754. Olorofim for treatment of invasive fungal infections (IFI) due to moulds in patients with limited or no treatment options: Interim results from a Phase 2b open-label study (NCT03583164, Study 32)

Abstract Background Olorofim, the first orotomide antifungal, selectively inhibits fungal dihydroorotate dehydrogenase (DHODH), a key enzyme in pyrimidine biosynthesis. Olorofim is active against Aspergillus (including azole-resistant and cryptic species), resistant moulds (e.g., Lomentospora prolificans, Scopulariopsis) dimorphic fungi Coccidioides). The drug given orally cleared by multiple CYP450 isoenzymes. Serial images via bronchoscope of Scopulariopsis infection at anastamosis lung transplant patient, pre- post-olorofim therapy. After transplant, airway obstruction anastomosis due to was unresponsive available antifungal agents. clear day 10 on olorofim monotherapy. Infection cured with 84 days olorofim. Methods Patients limited or no treatment options for proven invasive mycoses probable pulmonary aspergillosis (IA, as per 2020 EORTC-MSGERC criteria) received (loading dose 150mg BID 1, followed 90mg BID) up 90 days, extended therapy beyond allowed. primary endpoint DRC-adjudicated overall response rate pathogen 42 using EORTC-MSG criteria. Results At database lock 100 cases, infecting were species (53, including 13 L. prolificans (17), Scedosporium (11), Coccidioides other (8). Success (complete partial response) 44% 39% 84. When stable disease counted success, success 69% 59% respectively. Response seen patients highly active, uncontrolled (Figure). Overall all-cause mortality 14% 19% respectively (IA: 23% 30%; non-IA infections 4% 6% respectively). Safety: well tolerated over 84d median dosing duration (max 722 days). Altered hepatic biochemistry possibly 8% study subjects managed reduction/pause led discontinuation 2%. Mild, self-limiting GI intolerance noted Conclusion an oral, mechanistically novel anti-mould agent activity range mould which are difficult treat. has positive risk-benefit profile well-defined population considered all approved antifungals. Disclosures Johan A. Maertens, MD PhD, F2G Ltd: Advisor/Consultant|Gilead Sciences Advisor/Consultant|Mundipharma: Advisor/Consultant|Pfizer Inc: Advisor/Consultant George R. Thompson, III, MD, Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Astellas: Advisor/Consultant|Astellas: Support|Cidara: Advisor/Consultant|Cidara: Support|F2G: Advisor/Consultant|F2G: Support|Merck: Support|Pfizer: DSMB|Scynexis: Advisor/Consultant|Scynexis: Support Andrej Spec, MSCI, Astellas: Sarah P. Hammond, F2G: Support|GSK: Support|pfizer: Bart Rijnders, Lewis White, Associates Cape Cod: Honoraria|F2G: Advisor/Consultant|Gilead: Support|IMMY: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria Oliver Cornely, Prof. Dr., Abbott: Honoraria|Abbvie: Advisor/Consultant|Actelion: Board Member|Al-Jazeera Pharmaceuticals: Honoraria|Allecra Therapeutics: Member|Amplyx: Honoraria|Basilea: Advisor/Consultant|Basilea: Support|Biocon: Advisor/Consultant|Biosys: Advisor/Consultant|BMBF: Member|Cidara: Expert Testimony|Cidara: Support|CoRe Consulting: Stocks/Bonds|Da Volterra: Advisor/Consultant|DLR: Support|DZIF: Support|Entasis: Member|EU Directorate-General Resarch Innovation: Support|German Patent Trade Mark Office: German patent (DE 2021 113 007.7)|Gilead: Support|Grupo Biotoscana/United Medical/Knight: Honoraria|Hikma: Honoraria|IQVIA: Member|Janssen: Member|Matinas: Advisor/Consultant|Matinas: Support|MedPace: Advisor/Consultant|MedPace: Support|MedScape: Honoraria|MedUpdate: Honoraria|Menarini: Advisor/Consultant|Merck/MSD: Support|Merck/MSD: Honoraria|Molecular Partners: Advisor/Consultant|MSG-ERC: Support|Mylan: Honoraria|Noxxon: Advisor/Consultant|Octapharma: Support|Paratek: Member|Pardes: Honoraria|Projektträger Jülich: Support|PSI: Advisor/Consultant|PSI: Member|Pulmocide: Member|Scynexis: Support|Seres: Advisor/Consultant|Shionogi: Member|Wiley (Blackwell): Editor-in-Chief, Mycoses Lesley Fitton, BSc, Employee|F2G Stocks/Bonds Aaron Dane, MSc, Advisor/Consultant|AN2 therapeutics: Advisor/Consultant|Artizan: Advisor/Consultant|ContraFect: Advisor/Consultant|Correvio: Advisor/Consultant|Davolterra: Advisor/Consultant|Destiny Pharma: Advisor/Consultant|Entasis: Advisor/Consultant|F2G Limited: Advisor/Consultant|GSK: Advisor/Consultant|Humanigen: Advisor/Consultant|Kymab: Advisor/Consultant|Modis: Advisor/Consultant|Orca: Advisor/Consultant|Phico: Advisor/Consultant|Pled Advisor/Consultant|Rare Thyroid: Advisor/Consultant|Roche: Advisor/Consultant|Sinovent: Advisor/Consultant|Spero Advisor/Consultant|Transcrip: Advisor/Consultant|Venatorx: John H. Rex, Advent Life Sciences: Operating Partner|Advent Ownership Interest|AMR Action Fund: Advisor/Consultant|AstraZeneca: Stocks/Bonds|Basilea Pharmaceutica: Advisor/Consultant|Bugworks Research, Inc.: Advisor/Consultant|F2G, Employee|F2G, Stocks/Bonds|Forge Advisor/Consultant|GlaxoSmithKline: Honoraria|Sumitovant: Sharon C. Chen, PhD MBBS, PTy Support|MSD Australia: Support.