Olorofim for the treatment of invasive fungal diseases in patients with few or no therapeutic options: a single-arm, open-label, phase 2b study
- PMID: 40541222
- DOI: 10.1016/S1473-3099(25)00224-5
Olorofim for the treatment of invasive fungal diseases in patients with few or no therapeutic options: a single-arm, open-label, phase 2b study
Abstract
Background: Only a small number of antifungal therapies for invasive fungal disease (IFD) are currently available, and many pathogens are resistant to one or more of these therapies. Olorofim, the first orotomide antifungal agent to be developed, is active against fungi that are resistant to registered therapies. It impairs fungal pyrimidine biosynthesis, leading to cell death. We sought initial data on the efficacy and safety of olorofim as a therapy for IFD.
Methods: In this single-arm, open-label, phase 2b study, patients aged 16 years or older with few or no treatment options for proven IFD or probable invasive pulmonary aspergillosis were recruited from 22 centres in 11 countries. The first 58 patients received a weight-based loading dose of oral olorofim 180-300 mg in two to three divided doses on day 1 followed by 120-240 mg daily in two to three divided doses from day 2 onwards. On the basis of pharmacokinetic data from the first 25 patients, dosing was simplified from patient 59 onwards to a loading dose of 150 mg twice on day 1 followed by a fixed maintenance dose of 90 mg twice a day up to day 84 (main treatment phase) with extended therapy as needed. The primary endpoint was global response rate (based on a composite of clinical, radiological, and mycological responses) at day 42, determined as success (complete or partial improvement in all three components) or failure (stable disease or progression on any one component or death from any cause) by a data review committee (DRC). Secondary efficacy endpoints included global response rate at day 84 and all-cause mortality at day 42 and day 84. Global response rate with stable disease classified as success and response rate in the clinical component of the global response at day 42 and day 84 were also assessed. Efficacy was analysed for all patients who were confirmed by the DRC to have an IFD and who received at least one dose of olorofim (the modified intention-to-treat population). Safety was analysed in all patients who received at least one dose of olorofim (the safety population). This trial is registered with ClinicalTrials.gov, NCT03583164, and is completed.
Findings: Between June 6, 2018, and Sept 8, 2022, 204 patients were enrolled. Of these, 203 were treated with olorofim and 202 (124 male, 78 female) had DRC-adjudicated IFD. Causative pathogens were Aspergillus spp (n=101, including 22 azole-resistant strains), Lomentospora prolificans (n=26), Scedosporium spp (n=22), Coccidioides spp (n=41), and other fungi (n=12). Successful global response was confirmed in 58 of 202 patients (28·7%, 95% CI 22·6-35·5) at day 42 and in 55 patients (27·2%, 21·2-33·9) at day 84. Successful global response with stable disease included in the definition of success was seen in 152 patients (75·2%, 68·7-81·0) at day 42 and in 128 patients (63·4%, 56·3-70·0) at day 84. A successful clinical response was seen in 121 patients (59·9%, 52·8-66·7) at day 42 and in 109 patients (54·0%, 46·8-61·0) at day 84. All-cause mortality was documented in 24 patients (11·9%, 7·8-17·2) at day 42 and in 33 patients (16·3%, 11·5-22·2) at day 84. Mean dosing duration was 73 days (SD 25) for the 203 patients in the main treatment phase (median 84 days [range 2-99, IQR 78-87]) and 361 days (SD 220) for the 114 patients who received extended treatment after the main phase (median 309 days [38-988, 180-502]). Medically significant liver enzyme elevations adjudicated to be at least possibly due to olorofim occurred in 20 (10%) of 203 patients and were managed to resolution by dose modification in 14 (7%) patients or by discontinuation of treatment in six (3%). Gastrointestinal intolerance, which occurred in 20 (10%) patients, was predominantly reported as mild or moderate and self-limiting. There were no treatment-related deaths.
Interpretation: Olorofim showed efficacy and good tolerability in patients with IFD with few or no treatment options. Further studies will be needed to fully delineate the role of this new antifungal agent.
Funding: F2G.
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Conflict of interest statement
Declaration of interests JAM reports consulting fees, honoraria, and support for attending meetings or travel from F2G, Cidara, Pfizer, Gilead, MSD, Takeda, Mundipharma, Basilea, and Shionogi; participation on and payment for service on advisory boards from F2G, Cidara, and Basilea; and service in leadership or fiduciary roles at the European Conference on Infections in Leukaemia (past chair), outside the submitted work. GRT reports research support to his institution from F2G for the present study; research support to his institution from Astellas, Amplyx, Basilea, Cidara, GSK, Melinta, Mundipharma, Pfizer, and Scynexis; and consulting fees from F2G, Astellas, Amplyx, Basilea, Cidara, GSK, Melinta, Mundipharma, Pfizer, and Scynexis, outside the submitted work. ASp reports grants or funding from Astellas; and consulting fees from F2G, outside the submitted work. FMD reports research support to her institution from F2G for the present study. SPH reports research support to her institution for the present study from F2G; research support to her institution from Scynexis, Mundipharma, Cidara, and GSK; consulting fees from Seres Therapeutics; payment for training from Pfizer; and service on advisory boards for F2G, Pfizer, Melinta, and Roche, outside the submitted work. SSh reports grants from F2G, Anusn, and Zeteo Tech; consulting fees from Pfizer, Basilea, and Karius; honoraria from Avir, Prime Education, and PeerView; participation on advisory boards for Scynexis, Cidara, Pfizer, and Adamis; and service in leadership or fiduciary roles for the Board of Governors, American College of Physicians, outside the submitted work. RJ reports grants from the National Institutes of Health (NIH); payment for expert testimony in workers' compensation cases; travel support from the Centers for Disease Control and Prevention (CDC); leadership roles with the Coccidioidomycosis Study Group and the Community Medical Educational Research Foundation; and service on the board of Kern Medical Foundation, outside the submitted work. BR reports a grant to his institution from Gilead; and consulting fees from F2G, Shionogi, and Pfizer, outside the submitted work. JS reports grants from F2G, the NIH/National Institute of Allergy and Infectious Diseases, the Cystic Fibrosis Foundation, and Moderna; consulting fees from MedCure and OneLegacy; and honoraria from Eurofins, outside the submitted work. MH reports research funding from F2G, Gilead Sciences, Astellas, Mundipharma, Euroimmun, MSD, GSK, Basilea, Pulmocide, Scynexis, AiCuris, Melinta, IMMY, and Pfizer, outside the submitted work. COM reports research funding to her institution from MSD and Gilead Sciences; honoraria to her institution for talks from Gilead Sciences and Pfizer; and payments to her institution for participation in an advisory board meeting for Elion, outside the submitted work. SRM reports grants to his institution from F2G and the NIH, outside the submitted work. PK reports grants to his institution from the German Federal Ministry of Research and Education B-FAST (Bundesweites Forschungsnetz Angewandte Surveillance und Testung) and NAPKON (Nationales Pandemie Kohorten Netz, German National Pandemic Cohort Network) of the Network University Medicine and the State of North Rhine-Westphalia; consulting fees from Ambu, Gilead Sciences, Mundipharma Research, Noxxon, and Pfizer Pharma; honoraria from Akademie für Infektionsmedizin, Ambu, Astellas Pharma, BioRad Laboratories, the European Confederation of Medical Mycology, Gilead Sciences, GPR Academy Ruesselsheim, Helios Kliniken, Jazz Pharmaceuticals Germany, med-update, MedMedia, MSD Sharp & Dohme, Pfizer Pharma, Scilink Comunicación Científica, and University Hospital, LMU Munich; a German patent application (DE 10 2021 113 007.7, “Geschlossene Intubationssysteme mit verbessertem Atemwegszugang für Untersuchungsvorrichtungen”), which has been filed by the University of Cologne, listing PK as one of the three inventors; participation on advisory boards for Ambu, Gilead Sciences, Pfizer Pharma, Mundipharma Research, and Noxxon; and honoraria for reviews and royalties for book authorships from Elsevier; and was an unpaid Editor for Mycoses (Wiley) and Annals of Medicine (Taylor & Francis online), outside the submitted work. DLP reports grants to his institution from Shionogi, Merck, Pfizer, bioMerieux, and Gilead; consulting fees from AMR Action Fund, CARB-X, GARDP, Aurobac, and Menarini; speaker's honoraria from Shionogi, Pfizer, Merck, Zuellig, bioMerieux, and Cepheid; and service on the board of the Australasian Society for Infectious Diseases, outside the submitted work. MAS reports educational grants to her institution from F2G, Merck, and Pfizer; honoraria from Gilead; and payments to her institution for participation on advisory boards for F2G, Roche, Cidara, Basilea, Pfizer, Gilead, and Elion, outside the submitted work. JF reports lecture honoraria from Shionogi, Mundipharma, Advanz Pharma, Gilead, Pfizer, and MSD; and service on advisory boards for Gilead, Pfizer, and MSD, outside the submitted work. MHN reports research funding to her institution from F2G, Merck, Pulmocide, Astellas, Scynexis, and Mayne; and service on advisory boards for Pulmocide, Basilea, and T2 Biosystems, outside the submitted work. TFP reports grants to his institution from F2G, Basilea, and Scynexis; consulting fees from F2G, Basilea Pharmaceutica, Cidara Therapeutics, Elion Therapeutics, Gilead Sciences, and Scynexis; and participation on advisory boards for Scynexis and Cidara, outside the submitted work. FLVdV reports consulting fees from Takeda and GSK; and honoraria from Gilead and Sobi, outside the submitted work. PEV reports grants to his institution from F2G, Gilead, Mundipharma, and Shionogi; and honoraria to his institution from Gilead, outside the submitted work. BDA reports funding to her institution from F2G for the present study; funding from Scynexis for another study; royalties for chapter authorship from UpToDate; service on advisory boards for Scynexis, GSK, Astellas, Basilea, Pulmocide, HealthTrackRx, and TFF Pharmaceuticals; and board of directors' membership for the Mycoses Study Group, outside the submitted work. MC reports research grants to his institution from F2G, Shionogi, Cidara, AstraZeneca, Janssen, Pulmocide, Pfizer, BioMerieux, and Scynexis; speaker's honoraria from Pfizer, MSD, Takeda, Gilead, Sandoz, Atlanta, IMMY, and IQVIA; and service on advisory boards for Gilead, Pfizer, and MSD, outside the submitted work. VM reports research grants from Pfizer, Gilead, the Wellcome Trust, and the Medical Research Council; fees for participation on advisory boards from Cidara, Mundipharma, Pfizer, Sanofi, and Gilead; and speaker's honoraria from MSD, Cidara, Mundipharma, Takeda, Novartis, Jazz Pharma, Sanofi, Gilead, and Pfizer, outside the submitted work. MHM reports funding to her institution from F2G for the present study; funding from F2G, Scynexis, AN2 Therapeutics, Basilea, and Pulmocide; and consulting fees for work on a data review committee (DRC) from Scynexis, outside the submitted work. MKS reports support to her institution from F2G for the present study. ASo reports research funding to her institution from F2G and Vertex; honoraria from Vertex; consulting fees from Chiesi, Astellas, Vertex, Gilead, Pari, and Pfizer; and service on an advisory board for Chiesi, outside the submitted work. TJW reports grants to his institution from F2G, Allergan, Astellas, Gilead, Leadiant, Scynexis, Shionogi, T2 Biosystems, and Viosera; consulting fees from Abbott Laboratories, Gilead, Partner Therapeutics, Scynexis, Statera, and T2 Biosystems; service on advisory boards for F2G, Scynexis, T2 Biosystems, and Abbott Laboratories; leadership or board roles for the Center for Innovative Therapeutics and Diagnostics, the Henry Schueler Foundation, Save Our Sick Kids Foundation, the Medical Mycological Society of the Americas, the Mycoses Study Group–Education & Research Consortium, and CASA (Clothing And Sustenance from Assumption for all); and a consultancy role for MyCare, outside the submitted work. MM reports speaker's honoraria from Roche, AstraZeneca, Pfizer, Amgen, Novartis, Sandoz, and AbbVie, outside the submitted work. RR-R reports grants from F2G and Scynexis; and honoraria from Pfizer, Mundipharma, and Gilead, outside the submitted work. SSc reports consulting fees from Amgen, Pfizer, and SERB; honoraria from Akademie für Infektionsmedizin, Amgen, CSi Hamburg, Pfizer, and SERB; and support for attending meetings from Amgen, Pfizer, and SERB, outside the submitted work. SRW reports support to his institution from F2G for the present study; grants to his institution from Sanofi Pasteur, Moderna Tx, Vir Biotechnology, Worcester HIV Vaccine, Pfizer, Janssen Vaccines/Johnson & Johnson, and AbbVie; support for attending meetings from Sanofi Pasteur; and participation on advisory boards from Janssen Vaccines/Johnson & Johnson and BioNTech; and his spouse is an employee and holds stock and stock options in Regeneron Pharmaceuticals, outside the submitted work. MP reports support to his institution from F2G for the present study. RJB reports support from F2G for study activities and oversight of a central laboratory facility for the present study; grants from Gilead, Pfizer, and Mundipharma; consulting fees from F2G, Astellas, Gilead, MSD, Pfizer, Mundipharma, and Basilea; speaker's honoraria from Gilead and Pfizer; and service in a leadership or fiduciary role for Dutch Horizon Scan, outside the submitted work. OAC reports payments from IQVIA for work on the DRC for the present study; grants to his institution from F2G, AstraZeneca, Cidara, Gilead, Medpace, MSD, Mundipharma, Octapharma, Pfizer, and Scynexis; consulting fees from AbbVie, AiCuris, Basilea, Biocon, Cidara, Elion, Gilead, GSK, IQVIA, Janssen, Matinas, Medpace, Menarini, Molecular Partners, Melinta, Mundipharma, Noxxon, Octapharma, Pardes, Partner Therapeutics, Pfizer, PSI, Scynexis, Seres Therapeutics, and Seqirus; speaker's honoraria from Abbott, AbbVie, Al-Jazeera Pharmaceuticals/Hikma, AstraZeneca, Gilead, GSK, Grupo Biotoscana/United Medical/Knight, Ipsen Pharma, Medscape/WebMD, med-update, MSD, Moderna, Mundipharma, Noscendo, Paul-Martini-Stiftung, Pfizer, Sandoz, Seqirus, Shionogi, Streamed Up, Touch Independent, and Vitis; payment for expert testimony from Cidara; and participation on advisory boards for AstraZeneca, Boston Strategic Partners, Cidara, Janssen, Medpace, Melinta, PSI, Pulmocide, Shionogi, the Prime Meridian Group, and Vedanta Biosciences, outside the submitted work. LO-Z reports fees from F2G for work on the DRC for the present study; grants to his institution from Scynexis, Pfizer, T2 Biosystems, Pulmocide, the NIH/National Center for Advancing Translational Sciences, Basilea, and the CDC; honoraria from F2G, Scynexis, Pulmocide, Melinta, Basilea, GSK, Pfizer, and Eurofins; and leadership or fiduciary roles for the Mycoses Study Group as past president and board member, outside the submitted work. JAV reports fees from F2G for work on the DRC for the present study; and consulting fees and speaker's honoraria from Melinta, outside the submitted work. PLW reports funding to his institution from F2G for the provision of mycological services for the present study; consulting fees from F2G, Gilead, and Mundipharma; honoraria from Gilead, Pfizer, Mundipharma, and ACC; support for attending meetings from Gilead, Mundipharma, and IMMY; and participation on advisory boards for F2G, Gilead, Pfizer, and Mundipharma, outside the submitted work. KC, GGR, and LF are employees of F2G and have stock and stock options in F2G. AD is an employee of DaneStat Consulting and reports consulting fees from F2G, Adagio, AiCuris, Altesa, AN2, Bugworks, CARBX, Closed Loop Medicine, Da Volterra, Destiny, Evopoint, the Gates Foundation, GSK, Helix Nano, Italfarmaco, Liverpool University, Kymab, Melinta, Orca, Phico, Quince, Roche, SFunga, Scynexis, Sinovent, SNIPR Biome, Spero, Symbio, tranScrip, and VenatoRx; and acts as the independent statistician on data and safety monitoring boards for Aridis, AstraZeneca, Cerium, ContraFect, Egetis, Midatech, MoonLake, Pfizer, Rare Thyroid, Sanofi, and tranScrip, outside the submitted work. DZ is an employee of F2G and has stock in F2G. JHR is an employee of F2G; has stock and stock options in F2G; has stock in AstraZeneca and Advent Life Sciences; and is contracted to serve on the scientific advisory board for AMR Action Fund, outside the submitted work. SC-AC reports grants from F2G and Pfizer; and royalties from UpToDate, outside the submitted work. All other authors declare no competing interests.
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