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Epidemiological Data

Epidemiological Data. Invasive Fungal Infections. Invasive fungal infections account for considerable morbidity and mortality Risk factors Stem cell/organ transplants Cancer HIV/AIDS Intensive care unit patients Elderly patients Broad-spectrum antibiotic administration.

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Epidemiological Data

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  1. Epidemiological Data

  2. Invasive Fungal Infections • Invasive fungal infections account for considerable morbidity and mortality • Risk factors • Stem cell/organ transplants • Cancer • HIV/AIDS • Intensive care unit patients • Elderly patients • Broad-spectrum antibiotic administration

  3. Invasive Aspergillosis Patient group No. of cases Percent crude mortality, mean Pulmonary aspergillosis Bone marrow transplantation 254 90 Leukaemia, neutropenia, and aplastic anaemia 407 77 Renal transplantation 63 70 Heart transplantation 64 50 Lung transplantation 13 77 Liver transplantation 61 93 AIDS 115 81 Aspergillus rhinosinusitis Leukaemia, neutropenia, and bone marrow transplantation 90 66 Cerebral aspergillosis Immunocompromised 141 99 Nonimmunocompromised 15 13 Denning DW. Clin Infect Dis. 1996;23:608-615.

  4. Invasive Candidemia Infecting pathogen No. of cancer patients Percent crude mortality Overall 30-day mortality rate 249 39 Overall mortality Candida glabrata 23 61 Candida tropicalis 28 50 Candida krusei 22 45 Candida albicans 121 40 Candida parapsilosis 28 18 Other 26 19 Viscoli C, et al. Clin Infect Dis. 1999;28:1071-1079.

  5. AmBisome®Liposomal Amphotericin B for the Treatment of Life-Threatening Invasive Fungal Infections

  6. H OH OH H3C O H H OH O H OH H OH CH3 H OH H OH O H HO COOH H H H H OH H3C H NH2 H O OH O CH3 H H Conventional Amphotericin B AmBisome Summary of Product Characteristics. Cambridge, UK; 2001.

  7. Conventional Amphotericin B • Polyene antibiotic commercially available since the 1950s • Broad-spectrum of activity against yeasts and moulds1,2 • Affinity for ergosterol in fungal cell membranes • Affinity for cholesterol in mammalian cells results in toxicity 1Ellis D. J Antimicrob Chemother. 2002;49(suppl 1):7-10.2AmBisome Summary of Product Characteristics. Cambridge, UK; 2001.

  8. Lipid Formulations of Amphotericin B

  9. Lipid Formulationsof Amphotericin B • AmBisome®: liposomalamphotericin B • amphotericin Blipid complex • amphotericin B colloidal dispersion Hiemenz JW, et al. Clin Infect Dis. 1996;22(suppl 2):S133-S144.

  10. Amphotericin B Formulations Formulation Carrier1 Colloidal type1 Diameter, nm2,3 CAB Sodium deoxycholate Micelle < 25 AmBisome® DSPG* liposome Unilamellar 60 - 70 amphotericin B lipid complex DMC†/ DMPG‡structures Ribbon-like 1,600 - 11,000 amphotericin B colloidaldispersion Cholesteryl sulfate Disk-shaped complex 120 - 140 CAB = Conventional amphotericin B.* Distearoylphosphatidylglycerol.† Dimyristoylphosphatidylcholine.‡ Dimyristoylphosphatidylglycerol. 1. Khoo SH et al. J Antimicrob Chemother. 1994;33:203-213.2. Hiemenz JW, et al. Clin Infect Dis. 1996;22(suppl 2):S133-S144.3. Tripple M, et al. Am Rev Respir Dis. 1977;115:879-881.

  11. Murine LD50 200 AmBisome® 150 AmBisome had highest LD50,> 3-fold higher than the next-best lipid formulation 100 amphotericin B lipid complex 50 amphotericin B colloidal dispersion LD50, mg/kg CAB 0 CAB = Conventional amphotericin B. Viviani MA, et al. Infection. 1994;22:137-142.

  12. AmBisome® Structure, Function, and Mechanism of action

  13. AmBisome® Components Amount, mg Amphotericin B 50 Sucrose 900 Hydrogenated soy phosphatidylcholine 213 Distearoylphosphatidylglycerol 84 Cholesterol 52 Disodium succinate hexahydrate 27 -tocopherol 0.64 AmBisome Summary of Product Characteristics. Cambridge, UK; 2001.

  14. AmBisome® Schematic Representation Amphotericin B + + Hydrophilic region - - OH OH OH OH OH OH OH OH Hydrophilic region Hydrophobicregion OH OH OH OH - - OH OH + + Hydrophilic region OH OH Cholesterol Adler-Moore J, et al. J Antimicrob Chemother. 2002;49(suppl 1):21-30.

  15. An optimized delivery Infection site Direct diffusion due tocapillary permeability AmBisome® (1, 2) Monocytemigration Active accumulationin blood monocytes • A double mode of action • A fungicidal activity both on intracellular andextracellular agents • A significant tissue concentration in infection sites Hillery. Advanced Drug Delivery Rev 1997. Boswell. J Clin Pharmacol 1998. Janknegt. Clin Pharmacokinet 1992.

  16. Phospholipidbilayer Amphotericin Bmolecules AmBisome®Drug Delivery System • Amphotericin B intercalated within the phospholipid bilayer 1 • Negatively charged external surface increases affinity for fungal cells • Transition temperature(> 37°C) of the phospholipid components and addition of cholesterol contribute to liposome stability in vivo 2 • Amphotericin B molecules remain in liposomal bilayer rather than being released • Reduced exposure to free amphotericin B explains, in part, the lowered toxicity of AmBisome 2,3 1. Adapted from Hiemenz JW, et al. Clin Infect Dis. 1996;22(suppl 2):S133-S144.2. Adler-Moore J, et al. J Antimicrob Chemother. 2002;49(suppl 1):21-30.3. Boswell GW, et al. J Clin Pharmacol. 1998;38:583-592.

  17. Freeze fracture preparation of the yeast, Candida glabrata, incubated for four hours at 37 °C with AmBisome. Jill Adler-Moore, BMT,1994, 14 (suppl.5): S3-S7

  18. L L L Liposome Aggregation Around Fungal Cell Wall Surface Gold-labeled liposomes (L) lacking active drug Reproduced with permission fromAdler-Moore J. Bone Marrow Transplant. 1994;14(suppl 5):S3-S7.

  19. L L L AmBisome® Disrupts Integrityof Fungal Cell Membrane Gold-labeled lipid material (L) visible within cytoplasm Reproduced with permission fromAdler-Moore J. Bone Marrow Transplant. 1994;14(suppl 5):S3-S7.

  20. AmBisome® Pharmacokinetics

  21. AmBisome®Preclinical Pharmacokinetics Species Dose(mg/kg) Cmax(mg/L) AUC0-(µg•h/mL) Rat 1 7.2 64 3 30.3 374 9 141.3 1,136 Rabbit 2.5 53 207 5 132 838 10 287 2,223 Dog 1 1.9 11 4 18 164 8 72 986 Adler-Moore J, et al. J Antimicrob Chemother. 2002;49(suppl 1):21-30.

  22. AmBisome®Pharmacokinetics • Nonlinear pharmacokinetics at doses ranging from 1 to 15 mg/kg/day 1,2 • Consistent with reticuloendothelial uptakeand drug redistribution • Maximal AUC and Cmax occurs at 10 mg/kg/day 1 • Differential tissue uptake-drug accumulates in macrophages in reticuloendothelial system-related organs (eg, liver, spleen) 3,4 • With increasing doses, drug preferentially accumulates in non-RES tissues such as lung 4,5 1. Walsh TJ, et al. Antimicrob Agents Chemother. 2001;45:3487-3496. 2. Walsh TJ, et al. Antimicrob Agents Chemother. 1998;42:2391-2398. 3. Lee JW, et al. Antimicrob Agents Chemother. 1994;38:713-718. 4. Proffitt RT, et al. J Antimicrob Chemother. 1991;28(suppl B):49-61.5. Adler-Moore J, et al. J Antimicrob Chemother. 2002;49(suppl 1):21-30.

  23. AmBisome® Pharmacokinetic behaviour compared to conventional treatment and lipid formulations • AmBisome shows: • higher Cmax and AUC values • lower distribution • decreased clearance Fraschini F. et al., Hosp. Man., 19 (140) 3-10, 1998 - Hiemenz J.M. and Walsh T.J., Clin. Inf. Dis., 22, (2). 133-144; 1996 – Couckell A. and Brogden N., Drugs, 55 (4): 585-612, 1998 – Scaglione F. Gullo A., GRAM, 3-39, 1999 - Walsh T.J. et al., Ant.. Ag. Chem., 42: 2391-2398, 1998 - Heinemann V. et al., Ant. Ag. Chem.,Vol. 41, N°6, 1275-80, June 1997 - B.M.T. 14 (Suppl. 5): S8-S9, 1994 - Kintzel P. E., Pharmacy Practice News, 1997 - Jankgnegt R. et al., Clin. Pharmacokinet. (4): 279-291, 1992

  24. AmBisome® Pharmacokinetic behaviour compared to conventional treatment and lipid formulations Drug Cmaxmean value, mg/L(dose in mg/kg) Vdssmean value, L/kg(dose in mg/kg) Clearancemean value, mg/h•L(dose in mg/kg) AUCmean value, mg/h•L(dose in mg/kg) DAmB 0,98 (0,25) 2,9 (0,68) 4 (1,0) 0,76 (0,68) 0,43 (1,0) 0,76 (0,68) 8,6 (0,25) — — AmBisome 7,3 (1,0) 17,2 (2,5) 57,6 (5,0) Increased* 0,58 (1,0) 0,69 (2,5) 0,22 (5,0) Decreased* 0,27 (1,0) 0,33 (2,5) 0,17 (5,0) Decreased* 69 (1,0) 206 (2,5) 713 (5,0) Increased* ABLC 0,27 (0,5) 1,10 (2,5) Decreased* 3,9 (0,5) ND Similar* 1,3 (0,5) 3,6 (2,5) Increased* 2,8 (0,5) 8,9 (2,5) Decreased* ABCD 0,84 (0,5) 2,19 (1,0) 2,53 (1,5) Decreased* 5,7 (0,5) 7,2 (1,0) 7,9 (1,5) Increased* 0,42 (0,5) 0,36 (1,0) 0,47 (1,5) Similar* 21 (0,5) 46 (1,0) 57 (1,5) Decreased* Vdss: steady state distribution volume; AUC: under the curve area;* vs DAmB value; DAmB: amphotericin B deoxycholate;ABCD: amphotericin B colloidal dispersion; ABLC: amphotericin B lipid complex

  25. AmBisome® and conventional amphotericin B tissue concentrations Recovered amphotericin B (% of total dose) amphotericin B(6 cases)average cumulativedose of 1,3 g AmBisome(3 cases)*average cumulativedose of 1,7 g Liver 26,2 18,3 Spleen 1,0 3,0 Kidney 0,8 0,3 Lung 3,1 0,6 Heart 0,1 0,1 Brain (1 pt) — 0,1 Thyroid (1 pt) — 0,01 * Data obtained in non infected tissues. Inflammation may changedrug kinetics and distribution. RINGDEN O. et al.; J. Antim. Chem., 28 supp B: 73-82; 1991 CHRISTIANSEN K.J. et al.; J. Infect. Dis., 152 (5): 1037-1043, 1985

  26. The power to deliver high brain tissue levels Mean brain tissue levels 4 to 7 times higher* ABCD† 0.30 µg/g ABLC† 0.36 µg/g CAB† 0.53 µg/g AmBisome®† 2.33** µg/g ** p < 0.005 vs. CAB, ABLC, ABCD * In non-infected rabbits, in the absence of meningocerebral inflammation. † AmBisome 5 mg/kg/day x 7 days (n=5), CAB (Amphotericin B) 1 mg/kg/day x 7 days (n=5), ABLC (Amphotericin B Lipid Complex) 5 mg/kg/day x 7 days (n=4), ABCD (Amphotericin B Colloidal Dispersion) 5 mg/kg/day x 7 days (n=4). Groll A, Giri N, Gonzalez C, et al. Proc. 37th ICAAC, 1997. Abstract A-90.

  27. AmBisome® MaximumTolerated Dose (MTD) Study • Study design • 44 immunocompromised patients with Aspergillus, Fusarium, or Zygomycetes infections • AmBisome: 7.5, 10.0, 12.5, and 15.0 mg/kg/day • Evaluated pharmacokinetics, safety, and tolerability Walsh TJ, et al. Antimicrob Agents Chemother. 2001;45:3487-3496.

  28. AmBisome®MTD Study (2) • Pharmacokinetics • Nonlinear pharmacokinetics over dose range of 7.5 to 15 mg/kg/day • Cmax and AUC reached maximal values at a dose of 10 mg/kg/day Day 1 Dosage (mg/kg/day) n Cmax(mg/mL) AUC0-24(µg•h/mL) 7.5 8 76 692 10 7 120 1,062 12.5 7 116 860 15 11 105 554 MTD = Maximum tolerated dose. Walsh TJ, et al. Antimicrob Agents Chemother. 2001;45:3487-3496.

  29. AmBisome®MTD Study (3) • MTD was not reached with doses upto 15 mg/kg/day • Drug was well tolerated at all 4 dosing regimens • No dose-related differences observed for • Nephrotoxicity* • Infusion-related reactions • Drug discontinuations because of adverse events • Hepatotoxicity • Anaemia • Severe hypokalaemia observed at 12.5- and 15-mg/kg/day dose levels (9 of 26 [35%] patients) * Serum creatinine  2.0 × baseline.MTD = Maximum tolerated dose. Walsh TJ, et al. Antimicrob Agents Chemother. 2001;45:3487-3496.

  30. AmBisome®Clinical Experience • > 2,400 patients treated with AmBisome in sponsored clinical trials • Including > 400 paediatric (< 18 years old) patients • Since first licensed in 1991, over 226,000 patients have been treated with commercially supplied AmBisome Data on File. Gilead Sciences International, Ltd. Cambridge, UK. 2002.

  31. Efficacy

  32. AmBisome®Indications* • Treatment (primary or secondary) of patients with documented invasive fungal infections (eg, Candida, Aspergillus and other filamentous fungi, and Cryptococcus spp) • Patients refractory to CAB or in whom renal impairment or unacceptable toxicity precludes the use of CAB • Empiric therapy for presumed fungal infection in febrile neutropenic patients • Treatment of cryptococcal meningitisin HIV-infected patients • Treatment of visceral leishmaniasis *Composite of worldwide licensed indications.CAB = Conventional amphotericin B.

  33. In Vitro Activity MIC or MFC, µg/mL Species (isolates) Drug MIC50 MIC90 MFC90 Aspergillus spp. (13) CAB AmBisome® 2.50 1.25 2.50 1.25 — — Candidaalbicans (32) CAB AmBisome 1.25 0.62 1.25 0.62 1.25 1.25 Candidaparapsilosis (20) CAB AmBisome 1.25 0.62 1.25 0.62 2.50 2.50 Candidatropicalis (20) CAB AmBisome 1.25 0.62 1.25 0.62 2.50 1.25 Cryptococcus neoformans (32) CAB AmBisome 0.62 0.31 1.25 0.62 2.50 1.25 Fusarium spp. (8) CAB AmBisome 2.50 2.50 2.50 2.50 — — CAB = Conventional amphotericin B; — = No data available. Anaissie E, et al. Eur J Clin Microbiol Infect Dis. 1991;10:665-668.

  34. AMB FCZ ITZ VZ PCZ RCZ CF MF AF FungiCandida albicans Candida tropicalis Candida parapsilosis Candida krusei Candida glabrata Cryptococcus neoformans Aspergillus fumigatus Mucor spp Rhizopus spp Fusarium spp Moulds Polyene; AMB = AmBisome® Azole; FCZ = Fluconazole; ITZ = Itraconazole; VZ = Voriconazole;PCZ = Posaconazole; RCZ = Ravconazole Echinocandin; CF = Caspofungin; MF = Micafungin; AF = Anidulafungin Range of Activity forSelected Pathogens Adapted from JP Donnelly by Malcolm Richardson. Presented at: New Challenges and New Options in the Treatment of Invasive Fungal Infections in Stem Cell Transplant Patients, a Satellite Symposium at the 20th Annual Meeting of the EBMT; March 24, 2002; Montreux, Switzerland.

  35. Efficacy in Documented Invasive Fungal Infections

  36. AmBisome® Efficacyin Invasive Aspergillosis Randomised Leenders AC, et al 1 Ellis M, et al 2 CAB1 mg/kg/dayn = 29 AmBisome5 mg/kg/dayn = 26 AmBisome1 or 4 mg/kg/dayn = 87 Response, % 59 69 55 Survival, % 62* 81* 37† CAB = Conventional amphotericin B.* Overall survival.† Survival at 6 months. 1. Leenders AC, et al. Br J Haematol. 1998;103:205-212.2. Ellis M, et al. Clin Infect Dis. 1998;27:1406-1412.

  37. AmBisome® Efficacy inInvasive Aspergillosis (2) • 6 additional reports including open-label trials and retrospective analyses 1-6 supporting the findings of Leenders 7and Ellis 8 • 188 evaluable patients • Response rates ranged from 43% to 70% (weighted averages) • Survival rates ranged from 46% to 70%1, 2, 6 1. Walsh TJ, et al. Antimicrob Agents Chemother. 2001;45:3487-3496.2. Mills W, et al. Br J Haematol. 1994;86:754-760.3. Buell D, et al. Presented at: Focus on Fungal Infections. 1998. Abstract 026.4. Ringden O, et al. J Antimicrob Chemother. 1991;28(suppl B):73-82.5. Tollemar J, et al. Drug Invest. 1992;4:232-238.6. Ng TTC, et al. Arch Intern Med 1995;155:1093-1098.7. Leenders AC, et al. Br J Haematol. 1998;103:205-212.8. Ellis M, et al. Clin Infect Dis. 1998;27:1406-1412.

  38. AmBisome® Efficacyin Invasive Aspergillosis Reference Design (dose) Patients, n Response, % Survival, % Leenders AC,et al. 1998 Randomised, open, vs CAB (5 mg/kg) 26 69 81 Ellis M, et al.1998 Randomised(1 vs 4 mg/kg) 87 55 37 Walsh TJ, et al.2001 Open, MTD(7.5 - 15 mg/kg) 44 43 46 Mills W, et al.1994 Retrospective,2nd-line (NR) 57 56 70 Buell D, et al. 1998 Open, 2nd-line (NR) 27 70 NR Ringden O, et al.1991 Open, 2nd-line (0.5 - 5 mg/kg) 32 66 NR Tollemar J, et al.1992 Open, 2nd-line(0.5 - 4 mg/kg) 18 61 NR Ng TTC, et al.1995 Retrospective(0.4 - 5 mg/kg) 17 59 65 CAB = Conventional amphotericin B; MTD = Maximum tolerated dose;NR = Not reported.

  39. Lipid Preparations:Efficacy in Invasive Aspergillosis 61 46 34 ® n = 84 n = 163 n = 32 Ostrosky-Zeichner L. Update on lipid-polyene formulations.Presented at: Focus on Fungal Infections 12; March 20-22, 2002; Phoenix, AZ.

  40. Success in infections failingto respond to prior amphotericin B therapy In provenCandida infections… 84% 100% Having failed priorlipid therapy… 71% Ringden O et al. J Antimicrob Chemother 991;28(Suppl B):73-82. Chopra R et al. Leuk Lymphoma 1992;7:73-77. Buell D et al. Proceedings of Focus on Fungal Infections, March 1998. Abstract 26.

  41. AmBisome® Efficacy in Invasive Candidiasis 4 1-3 n = 70 n = 103 CAB = Conventional amphotericin B. *Complete or partial response in patients with proven or probable infection. 1. Ringden O, et al. J Antimicrob Chemother. 1991;28(suppl B):73-82.2. Ng TTC, et al. Arch Intern Med. 1995;155:1093-1098. 3. Tollemar J, et al. Drug Invest. 1992;4:232-238.4. Rex JH, et al. N Engl J Med. 1994;331:1325-1330.

  42. AmBisome®Efficacy in Cryptococcosis CAB = Conventional amphotericin B. Hamill RJ, et al. Abstracts of the 39th ICAAC. September 1999:489. Abstract 1161.

  43. Success in invasive infections Earlier CSF culture conversion in patients withAIDS-associated cryptococcal meningitis Within 7 days - 40% Within 14 days - AmBisome® * 67% Within 21 days - 73% Within 7 days - 8% Within 14 days - Amphotericin B* 11% Within 21 days - 38% *AmBisome 4 mg/kg/day x 3 weeks (n=15), amphotericin B 0.7 mg/kg/day x 3 weeks (n=13)

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