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New Antifungal Pipeline 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 eLibrary 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.
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