Slide 1: SCY-247 is efficacious in a murine model of invasive candidiasis caused by Candida glabrata
The novel second-generation IV/oral triterpenoid SCY-247 is efficacious in an experimental murine model of invasive candidiasis caused by Candida glabrata Nathan P. Wiederhold, PharmD Fungus Testing Laboratory Department of Pathology & Laboratory Medicine South Texas Reference Laboratories
Slide 2: Disclosures
Disclosures Funding to FTL Collaborations through NIH • bioMerieux • Amplyx • Bruker • F2G • F2G • Fujifilm/Toyama/Appili • Mycovia • Scynexis • Mycovia • Scynexis • Sfunga Member, CLSI Antifungal Susceptibility Subcommittee
Slide 3: Candida glabrata as a priority fungal pathogen
• Candida glabrata (Nakaseomyces glabratus) identified as a priority fungal pathogen by WHO • 2nd most common Candida species cultured from patients with invasive disease at many institutions 2022 WHO Fungal • Reduced susceptibility to fluconazole Priority Pathogens List to Guide Research, • Elevate
Slide 4: SCY-247
SCY-247 • Semi-synthetic derivative of natural product SCY-247 • Potent (1,3)-β-D-glucan synthase inhibitor (GSI) • Same target as echinocandin antifungals • 2nd member of a new class of antifungals (triterpenoid – same class as ibrexafungerp [SCY-078]) • Broad-spectrum demonstrated against limited
Slide 5: Objective
Objective • Evaluate the activity of SCY-247 against Candida glabrata • In vitro activity against wild-type and resistant C. glabrata (including strains with defined FKS point mutations) • In vivo activity in an established murine model of disseminated candidiasis
Slide 6: Methods – In vitro Activity
Methods – In vitro Activity • CLSI M27ed4 broth microdilution method • >50% inhibition of growth at 24 hours at 35°C • 50 Candida glabrata clinical isolates • Submitted to the UT Health San Antonio Fungus Testing Laboratory for clinical diagnostic testing • 10 echinocandin-susceptible isolates • 40
Slide 7: Results – In vitro Activity
Results – In vitro Activity MIC Echinocandin Echinocandin Parameter Susceptible Resistant MIC Range 0.06 – 0.25 0.06 - 4 MIC50 0.125 0.25 MIC90 0.25 0.5 GM MIC 0.133 0.406 Mode 0.125 0.25
Slide 8: Methods – Infection Model
Methods – Infection Model • Neutropenic male ICR mice • 5-fluorouracil 5 mg/mouse IV 1 day prior to IV infection • Infecting organism – C. glabrata 05-761 • Echinocandin-susceptible clinical isolate • IV inoculation Agent SCY-247 SCY-247 Fluconazole Caspofungin 50% inhibition 100% inhibition 50% inh
Slide 9: Methods – Infection Model
Methods – Infection Model • Treatment Groups • 24-hour fungal burden • Vehicle control – 0.5% w/v methyl cellulose • SCY-247 16 mg/kg orally twice daily • SCY-247 32 mg/kg orally twice daily • SCY-247 48 mg/kg orally twice daily • Fluconazole 20 mg/kg orally twice daily • Caspofungin 5 mg/kg by intr
Slide 10: Results – In vivo Activity
Results – In vivo Activity • Significant and dose- dependent reductions in kidney fungal burden observed with SCY-247 • Reductions vs. 24 hr control 1.14-2.84 log10 CFU/g • Cidal activity • Significant reductions also observed with caspofungin Group 24-hour Vehicle SCY-247 SCY-247 SCY-247 Fluconazol
Slide 11: Results – In vivo Activity
Results – In vivo Activity • Significant and dose- dependent reductions in lung fungal also burden observed with SCY-247 • Reductions vs. vehicle control 0.34-1.73 log10 CFU/g • Cidal activity with SCY-247 16 and 32 mg/kg doses • No reductions observed with caspofungin Group 24-hour Vehicle SCY-247
Slide 12: Summary and Future Steps
Summary and Future Steps • SCY-247 was effective at reducing fungal burden • Significant reductions occurred in both the kidneys and lungs of neutropenic mice infected with an echinocandin susceptible strain of C. glabrata • Cidal activity (>1 log10 reduction in CFU counts) achieved • In vivo result
Slide 13: Acknowledgements
Acknowledgements Patterson Lab Fungus Testing Laboratory Tom Patterson, MD Hoja Patterson Laura Najvar Rosie Jaramillo Scynexis Marcos Olivo David Angulo, MD Katyna Borroto-Esoda, PhD Tom Chen Steven Wring, PhD This project utilized the preclinical services program offered by the National institute