New (& Nearly New) Antifungal Drugs for Coccidioidomycosis

Thomas F. Patterson, MD, FACP, FIDSAProfessor of Medicine

Vice-Chair for Faculty DevelopmentChief, Division of Infectious Diseases

Director, San Antonio Center forMedical Mycology

UT Health San Antonio, Texas

Presenter Disclosures

The following relationships with commercial interests related to this presentation existed during the past 24 months:

Thomas F Patterson MD

Company Name:

Nature of Relationship: Consultant, Speakers Bureau, Sponsored Research, Other

Grant support None

Consultant Astellas, Basilea, Gilead, Merck, Scynexis,Toyama

Speakers' bureau

None

Major Stock holder

None

Other material support

NIH/NIAID (Amplyx, Cidara, F2G, Matinas, Mirati, Scynexis, Toyama, Viamet, Vical, Valley Fever Solutions)

Current and (selected!) new agentsfor invasive fungal infections

Azoles• fluconazole• itraconazole• voriconazole• posaconazole • isavuconazole• itra nanoparticles

Echinocandins• caspofungin• micafungin• anidulafungin• aminocandin• biafungin (CD101)

Polyenes• AmB deoxycholate• lipid AmB formulations• AmB nanoparticles• AmB cochleates

Note: AmB=amphotericin B; GPI=glycosylphosphatidylinositolBlue text, earlier development

Others• flucytosine• terbinafine• miltefosine• nikkomycin Z (VFS-1)• arylamides (T-2307)• enfumafungin (SCY-078)• GPI inhibitors (APX001)• Immunotherapy (C-403)

• histone deacetylase inhibitors(MGCD290)

• novel CYP inhibitors (VT1129/1161/1598)• calcineurin inhibitors/combinations• other essential enzymes/targets (BDM-I;

F901318, ASP2397, AR-12, others) • repurposed drugs: sertraline, auranofin• etc., etc.

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%

Thompson GR, et al. Antimicrob Agents Chemother 2017;17 April.

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

New Agents of Available Classes• Isavuconazole (Basilea, Astellas)

– Broad-spectrum triazole– Oral & IV formulations

• Prodrug (BAL-8557) cleaved to active component (BAL-4815) by plasma esterases

– Long t1/2– Broad spectrum: yeasts, moulds

including Mucorales, endemics (cocci)• Clinical studies

– Phase III clinical trials• Invasive aspergillosis (NCT

00412893)• Rare fungi (NCT 00644049) including

mucormycosis, endemics: cocci• Candidemia (NCT 00413218)

Isavuconazonium (BAL-8557)

Isavuconazole (BAL-4815)

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 FormulationsUT Health Science Center Experience

• 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

Since December 2013Prior to December 2013

Wiederhold NP et al. Antimicrob Agents Chemother 2014;58:424-31.Unpublished data (UT Health Science Center San Antonio Fungus 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

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.

Clinical US trials in development with MSG

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

http://valleyfeversolutions.com/

Shubitz LF, et al. J Infect Dis 2014;209:1949-54; Hector RF, et al. AntimicrobAgents Chemother 1990;34:587-93; Najvar LK, et al. ICAAC, 2015

Novel Cyp51 Inhibitors VT-1129/1161/1598(Viamet Pharmaceuticals, Inc.)

Hoekstra WJ et al. Bioorg Med Chem Lett 2014;24:3455-8.Warrilow AG et al. Antimicrob Agents Chemother 2014:58:7121-7.

VT-1161

• Investigational fungal Cyp51 inhibitors

• MOA similar to azoles

• Highly selective for fungal Cyp51 enzyme vs human Cyp450 enzymes (more so than the azoles)– Kd against fungal Cyp51 ≤39 nM– Failed to inhibit human CYP450 at 50 μM

VT-1129 & VT-1161 In vitro Potency

Antifungal VT-1129 VT-1161 FLU CASCryptococcus neoformans

MIC50 0.015 0.03 2 NTMIC90 0.06 0.125 8 NTGM MIC 0.03 0.04 2.32 NT

Cryptococcus gattiiMIC50 0.06 0.06 2 NTMIC90 0.125 0.25 4 NTGM MIC 0.05 0.08 2.28 NT

Candida albicansMIC50 0.03 0.03 0.125 0.125MIC90 0.03 0.03 0.25 0.125GM MIC 0.03 0.03 0.15 0.1

Potent in vitro activity against Cryptococcus & Candida species

Fothergill AW et al. ICAAC 2010.

Cryptococcal Meningitis - VT-1129

• 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 combinationsWiederhold et al. ICAAC 2010. Wiederhold et al. ECCMID 2011.

Monotherapy Combined with single dose AMBd

Invasive Candidiasis – VT-1161

• Echinocandin and azole 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

High dose – (29/6 mg/kg) – 12 dogs Mean entrance score: 13.3

Mean exit score: 5.0

Mean plasma concentration: 36 ±14 µg/ml*

9/12 dogs (75%) experienced 75%-100% reduction in clinical signs; 1 dog removed for progressive lung consolidation on day 35

66% of dogs had at least one dilution reduction in titer and 66% had reduction or resolution of CBC/serum chemistry abnormalities

Radiographic improvement was mixed, ranging from no change to 90% improvement

Low Dose (10/1.6 mg/kg) – 10 dogs Mean entrance score: 14.4

Mean exit score: 4.7

Mean plasma concentration: 19 ± 8 µg/ml*

All 10 dogs experienced clinical improvement though 1 had radiographic progression and increased titer

60% of dogs had at least 1 dilution reduction in titer and 80% had reduction or resolution of CBC/serum chemistry abnormalities

Radiographic improvement mixed, ranging from no change to 85% improvement

*In vitro MIC90 and MIC range of 2 and 1-4 µg/ml for 52 clinical isolates of Coccidioides

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

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 Meningitisafter Treatment with VT-1161 or VT-1598

Swiss-Webster mice, 65 spores intracerebrally

Days Survived

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3.2 mpk 15988 mpk 1598 20 mpk 1598 20 mpk 1161Placebo

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 fungistaticmechanism 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

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

1598 4 mpk 1598 20 mpk 1161 20 mpk Placebo

Log 1

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Controls died on days 6-9; drug-Tx’d survived Both doses of 1598 significantly reduced brain

fungal burden compared to 1161 (P<0.001) With 20 mg/kg VT-1598, 4/10 animals had

undetectable brain CFUs (range 0-18 CFU/g) Both doses of VT-1598 prevented dissemination

Shubitz L, et al. 60th CSG.

In vitro activity of VT-1598, Posaconazole, & Fluconazole against C. immitis & C. posadasii

Wiederhold NP, et al. Microbe. 2017.

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

Group Control VT-1598 5 mg/kg

VT-1598 15 mg/kg

VT-1598 45 mg/kg

Fluconazole 25 mg/kg

Median Survival (days)

9 days >30 days*p<0.0001

>30 days*p<0.0001**p=0.0044

>30 days*p<0.0001**p=0.0044

29 days*p<0.0001

PercentSurvival (days)

0% 70%*p=0.0031

100%*p<0.0001**p=0.0108

100%*p<0.0001**p=0.0108

40%*p=0.0867

*p-value vs. Control; **p-value vs. FluconazoleWiederhold NP, et al. Poster presentation; 7th Int’l CSG 2017

VT-1598 in Murine CNS Coccidioidomycosis: Survival at Day 30

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.

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– But, > 2000-fold difference in IC50 between

human and fungal enzymes

• Spectrum of activity: highly active against moulds/endemics

F901318 structure

In vitro activity is consistent across all major Aspergillus spp., including A. terreus

F901318 Itraconazole Posaconazole Voriconazole Amphotericin BA. fumigatus

n = 80Geo mean 0.008 1.00 0.30 0.46 0.68Range 0.004-0.016 0.06-16 0.03-16 0.06-16 0.25-1

A. terreusn =45

Geo mean 0.006 0.25 0.14 0.18 1.49Range 0.002-0.008 0.06-1 0.06-2 0.03-0.5 0.125-4

A. flavusn = 50

Geo mean 0.007 0.21 0.087 0.26 0.79Range 0.004-0.008 0.125-1 0.03-1 0.06-1 0.5-2

A. nigern=46

Geo mean 0.007 0.62 0.16 0.51 0.46Range 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

Intrinsic resistanceto ampho B

Other moulds

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

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

F901318 in vitro activity against Coccidioides spp.

Species Isolate No. F901318Coccidioides sp. Cocci1 0.015

Cocci2 0.015Cocci3 ≤0.008Cocci4 0.015Cocci5 ≤0.008Cocci6 0.015Cocci7 ≤0.008Cocci8 ≤0.008Cocci9 ≤0.008

Cocci10 ≤0.008Cocci11 0.015Cocci12 0.03Cocci13 0.015Cocci14 0.015Cocci15 0.03Cocci16 0.015Cocci17 0.015Cocci18 0.03Cocci19 0.015Cocci20 0.06

Data courtesy Nathan Wiederhold, UTHSA Fungus Testing Laboratory & Mike Birch, F2G

• Coccidioides MICs (20 isolates)• Range: ≤0.008-0.03• Geometric mean: 0.015

• Animal models in progress

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 ActivityOrganism 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 EfficacyIn vivo efficacy demonstrated in murine models of invasive fungal infections

Invasive Candidiasis (C. albicans)

Invasive Pulmonary Aspergillosis (A. flavus)

Disseminated Fusariosis (F. solani)

PK parameter Tmax Bioavailability Half-life

1 mg/kg PO X1 0.5 hours 57.5% 2.2 hours

Hata et al. Antimicrob Agents Chemother 2011; 55: 4543 – 51;Wiederhold NP, et al. Antimicrob Agents Chemother 2015;59:690-2.

Efficacy also demonstrated in vitro and in vivo against echinocandin-resistant Candida albicans

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)

Structural modification yields chemical stability & enhanced biological properties

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

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ICAAC 2015: multiple posters

CD101 IV dosing designed to optimize outcome

CD101 MIC90 range for echinocandin–resistant Candida

10

5

00 2 4 6 8 10 12 14 16

CD101 IV200 mg IV Q7D; AUC = 700 µg.hr/mL per dose

Days

Concentrationin Plasma (µg/mL)

For Echinocandinsexposure

improves outcomes

Above graphic is a model

CD101 IV vs. echinocandin-resistant strains

97,740

3,294

4,698

5,212

32,040,000

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

Micafungin 5 mg/kg

CD101 60 mg/kg

CD101 40 mg/kg

CD101 20 mg/kg

Vehicle

P <0.01*

Log10 (CFU/g) in kidney

Heterozygous FKS Mutant (S645P) in Mice48h post infection; MIC (µg/ml) Micafungin & CD101 = 0.5

P <0.01*

P <0.01*

* P value compared with Micafungin 5 mg/kg

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 echinocandinantifungals (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• Phase I/II - generally well tolerated with

good pharmacokinetics (QD)

ICAAC 2015 posters:F-745, A-468, F-744

In vitro Activity of MK-3113 [SCY-078] against Candida species

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

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

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 ergosterol biosynthesis

pathway (ERG1 & ERG11)

• Reduced transcription (50%) when fluconazole or terbinafine combined with trichostatin A (TSA)– Non-specific histone deacetylase inhibitor

Smith, Edlind. Antimicrob Agents Chemother 2002; 46: 3532.

MGCD290(Mirati [MethylGene])

• Synergistic with azoles against yeast & moulds

• 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

MGCD290 Combined with…

Percent Synergy Percent Antagonism

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)

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)

EFFECTOR MOIETYTARGETING MOIETY

Microbe ImmuneComponent

TM EM

Antibacterials

Antifungals

Neutrophil recruiter

IgM/IgG engager

Macrophage recruiter

NK/T cell engagers*

ADCC/CDC

Antivirals

C-403 Dual Mechanism

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

Fungal pathogen

1

Immunomodulatory: EM recruits and initiates an innate immune system response

2

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!

AcknowledgmentsIAAM/AMoID InvestigatorsUTHSCSANathan WiederholdLaura NajvarGabriel CatanoWilliam R. KirkpatrickBrian WickesDavid KadoshAnnette FothergillFungus Testing LabHarbor-UCLAScott FillerAshraf IbrahimJack EdwardsMcGillDon SheppardManchesterPeter WarnDavid DenningCincinnati Melanie CushionUTSAChiungyu Hung

NIAIDDennis DixonRory DuncanMaliha IliasErin ZeituniDona LoveNCATSLiz Ottinger

NIAID ContractsIAAM:N01-AI-30041 (IAAM)AMoID:HHSN27201000038IHHSN27200001 (A13) HHSN27200002 (A05)HHSN27200005 (A93) HHSN27200006 (A98)HHSN27200009 (A107)HHSN27201100018I/ HHSN27200009 (A21)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