A NOVEL antifungal therapy has shown early signs of success in treating invasive fungal disease (IFD) in patients with limited options, according to findings from a recently completed Phase 2b clinical trial. The orotomide olorofim demonstrated activity against difficult-to-treat fungal infections, including azole-resistant strains, with an acceptable safety profile.
In this single-arm, open-label trial, investigators enrolled 204 patients aged ≥16 years from 22 centres across 11 countries between 2018–2022. Eligible participants had proven IFD or probable invasive pulmonary aspergillosis and few or no alternative treatment options. Oral olorofim was administered using weight-based dosing in the first 58 patients and a fixed dose regimen in subsequent participants, with treatment extending up to 84 days and beyond as required. The primary endpoint was global response at Day 42, assessed by a data review committee based on clinical, radiological, and mycological improvement.
Among the 202 evaluable patients, 28.7% (95% CI: 22.6–35.5) achieved a successful global response at Day 42, and 27.2% (21.2–33.9) by Day 84. When stable disease was included in the definition of success, these rates rose to 75.2% and 63.4%, respectively. Clinical improvement alone was noted in 59.9% at Day 42 and 54.0% at Day 84. The all-cause mortality rate was 11.9% at Day 42 and 16.3% at Day 84. Pathogens included Aspergillus spp (n=101), Lomentospora prolificans (n=26), Scedosporium spp (n=22), and Coccidioides spp (n=41), many of which were resistant to existing antifungal therapies.
Adverse events were manageable. Liver enzyme elevations deemed possibly related to treatment occurred in 10% of patients, with most cases resolving through dose adjustment or discontinuation. Gastrointestinal intolerance was also reported in 10% of patients but was generally mild and self-limiting. Importantly, there were no treatment-related deaths.
These findings suggest olorofim may fill a critical gap in antifungal treatment for patients with resistant IFD, although further trials are necessary to define its place in therapy.
Reference
Maertens JA et al. 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 Infect Dis. 2025; DOI: 10.1016/S1473-3099(25)00224-5.
