Novel Antifungal Offers Hope in Resistant Fungal Infections
Olorofim, a first-in-class orotomide antifungal agent, was effective in treating invasive fungal diseases (IFDs) in nearly one third of patients with limited treatment options. Drug-induced liver injuries were few and mostly managed with dose adjustments, supporting its potential as a promising therapy for IFDs.
METHODOLOGY:
Olorofim is a first-in-class orotomide antifungal agent that blocks fungal pyrimidine biosynthesis, leading to cell death. In vitro studies have found it to be effective against fungi that are resistant to existing antifungal agents.
Researchers conducted a phase 2b, single-arm study between June 2018 and September 2022 across sites in 11 countries to assess the efficacy and safety of oral olorofim in IFDs.
They enrolled 204 patients (mean age, 52.9 years; 61% men) with proven IFD or probable invasive pulmonary aspergillosis administered oral olorofim at a maintenance dose of 90 mg twice daily up to day 84, with extended therapy as needed.
The primary endpoint was the global response rate (a composite of clinical, radiologic, and mycologic responses) at day 42, where success meant complete or partial improvement in all three components and failure meant stable disease, progression in any one component, or death from any cause.
Other important outcomes assessed were the global response rate at day 84, all-cause mortality at days 42 and 84, and safety.
TAKEAWAY:
The global response rate was 28.7% (95% CI, 22.6%-35.5%) at day 42 and 27.2% (95% CI, 21.2%-33.9%) at day 84, with stable disease, progression, and death from any cause being the main reasons for failure.
No patients with coccidioidomycosis achieved a successful global response at day 42 or 84.
All-cause mortality was 11.9% (95% CI, 7.8%-17.2%) at day 42 and 16.3% (95% CI, 11.5%-22.2%) at day 84, with deaths occurring primarily in patients with invasive aspergillosis who had immunosuppression.
Treatment-emergent adverse events were primarily infections (1%) and gastrointestinal disorders (10%). Drug-induced liver injury occurred in 10% of patients; 3% permanently discontinued olorofim, whereas others were managed with dose adjustments or temporary discontinuation. No treatment-related deaths were reported.
IN PRACTICE:
'Overall, these important findings underscore olorofim's clinical value in addressing unmet needs in the management of difficult-to-treat fungal infections across a diverse patient population,' the authors of the linked commentary added.
SOURCE:
The study was led by Johan A. Maertens, MD, Department of Hematology, University Hospitals Leuven, Leuven, Belgium. It was published online on June 17, 2025, in The Lancet Infectious Diseases.
LIMITATIONS:
The study was limited mainly by its single-arm, open-label design.
DISCLOSURES:
The study was funded by F2G. Five authors reported being employees of or holding stocks or stock options in the funding company. Several other authors disclosed having financial ties with multiple pharmaceutical companies, including F2G, AstraZeneca, Cidara, Pfizer, Roche, Gilead, MSD, Takeda, Mundipharma, Basilea, and Shionogi.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.
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