan, Italy. * 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 12 th European Congress of Clinical Microbiology and Infectious Diseases. April 24-27, 2002. Milan, Italy. Crude Mortality** (p=0.528) Crude Mortality** (p=0.528) 0 0 10 20 30 40 4.4% 34.2% 50 30.4% 7.2% Caspofungin 70/50 mg Amphotericin B 0.6–1.0 mg/kg Caspofungin 70/50 mg Amphotericin B 0.6–1.0 mg/kg Attributable Mortality* (p=0.566) Attributable Mortality* (p=0.566)

24. Download from www.cancidas.aewww.cancidas.ae Protocol 014: Caspofungin Demonstrates a Favorable Safety Profile vs. Amphotericin B* AE=adverse event. Data on file, MSD. AE=adverse event. Data on file, MSD. 0 0 10 20 30 40 50 60 70 80 90 100 Percentage of Patients 42.1% 75.2% 2.6% 23.2% 20.2% 48.8% 11.4% 26.4% 8.4% 24.8% All drug-related AEs Infusion- related systemic AEs Drug-related discontinuations due to AEs Hypokalemia requiring potassium treatment Nephrotoxicity 48/114 94/125 3/114 29/125 23/114 61/125 13/114 33/125 8/95 26/105 *All p values were <0.03; 95% CI for relative risk of caspofungin vs. amphotericin B was <1. Caspofungin 70/50 mg Amphotericin B 0.6–1.0 mg/kg Caspofungin 70/50 mg Amphotericin B 0.6–1.0 mg/kg

25. Download from www.cancidas.aewww.cancidas.ae 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 30% (212) of 707 amphotericin B–treated patients: acute renal failure (ARF) High mortality rate: 27% of 707 amphotericin B patients 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. 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. Patients with acute renal failure 16% 54% 50 40 30 20 10 0 0 100 90 80 70 60 Patients without ARF n=707 79/495 115/212

26. Download from www.cancidas.aewww.cancidas.ae 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 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.

27. Download from www.cancidas.aewww.cancidas.ae 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 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.

28. Download from www.cancidas.aewww.cancidas.ae 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* 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. *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.

29. Download from www.cancidas.aewww.cancidas.ae 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 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.

30. Download from www.cancidas.aewww.cancidas.ae References

31. Download from www.cancidas.aewww.cancidas.ae References