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Home , Micafungin

New (& Nearly New) Drugs for Coccidioidomycosis

Thomas F. Patterson, MD, FACP, FIDSA Professor of Medicine Vice-Chair for Faculty Development Chief, Division of Infectious Diseases Director, San Antonio Center for Medical Mycology

UT Health San Antonio, Texas Presenter Disclosures Thomas F Patterson MD The following relationships with commercial interests related to this presentation existed during the past 24 months: Company Nature of Relationship: Consultant, Speakers Name: Bureau, Sponsored Research, Other Grant support None Consultant Astellas, Basilea, Gilead, Merck, Scynexis,Toyama Speakers' None bureau Major Stock None holder Other material NIH/NIAID (Amplyx, Cidara, F2G, Matinas, Mirati, support Scynexis, Toyama, Viamet, Vical, Valley Fever Solutions) Current and (selected!) new agents for invasive fungal infections Polyenes • AmB deoxycholate • • • lipid AmB formulations • • micafungin • AmB nanoparticles • • • AmB cochleates • • aminocandin • isavuconazole • biafungin (CD101) • itra nanoparticles Others • • histone deacetylase inhibitors • (MGCD290) • • novel CYP inhibitors (VT1129/1161/1598) • nikkomycin Z (VFS-1) • calcineurin inhibitors/combinations • arylamides (T-2307) • other essential enzymes/targets (BDM-I; • enfumafungin (SCY-078) F901318, ASP2397, AR-12, others) • GPI inhibitors (APX001) • repurposed drugs: sertraline, auranofin • Immunotherapy (C-403) • etc., etc.

Note: AmB=; GPI=glycosylphosphatidylinositol Blue text, earlier development The Antifungal Pipeline: A Reality Check

Perfect JR. Nat Rev 2017;12 May. The Antifungal Armamentarum: Key Questions for Coccidioidomycosis • Unmet need: burden of infection; impact of resistance • Clinical agents with activity in cocci . Isavuconazole . Posaconazole tablets/IV . SUBA-itraconazole • Drugs with in vitro / in vivo activity in coccidioidomycosis . Nikkomycin Z (VFS-1) . VT 1161/1598 . F901318 . AXP001 • Other drugs in the pipeline: unknown cocci activity . AmB cochleates . Glucan synthase inhibitors (CD101, SCY-078) . Others: histone deacytelase inhibitors (MGCD290), sertraline, immunotherapy (C-403) • Urgent need for efficient diagnostic tests • Safe and effective new drugs and vaccines Sci Trans Med 19 Dec 2012; 4,165rv13 Large-scale Susceptibility Testing of Coccidioides Isolates

• Coccidioides isolates (n = 581) • Elevated MIC values: . Flu: ≥16 μg/ml, 37.3%; ≥32 μg/ml, 7.9% . Itra: ≥2 μg/ml, 1.0% . Posa: ≥1 μg/ml, 1.0% . Vori: ≥2 μg/ml, 1.2%

 Mould-active azoles low MICs for majority of isolates  Clinical correlation with outcomes needed

Thompson GR, et al. Antimicrob Agents Chemother 2017;17 April. New Agents of Available Classes • Isavuconazole (Basilea, Astellas) – Broad-spectrum – Oral & IV formulations • Prodrug (BAL-8557) cleaved to active component (BAL-4815) by plasma esterases

– Long t1/2 (BAL-8557) – Broad spectrum: yeasts, moulds including Mucorales, endemics (cocci)

• Clinical studies Isavuconazole (BAL-4815) – Phase III clinical trials • Invasive aspergillosis (NCT 00412893) • Rare fungi (NCT 00644049) including mucormycosis, endemics: cocci • Candidemia (NCT 00413218) Warn PA et al, JAC 2006;58:1198-1207; Thompson GR et al, AAC 2009;53:309-11; Verweij PA, J Chemother 2009;21:272-81; Thompson GR, JAC. 2009;64:79-83; Thomspon GR, Wiederhold NP. Mycopathologia 2010;170:291-313; Thompson GR, et al. Clin Infect Dis 2016; 63:356-62; Maertens J, et al. Lancet. 2016 Feb 20;387(10020):760-9 Isavuconazole (ISAV) for Endemic Fungi & Cryptococcosis

• Coccioidomycosis: primary therapy . Pulmonary • ISA: 200mg tid X 2 days then 200 mg/d • Median duration: 180d • DRC Clinical Response: 9/9 • MICs 0.06-0.12 • Well tolerated • Serum Levels: . D7: 3.20 μg/ml (0.6-5.08) . D14: 3.86 μg/ml(0.88-5.98) . D28: 4.01 μg/ml(0.78-7.80) . Steady state: 4.05 μg/ml (1.09-8.96)

Thompson GR, et al. Clin Infect Dis 2016; 63:356-62. Posaconazole With New Formulations UT Health Science Center Experience Prior to December 2013 Since December 2013

• Shift in posaconazole concentrations to higher levels – Higher percentage of patients with concentrations ≥1 μg/ml – Fewer patients with concentrations <0.5 μg/ml – ~10% with posaconazole concentrations >3.5 μg/ml • Clinical relevance of high levels unknown • Limited clinical data with new formulation • Further clinical trials in development

Wiederhold NP et al. Antimicrob Agents Chemother 2014;58:424-31. Unpublished data (UT Health Science Center San Antonio Testing Laboratory) Thanks! Nathan SUBA-itraconazole (Mayne Pharmaceuticals) • ‘SUBA’ technology: proprietary ‘SUperBioAvailable formulation of itraconazole: spray drying technology to create nano-particles (<40µm) of itraconazole in a polymer matrix=increased solubility . Better bioavailability (55% vs ~100%) . Lower inter- and intra-patient variability . Less food effectustralian approved bioequivalence dosing at 50mg vs 100mg conventional itraconazole

 Clinical US trials in development with MSG

Mudge S, et al. Poster presented at the Annual Scientific Meeting of the Australian Society of Infectious Disease 2014. Adelaide, Australia. Poster 68; Australian Approved LOZANOC 50mg Capsules Product Information dated 16 April 2014. Nikkomycin Z (VFS1) (Valley Fever Solutions)

• Nikkomycin Z (NikZ) is first in a new class of antifungal, chitin synthase inhibition . Novel mechanism of action, significant unmet medical need . Activity against Coccidioides, Blastomyces, Histoplasma, Aspergillus, others . Selective to fungal cells - thus far no safety concerns in mammals - Efficacy in murine models - Efficacy in naturally occurring pulmonary coccioidomycosis in dogs . May enhance other anti-fungal treatments in combination with other drugs . In 2014, GAIN Act QIDP designation—providing 7 and 5 years sequential market exclusivity after marketing approval. . Scaled up trial material in process, Phase IIa trials in clinical infection, Summer 2017

Shubitz LF, et al. J Infect Dis 2014;209:1949-54; Hector RF, et al. Antimicrob Agents Chemother 1990;34:587-93; Najvar LK, et al. ICAAC, 2015 http://valleyfeversolutions.com/ Novel Cyp51 Inhibitors VT-1129/1161/1598 (Viamet Pharmaceuticals, Inc.) • Investigational fungal Cyp51 inhibitors

• MOA similar to azoles

• Highly selective for fungal Cyp51 enzyme vs human Cyp450 enzymes VT-1161 (more so than the azoles)

– Kd against fungal Cyp51 ≤39 nM – Failed to inhibit human CYP450 at 50 μM

Hoekstra WJ et al. Bioorg Med Chem Lett 2014;24:3455-8. Warrilow AG et al. Antimicrob Agents Chemother 2014:58:7121-7. VT-1129 & VT-1161 In vitro Potency Potent in vitro activity against Cryptococcus & Candida species

Antifungal VT-1129 VT-1161 FLU CAS Cryptococcus neoformans MIC50 0.015 0.03 2 NT MIC90 0.06 0.125 8 NT GM MIC 0.03 0.04 2.32 NT Cryptococcus gattii MIC50 0.06 0.06 2 NT MIC90 0.125 0.25 4 NT GM MIC 0.05 0.08 2.28 NT Candida albicans MIC50 0.03 0.03 0.125 0.125 MIC90 0.03 0.03 0.25 0.125 GM MIC 0.03 0.03 0.15 0.1

Fothergill AW et al. ICAAC 2010. Cryptococcal Meningitis - VT-1129 Monotherapy Combined with single dose AMBd

• Effective as monotherapy & in combination with amphotericin B against cryptococcal meningitis – Murine model with intracranial inoculation – Improvements in survival & significant reductions in fungal burden (>4 log reduction CFU/g when combined with AMB) – Rapid fungicidal activity and tissue sterilization—not seen with other antifungal agents or combinations Wiederhold et al. ICAAC 2010. Wiederhold et al. ECCMID 2011. Invasive – VT-1161

• and resistant Candida albicans – Improved survival and reductions in kidney fungal burden vs. caspofungin and fluconazole

Najvar LK, et al. ISHAM 2012. VT-1161 in Naturally Infected Dogs with Coccidioidomycosis  Enrolled respiratory cases based on clinical signs, radiographs, serology, clinical pathology  60 days of medication: 14 days loading dose, followed by 46 days maintenance at ~5-fold lower dose High dose – (29/6 mg/kg) – 12 Low Dose (10/1.6 mg/kg) – 10 dogs dogs  Mean entrance score: 13.3  Mean entrance score: 14.4  Mean exit score: 5.0  Mean exit score: 4.7  Mean plasma concentration: 36 ±14 µg/ml*  Mean plasma concentration: 19 ± 8 µg/ml*  9/12 dogs (75%) experienced 75%-100%  All 10 dogs experienced clinical improvement reduction in clinical signs; 1 dog removed for progressive lung consolidation on day 35 though 1 had radiographic progression and increased titer  66% of dogs had at least one dilution reduction in titer and 66% had reduction or  60% of dogs had at least 1 dilution reduction in resolution of CBC/serum chemistry titer and 80% had reduction or resolution of abnormalities CBC/serum chemistry abnormalities  Radiographic improvement was mixed,  Radiographic improvement mixed, ranging ranging from no change to 90% from no change to 85% improvement improvement

*In vitro MIC90 and MIC range of 2 and 1-4 µg/ml for 52 clinical isolates of Coccidioides Shubitz LF, Antimicrob Agents Chemother 2017;Apr 24;6(5). Shubitz L, et al. 60th CSG. Thanks! Lisa! VT-1161 & VT-1598 in Murine CNS Coccidioidomycosis

Survival from Coccidioidal Meningitis after Treatment with VT-1161 or VT-1598 Swiss-Webster mice, 65 spores intracerebrally

1.0

0.8

3.2 mpk 1598 0.6 8 mpk 1598 20 mpk 1598 20 mpk 1161 Placebo 0.4

0.2 Proportion of Mice Surviving Mice of Proportion

0.0 0 10 20 30 40 50 Days Survived

 VT-1161’s prolonged survival benefit is tied to its very long half-life (6-8 days)  Half-life of VT-1598 ~1d in mouse; survival wanes due to fungistatic mechanism of drug  By comparison with prior 1161/flu study (left graph), VT-1598 appears to improve survival at least as well as fluconazole (25 mg/kg BID) even at lowest tested dose (3.2 mg/kg/day)

Shubitz LF, et al. 60th CSG; Shubitz LF, et al. Antimicrob Agents Chemother 2015;59:7249-54 Murine Coccidioidomycosis – Brain Fungal Burden and Dissemination

7

6

5  Controls died on days 6-9; drug-Tx’d survived

4  Both doses of 1598 significantly reduced brain fungal burden compared to 1161 (P<0.001)

CFU/g Brain 3

10  2 With 20 mg/kg VT-1598, 4/10 animals had Log undetectable brain CFUs (range 0-18 CFU/g) 1  Both doses of VT-1598 prevented dissemination 0

1598 4 mpk 1598 20 mpk 1161 20 mpk Placebo

 Conclusion: VT-1598 yielded greater fungal burden reduction at 1/5 the dose of VT- 1161; therefore ~10-fold more potent in vivo

Shubitz L, et al. 60th CSG. In vitro activity of VT-1598, Posaconazole, & Fluconazole against C. immitis & C. posadasii

Species Coccidioides immitis (n = 17) Coccidioides posadasii (n = 23) Antifungal VT-1598 Posaconazole Fluconazole VT-1598 Posaconazole Fluconazole MIC range 0.06-0.25 0.12-0.25 2-16 0.06-0.5 0.06-0.5 2-32 MIC50 0.25 0.12 8 0.25 0.25 8 MIC90 0.25 0.25 16 0.5 0.25 16 GM MIC 0.180 0.153 7.08 0.250 0.179 8.00

Wiederhold NP, et al. Microbe. 2017. VT-1598 in Murine CNS Coccidioidomycosis: Survival at Day 30

Group Control VT-1598 VT-1598 VT-1598 Fluconazole 5 mg/kg 15 mg/kg 45 mg/kg 25 mg/kg Median 9 days >30 days >30 days >30 days 29 days Survival *p<0.0001 *p<0.0001 *p<0.0001 *p<0.0001 (days) **p=0.0044 **p=0.0044

Percent 0% 70% 100% 100% 40% Survival *p=0.0031 *p<0.0001 *p<0.0001 *p=0.0867 (days) **p=0.0108 **p=0.0108

*p-value vs. Control; **p-value vs. Fluconazole Wiederhold NP, et al. Poster presentation; 7th Int’l CSG 2017 VT-1598 in Murine CNS Coccidioidomycosis: Tissue Fungal Burden

Tissue burden in fungal burden arm (day 9: A); and survival arm after 14 days of treatment wash-out (B). Lower Limit of Detection = 10 CFU/g.

Wiederhold NP, et al. Poster presentation; 7th Int’l CSG 2017 Orotomide: F901318 (F2G) Mechanism of Action, Spectrum • F901318 is a potent inhibitor of A. fumigatus DHODH – DHODH (Dihydroorotate dehydrogenase) is a key enzyme involved in pyrimidine biosynthesis • Mechanism was identified using genetic studies in Aspergillus nidulans – Confirmed by in vitro enzyme assays

• Humans also have this enzyme F901318 structure – But, > 2000-fold difference in IC50 between human and fungal enzymes • Spectrum of activity: highly active against moulds/endemics In vitro activity is consistent across all major Aspergillus spp., including A. terreus

F901318 Itraconazole Posaconazole Voriconazole Amphotericin B A. fumigatus Geo mean 0.008 1.00 0.30 0.46 0.68 n = 80 Range 0.004-0.016 0.06-16 0.03-16 0.06-16 0.25-1

Intrinsic A. terreus Geo mean 0.006 0.25 0.14 0.18 1.49 resistance to ampho B n =45 Range 0.002-0.008 0.06-1 0.06-2 0.03-0.5 0.125-4

A. flavus Geo mean 0.007 0.21 0.087 0.26 0.79 n = 50 Range 0.004-0.008 0.125-1 0.03-1 0.06-1 0.5-2

A. niger Geo mean 0.007 0.62 0.16 0.51 0.46 n=46 Range 0.004-0.016 0.125-16 0.03-2 0.125-16 0.125-1

MICs in mg/L , Isolates from UK and Austria Other moulds n MIC Range (mg/L) Scedosporium (L.) prolificans 3 <0.06 Scedosporium apiospermum 2 <0.06 Aspergillus lentulus 4 <0.06 Paecilomyces variotii 3 <0.06 Sporothrix schenckii 5 <0.06 Acremonium sp. 5 <0.06 - 1 Scopulariopsis brevicaulis 5 <0.06 Penicillium chrysogenum 5 <0.06 Penicillium marneffii 5 <0.06 Coccidioides immitis 5 <0.06 Blastomyces dermatitidis 5 <0.06 Histoplasma capsulatum 5 <0.06-0.125

Activity against S. (Lomentospora) prolificans and other Scedosporium species has been confirmed in a larger study. Variable activity vs. Fusarium spp. Not active vs. Candida, Cryptococcus, or Mucorales F901318 in vitro activity against Coccidioides spp.

Species Isolate No. F901318 • Coccidioides MICs (20 isolates) Coccidioides sp. Cocci1 0.015 Cocci2 0.015 • Range: ≤0.008-0.03 Cocci3 ≤0.008 • Geometric mean: 0.015 Cocci4 0.015 Cocci5 ≤0.008 Cocci6 0.015 • Animal models in progress Cocci7 ≤0.008 Cocci8 ≤0.008 Cocci9 ≤0.008 Cocci10 ≤0.008 Cocci11 0.015 Cocci12 0.03 Cocci13 0.015 Cocci14 0.015 Cocci15 0.03 Cocci16 0.015 Cocci17 0.015 Cocci18 0.03 Cocci19 0.015 Cocci20 0.06 Data courtesy Nathan Wiederhold, UTHSA Fungus Testing Laboratory & Mike Birch, F2G GPI Biosynthesis Inhibition – APX001 (Amplyx) Fungal adhesion ligands derived from GPI-anchored proteins – Candida albicans possess ~115 GPI-anchored proteins – Als protein family members

GWT1 gene encodes Gwt1p – an inositol acyltransferase in early GPI biosynthesis pathway

1-(4-butylbenzyl)isoquinoline (BIQ)

APX001 [E1210] – (3-(3-{4[(pyridin-2-yloxy)methyl]benzyl}isoxazol-5-yl)pyridin-2-amine – Selectively inhibits fungal inositol acyltransferase – Reduces expression of Als1p on C. albicans cell surface

Umemura et al. J Biol Chem 2003; 278: 23639 – 47. Watanabe et al. Antimicrob Agents Chemother 2012: 56: 960 – 71. APX001[E1210] In vitro Activity

Organism Range MIC50 MIC90 C. albicans (52) < 0.008 – 0.016 < 0.008 < 0.008 C. glabrata (44) < 0.008 – 0.06 0.06 0.06 C. tropicalis (23) < 0.008 – 0.03 0.016 0.03 C. parapsilosis (26) < 0.008 – 0.016 < 0.008 0.016 A. fumigatus (20) 0.03 – 0.13 0.06 0.13 A. terreus (23) 0.015 – 0.06 0.03 0.06 F. solani (23) 0.03 – 0.12 0.12 0.12 F. oxysporum (15) 0.03 – 0.25 0.06 0.12 S. prolificans (28) 0.03 – 0.25 0.06 0.12 S. apiospermum (28) 0.03 – 0.12 0.06 0.12

*50% inhibition of growth for Candida; MEC endpoint for moulds (static activity) **Inactive against C. krusei and members of the Order Mucorales Active against fluconazole-resistant Candida (MIC90 - 0.03 μg/mL) Miyazaki et al. Antimicrob Agents Chemother 2011; 55: 4652 – 58. Castanhelra et al. Antimicrob Agents Chemother 2012; 56: 352 – 57. Pfaller et al. Antimicrob Agents Chemother 2011; 55: 5155 – 58. Wiederhold NP, et al. Antimicrob Agents Chemother 2015;59:690-2. APX001[E1210] – In vivo Efficacy In vivo efficacy demonstrated in murine models of invasive fungal infections Invasive Pulmonary Disseminated (C. albicans) Aspergillosis (A. flavus) Fusariosis (F. solani)

PK parameter Tmax Bioavailability Half-life 1 mg/kg PO X1 0.5 hours 57.5% 2.2 hours  Efficacy also demonstrated in vitro and in vivo against echinocandin-resistant Candida albicans Hata et al. Antimicrob Agents Chemother 2011; 55: 4543 – 51; Wiederhold NP, et al. Antimicrob Agents Chemother 2015;59:690-2. Efficacy of APX001-A in vitro and in vivo against Coccidioides • In vitro testing using agar dilution: – MICs (2): C. immitis 0.019, C. posadasii 0.16 • Murine pulmonary coccidioidomycosis – 50 mg/kg bid starting d 4 and continuing for 14d – 3-log reduction in lung CFU treated vs untreated controls – No dissemination to spleen (0/10) vs controls (8/10); GM fungal burden 3.7 log10

Fierer J et al. Poster presentation, 60th CSG, 2016 AmB Cochleates (MAT2203) (Matinas)

• Cochleate targeted nano- particle delivery – Reduced toxicity – Targeted delivery – Oral delivery • MAT2203 – Animal studies – Human Phase I tolerability CD101 (Biafungin) A novel echinocandin antifungal (Cidara)

+ + O N - N O OH O O O HO N H H N O H C 3 N O H3C O HN OH

HO NH O CH3 O O H N N HO Structural modification yields OH O chemical stability & enhanced OH Biafungin (CD101 Acetate) biological properties HO Permanent charge and highly stable ring structure… • Prolongs PK: once weekly dosing • Eliminates toxic degradation products: improved safety & dose range • Allows high exposures: treats less susceptible pathogens • Enables multiple formulations: systemic and topical

ICAAC 2015: multiple posters CD101 IV dosing designed to optimize outcome

CD101 IV 200 mg IV Q7D; AUC = 700 µg.hr/mL per dose

For Echinocandins 10 exposure improves outcomes Concentration in Plasma (µg/mL)

5

CD101 MIC90 range for echinocandin–resistant Candida 0 0 2 4 6 8 10 12 14 16 Days

Above graphic is a model CD101 IV vs. echinocandin-resistant strains

Heterozygous FKS Mutant (S645P) in Mice 48h post infection; MIC (µg/ml) Micafungin & CD101 = 0.5

Vehicle 32,040,000

CD101 20 mg/kg 5,212 P <0.01*

CD101 40 mg/kg 4,698 P <0.01*

CD101 60 mg/kg 3,294 P <0.01*

* P value compared with Micafungin 5 mg/kg 97,740 Micafungin 5 mg/kg

1.E+00 1.E+03 1.E+06 1.E+09

Log10 (CFU/g) in kidney

Y. Zhao, D.S. Perlin, et al. Efficacy of CD101 to Treat Echinocandin-resistant Candida albicans in a Murine Model of Invasive Candidiasis (F-748),ICAAC 2015 Glucan Synthase Inhibitors: Enfumafungins – SCY-078 (Scynexis) • Semi-synthetic derivative of natural product • New molecular class • Potent β 1,3 glucan synthesis inhibitor (GSI) • Same target as echinocandin (marketed) • Blocks synthesis of essential component of cell wall of pathogenic fungi • Unique target not in mammalian cells • Excellent in vitro & in vivo activity against Candida and Aspergillus • Active in vitro against azole & echinocandin resistant strains • Orally bioavailable – current marketed GSIs are IV only; IV under development • Extensive tissue distribution: kidney, lungs ICAAC 2015 posters: • Phase I/II - generally well tolerated with F-745, A-468, F-744 good (QD) In vitro Activity of MK-3113 [SCY-078] against Candida species

•31 strains with fks mutations: SCY-078 MIC <2 100%; <1 in 71%

Pfaller MA, et al. JAC 2013;68:658-63 Histone Deacetylase Inhibitors

• Azoles deacetylate promotors of transcription resulting in downregulation of repression (upregulate resistance genes) • Histone deacetylase inhibitors may enhance susceptibility of fungi to azoles – Reduction in azole-dependent upregulation of efflux pumps (CDR1 & CDR2) – Reduction in transcription of genes encoding biosynthesis pathway (ERG1 & ERG11) • Reduced transcription (50%) when fluconazole or terbinafine combined with (TSA) – Non-specific histone deacetylase inhibitor

Smith, Edlind. Antimicrob Agents Chemother 2002; 46: 3532. MGCD290 (Mirati [MethylGene]) • Synergistic with azoles against yeast & moulds

MGCD290 Combined Percent Synergy Percent Antagonism with… Fluconazole 60% (50/91 isolates) 1.1% (1/91 isolates) Posaconazole 51% (46/91 isolates) 1.1% (1/91 isolates) Voriconazole 53% (48/91 isolates) 3.3% (3/91 isolates) • Synergy when combined with fluconazole – 87% Candida isolates (all that were fluconazole resistant [>64 μg/mL] became susceptible [<8 μg/mL]) • All 5 C. krusei isolates – 60% (6/10) Aspergillus isolates

Pfaller MA et al. J Clin Microbiol 2009;47: 3797-3804. Sertraline • Serotonin-reuptake inhibitor – Activity against other fungi (Cryptococcus) • In vitro activity again C. immitis vs fluconazole and in combination

Simon P et al. Poster presentation, 60th CSG, 2016 C-403: Cloudbreak Antifungal Immunotherapy (Cidara)

Immune Microbe TM EM Component

TARGETING MOIETY EFFECTOR MOIETY

Antibacterials Neutrophil recruiter Antifungals Macrophage recruiter Antivirals NK/T cell engagers* ADCC/CDC IgM/IgG engager C-403 Dual Mechanism

Fungal pathogen

1 Direct kill: novel TM tightly binds conserved target to kill fungi

2 Immunomodulatory: EM recruits and initiates an innate immune system response

 Efficacy in vitro, ex vivo and in animal models New Antifungals for Cocci: What Do We Need? • Significant unmet medical needs: resistance, toxicity, drug interactions, oral bioavailability • Many new potential targets and compounds under early stages of investigation . New methods of delivery for old drugs . New uses for existing compounds . New agents in currently used classes . New compounds with novel mechanisms of action! Acknowledgments IAAM/AMoID Investigators NIAID UTHSCSA Nathan Wiederhold Dennis Dixon Laura Najvar Rory Duncan $ Gabriel Catano Maliha Ilias William R. Kirkpatrick Brian Wickes Erin Zeituni David Kadosh Dona Love NIAID Contracts Annette Fothergill NCATS IAAM: Fungus Testing Lab Liz Ottinger N01-AI-30041 (IAAM) Harbor-UCLA Scott Filler AMoID: Ashraf Ibrahim HHSN27201000038I Jack Edwards HHSN27200001 (A13) McGill HHSN27200002 (A05) Don Sheppard HHSN27200005 (A93) Manchester Peter Warn HHSN27200006 (A98) David Denning HHSN27200009 (A107) Cincinnati HHSN27201100018I/ Melanie Cushion HHSN27200009 (A21) UTSA Chiungyu Hung HHSN27200012 (A28) NCI/NCATS-TRND: SAIC-F 12XS348 Thank you!

Special Thanks! Drs. Nathan Wiederhold, GR Thompson, Lisa Shubitz, Ken Bartizal, Kevin Forrest, Mike Birch, Paula Fenwick, Ed Garvey, Doug Kling