Olorofim for the treatment of invasive fungal diseases in patients with few or no therapeutic options: a single-arm, open-label, phase 2b study
3
Issued Date
2025-01-01
Resource Type
ISSN
14733099
eISSN
14744457
Scopus ID
2-s2.0-105008516638
Journal Title
Lancet Infectious Diseases
Rights Holder(s)
SCOPUS
Bibliographic Citation
Lancet Infectious Diseases (2025)
Suggested Citation
Maertens J.A., Thompson G.R., Spec A., Donovan F.M., Hammond S.P., Bruns A.H.W., Rahav G., Shoham S., Johnson R., Rijnders B., Schaenman J., Hoenigl M., Morrissey C.O., Mehta S.R., Heath C.H., Koehler P., Paterson D.L., Slavin M.A., Fortún J., Nguyen M.H., Patterson T.F., Uspenskaya O., Van de Veerdonk F.L., Verweij P.E., Aoun M., Georgala A., Alexander B.D., Chayakulkeeree M., Mehra V., Miceli M.H., Sikka M.K., Solé A., Walsh T.J., Aguado J.M., Holland S.M., Moussa M., Rautemaa-Richardson R., Bazaz R., Schwartz S., Walsh S.R., Plate M., Yehudai-Ofir D., Brüggemann R.J., Cornely O.A., Ostrosky-Zeichner L., Vazquez J.A., White P.L., Cornelissen K., Ross G.G., Fitton L., Dane A., Zinzi D., Rex J.H., Chen S.C.A. Olorofim for the treatment of invasive fungal diseases in patients with few or no therapeutic options: a single-arm, open-label, phase 2b study. Lancet Infectious Diseases (2025). doi:10.1016/S1473-3099(25)00224-5 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/111047
Title
Olorofim for the treatment of invasive fungal diseases in patients with few or no therapeutic options: a single-arm, open-label, phase 2b study
Author(s)
Maertens J.A.
Thompson G.R.
Spec A.
Donovan F.M.
Hammond S.P.
Bruns A.H.W.
Rahav G.
Shoham S.
Johnson R.
Rijnders B.
Schaenman J.
Hoenigl M.
Morrissey C.O.
Mehta S.R.
Heath C.H.
Koehler P.
Paterson D.L.
Slavin M.A.
Fortún J.
Nguyen M.H.
Patterson T.F.
Uspenskaya O.
Van de Veerdonk F.L.
Verweij P.E.
Aoun M.
Georgala A.
Alexander B.D.
Chayakulkeeree M.
Mehra V.
Miceli M.H.
Sikka M.K.
Solé A.
Walsh T.J.
Aguado J.M.
Holland S.M.
Moussa M.
Rautemaa-Richardson R.
Bazaz R.
Schwartz S.
Walsh S.R.
Plate M.
Yehudai-Ofir D.
Brüggemann R.J.
Cornely O.A.
Ostrosky-Zeichner L.
Vazquez J.A.
White P.L.
Cornelissen K.
Ross G.G.
Fitton L.
Dane A.
Zinzi D.
Rex J.H.
Chen S.C.A.
Thompson G.R.
Spec A.
Donovan F.M.
Hammond S.P.
Bruns A.H.W.
Rahav G.
Shoham S.
Johnson R.
Rijnders B.
Schaenman J.
Hoenigl M.
Morrissey C.O.
Mehta S.R.
Heath C.H.
Koehler P.
Paterson D.L.
Slavin M.A.
Fortún J.
Nguyen M.H.
Patterson T.F.
Uspenskaya O.
Van de Veerdonk F.L.
Verweij P.E.
Aoun M.
Georgala A.
Alexander B.D.
Chayakulkeeree M.
Mehra V.
Miceli M.H.
Sikka M.K.
Solé A.
Walsh T.J.
Aguado J.M.
Holland S.M.
Moussa M.
Rautemaa-Richardson R.
Bazaz R.
Schwartz S.
Walsh S.R.
Plate M.
Yehudai-Ofir D.
Brüggemann R.J.
Cornely O.A.
Ostrosky-Zeichner L.
Vazquez J.A.
White P.L.
Cornelissen K.
Ross G.G.
Fitton L.
Dane A.
Zinzi D.
Rex J.H.
Chen S.C.A.
Author's Affiliation
Harvard Medical School
University of California, San Diego
University of Melbourne
National University of Singapore
Monash University
University of Pittsburgh
Johns Hopkins University School of Medicine
Washington University School of Medicine in St. Louis
University of Michigan Medical School
Charité – Universitätsmedizin Berlin
The University of Western Australia
David Geffen School of Medicine at UCLA
Cardiff University
Technion - Israel Institute of Technology
Weill Cornell Medicine
Erasmus MC
Universitat de València
University of Texas Health Science Center at Houston
Radboud University Medical Center
University Medical Center Utrecht
Duke University School of Medicine
Dana-Farber Cancer Institute
Ain Shams University
KU Leuven– University Hospital Leuven
Joe R. & Teresa Lozano Long School of Medicine
OHSU School of Medicine
National Institute of Allergy and Infectious Diseases (NIAID)
Medical College of Georgia
Universidad de Alcalá
Faculty of Medicine and Health
Uniklinik Köln
NUS Yong Loo Lin School of Medicine
Medizinische Universität Graz
King's College Hospital
Hospital Universitario Ramón y Cajal
Faculty of Biology, Medicine and Health
Hospital Universitario 12 de Octubre
Westmead Hospital
Hospital Universitari i Politècnic La Fe
VA San Diego Healthcare System
Siriraj Hospital
Health Innovation Manchester
University Hospital of Wales
Rambam Health Care Campus Israel
Ariel University
UC Davis Medical Center
Institut Jules Bordet
Instituto Ramón y Cajal de Investigación Sanitaria
Universidad Complutense de Madrid, Facultad de Medicina
The Sir Peter MacCallum Department of Oncology
Fiona Stanley Hospital
Centro de Investigación Biomédica en Red de Enfermedades Infecciosas
Departement Microbiologie, Immunologie en Transplantatie
Alfred Health
BioTechMed-Graz
Valley Fever Center for Excellence
Leningrad Regional Clinical Hospital
Kern Medical
Partner Site Bonn-Cologne
Center for Innovative Therapeutics and Diagnostics
DaneStat Consulting
F2G
University of California, San Diego
University of Melbourne
National University of Singapore
Monash University
University of Pittsburgh
Johns Hopkins University School of Medicine
Washington University School of Medicine in St. Louis
University of Michigan Medical School
Charité – Universitätsmedizin Berlin
The University of Western Australia
David Geffen School of Medicine at UCLA
Cardiff University
Technion - Israel Institute of Technology
Weill Cornell Medicine
Erasmus MC
Universitat de València
University of Texas Health Science Center at Houston
Radboud University Medical Center
University Medical Center Utrecht
Duke University School of Medicine
Dana-Farber Cancer Institute
Ain Shams University
KU Leuven– University Hospital Leuven
Joe R. & Teresa Lozano Long School of Medicine
OHSU School of Medicine
National Institute of Allergy and Infectious Diseases (NIAID)
Medical College of Georgia
Universidad de Alcalá
Faculty of Medicine and Health
Uniklinik Köln
NUS Yong Loo Lin School of Medicine
Medizinische Universität Graz
King's College Hospital
Hospital Universitario Ramón y Cajal
Faculty of Biology, Medicine and Health
Hospital Universitario 12 de Octubre
Westmead Hospital
Hospital Universitari i Politècnic La Fe
VA San Diego Healthcare System
Siriraj Hospital
Health Innovation Manchester
University Hospital of Wales
Rambam Health Care Campus Israel
Ariel University
UC Davis Medical Center
Institut Jules Bordet
Instituto Ramón y Cajal de Investigación Sanitaria
Universidad Complutense de Madrid, Facultad de Medicina
The Sir Peter MacCallum Department of Oncology
Fiona Stanley Hospital
Centro de Investigación Biomédica en Red de Enfermedades Infecciosas
Departement Microbiologie, Immunologie en Transplantatie
Alfred Health
BioTechMed-Graz
Valley Fever Center for Excellence
Leningrad Regional Clinical Hospital
Kern Medical
Partner Site Bonn-Cologne
Center for Innovative Therapeutics and Diagnostics
DaneStat Consulting
F2G
Corresponding Author(s)
Other Contributor(s)
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.