Recent advances in the treatment of IFIs Newer antifungals: what s in the pipeline

Recent advances in the treatment of IFIs Newer antifungals: what s in the pipeline George Petrikkos, MD, Professor of Internal Medicine and Infectious Diseases National and Kapodistrian University of Athens Greece petrikos@hol.gr

The History of Antifungals 1950s Nystatin Amphotericin B Griseofulvin 1990s Fluconazole Itraconazole caps Itraconazole soln Terbinafine Lipid Ampho 1960s Miconazole Clotrimazole 2000s Caspofungin Voriconazole Posaconazole Anidulafungin Micafungin 1970s Flucytosine 1980s Ketoconazole 2010s Isavuconazol Ravuconazol Albaconazol Aminocandin ets

The ideal antifungal agent Broad spectrum of activity (yeasts and filamentous fungi) Rapidly and highly fungicidal, stable to resistance Potent in vivo activity (even in neutropenia) Both oral and parenteral formulations Low toxicity, minimal drug-drug interactions Good pharmacokinetics (AUC) Good penetration into all tissue compartments Cost effective HEM/00223M

DRUG Νew azoles INITIAL APPROVAL FROM EMEA LAST REVISION OF APROVED INDICATIONS VORICONAZOLE 2002 2005 POSACONAZOLE 2005 2006 RAVUCONAZOLE ISABUCONAZOLE ALBACONAZOLE Announced a few years ago but without new data beyond limited information of Phase I/II studies

OUTLINE Νew azoles Overview of characteristics and new data about the new azoles: Spectrum, Efficacy, Pharmacology Advantages and disadvantages from their profile and new data

Νew azoles : Pharmacology Voriconazole Posaconazole Parent drug Fluconazole Itraconazole Formulation IV, Oral Oral Bioavailability 90% 8-47% Administration with food, fat, beverage NO (empty stomach) YES Saturated absorption NO YES Loading dose YES NO pharmacokinetic nonlinear linear Daily dose 3-6 mg/kg bid 800 mg in divided doses

Νew azoles : Pharmacology Voriconazole Posaconazole Protein binding 58% 99% Half life 6h 25 31 h Volume of distribution 2-4.6 L 343-1341 L CSF penetration YES YES Dose adjustment in renal failure Dose adjustment in liver failure Variability in levels (NEED FOR TDM) Time to steady state YES (only the IV form) YES YES 3-5 d (1d with loading dose) NO NO YES 7d

Nausea, vomiting diarrhoea Νew azoles : Safety Voriconazole Posaconazole - 8-18% Hepatotoxicity 10-23% 2-3% Skin rash 5% - Visual disturbances 1-30% - Headache - 5-17% QT prolongation rare rare JAC 2010;65:410-6, Drugs 2008;68:993

Candida spp (FLU R) Aspergillus spp Cryptococcus sp Δραστικότητα έναντι: Endemic fungi (Histoplasma, Blastomyces, Coccidioedomyces) Fusarium Scedosporium sp Zygomycetes NEW AZOLES: SPECTRUM phaehyphomycetes Dermatophytes EXTENDED FOR BOTH VORICONAZOLE IS NOT ACTIVE

ALL Aspergillus(372) ALL Filamentous(448) A. fumigatus (256) AMB ITRA VORI POSA CAS 1 1 0.5 0.25 0.06 2 2 1 1 0.12 1 2 0.5 0.5 0.06 A. flavus (30) 2 1 1 0.5 0.06 A. terreus (16) 2 0.5 1 0.25 0.06 A. niger (29) 1 2 2 1 0.03 A. versicolor (20) 2 2 1 1 0.12 Penicillium sp (35) New azoles: in vitro activity against hyphomycetes(εcv) MIC90 (mg/l) 2 2 2 1 0.12 Fusarium sp (11) 2 >8 >8 >8 >8 Diekema DJ, et al. J Clin Microbiol 2003; 41: 3623-6

CLSI 2011 Clinical breakpoints for azoles against Candida sp (MIC: mg/l) C. C. C. C. C. albicans tropicalis parapsilosis glabrata krusei fluconazole >4 >4 >4 >32 R itraconazole >0.5 >0.5 >0.5 >0.5 >0.5 voriconazole >2 >2 >2 >2 >2 posaconazole >2 >2 >2 >2 >2 Diagn Microbiol Infect Dis 2011;69: 45 50

SENTRY PROGRAM 2009. 884 Candida blood isolates Resistance rates to azoles C. albicans (422) C. glabrata (159) C. Parapsilosis (162) C. tropicalis (93) FLU ITR VORI POSA 0% 0.2% 0% 0% 2.5% 39 % 2.5 % 3.8% 6.8% 0% 0% 0% 3.2% 3.2% 1.1% 1.1% C. krusei (16) - 43.8 % 0% 0% Diagn Microbiol Infect Dis 2011;69: 45 50

Voriconazole : Clinical Indications Treatment of choice for IFD due to Aspergillus Step down therapy for candida infections due to Fluconazole-resistant strains difficult mold infections like fusariosis and scedosporiosis Nor proved non inferior to AMB in empric antifungal treatment of neutropenic fever Increased use related to increase in zygomycosis against which is not effective Cross resistance (30%) to fluconazole IJAA 2007; 108-117, Infect Drug Res 2011;44-53

Posaconazole : Clinical Indications 200mg X3 Prophylaxis of IFD in high risk hematology patients (HSCT, AML/MDS with severe and prolonged neutropenia (<100 pmn for >7d) In two randomised, multicentre studies PCZ was shown to be superior to FLC in preventing death from invasive fungal disease in highly immunosuppressed patients, and this effect was principally due to reducing infections from Aspergillus spp. NEJM 2007; 356; 335/348

Posaconazole : Clinical Indications refractory oropharyngeal or esophageal candidiasis in immunocompromised patients Salvage therapy of refractory IFD due to various fungi (aspergillosis, fusariosis, blastomycosis, coccidoidomycosis) Posaconazole has been shown effective as salvage treatment in zygomycosis though without approved indication yet. Oral formulation Not studied in Candidemia 800mg /d bid or qid IJAA 2007; 108-117, Infect Drug Res 2011;44-53

Νew azoles: Drug Interactions Azoles exhibit a wide range and a variety of drug-drug interactions. They are a substrate for and inhibitors cytochrome P450 (CYP450) enzymes and of membrane transporters such as P- glycoprotein (P-gp). In vivo no concrete relationship between P- gp and azoles has been established. CID 2009; 48: 1441-58 Infect Drug Res 2011;4:43-53 Br J Clin Pharmacol 2011;70:471-80

In Vivo Cytochrome P450 Inhibition Potential vs Azoles CYP3A4 CYP2C8/9 CYP2C19 Drug Inhibitor Substrate Inhibitor Substrate Inhibitor Substrate Fluconazole 2,3 Itraconazole 2,3,4 Ketoconazole 2,3,5 Voriconazole 3,6,7 Posaconazole 1 1. Wexler D et al. Eur J Pharm Sci. 2004;21:645-653. 2. Cupp MJ et al. Am Fam Phys. 1998;57:107-116. 3. Drug interactions. Med Letter. 2003;45(W1158B):46-48. 4. Sporanox IV [summary of product characteristics]. Bucks, UK; Janssen-Cilag Ltd; 2005. 5. Nizoral tablets [summary of product characteristics]. Bucks, UK; Janssen-Cilag Ltd; 2001. 6. Hyland R et al. Drug Metab Dispos. 2003;31:540-547. 7. VFEND [summary of product characteristics]. Kent, UK; Pfizer Ltd; 2005.

Νew azoles: Drug Interactions VORICONAZOLE CARBAMAZEPINE LA BARBITURATES RIFAMPIN ASTEMIZOLE CIZAPRIDE ERGOT ALKALOIDS QUINIDINE SIROLIMUS TERFENADINE DRUGS NEEDING MONITORING AND DOSAGE MODIF.: Cyclosporine, Tacrolimus, omeprazole, Warfarin, Phenytoin, Efavirenz POSACONAZOLE RIFAMPIN ASTEMIZOLE CIZAPRIDE ERGOTAMINE QUINIDINE SIROLIMUS, CIMETDINE TERFENADINE Phenytoin, Tacrolimus, cyclosporine

Νew azoles:therapeutic Drug Monitoring (TDM) Voriconazole concentrations in serum may vary up to 100- fold from one patient to the next or within an individual patient depending on age, drug dose, concurrent illness, underlying liver function, drug-drug interactions, or genetic polymorphisms affecting cytochrome CYP2C19-mediated metabolism Posaconazole also exhibits intrapatient and interpatient pharmacokinetic variability mostly due to variability in absorption The therapeutic and toxicity profile has been related to drug levels Montoring of new azole levels is emerging as a necessity

Νew azoles:therapeutic Drug Monitoring (TDM) Therapeutic target failure more often when stepdown to oral treatment Therapeutic window for voriconazole : 1-5.5 mg/l Liver and CNS toxicity related to levels >5.5mg/L PD: max probability of response with a troughc/mic of 2-5mg/L (proposed Pascual et al target CID 2008;46 for Matsumoto et al IJAA 2009;34 TDM) AAC 2011;55: 4782-8 AAC 2011;55:5172-7

Νew azoles:therapeutic Drug Monitoring (TDM) Trough concentrations of at least 0.5 1.5 mg/l appear to be warranted in patients with IFI measured 4 7 days after the start of therapy. Preliminary data (posaconazole as antifungal prophylaxis 200 mg tid) indicated a lower risk of proven or probable IFI in patients with plasma drug concentrations >0.7mg /L 3 5 h after drug administration on day 7 Antimicrob Agents Chemother 2009; 53: 24 34, Br J Clin Pharmacol

TDM may not be enough to explain the activity, effectiveness and propability of therapeutic success for posaconazole AAC 2010; 54:2928-31 Br J Clin Pharmacol 2011;70:471-80

Multi-azole-resistant A. fumigatus is present in the environment in Denmark. The resistance mechanism is identical to that of environmental isolates in the Netherlands. The TR/L98H mutation of cyp51a is responsible The risk of emerging azole resistant against Aspergillus with non-rational azole use, is real! AAC 2010; 54: 4545 Future Microbiol. 2011 Mar;6:335.

Echinocandins Formerly known as Pneumocandins due to activity against Pneumocystis carinii Rapidly fungicidal against most Candidae including azole-resistant strains Fungistatic against most Aspergillus spp Limited or no activity against Fusarium spp and Zygomycetes. No activity against Cryptococcus neoformans

In vitro activity 1 Minimum inhibitory concentrations of the echinocandins against Candida species Candida species Anidulafungin Micafungin* Caspofungin MIC50 (µg/ml) MIC90 (µg/ml) MIC50 (µg/ml) 1- Cappelletty D. et al. Reviews of therapeutics : the echinocandins Pharmacotherapy 2007, 27(3):369-388. MIC90 (µg/ml) MIC50 (µg/ml) albicans 0.03 0.03 0.015-0.03 0.03 0.03-0.5 0.06-1 glabrata 0.03 0.13 0.015-0.03 0.015-0.06 0.03-1 0.06-2 tropicalis 0.03 0.13 0.03 0.06 0.12-0.5 0.25-1 dubliniensis 0.03 0.06 0.03 0.033 0.25-0.5 0.5 krusei 0.06 0.13 0.06-0.13 0.06-0.25 0.12-2 0.25-2 lusitaniae 0.06 0.25 0.06 2 0.5-1 1-2 parapsilosis 2 2 1 2 1-2 1-4 guilliermondii ND 1 ND 0.5 2 -> 8 2 -> 8 MIC50 or MIC90 = minimum inhibitory concentration for 50% or 90%, respectively, of tested strains; ND = not done. * Micafungin has not yet been approved in the EU. MIC90 (µg/ml)

Echinocandins IV administration Long half life CNS penetration: poor Dose: once daily Little infusion related toxicity Little or no renal and hepatic toxicity Drug-drug interaction with cyclosporin Potential use in combination with other antifungals (AMB or azoles) Animal data suggest synergistic effect Commercially available Echinocandins Caspofungin Micafungin Anidulafungin

Pharmacokinetic profile of Echinocandins Anidulafungin Chemical Degradation * Micafungin has not yet been approved in the EU. Micafungin * Enzymatic Biotranformation Hepatic Metabolism Caspofungin Chemical Degradation Hepatic Metabolism Renal Elimination 1- ECALTA SPC. 2- Cancidas for Injection [package insert]. Whitehouse Station, NJ: Merck & Co, Inc. February 2005. 3- Mycamine for Injection [package insert]. Tokyo, Japan: Astellas Pharma, Inc. June 2006. 4- Balani S.K., Xu X., Arison B.H. et al. Metabolites of caspofungin acetate, a potent antifungal agent, in human plasma and urine. Drug Metab Dispos. 2000;28:1274-1278. 5- Raasch RH. Anidulafungin: review of a new echinocandin antifungal agent. Expert Rev Anti Infect Ther. 2004;2:499-508.

Caspofungin for the treatment of fungal infections: a systematic review of randomized controlled trials. Falagas ME, Ntziora F, Betsi GI, Samonis G, Int J Antimicrob Agents. 2007 Feb;29:136-43 Several RCTS have evaluated effectiveness of caspo vs other antifungals Six RCTs comparing caspo with ampb (deoxycholate in four, liposomal in one) or fluconazole (in one), withh a total of 1974 patients, were reviewed Success was achieved in 53% of the caspo-treated patients and in 45% of the ampb treated patients Discontinuation due toxicity was significantly less in caspo groop Caspofungin was associated with better clinical outcomes

Anidulafungin Molecular structure Anidulafungin is a derivative of the naturally occurring candin, echinocandin B, produced by Aspergillus nidulans 1 Echinocandins share a similar common nucleus of 6 amino acids, 2 but the key to their activity is a fatty acid side chain (circled area) attached at the N-terminus of the nucleus 1 Anidulafungin chemical structure 1- Ghannoum M., D Angelo M. Anidulafungin: potent antifungal that targets Candida and Aspergillus. Infect Dis Clin Pract. 2005;13(4):165-178. 2- Debono M., Turner W.W., LaGrandeur L. et al. Semisynthetic chemical modification of the antifungal lipopeptide echinocandin B (ECB): structure-activity studies of the lipophilic and geometric parameters of polyarylated acyl analogs of ECB. J Med Chem. 1995;38(17):3271-3281.

Pharmacokinetic profile (1) The long elimination half-life (~ 24 hours) of anidulafungin: allows for once-daily dosing 1 Anidulafungin undergoes a chemical non-enzymatic degradation to an inactive peptide and is then converted to peptidic degradants eliminated in faeces: 1 1- ECALTA SPC. Hepatic metabolism of anidulafungin has not been observed Anidulafungin is not an inducer nor an inhibitor of cytochrome P450 Anidulafungin has negligible renal clearance

Pharmacokinetic profile (2) Because of this specific pharmacokinetic profile of anidulafungin: 1 No dosage adjustments are required in patients with mild to severe hepatic insufficiency No dosage adjustments are required in patients with any degree of renal insufficiency It is unlikely that anidulafungin will have clinically relevant effect on drugs metabolized by the cytochrome P450 system Clinical studies have shown no clinically relevant interaction between anidulafungin and: Cyclosporine Voriconazole Tacrolimus AmBisome (liposomal amphotericin B) Rifampin No dosage adjustments are required in co-administration 1- ECALTA SPC.

Anidulafungin and Biofilms In an in vitro study, Anidulafugin was able to penetrate biofilms caused by C. albicans 1,2 In an in vitro study, Anidulafugin at concentrations of 1 μg/ml was able to reduce the amount of biofilm components seen on confocal microscopy 1 The clinical significance of these findings is not yet known 2 1- Ghannoum M., D Angelo M. Anidulafungin: a potent antifungal that targets Candida and Aspergillus. Infect Dis Clin Pract. 2005;13(4):165-178. 2- Schinabeck M.K., D Angelo M., Chandra J. et al. Anidulafungin inhibits Candida albicans biofilms in vitro [Abstract M-41]. Presented at: The 44th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC; October 30-November 2, 2004.

Anidulafungin Clinical data Anidulafungin vs Fluconazole Reboli A.C. et al. Anidulafungin versus Fluconazole for Invasive Candidiasis. N Engl J Med 2007;356:2472-82.

Treatments 1 Patients stratified by APACHE II score ( 20 and > 20) and Absolute neutrophil count ( 500 or > 500/mm 3 ) ECALTA (n=127) Loading dose: 200 mg Maintenance dose: 100 mg FLUCONAZOLE IV (n=118) Loading: 800 mg Maintenance: 400 mg Either agent could be followed by oral fluconazole after day 10 Treatment duration was at least 14 days and not more than 42 days. 1- Reboli A.C., Rotstein C., Pappas P.G. et al. Anidulafungin versus Fluconazole for Invasive Candidiasis. N Engl J Med 2007;356:2472-82.

Candida albicans was most common baseline isolate 1 C. parapsilosis C. tropicalis C. glabrata 10% 12% Other non-albicans spp. Anidulafungin 16% 5% (n = 127) C. albicans 64% C. albicans 54% Fluconazole (n = 118) 25% 3% C. glabrata 9% 14% C. parapsilosis C. tropicalis Other non-albicans spp. 1- Reboli A.C., Rotstein C., Pappas P.G. et al. Anidulafungin versus Fluconazole for Invasive Candidiasis. N Engl J Med 2007;356:2472-82.

Primary endpoint 1 Global success at the end of IV therapy ECALTA demonstrated superiority vs fluconazole: Significantly greater response rate in the anidulafungin group Difference: 15.4% (95% CI: 3.9% to 27.0%) Mean (median) duration of IV therapy: fluconazole: anidulafungin: 12.1 (11) days 13.5 (14) days 1- Reboli A.C., Rotstein C., Pappas P.G. et al. Anidulafungin versus Fluconazole for Invasive Candidiasis. N Engl J Med 2007;356:2472-82.

Secondary endpoint 1 Global success at the end of all therapies At the end of all antifungal treatments: Significantly greater response rate in the anidulafungin group Difference: 17.2% (95% CI: 5.5% to 29.0%) Mean (median) exposure to all study drugs: fluconazole: anidulafungin: 14.4 (14) days 15.9 (15) days 1- Reboli A.C., Rotstein C., Pappas P.G. et al. Anidulafungin versus Fluconazole for Invasive Candidiasis. N Engl J Med 2007;356:2472-82.

Adverse events 1 Leading to discontinuation Fewer adverse events leading to discontinuation of the study drug occurred in the Anidulafungin group 1- Reboli A.C., Rotstein C., Pappas P.G. et al. Anidulafungin versus Fluconazole for Invasive Candidiasis. N Engl J Med 2007;356:2472-82.

Conclusion 1 Anidulafungin, potent efficacy, favourable tolerability Anidulafungin was shown to be superior to fluconazole in the treatment of invasive candidiasis (primary endpoint global success at end of IV therapy) Efficacy of anidulafungin has been demonstrated in a wide range of patients including co-morbid patients: Mean age was 57 (range: 16-89) 36% of patients had renal failure or insufficiency 22% of patients had cancer disease 42% of patients had undergone recent surgery Anidulafungin has a favourable tolerability with fewer adverse events leading to treatment discontinuation than fluconazole 1- Reboli A.C., Rotstein C., Pappas P.G. et al. Anidulafungin versus Fluconazole for Invasive Candidiasis. N Engl J Med 2007;356:2472-82.

Micafungin Preclinical data Micafungin acts by inhibiting the synthesis of an essential cell wall component, 1,3-β-D-glucan Micafungin is a fungicidal agent with potent, broad-spectrum activity against all major Candida species Micafungin demonstrates higher in vitro potency than other echinocandins against C. glabrata Micafungin remains effective against Candida spp. that are resistant to azole antifungal agents A susceptibility breakpoint of 2 µg/ml has been suggested for micafungin Micafungin has a low potential for the development of resistance Micafungin has excellent activity against Candida species when growing as biofilms commonly found on catheters

Administration to special populations There is no requirement for micafungin dose adjustments in special populations Age Gender Renal impairment Mild-to-moderate hepatic impairment 1 3 Micafungin has not been studied in patients with severe hepatic impairment 2,4 1. Groll AH, et al. Expert Opin Investig Drugs 2005; 14:489 509; 2. Astellas Pharma US, Inc. MYCAMINE (micafungin sodium) for injection US Prescribing Information 2008. Available at: http://www.fda.gov/medwatch/safety/2008/jan_pi/mycamine_pi.pdf (accessed February 2009); 3. Hebert MF, et al. J Clin Pharmacol 2005; 45:1018 24; MYCAMINE (micafungin sodium) for injection SmPC. Astellas Pharma Europe Ltd., September 2008

Phase III study micafungin vs. L-AmB: study design *2.0 mg/kg/day in patients weighing 40 kg Treatment continued until at least one week after resolution of clinical signs and symptoms and obtaining of two sequential negative blood cultures Maximum 8 weeks in chronic disseminated candidiasis, Candida osteomyelitis or Candida endocarditis Micafungin 100 mg/day* Randomisation (1:1) Treatment period 2 4 Post-treatment period Kuse ER, et al. Lancet 2007; 369:1519 27 weeks 12 weeks L-AmB 3 mg/kg/day

Phase III study micafungin vs. L-AmB: overall treatment success Treatment success rate (%) 100 80 60 40 20 0 74.1 Micafungin mitt 69.6 Kuse ER, et al. Lancet 2007; 369:1519 27 L-AmB 89.6 PP 89.5 n = 247 247 202 190 mitt = modified intent-to-treat; PP = per-protocol set

Phase III study micafungin vs. caspofungin: study design Patients were stratified by region and APACHE II score ( 20 or > 20) Micafungin 100 mg/day Treatment period Max 4 weeks Post-treatment period 6 weeks Randomisation (1:1:1) Micafungin 150 mg/day *70 mg loading dose on Day 1 8 weeks in chronic disseminated candidiasis or Candida endophthalmitis; switch to oral fluconazole permitted after 10 days in patients meeting protocol-specified criteria Time from last dose day of protocol-defined antifungal therapy to final evaluation Pappas PG, et al. Clin Infect Dis 2007; 45:883 93 CAS 50 mg/day* CAS = caspofungin

Phase III study micafungin vs. caspofungin: Treatment success rate (%) 80 60 40 20 0 76.4 treatment success n = 191 n = 199 n = 188 Pappas PG, et al. Clin Infect Dis 2007; 45:883 93 71.4 72.3 n = 191 199 188 Micafungin 100 mg/day Micafungin 150 mg/day Caspofungin 50 mg/day* *Loading dose 70 mg; mitt population

Summary of invasive candidiasis studies Micafungin is at least as effective as L-AmB in the treatment of SCIs in both neutropenic and nonneutropenic patients Micafungin is at least as effective as caspofungin in the treatment of SCIs in both neutropenic and nonneutropenic patients Micafungin has demonstrated numerically higher success rates than caspofungin in C. glabrata

Prophylaxis against invasive fungal infections in HSCT patients

Phase III study micafungin vs. fluconazole: study endpoints Primary endpoint: treatment success (absence of proven, probable, or suspected systemic fungal infection until the end of prophylaxis therapy and the absence of a proven or probable systemic fungal infection until the end of the 42-day post-treatment period) Secondary endpoints included: use of systemic antifungal agents for treatment of suspected fungal infections; frequency of proven or probable fungal infections throughout the posttreatment period; pathogen-based frequency of proven infections van Burik JA, et al. Clin Infect Dis 2004; 39:1407 16

Phase III study micafungin vs. fluconazole: overall treatment success Treatment success (%) 90 80 70 60 50 40 30 20 10 0 80.0 Micafungin Micafungin van Burik JA, et al. Clin Infect Dis 2004; 39:1407 16 p = 0.03 Fluconazole 73.5 n = 425 457 Fluconazole

Summary of prophylaxis studies Micafungin demonstrates efficacy superior to fluconazole as prophylaxis against invasive fungal infections overall treatment success rates were significantly superior with micafungin compared with fluconazole the Kaplan-Meier estimate of treatment success was significantly greater with micafungin than with fluconazole overall incidence of proven or probable breakthrough infection was lower with micafungin than with fluconazole empirical antifungal therapy was required in fewer micafungin- than fluconazole-treated patients

Summary of oesophageal candidiasis studies Micafungin shows a clear dose response pattern in the treatment of oesophageal candidiasis, with higher doses resulting in improved efficacy Micafungin is at least as effective as fluconazole in the treatment of oesophageal candidiasis

Paediatric sub-study to Phase III micafungin study vs. L-AmB: study design Almost identical to study design of adult trial Treatments dosed by body weight (micafungin: 2 mg/kg/day; L-AmB: 3 mg/kg/day) Dose increases permitted: Micafungin: up to 4 mg/kg/day L-AmB: up to 5 mg/kg/day Dose decrease of 50% permitted for L-AmB in cases of nephrotoxicity Queiroz-Telles F, et al. Pediatr Infect Dis J 2008; 27:820 6

Paediatric sub-study micafungin vs. L-AmB: treatment success by neutropenic status Treatment success rate (%) 100 80 60 40 20 0 Overall 73 n = 48 42 6 83 76 77 72 76 Micafungin Non-neutropenic Queiroz-Telles F, et al. Pediatr Infect Dis J 2008; 27:820 6 Neutropenic 50 37 13 L-AmB mitt population

Summary: efficacy of micafungin in paediatric patients Micafungin is the only echinocandin licensed for use in infants < 12 months of age, including premature neonates Micafungin has demonstrated efficacy in paediatric patients with SCIs Micafungin is as effective as L-AmB in both neutropenic and non-neutropenic patients Micafungin is effective against both C. albicans and nonalbicans Candida species Micafungin is effective as prophylaxis against invasive fungal infections in children undergoing HSCT

Adverse events observed more commonly in paediatric patients than in adults System organ class Blood and lymphatic system disorders Cardiac disorders Vascular disorders Hepatobiliary disorders Renal and urinary disorders Adverse event Thrombocytopenia Tachycardia Hypertension Hypotension Hyperbilirubinaemia Hepatomegaly Acute renal failure Blood urea increased MYCAMINE (micafungin sodium) for injection SmPC. Astellas Pharma Europe Ltd., September 2008

Micafungin pooled safety data: most frequently observed adverse events Pooled analysis of safety data from all 3,028 patients included in micafungin clinical trials, including paediatric patients Age group, patients, n (%) Overall Adults, Adults, Paediatrics, non-elderly elderly ( including Adverse event n = 3,028 (16 64 years) n = 2,345 65 years) n = 387 premature infants and neonates n = 296 Hypokalaemia 63 (2.1) 45 (1.9) 9 (2.3) 9 (3.0) Phlebitis 75 (2.5) 65 (2.8) 7 (1.8) 3 (1.0) Diarrhoea 61 (2.0) 52 (2.2) 6 (1.6) 3 (1.0) Vomiting 75 (2.5) 62 (2.6) 9 (2.3) 4 (1.4) Nausea 84 (2.8) 73 (3.1) 8 (2.1) 3 (1.0) Pyrexia 63 (2.1) 51 (2.2) 8 (2.1) 4 (1.4) AST increased 71 (2.3) 63 (2.7) 2 (0.5) 6 (2.0) ALT increased 61 (2.0) 49 (2.1) 3 (0.8) 9 (3.0) Blood alk. phos. NOS increased 81 (2.7) 65 (2.8) 10 (2.6) 6 (2.0) Alk. phos.: alkaline phosphate; ALT: alanine aminotransferase; AST: aspartate aminotransferase; NOS: not otherwise specified Cornely OA, et al. 47th ICAAC. Chicago, IL, USA, 17 20 Sep 2007; Poster M-1175

Conclusions The echinocandins and new triazoles offer more choice There is too little known about the optimum dosage, the need for monitoring and the potential DRAE s Acquisition costs will be high Flexible administration is now demanded Who should get what and when remains unclear Targeting the drugs will require better identification of those at risk and assessment of that risk Further studies are need to establish the place of these drugs in clinical practice PREVENTION IS BETTER THAN CURE

Antifungals in the pipeline : Is there anything on the horizon?

Newer treazols for the treatment of IFI Posaconazol (new formulations: tabl, IV) Ιsavuconazole (po and iv) Ravuconazole Others under developement (π.χ., albaconazole empeconazole)

Posaconazole (Posa) Oral suspension approved 2007 Unpredictable PK Availability of an intravenous and a solid oral formulation is critical to its future development as a broad antifungal agent Studies of primary therapy with posa for IA, zygo, probably invasive candidiasis, provided that iv and/or solid oral formulation available

Isavuconazole (ISV) Prodrug is metabolized to ISV Excellent in vitro activity vs. Aspergillus spp, Candida spp, and Cryptococcus spp. Available po and iv Potentially fewer drug-drug interactions (induces CYP3A4) More predictable kinetics, once daily dosing, prolonged T1/2 Favorable results in Phase I and II studies

Isavuconazole Phase III studies on hold presently: 1. Invasive aspergillosis (compared to voriconazole, excellent enrollment thusfar) 2. Candidemia and invasive candidiasis (compared to echinocandin, then vori) 3. Patients with IA and renal failure, rare moulds (open label)

Ravuconazole (RAV) Extended spectrum triazole, similar spectrum to voriconazole 1 Offers prolonged serum T1/2 Safety profile, drug-drug interactions possible fewer than vori and posa Phase II studies; pending decisions re: Phase III 1 Baddley JW et al. JCM 2009;77:3271

Albaconazole Similar spectrum to voriconazole, ravuconazole versus pathogenic moulds 1 Especially active vs. Cryptococcus spp, including C. gattii 2 Development on hold 1 Capilla et al AAC 2001; 45:2635 2 Miller JL et al AAC 2004;48:384

Aminocandin Currently in vitro and animal studies suggest excellent activity vs. Candida spp, including caspofungin-resistant isolates 1 Available only iv Prolonged T 1/2 may favor less frequent dosing No large safety, kinetic or efficacy studies in humans to date Brzankalski JAC 2008;62: 1094

MSG-01: A randomized, double-blind, placebo-controlled trial of caspofungin prophylaxis followed by pre-emptive therapy for invasive candidiasis in high-risk adults in the critical care setting PI: Luis Ostrosky-Zeichner

MSG 01 Clinical scoring system: ICU for 72 hrs, CVC, IV antibacterials, ventilator dependent, plus 1 other risk factor (eg pancreatitis, recent surgery) Colonization data being collected, but not incorporated as part of the clinical score Randomized to caspofungin vs placebo Primary endpoint: development of IC 185 pts enrolled to date

Empiric Echinocandin Therapy MSG 04 will be designed to enroll approx 120 pts in this feasibility study of empiric caspofungin in high risk ICU pts Identify pts who have clinical evidence of an infection, (eg unexplained fever, leukocytosis) Utilizing a clinical scoring system (+/- Candida colonization), determine high risk ICU pts for intervention, comparing echinocandin to placebo Study design, endpoints, use of 1,3 β-d glucan assay under development

Echinocandins demonstrate limited in vitro activity vs. the zygomycetes Retrospective data suggests better outcome in patients with zygo when treated with AmB and echinocandin Complicated study design would make this a challenging clinical trial

An iron chelating agent that does not act as a siderophore for fungi Demonstrates in vitro activity vs. certain zygomycetes Animal models suggest important antifungal activity Clinical case reports suggest success in a small number of patients, along with surgery and/or antifungal therapy

Adjunctive agent with LFAmB, +/- echinocandin Role for surgery Study design will be a difficult challenge Limited number of patients, absence of a serologic marker another major challenge The final results or the clinical trial not encouraging

Licensed as an antiparasitic agent versus Leishmania spp. and Trypanosoma cruzi Demonstrates excellent in vitro activity vs a range of fungal pathogens; appears to be fungicidal for C. neoformans, other fungi Target enzyme is fungal phospholipase B (PLB1) Recent reports of successful therapy with adjunctive miltefosine for S. prolificans osteomyelitis 1 1 Kesson AM et al. Clin Infect Dis 2009;48:1257-61

mab directed against HSP-90 Mechanism of action incompletely understood Two clinical trials (IC and CNS crypto) yielded some interesting results, though IC study results were greeted with skepticism 1 Toxicity may be an issue (from crypto study) Current status: Novartis is reformulating the compound, doing more preliminary preclinical work, discussing next moves 1 Pachl J et al. Clin Infect Dis 2006;42:1404-13

F2G compounds No products that are ready for prime time, but a novel mechanism of action would be an interesting development in the antifungal world. We are anxious to see if these compounds have real potential for use in humans.

Overall summary Changes in the epidemiology and microbiology of Candida species are driving the need for newer, more effective antifungal agents Newer ecinocandins have potent, broad-spectrum activity against all major Candida species Their pharmacokinetics and pharmacodynamics allow for simple dosing regimens with no need for dose adjustments The drugs are effective in a broad range of patient types in a number of different treatment settings They offer a good clinical safety profile, in some cases superior to that of current agents Echinocandins have been studied in comprehensive clinical trials in a big number of patients New molecules are in the pipelines

Future Antifungal Strategies DIAGNOSTICS HYGIENE ISOLATION ELIMINATION OF RISK FACTORS INTERFERON INTERLEUKINS G(M)-CSF ANTIFUNGALS ALONE OR IN COMBINATION SURGERY