TY - JOUR
T1 - Olorofim in combination with azole antifungals
T2 - results from the Phase 2 salvage therapy study
AU - Phase 2b Olorofim Salvage Therapy Study Group
AU - Maertens, Johan
AU - Chen, Sharon C.A.
AU - Thompson, George R.
AU - Donovan, Fariba
AU - Dane, Aaron
AU - Birch, Mike
AU - Pinder, Corinne
AU - Bennett, Jill
AU - Ravenna, Valerie
AU - Marin Fernandez, Omar
AU - Ross, Geoff
AU - Zinzi, Daniela
AU - Rex, John H.
AU - Aguado, Jose Maria
AU - Alexander, Barbara D.
AU - Aoun, Mickael
AU - Bazaz, Rohit
AU - Brüggemann, Roger J.
AU - Bruns, Anke H.W.
AU - Chayakulkeeree, Methee
AU - Cornelissen, Karen
AU - Cornely, Oliver A.
AU - Fitton, Lesley
AU - Fortún, Jesus
AU - Georgala, Aspasia
AU - Hammond, Sarah P.
AU - Heath, Christopher H.
AU - Hoenigl, Martin
AU - Holland, Steven M.
AU - Johnson, Royce
AU - Koehler, Philipp
AU - Mehra, Varun
AU - Mehta, Sanjay
AU - Miceli, Marisa H.
AU - Morrissey, Catherine Orla
AU - Moussa, Mohamed
AU - Nguyen, M. Hong
AU - Ostrosky-Zeichner, Luis
AU - Paterson, David L.
AU - Patterson, Thomas F.
AU - Plate, Markus
AU - Rahav, Galia
AU - Rautemaa-Richardson, Riina
AU - Rijnders, Bart
AU - Schaenman, Joanna
AU - Schwartz, Stefan
AU - Shoham, Shmuel
AU - Sikka, Monica K.
AU - Slavin, Monica A.
AU - Brüggemann, Roger J.
N1 - © The Author(s) 2026. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.
PY - 2026/4
Y1 - 2026/4
N2 - Background: Olorofim is an antifungal agent with a novel mechanism of action against Aspergillus spp., rare moulds and dimorphic fungi. Preclinical studies reported unidirectional antagonism between olorofim and mould-active azoles (e.g. azoles other than fluconazole) against Aspergillus fumigatus in which the azole reduces the antifungal effect of olorofim. Methods: To assess the potential clinical impact of this preclinical finding, we compared outcomes of olorofim with and without concomitant azoles from a Phase 2b salvage study in patients with invasive fungal diseases with few or no treatment options. Results: Analyses are limited by the study size but outcomes were similar for olorofim with and without an azole in combination (whether mould-active or not) at Days 42 (the primary study endpoint) and 84 for both Mycoses Study Group–European Organization for Research and Treatment of Cancer (MSG-EORTC) responses and for all-cause mortality in patients with aspergillosis (77 not receiving an azole, 24 receiving an azole in combination), in patients with coccidioidomycosis (11 not receiving an azole, 30 receiving an azole in combination) and in patients with other fungal infections (50 not receiving an azole, 10 receiving an azole in combination). In addition, the rate of drug-induced liver injury was not increased in patients receiving combination with an azole. Conclusions: Although limited by small numbers of patients for individual fungi, this analysis did not demonstrate a pattern of reduced clinical efficacy or tolerability of olorofim when given in combination with either the mould-active azoles or with fluconazole. Trial registration number. NCT03583164.
AB - Background: Olorofim is an antifungal agent with a novel mechanism of action against Aspergillus spp., rare moulds and dimorphic fungi. Preclinical studies reported unidirectional antagonism between olorofim and mould-active azoles (e.g. azoles other than fluconazole) against Aspergillus fumigatus in which the azole reduces the antifungal effect of olorofim. Methods: To assess the potential clinical impact of this preclinical finding, we compared outcomes of olorofim with and without concomitant azoles from a Phase 2b salvage study in patients with invasive fungal diseases with few or no treatment options. Results: Analyses are limited by the study size but outcomes were similar for olorofim with and without an azole in combination (whether mould-active or not) at Days 42 (the primary study endpoint) and 84 for both Mycoses Study Group–European Organization for Research and Treatment of Cancer (MSG-EORTC) responses and for all-cause mortality in patients with aspergillosis (77 not receiving an azole, 24 receiving an azole in combination), in patients with coccidioidomycosis (11 not receiving an azole, 30 receiving an azole in combination) and in patients with other fungal infections (50 not receiving an azole, 10 receiving an azole in combination). In addition, the rate of drug-induced liver injury was not increased in patients receiving combination with an azole. Conclusions: Although limited by small numbers of patients for individual fungi, this analysis did not demonstrate a pattern of reduced clinical efficacy or tolerability of olorofim when given in combination with either the mould-active azoles or with fluconazole. Trial registration number. NCT03583164.
KW - Invasive Fungal Infections/drug therapy
KW - Piperazines
KW - Humans
KW - Salvage Therapy/methods
KW - Middle Aged
KW - Pyrroles
KW - Male
KW - Treatment Outcome
KW - Aspergillus fumigatus/drug effects
KW - Drug Therapy, Combination/methods
KW - Aspergillosis/drug therapy
KW - Pyrimidines
KW - Coccidioidomycosis/drug therapy
KW - Female
KW - Adult
KW - Aged
KW - Acetamides
KW - Antifungal Agents/therapeutic use
KW - Azoles/therapeutic use
UR - https://www.scopus.com/pages/publications/105034704815
UR - https://www.mendeley.com/catalogue/d9cda20f-c979-30fd-8cdc-05d141efbbdc/
U2 - 10.1093/jac/dkag118
DO - 10.1093/jac/dkag118
M3 - Article
C2 - 41914555
AN - SCOPUS:105034704815
SN - 0305-7453
VL - 81
JO - Journal of Antimicrobial Chemotherapy
JF - Journal of Antimicrobial Chemotherapy
IS - 4
ER -