author by

John eLibraryR. Perfect Duke University Medical Center Durham, NC [email protected] ESCMID

Conflicts: consulting/advisory© committee/research grants. Astellas, Merck, F2G, Cidara, Pfizer, Scynexis, Viamet, Amplyx, Vical, Matinas, Minnetronix author by

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ESCMID © Denning and Bromley. Science 347: 1414-16, 2015 Why? 1. Attributable Mortality author Candidiasis 40% * by Cryptococcosis 20-30% t Aspergillosis 20%□ 2. Fungicidal Activity ( We treat too long for success!!!) 3. Optimize Combination eLibrary 4. Increasing Spectrum of Antifungal Activity (ex. Lomentospora prolificans) 5. Safety

ESCMID * Basettii et al Int. Care Med, 2015 © t Bratton et al PLoS One, 2013 □ Marr et al Ann. Intern Med, 2015 + O N - O OH O O O HO authorH N H N H C 3 N O OHHN + byH3C O HO NH O CH3 N O O H N N HO OH O O OH Biafungin (CD101 Acetate)

HO

Structural modification yields improvedeLibrary chemical & biological properties

• Designed for prolonged PK once weekly dosing in clinical studies potential for improved efficacy vs • Designed for high exposures Candida and Aspergillus infections • Eliminates toxic degradation products potential for improved safety ESCMID intravenous; subcutaneous under • Enables multiple formulations© development ICAAC 2015 Day 14 –STRIVE Study mITT Population Rezafungin Rezafungin Caspofungin 400 mg/400 mg (QWk) 400 mg/200 mg (QWk) 70 mg/50 mg (QD) Response N= 33 N= 31 N= 28 n (%) Overall Response- Success 19 (57.6) 22 (71.0)author 18 (64.3) - Failure 7 (21.2) 6by (19.4) 8 (28.6) - Indeterminate 7 (21.2) 3 (9.7) 2 (7.1)

Excluding Indeterminate Response

Success 19/26 (73.1) 22/28 (78.6) 18/26 (69.2) Failure 7/26 (26.9)eLibrary6/28 (21.4) 8/26 (30.8) Indeterminate response indicates inability to assess outcome due to missing data point(s) Clinical Cure 25 (75.8) 24 (77.4) 20 (71.4) - Failure 7 (21.2) 4 (12.9) 8 (28.6) - Indeterminate ESCMID1 (3.0) 3 (9.7) 0 Excluding Indeterminate© Response Success 25/32 (78.1) 24/28 (85.7) 20/28 (71.4) 16 Failure 7/32 (21.9) 5 4/28 (14.3) 8/28 (28.6) Phase 3 Pivotal Clinical Treatment Trial Global Response: Clinical and Mycological Responseauthor (DRC determined) EOT (latest): Global Global Response: 1° Response Global Response Global ResponseEMA ENDPOINT by All Cause Mortality: Rezafungin Dose Optional dose 1° FDA ENDPOINT Week 1 2 3 4 5 6 7 8 9 400 mg then 1 5 8 15 22 28 35 42 45 52 56 59 200mg qWk n=92 Day eLibrary 70mg 50mg Dose Dose→ Caspofungin Week 1 2 3 4 5 6 7 8 9 70 mg then 50mg qDay =92 1 5 8 15 22 28 35 42 45 52 56 59 Day ESCMID © Day -10 0 10 20 30 40 50 author60 70 80 SOC for Candida and Aspergillus by Rezafungin

SOC for Pneumocyctis (PCP) eLibrary High Candida Pneumocystis Risk of IFI Aspergillus Aspergillus Low Pneumocystis Candida

Pre-engraftment Post-engraftment Transplant Engraftment

Day -10 ESCMID0 10 20 30 40 50 60 70 80 © F2G author by MW = 499

Formula = C28H27FN6O2 Robust low cost multi kg eLibrary GMP scale manufacture Orotomides

ESCMID © author • F901318 is a potent inhibitor of A. fumigatus DHODH DHODH (Dihydroorotate dehydrogenase) is a keyby enzyme involved in pyrimidine biosynthesis • Humans also have this enzyme But, > 2000-fold difference in IC50 between human and fungal enzymes • Pyrimidine inhibition has profound effects on the cell. Affecting; DNA synthesis and cell cycleeLibrary regulation RNA synthesis and protein production Cell wall synthesis Phospholipid synthesis

ESCMID © Oliver et al. PNAS 113:12809-14, 2016. author by 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

A. terreus Geo mean 0.006 0.25 0.14 0.18 1.49 Intrinsic resistance n =45 Range 0.002-0.008 0.06-1 0.06-2 0.03-0.5 0.125-4 to ampho B eLibrary 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 ESCMIDMICs in mg/L , Isolates from UK and Austria © n MIC Range (mg/L) Scedosporium (L.) prolificans 3 <0.06author Scedosporium apiospermum 2 <0.06 Aspergillus lentulus 4 by<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 eLibrary5 <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, ESCMIDCryptococcus, or the Zygomycetes © author by

Azole resistant A. fumigatus oral dosing

eLibrary Amphotericin B resistant A. terreus oral and IV dosing

* Data From A. Seyedmousavi and J Kwon-Chung NIH ESCMID © author by

eLibrary

ESCMID Data From A. Seyedmousavi and J Kwon-Chung NIH © Novel Glucan Synthase Inhibitor (GSI) Key Attributes

• Activity against:author • Candida spp. • Aspergillusby spp. • Pneumocystis spp.

• Active against azole- and most echinocandin- resistant strains eLibrary Structurally distinct • Oral and IV formulations from other GSIs (echinocandins) • Favorable safety profile > 500 exposed CAS • Low risk of drug-drug Interactions • Different enzyme-drug interaction → lower impact of commonESCMID FKS mutations • Extensive tissue distribution • Oral bioavailability© • (Vdss > 8 L/kg) Indications Preclinical Phase 1 Phase 2 Phase 3 author

Invasive Phase 2a completed by Candidiasis

Vulvovaginal DOVE Phase 2b completed Candidiasis eLibrary Invasive Aspergillosis Phase 2 study in start up Combo

FURI (open-label, refractory IFIs) Ongoing Refractory Invasive Fungal Infections ESCMIDCARES (open-label, C. auris) Ongoing © Additional indications under consideration: Chronic Fungal Infections, Prophylaxis SCY-078author MECby Range MEC50 MEC90 A. fumigatus (n=134) <0.06 – 4 <0.06 0.125 A. flavus (n=54) <0.06 – 0.25 <0.06 <0.06 <0.06 – 0.5 <0.06 <0.06 A. niger (n=27) eLibrary A. terreus (n=72) <0.06 – 0.125 <0.06 0.125 Other spp. (n=24) <0.06 – 0.25 <0.06 <0.06 All isolates (n=311) <0.06 – 4 <0.06 0.125 ESCMID ©

Ghannoum M., et al. AAC June 2018; 62(6) • Neutropenic mouse model 110 of disseminated 100 author aspergillosis (IV inoculum) 90 80 by • Treatment for 7 days: 70 60 • SCY-078 PO at 7.5 and 10 50 mg/kg q12h VehicleVehicle F16216 - Vehicle PO q12h

Percent survival Percent 40 SCY-SCY-078078 7.5mg 7.5mg dose dose • Caspofungin IP at 5mg/kg F16216 - SCY-078 7.5mg/kg PO q12h 30 SCY-SCY-078078 10mg 10mg dose dose • Ambisome IV at 10mg/kg eLibraryF16216CaspofunginCaspofungin - SCY-078 10mg/kg PO q12h 20 F16216AmbisomeAmbisome - Caspofungin 5mg/kg IP q24h F16216 - AmBisome 10mg/kg IV q24h • Observation for 14 days 10 0 0 50 100 150 200 250 300 350 Treatment Monitoring • SCY -078 exposure needed Number of hours post-infection for efficacy A. fumigatus (F16216) • AUC0-24hr 15 - ESCMID20 μM•hr © Azole-resistant - TR34 L98H Barat S. at TIMM 2017 Design: Oral SCY-078 – 1000mg (D1), 500mg QD author Echinocandin IV Oral SCY-078 – 1250mg (D1), 750mg QD

3 to 10 Days Randomized by Standard of Care Fluconazole 400mg/d po or Micafungin 100mg IV/d 14 to 28 days (at least 14 days after first negative culture) Results: Pop PK = SCY-078 PO, 750mg QD achieves target exposure (AUC0-24hr of 15 µM·hr) AEs frequency and severity - comparableeLibrary for all groups Global Response at EOT Favorable Reasons for Unfavorable SCY-078 500 mg 1. Never received study drug 5 N = 7 2. Discontinued due to a non-drug related AE SCY-078 750 mg 6 1. Withdrew consent after one dose N = 7 Fluconazole 400 mg ESCMID 1. Died (abdominal sepsis) 5 N =7 © 2. Discontinued (new + blood culture for Candida spp.) Efficacy Evaluation at Day 24 (culture-confirmed VVC)

SCY-078 SCY-078 SCY-078 Fluconazole author % ∆ SCY-078 N 1250mg (D1), 1250mg (D1), (Combined) 150mg (D1) (combined) vs. Rate % 750mg (D2-3) 750mg (D2-5) Fluconazole (n= 24) (n= 26) (n= 50)by (n= 20)

19 19 38 13 Clinical Cure +11% 79.2% 73.1% 76% 65% Efficacy Evaluation at Month 4 Recurrences Requiring 1 1 2 3 -11% Antifungal Therapy 4.2% 3.8%eLibrary4% 15%

• The rate of mycological eradication at Day 24 and Month 4 was 70% and 74% for the SCY-078 combined arms vs. 65% and 60% for the fluconazole arm • There were no severe or serious adverse events in any treatment groups. A higher rate of GI adverse events (e.g.,ESCMID nausea, diarrhea) were reported in the SCY-078 treatment arms, which were mild to moderate© in severity and transient in nature FURI: Phase 3, open-label study in patients with Candida spp. infections that are refractory to or intolerant of approved antifungal agentsauthor • Intended population includes: invasive candidiasis, chronic disseminated candidiasis, severe mucocutaneous candidiasis by Sites opened in the US, Germany, Austria, Netherlands, UK and Spain

CARES: Phase 3, open-label study in patientseLibrary with Candida auris infections • Sites in US and India

Phase 2 study in Invasive Pulmonary Aspergillosis (Start up Phase) • SCY-078 in CombinationESCMID with Azole • Recruiting sites in US and Europe © author by

Alkaline Phosphatase eLibrary APX001A APX001 (Active Moiety) (Prodrug)

ESCMID © author • APX001A is active against Gwt1 enzyme, but by does not inhibit related mammalian protein, PIGW • Gwt1 is an early step in glycosylphosphatidylinositol (GPI)-anchor biosynthesis eLibrary • Gwt1 is essential for trafficking and anchoring mannoprotein to the outer cell wall • Mannoprotein is required for cell wall integrity, adhesion, pathogenicity, and evading host immune system recognition Modified from ESCMID 2012 McLellan et al, ACS Chem Biol. © • APX001A has shown very good activity (low MIC/MEC) against most strains tested, including strains resistant to existing treatments author by • APX001A is broadly active against Candida: MIC90 range; 0.008 - 0.06 µg/mL

• Significant activity vs C. auris (MIC90 0.03 µg/mL; 0.06 µg/mL) • APX001A has shown less activity against C. krusei, a rare infection

• APX001A is broadly active against the more common Aspergillus (MEC90 ≤0.06 μg/mL), with rarer Aspergillus specieseLibrary demonstrating similarly good activity

• Rare molds: • Generally has shown good activity against Scedosporium and Fusarium spp. • Mucorales MEC values are higher but in vivo activity is promising ESCMID ©

23 • APX001 survival 80-100% author • APX001 reduces lung, kidney and brain CFUs by

*P ≤ 0.0001 vs vehicle control †P ≤ 0.05 versus anidulafungin

eLibrary

ESCMID © 2018 Hager et al, AAC (62) APX001 Phase Population authorn Dosing Endpoints AML patients • Multiple doses in target patient populationby Safety and PK in 103 1b • APX001 in combo with Standard of care 20 IV & oral at-risk patient Enrolling chemo & azole prophylaxis population

Candidemia • Enriched for resistance IV with 1 – Clearance in 201 2 POC - Candida auris 20 switch to blood - Candida glabrata eLibrary oral 2 – Safety Invasive Aspergillus & rare molds • Enriched for rare molds IV with 1 – Survival at In Startup Startup In 202 2 POC - Scedosporium 100 switch to day 42 - Fusarium - Mucorales fungi oral 2 - Safety - resistant Aspergillus ESCMID © • First-in-class, highly differentiated product for life threatening invasive fungal infections • Novel target and MOA with broad-spectrum activity, including MDR strains • Efficacy demonstrated in multiple animal models author  Wide tissue distribution (lung, kidney, brain, eye) • Potential to be first novel antifungal since 2001by • Completed Phase 1 clinical development IV and Oral • Entering Phase 2 development in 2018 • Anticipate streamlined development and accelerated regulatory pathway in multiple indications  Orphan Drug designations foreLibrary 6 indications, including pathogens of highest mortality  Qualified Infectious Disease Product (QIDP) designations in 4 indications, allowing for accelerated regulatory review and extended market exclusivity. Recent FDA approval of Cryptococal meningitis as neglected Tropical Disease

ESCMID 26 © • Disseminated model C. neoformans H99, non-immunocompromisedauthor ─ Treatment initiated 1 h post-infection and continued for 7 days. ─ 100 mg/kg ABT administered 2 h prior to each APX dose by • Administration of APX2096 results in striking reductions in both brain and lung CFU vs APX001 and APX2097 – Sterilization of lung tissue/near sterilization of brain eLibrary

*P ≤0.05; ** P ≤0.01

ESCMID © author APX2039 (active moiety of APX2096 prodrug) is 32-fold more potent thanby APX001A vs Cryptococcus, but is less active vs C. albicans and A. fumigatus eLibrary

ESCMID © • Disseminated model C. neoformans H99, non-immunocompromisedauthor ─ Treatment initiated 24 h post-infection and continued for 7 days. ─ 100 mg/kg ABT administered 2 h prior to each APX2096 dose by ─ Mice were sacrificed 24 h after the last dose • APX2096 demonstrated activity better than or equal to amphotericin B in both lung and brain

eLibrary

*P ≤0.05; ** P ≤0.01

ESCMID © • Metalloenzymes are proven drug targets author − ~10% of marketed drugs by Backbone block metalloenzymes of drug • Many blockers contain a metal- binding group that inhibits enzyme activity eLibrary Metal-binding group of drug • Viamet’s insight: The metal- Metal in binding group in many drugs has enzyme not been optimized ESCMID © 2015 Confidential © Active Site of Metalloenzyme Property of Viamet Viamet acquired by Nova Quest Capital Management Vt 1161 for onychomycosis/vaginal Pharmaceuticals, Inc. Candidiasis author by

eLibrary

• Crystal structure of VT-1598 and A. fumigatus CYP51  4- nitrogen of the VT-1598’s tetrazole interacts with heme iron  H-bond betweenESCMID phenoxymethyl oxygen and invariant H374 provides rationale© for broad and potent antifungal coverage Galina Lepesheva, Vanderbilt University; published in Hargrove et al. AAC, 2017 Large Panel of Clinical Mold Isolates, Geometric Mean MIC* (µg/ml)

Species (# clinical isolate) VT-1598 POS authorVOR Aspergillus fumigatus (N=41) 0.87 0.41by 0.40 FLU-resistant A. fumigatus (N=9) >16 2.3 11

A. flavus (N=11) 0.68 0.57 0.83

A. terreus (N=11) 0.53 0.30 0.57 A. niger (N=12) eLibrary1.8 1.0 1.3 Species (# clinical isolate) VT-1598 POS AMB

Rhizopus arrhizus (N=11) 3.5 1.1 0.60

*MIC = 100% inhibition of growth; POS = posaconazole; VOR = voriconazole; AMB = amphotericin B

ESCMID Nathan Wiederhold,© Fungal Testing Lab (UTHSCSA); published in Wiederhold et al. JAC 2017 Large Panel of Clinical Endemic Isolates, Geometric Mean MIC*author (µg/ml) Species (# clinical isolate) VT-1598 FLUby POS Coccidioides spp. (N=40)** 0.22 7.6 0.17

Histoplasma capsulatum (N=13) 0.089 23 0.049

Blastomyces dermitiditis (N=12) 0.057 14 0.081

*MIC = 80% inhibition of growth. **Equal mix ofeLibrary C. posadasii and C. immitis , with MIC potencies essentially the same; FLU = fluconazole; POS = posaconazole

ESCMID Nathan Wiederhold,© Fungal Testing Lab (UTHSCSA); published in Wiederhold et al. JAC 2017 33 3.25Log10 7.74Log10 3.39Log10 2.36Log10 1.82Log10 3.16Log10 3.86Log10 109 cfu/g cfu/g cfu/g cfu/g cfu/g cfu/g cfu/g P < 0.0001 <0.0001 P < 0.0001 P < 0.0001 P < 0.0001 108

107 106 author 105

104 by CFU/g brain

103

102

101

100 eLibrary

Pre-treatment controlVehicle control PO QD VT-1598 5mg/kg PO QD VT-1598 15mg/kg PO QDVT-1598 50mg/kg PO QD AmBisome 10mg/kg IV QD Fluconazole 25mg/kg PO BD

• VT-1598 mid and high doses reduced burden to below level at the start of treatment • VT-1598 plasma levelsESCMID 1-day after last dose: 2.2 µg/ml (low dose), 6.7 µg/ml (mid dose), and 17 µg/ml© (high dose) author by

eLibrary

• At 20 mg/kg VT-1598, 4/10 animals had undetectable CFUs • No dissemination to lungs, spleen or liver in VT-1598 treated mice c/w 70-80% ofESCMID control animals © • Invasive Candidiasis  Acute tail-vein fungal burden model: dose-dep. decreases in kidney fungal burden, with top dose suppressing CFU/g to below levels prior to dosing author  Survival model: dose-dep increase inby survival (70% survival at 3 mg/kg to 100% survival at 30 mg/kg); 0% survival in vehicle control • Invasive Aspergillosis  Acute tail-vein fungal burden model: dose-dep. decreases in kidney fungal burden  PK/PD studies demonstrateeLibrary AUC/MIC ratios in between those published for posaconazole and isavuconazole (2018 IDWeek) • Invasive Mucormycosis  VT-1598 treatment significantly reduced lung fungal burden andESCMID prolonged survival in a Rhizopus oryzae inhalation© model 36 • Discovered by Astellas Pharma from leaf litter fungus in Malaysia in 2007 author  Extensive nonclinical development studies bywere conducted  Vical in-licensed in March 2015 • Naturally-occurring siderophore isolated from Acremonium • Cyclic hexapeptide resembling ferrichrome • IV formulation eLibrary

ESCMID © VL-2397 Antifungal Plasma Cell Wall • VL-2397 Membrane Echinocandins: represents a potentially new Azoles: β-glucan synthesisauthor Ergosterol inhibitor class of antifungal synthesis by agents inhibitor Polyenes: • Active transport Ergosterol into A. fumigatus binding; occurs via Sit1 membrane Intracellular Target Mammalian disruption eLibrarySit1 cells lack Sit1 transporter VL-2397 • Activity results from effect on an intracellular target ESCMID © Adapted from Denning Science 2015 VL-2397 Antifungal Control VL-2397 1 x MIC Rapid Onset of authorVL-2397 16 x MIC VRCZ 1 x MIC Antifungal by VRCZ 16 x MIC Activity in Vitro

eLibrary Control Activity vs. VL-2397 4 mg/kg BID VL-2397 8 mg/kg BID Azole-Resistant PSCZ 10 mg/kg BID Aspergillus N = 10 mice /group in Vivo ESCMID PSCZ: Posaconazole ©

Nakamura, ICAAC, 2014 VL-2397 Antifungal • Global, multicenter, randomized, open-label study • N=200 adults with AML, ALL or allo HCT recipientsauthor • 2:1 randomization VL-2397 to active comparatorby  Comparator: Physician’s choice of voriconazole, isavuconazole or liposomal amphotericin B • 6 weeks of antifungal treatment  4 weeks of VL-2397 followedeLibrary by 2 weeks of comparator • Primary endpoint: All-cause mortality at 4 weeks  Key secondary endpoint: ACM at 6 weeks • Noninferiority design ESCMID © VL-2397 Antifungal • Adjunctive Sertraline* for treatment of authorHIV-associated cryptococcal meningitis (ASTRO-CM)by

• Tamoxifen for cryptococcosist • Amphotericin B formulationseLibrary (cochleates/umbrellas) + • Suba Itraconazole • Calcineurin InhibitorsESCMID *Zhai et al AAC 56:3758-66, 2012 © t Butts et al PLoS one 10:e0125927 + Janout et al Bio Conj. Chemistry, 2015 • Trial stopped for futility after author enrolling 460 of planned 550 by subjects • 18-week mortality − 52% in sertraline group vs. 400mg − 46% in the placebo group − Hazard ratio for sertraline: 1.21 eLibrary (95% CI, 0.93-1.57; p=0.15) • Mortality was similar among HIV therapy naïve and experienced

ESCMID

© Rhein J et al. CROI 2018 • Selective Estrogen Receptor Modulator (SERM)author • Orally bioavailable by • Widely available • Safe and well tolerated eLibrary • Extensive 4 decades of patient experience (1977) • Off-patent US$ 0.0325 for 20mg tab ESCMID © Courtesy of Prof. Jeremy Day author by

eLibrary

ESCMID

Courtesy of Prof.© Jeremy Day Failed to Improve author by

eLibrary

ESCMID © • Activity of oral cAMB + flucytosine (5FC)= IV ampho + 5FC author by

eLibrary

ESCMIDData courtesy of Peter Williamson, NIAID © • Phase 2 study of MAT2203 was a multi-center trial of 137 women with vulvovaginalauthor candidiasis by • cAMB 200 mg/day x5 days => 52% clinical cure • cAMB 400 mg/day x5 days => 55% clinical cure eLibrary • F luconazole 150 mg => 75% clinical cure ESCMID • Tolerability© / Safety were excellent • Phase 2 study of MAT2203 was a multi-center trial of 137 women with vulvovaginalauthor candidiasis by • cAMB 200 mg/day x5 days => 36% mycologic cure • cAMB 400 mg/day x5eLibrary days => 32% mycologic cure • Fluconazole 150 mg => 81% mycologic cure ESCMID • Vaginal ©candidiasis is not an ideal model • Proprietary lipid carrier system • Lymphatic transport mechanism Expanding theauthor Amphotericin B market involved with an oralby reformulation • Development of oral Amphotericin B – efficacy demonstrated in Potential to deliver other highly multiple pre-clinical models insoluble assets in carrier system • A Phase 1, Placebo-controlled, Dose Escalation Study in Healthy Volunteers completed eLibrarySignificant non-dilutive funding to date (~$2M CDN) • Study met its primary endpoint of safety and tolerability • PK results demonstrate enhanced plasma AUC measures versus direct competitionESCMID • Phase II study© pending (Q4 2018)

49 More predictable absorption and improved bioavailability  16 healthy adult volunteers  Subjects received 2 capsules of SUBATM-itraconazole or conventional 100mg itraconazole twice daily for 14.5 days under fed conditions  The relative bioavailability (Frel) of the SUBATM-itraconazile 65mg capsule was approximatelyauthor 1.8 that of the conventional 100mg capsule making the extent of itraconazole exposure equivalent.  Subjects receiving SUBATM-itraconazole 65mg, not only achieved therapeutic levels of 1000ng/ml, but also went on to reach levels of 1200ng/ml or higher by

TM Relative Bioavailability of SUBA -itraconazole to % of Patients with Ctrough Geometric Mean Conventional Itraconazole Under Fed Conditions of 1034 ng/ml or higher

90%

1500 81% 1400 eLibrary80% 1300 1200 70%

1100 1000 60% 900 50% 800 44% 700 40% 600 500 30%

Plasma Itraconazole (ng/mL) Itraconazole Plasma 400 300 20% 200 100 10% 0 0 1 2 3 4 5 6 ESCMID7 8 9 10 11 12 13 14 15 0% Time Relative to First drug administration (Day) SUBA™-itraconazole Conventional itraconzaole A: SUBA-itraconazole 2x65 mg capsules 65mg Capsules 100mg Capsule B: Sporanox® 2X100 mg capsules ©

FOR SCIENTIFIC EXHANGE ONLY, NON-PROMOTIONAL, DO NOT COPY, MODIFY, OR DISSEMINATE. All trademarks ™ and registered trademarks ® are the property of their respective owners Is a unique validated spray drying technology developed by Mayne Pharma to SUBATM improve the bioavailability of poorlyauthor soluble drugs by Is a novel formulation of itraconazole developed to address the core SUBATM-itraconazole pharmacokinetic issues generally associated with the conventional itraconazole formulation

Produces microencapsulated particles of itraconazole dispersed in a polymer TM matrix, that are less soluble in the acidic environment of the stomach but have The SUBA process significantlyeLibrary improved solubility in the higher pH of the small intestine. This results in improved absorption compared to conventional itraconazole

ESCMID

© Itraconazole drug substance SUBATM-itraconazole prior to formulation after formulation

FOR SCIENTIFIC EXHANGE ONLY, NON-PROMOTIONAL, DO NOT COPY, MODIFY, OR DISSEMINATE. All trademarks ™ and registered trademarks ® are the property of their respective owners Design: Phase IIB multi-center, open-label, randomized comparative trial Expected Site Distribution: Population: • ~ 80 adults infected with one of the endemic mycoses living in the author United States and Central/South America approximately • 40 Histoplasmosis, 20 Coccidioidomycosis, 20 other endemic mycoses)by Principle George R. Thompson III, M.D.; Andrej Spec, M.D.; Peter G. Pappas, M.D Investigators:

Timeline: FPI: AUG 2018; LPO: JUN 2019 (estimated) Objectives: PK, tolerance, safety, and efficacy of SUBA-Itraconazole study drug vs. conventional itraconazole oral capsules

Stage I - Randomized, Open-Label, Parallel eLibrary Primary Objective Secondary Objective • PK at Day 14 • PK at Day 7 (new) • Tolerability at Day 42 • PK at Day 42 • Efficacy by Day 42 • Safety by Day 42 • QOL (including hospital/ICU visits) Assessments by Day 42

Stage II – Open Label Extension Primary Objective Secondary Objective • Efficacy by Day 180 ESCMID• Safety by 180 • Tolerability by Day© 180 • QOL (FS-12) Assessments by Day 180 (including hospital/ICU visits)

FOR SCIENTIFIC EXHANGE ONLY, NON-PROMOTIONAL, DO NOT COPY, MODIFY, OR DISSEMINATE. All trademarks ™ and registered trademarks ® are the property of their respective owners • Calcineurin is required for virulence forauthor Aspergillus, Candida, and Cryptococcus by • Calcineurin is required for drug resistance Calcineurin inhibitors exhibit synergy with other • eLibrary antifungals in vitro and in vivo • Known molecules have high potency for calcineurin inhibition and are FDA approved drugs ESCMID • Chemistry© to modify scaffold is well-presented author

Cytoplasm by

P FKBP12 Crz1 Crz1 eLibrary complex FK506 Calcineurin 1. FK506/FKBP12 complex inhibits calcineurin 1. FK506/FKBP12 complex inhibits calcineurin Crz1 ESCMID2. Transcription factor Crz1 is not dephosphorylated 2. Transcription factor Crz1 is not dephosphorylated and consequently does not enter the nucleus and consequently does not enter the nucleus Nucleus© 3. Fungal cell wall synthesis and repair are disrupted Compound IL-2 IC50 A. fumigatus "Therapeutic Index" Suppression MEC (μg/mL) = IL2 IC50 /MEC (nM) author

FK506 0.05 0.06 by0.9

APX1132 42 1 42

APx1170 >10,000 eLibrary>32 NA

APX1280 110 4 28 ESCMID © Tokoyama NH NH O N O author NH NH 2 by 2 4-{3-[1-(3-{4-[amino(imino)-methyl]phenoxy}propyl)piperidin-4yl] propoxy}benzamidine

Novel mechanism of action Selective transportation/accumulationeLibrary into fungal cells and inhibition of mitochondrial membrane potential Broad and potent in vitro/vivo antifungal activity against CandidaESCMIDspp., Cryptococcus spp. and Aspergillus© spp. including resistant strains  T-2307 showed broad and potent antifungal activity against pathogenic yeasts and fungi.

MIC*(µg/mL) Organism author T-2307 FLC VRC MCFG AMB C. albicans ATCC 10261 0.001 0.125 by0.0039 0.0313 1 C. glabrata ATCC 90030 0.0039 8 0.25 0.0313 1 C. guilliermondii IFO 10279 0.002 4 0.0625 0.5 0.5 C. krusei IFO 0584 0.001 32 0.125 0.125 2 C. parapsilosis NBRC 10219 0.001 1 0.0313 2 1 C. tropicalis IFO 1400 0.0005eLibrary2 0.0625 0.0625 1 Crypt. neoformans ATCC 90112 0.0078 1 0.0313 >64 1 A. flavus NBRC 6343 0.5 >64 0.5 0.0625 2 A. fumigatus ATCC 16424 0.125 >64 0.25 0.0313 1 A. nidulans NBRC 33017 0.0156 64 0.125 0.0313 2 A. niger NBRC 33023 ESCMID0.0625 >64 0.5 0.0313 2 A. terreus NBRC 33026© 0.125 >64 0.5 0.0313 2 * Microdilution method recommended by CLSI Mitsuyama J, et. al. Antimicrob. Agents Chemother. 2008; 52: 1318-24  T-2307 markedly improved survival rate until Day 56. Administration (1W) author T-2307 2 mg/kg 100 by *** 80 ** *** *** T-2307 1 mg/kg

60 AMB 1 mg/kg * 40 FLC 40 mg/kg Survival rate Survival(%) rate eLibrary

20 Control

0 0 10 20 30 40 50 *P<0.05, **P<0.01, Time after infection (days) ***P<0.001 (logrank test) ESCMID  Animals: Immunosuppressed mice (4w-old male ICR mice, N=10)  Infection: Intranasal infection rd  Administration:© Once a day for 7 days from Day 7 post infection 53 ICAAC (2013) M-771  Route; T-2307 and FLC, s.c.; AMB, i.v.  Evaluation: Survival rate until Day 56 post infection author O

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• The Antifungal Attack is alive and vibrant !! eLibrary

• Potential to be realized is here – game on !!! ESCMID ©