Highlights
– Olorofim (an orotomide antifungal) demonstrated a DRC‑adjudicated global response in 28.7% of heavily pretreated patients with invasive fungal disease (IFD) at day 42; clinical improvement was seen in ~60%.
– Active against pathogens with limited therapeutic options, including 22 azole‑resistant Aspergillus spp, Lomentospora prolificans, Scedosporium spp, and Coccidioides spp.
– Safety was manageable: liver enzyme elevations attributed at least possibly to olorofim occurred in 10% (resolved with dose modification or discontinuation in most), gastrointestinal intolerance occurred in 10%, and no treatment‑related deaths were reported.
– Single‑arm design and heterogenous salvage population limit definitive efficacy claims; randomized studies are needed to define comparative effectiveness and optimal use.
Background: unmet need in invasive fungal disease
Invasive fungal diseases cause substantial morbidity and mortality in immunocompromised and critically ill patients. Therapeutic options are limited to a few drug classes (polyenes, azoles, echinocandins), and emerging intrinsic or acquired resistance has eroded effectiveness for key pathogens. Azole resistance in Aspergillus fumigatus and intrinsic resistance of organisms such as Lomentospora prolificans and many Scedosporium species create clinical scenarios in which standard therapy is ineffective and outcomes are poor. New agents with novel mechanisms of action are therefore a high priority.
Olorofim (F901318) is the first clinical agent in the orotomide class. It selectively inhibits fungal pyrimidine biosynthesis through blockade of fungal dihydroorotate dehydrogenase, disrupting nucleic acid synthesis and leading to growth inhibition and cell death in susceptible fungi. Preclinical data have shown activity against many moulds and dimorphic fungi that are refractory to available antifungal drugs, positioning olorofim as a candidate for salvage therapy in patients with few or no options.
Study design
Design, setting, and population
Maertens and colleagues conducted a single‑arm, open‑label, international phase 2b study (ClinicalTrials.gov NCT03583164) across 22 centres in 11 countries, enrolling adults (≥16 years) with proven invasive fungal disease or probable invasive pulmonary aspergillosis who had few or no available therapeutic options. The trial intentionally enrolled a heterogeneous, high‑need salvage population, including patients with azole‑resistant Aspergillus and infections caused by intrinsically resistant moulds.
Intervention and dosing
Patients initially received weight‑based loading and maintenance oral dosing. After pharmacokinetic data from the first 25 patients, dosing was simplified: from patient 59 onward the regimen was an oral loading dose of 150 mg twice on day 1 followed by 90 mg twice daily through day 84 (main treatment phase), with extended therapy permitted if clinically indicated. The study evaluated treatment durations reflecting both the main 84‑day phase and prolonged courses for chronic or refractory disease.
Endpoints and analysis populations
The primary endpoint was DRC‑adjudicated global response at day 42, defined as a composite of clinical, radiological, and mycological responses; success required complete or partial improvement in all three domains, whereas failure included stable disease or progression in any domain or death. Secondary endpoints included global response at day 84 and all‑cause mortality at days 42 and 84. Analyses used a modified intention‑to‑treat population (patients confirmed by DRC to have IFD and who received ≥1 dose) for efficacy and the safety population of all treated patients for safety analyses.
Key findings and interpretation
Population and pathogens
Between June 2018 and September 2022, 204 patients were enrolled; 203 received olorofim and 202 had DRC‑adjudicated IFD (124 male, 78 female). Pathogens included Aspergillus spp (n=101; 22 azole‑resistant), Lomentospora prolificans (n=26), Scedosporium spp (n=22), Coccidioides spp (n=41), and other fungi (n=12). This spectrum reflects the trial’s focus on difficult‑to‑treat organisms and resistant phenotypes.
Efficacy outcomes
– Primary endpoint: DRC‑adjudicated successful global response at day 42 was achieved in 58 of 202 patients (28.7%; 95% CI 22.6–35.5).
– Day 84 global success was similar: 55 of 202 patients (27.2%; 95% CI 21.2–33.9).
– When stable disease was counted as success, global response rates rose substantially to 75.2% (152/202) at day 42 and 63.4% (128/202) at day 84. This alternative analysis reflects disease control in a salvage population where halting progression may be clinically meaningful.
– Clinical component: improvement in the clinical domain alone was observed in 121 patients (59.9%; 95% CI 52.8–66.7) at day 42 and in 109 (54.0%; 95% CI 46.8–61.0) at day 84.
– Mortality: all‑cause mortality was 11.9% (24/203; 95% CI 7.8–17.2) at day 42 and 16.3% (33/203; 95% CI 11.5–22.2) at day 84.
Interpretation: In a cohort enriched for patients with limited or no approved options, a near‑30% stringent DRC‑adjudicated global success at day 42 — and clinical improvement in ~60% — indicates meaningful activity. The large increase in apparent benefit when counting stable disease underscores that in salvage settings disease control (prevention of progression) is often clinically important. The relatively low short‑term mortality compared with historical expectations in some refractory infections suggests potential clinical benefit, although comparators are lacking.
Safety and tolerability
– Hepatic events: Medically significant liver enzyme elevations adjudicated as at least possibly related to olorofim occurred in 20 of 203 patients (10%). Most were managed successfully with dose modification (14/203, 7%) or treatment discontinuation (6/203, 3%). Events resolved in those managed.
– Gastrointestinal intolerance: Reported in 20 patients (10%), predominantly mild to moderate and self‑limiting.
– No treatment‑related deaths were recorded.
Overall, the safety profile was acceptable for a salvage population, but the signal for hepatic enzyme elevations warrants careful monitoring and further characterization in larger and comparator trials.
Expert commentary and contextualization
Olorofim addresses a high unmet need: treatment‑resistant Aspergillus and intrinsically resistant moulds have poor outcomes with current agents. The mechanism of action — inhibition of fungal dihydroorotate dehydrogenase and disruption of pyrimidine biosynthesis — is novel among clinically available antifungals and provides activity where azoles, echinocandins, and amphotericin B may fail.
Strengths of the study include its international, multicentre scope; enrollment of a real‑world salvage population; and adjudication of endpoints by an independent DRC. These features improve relevance to clinical practice for severe, hard‑to‑treat IFD.
Key limitations temper interpretation. The single‑arm, open‑label design precludes direct comparison with standard therapy or with combination regimens. Heterogeneity in pathogens, infection sites, and prior therapies complicates subgroup inferences. The primary composite endpoint is stringent — requiring improvement across clinical, radiological, and mycological domains — which was appropriate for regulatory rigor but may underestimate clinically meaningful benefit in salvage contexts where stabilization or symptomatic improvement is valuable. Conversely, counting stable disease as success inflates apparent benefit and may include patients with minimal net therapeutic effect. Finally, pharmacokinetic and dosing adjustments during the trial (streamlining to fixed dosing after interim PK review) introduce some variability in exposure across the cohort.
Clinical takeaways
– For patients with azole‑resistant Aspergillus, Lomentospora, Scedosporium, or other difficult mould infections with limited options, olorofim appears to offer active salvage therapy with an acceptable safety profile.
– Hepatic monitoring is essential given the 10% rate of liver enzyme elevations possibly related to drug exposure.
– Olorofim’s oral dosing and prolonged treatment durations (median main‑phase exposure 84 days; many patients received extended therapy) suggest suitability for both acute salvage and chronic suppressive strategies where indicated.
Unanswered questions and future research
– Comparative effectiveness: randomized trials versus best available therapy (or standard of care) are needed to quantify benefit and establish indications — e.g., first‑line treatment for azole‑resistant Aspergillus versus salvage therapy.
– Pharmacokinetics/pharmacodynamics and therapeutic drug monitoring: optimal dosing, exposure–response relationships, and drug–drug interactions, particularly in polypharmacy transplant and oncology populations, require definition.
– Combination therapy: the role of olorofim in combination with other antifungals (to broaden spectrum or prevent resistance) should be evaluated.
– Long‑term safety: extended courses were used in many patients; systematic long‑term hepatic and other safety monitoring data are needed.
– Resistance emergence: surveillance for emergence of olorofim resistance in clinical isolates will be important as use expands.
Conclusion
This phase 2b single‑arm study provides the first robust clinical evidence that olorofim has activity in a challenging population of patients with invasive fungal disease and few or no therapeutic options. The agent demonstrated DRC‑adjudicated global responses in a meaningful minority of patients and clinical improvement in roughly 60% at day 42, with manageable toxicity in most cases. While encouraging, these data are hypothesis‑generating; randomized controlled trials and detailed pharmacologic and safety studies are required to define the precise role of olorofim in the armamentarium against invasive mould and dimorphic fungal infections.
Funding and registration
The study was funded by F2G. ClinicalTrials.gov identifier: NCT03583164.
Selected references
1. Maertens JA, Thompson GR 3rd, Spec A, 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 Nov;25(11):1177–1188. doi:10.1016/S1473-3099(25)00224-5.
2. Patterson TF, Thompson GR, Denning DW, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63(4):e1–e60.
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