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)
Authors: Maertens Johan A , Thompson George R , Spec Andrej , Hammond Sarah P , Rijnders Bart , Lewis White P , Cornely Oliver A , Fitton Lesley , Dane Aaron , Rex John H , Chen Sharon C 
Published: December 2022

Abstract

Background
Olorofim, the first orotomide antifungal, selectively inhibits fungal dihydroorotate dehydrogenase (DHODH), a key enzyme in fungal pyrimidine biosynthesis. Olorofim is active against Aspergillus (including azole-resistant and cryptic species), resistant moulds (e.g., Lomentospora prolificans, Scopulariopsis) and dimorphic fungi (e.g., Coccidioides). The drug is given orally and cleared by multiple CYP450 isoenzymes.
Serial images via bronchoscope of Scopulariopsis infection at the anastamosis in a lung transplant patient, pre- and post-olorofim therapy.
After lung transplant, airway obstruction at the anastomosis due to Scopulariopsis was unresponsive to available antifungal agents. The airway was clear by day 10 on olorofim monotherapy. Infection was cured with 84 days of olorofim.

Methods
Patients with limited or no treatment options for proven invasive mycoses or probable pulmonary invasive aspergillosis (IA, as per 2020 EORTC-MSGERC criteria) received olorofim (loading dose of 150mg BID on day 1, followed by 90mg BID) for up to 90 days, with extended therapy beyond day 90 allowed. The primary endpoint was DRC-adjudicated overall response rate by pathogen at day 42 using the EORTC-MSG response criteria.

Results
At database lock for the first 100 cases, infecting fungi were Aspergillus species (53, including 13 azole-resistant species), L. prolificans (17), Scedosporium (11), Coccidioides (11), and other fungi (8). Success (complete or partial response) was 44% at day 42 and 39% at day 84. When stable disease was counted as success, the success rate was 69% and 59% respectively. Response was seen in patients with highly active, uncontrolled infection (Figure). Overall all-cause mortality was 14% and 19% at day 42 and 84 respectively (IA: 23% and 30%; non-IA infections 4% and 6% respectively).
Safety: Olorofim was well tolerated over the 84d median dosing duration (max 722 days). Altered hepatic biochemistry possibly due to olorofim was seen in 8% of study subjects and managed by dose reduction/pause and led to discontinuation in 2%. Mild, self-limiting GI intolerance was noted in 2%.

Conclusion
Olorofim is an oral, mechanistically novel anti-mould agent with activity against a range of mould infections which are difficult to treat. Olorofim has a positive risk-benefit profile in a well-defined population of patients with infections due to moulds including species considered resistant to all approved antifungals.

Disclosures
Johan A. Maertens, MD PhD, F2G Ltd: Advisor/Consultant|Gilead Sciences Ltd: 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: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Merck: Grant/Research Support|Pfizer: DSMB|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support Andrej Spec, MD, MSCI, Astellas: Grant/Research Support Sarah P. Hammond, MD, F2G: Advisor/Consultant|F2G: Grant/Research Support|GSK: Grant/Research Support|Merck: Grant/Research Support|pfizer: Advisor/Consultant|Scynexis: Grant/Research Support Bart Rijnders, MD, PhD, F2G: Advisor/Consultant P. Lewis White, PhD, Associates of Cape Cod: Honoraria|F2G: Advisor/Consultant|Gilead: Grant/Research Support|IMMY: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria Oliver A. Cornely, Prof. Dr., Abbott: Honoraria|Abbvie: Advisor/Consultant|Actelion: Board Member|Al-Jazeera Pharmaceuticals: Honoraria|Allecra Therapeutics: Board Member|Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Astellas: Honoraria|Basilea: Advisor/Consultant|Basilea: Grant/Research Support|Biocon: Advisor/Consultant|Biosys: Advisor/Consultant|BMBF: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Board Member|Cidara: Expert Testimony|Cidara: Grant/Research Support|CoRe Consulting: Stocks/Bonds|Da Volterra: Advisor/Consultant|DLR: Grant/Research Support|DZIF: Grant/Research Support|Entasis: Board Member|EU Directorate-General for Resarch and Innovation: Grant/Research Support|F2G: Grant/Research Support|German Patent and Trade Mark Office: German patent (DE 10 2021 113 007.7)|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Grupo Biotoscana/United Medical/Knight: Honoraria|Hikma: Honoraria|IQVIA: Board Member|Janssen: Board Member|Matinas: Advisor/Consultant|Matinas: Grant/Research Support|MedPace: Advisor/Consultant|MedPace: Grant/Research Support|MedScape: Honoraria|MedUpdate: Honoraria|Menarini: Advisor/Consultant|Merck/MSD: Grant/Research Support|Merck/MSD: Honoraria|Molecular Partners: Advisor/Consultant|MSG-ERC: Advisor/Consultant|Mundipharma: Grant/Research Support|Mylan: Honoraria|Noxxon: Advisor/Consultant|Octapharma: Advisor/Consultant|Octapharma: Grant/Research Support|Paratek: Board Member|Pardes: Advisor/Consultant|Pfizer: Grant/Research Support|Pfizer: Honoraria|Projektträger Jülich: Grant/Research Support|PSI: Advisor/Consultant|PSI: Board Member|Pulmocide: Board Member|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support|Seres: Advisor/Consultant|Shionogi: Board Member|Wiley (Blackwell): Editor-in-Chief, Mycoses Lesley Fitton, BSc, F2G Ltd: Employee|F2G Ltd: Stocks/Bonds Aaron Dane, MSc, Amplyx: Advisor/Consultant|AN2 therapeutics: Advisor/Consultant|Artizan: Advisor/Consultant|Cidara: 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|Pfizer: Advisor/Consultant|Phico: Advisor/Consultant|Pled Pharma: Advisor/Consultant|Rare Thyroid: Advisor/Consultant|Roche: Advisor/Consultant|Scynexis: Advisor/Consultant|Sinovent: Advisor/Consultant|Spero Therapeutics: Advisor/Consultant|Transcrip: Advisor/Consultant|Venatorx: Advisor/Consultant John H. Rex, MD, Advent Life Sciences: Operating Partner|Advent Life Sciences: Ownership Interest|AMR Action Fund: Advisor/Consultant|AstraZeneca: Stocks/Bonds|Basilea Pharmaceutica: Advisor/Consultant|Bugworks Research, Inc.: Advisor/Consultant|F2G, Limited: Employee|F2G, Limited: Stocks/Bonds|Forge Therapeutics: Advisor/Consultant|GlaxoSmithKline: Advisor/Consultant|Pfizer Pharmaceuticals: Honoraria|Sumitovant: Advisor/Consultant Sharon C. Chen, PhD MBBS, F2G PTy Ltd: Grant/Research Support|MSD Australia: Grant/Research Support.