Oral Olorofim Noninferior to AmBisome in Phase 3 OASIS Trial

Oral olorofim (F2G/Shionogi) was noninferior to liposomal amphotericin B (AmBisome; Gilead Sciences) followed by standard of care for invasive aspergillosis in patients unsuited to mold-active azole therapy, meeting the primary end point of the phase 3 OASIS trial (NCT05101187).^1,2 Day 42 all-cause mortality was 23.8% (36/151) with olorofim vs 24.3% (18/74) with AmBisome plus standard of care (difference, −0.5%; 95% CI, −13.1% to 10.8%).¹ The late-breaking results were presented October 22 at IDWeek 2026 in Washington, DC.¹

Azoles are preferred therapy for invasive aspergillosis, but rising resistance, breakthrough infection on prophylaxis, drug-drug interactions, and intolerance can rule them out.¹ A lipid-associated amphotericin B regimen is the current recommended alternative, which keeps patients on intravenous therapy. Olorofim is a first-in-class orotomide that blocks pyrimidine biosynthesis by selectively inhibiting fungal dihydroorotate dehydrogenase, giving it fungicidal activity against Aspergillus species, including azole-resistant strains.^1,2

"Olorofim is a first-in-class molecule with a novel mechanism of action, the first such advance in more than 20 years," John H. Rex, MD, chief medical officer of F2G, and who presented the data, said in a statement.²

OASIS Phase 3 Mortality and Global Response Results for Olorofim

The global, randomized, adjudicator-blinded trial enrolled 225 adults with proven invasive aspergillosis or probable pulmonary invasive aspergillosis at 140 sites between April 29, 2022, and November 18, 2025.¹ Patients diagnosed within the prior 4 days entered for known or suspected azole resistance, prophylaxis breakthrough, or drug-drug interactions.¹ Patients treated with an azole for 8 to 28 days entered for failure of initial therapy.¹

READ MORE: Isavuconazole Has Lowest Hepatotoxicity Signal Among Azoles in FAERS

Participants were randomized 2:1 to up to 84 days of oral olorofim (n = 151; 150 mg twice daily on day 1, then 90 mg twice daily) or intravenous AmBisome (n = 74; 3 mg/kg daily) for at least 10 days followed by standard-of-care antifungals.¹ About 79% had hematologic malignancy or prior stem cell transplant, 11% had received a solid organ transplant, and roughly 40% were neutropenic at or near enrollment.²

The trial used an FDA- and EMA-agreed noninferiority margin of 20% for Day 42 all-cause mortality in the intention-to-treat population.¹ Day 84 all-cause mortality was 32.5% (49/151) with olorofim vs 29.7% (22/74) with the comparator (difference, 2.7%; 95% CI, −10.6% to 15.0%).²

Global response adjudicated by a blinded Data Review Committee was 26.5% (40/151) with olorofim vs 31.1% (23/74) with the comparator at Day 42, and 30.5% (46/151) vs 28.4% (21/74) at Day 84.² The MSG-EORTC measure requires improvement across clinical, radiological, and mycological components.²

Olorofim Safety, Renal Events, and Regulatory Path in Invasive Aspergillosis

Overall adverse events and serious treatment-emergent adverse events were similar between arms, and no new olorofim safety findings emerged.¹ Drug-related events diverged: at least 1 drug-related adverse event occurred in 35.8% (54/151) of olorofim recipients vs 63.9% (46/72) of comparator recipients, and serious drug-related events occurred in 4.0% vs 18.1%.²

Renal toxicity drove the difference, with drug-related renal adverse events in 1.3% (2/151) of olorofim patients vs 22.2% (16/72) of those receiving AmBisome plus standard of care.^1,2 Patients treated with olorofim were discharged earlier, at a mean of 17 days (SD, 15) vs 28 days (SD, 25).²

Drug-induced liver injury remains a recognized signal for olorofim and other antifungals.² Events adjudicated as at least possibly related to study therapy occurred in 4.6% (7/151) of olorofim patients and 4.2% (3/72) of comparator patients.²

"Having an oral option like olorofim, with data supporting its safety in challenging patients, including those with complex drug interactions, would give me another valuable tool in the fight against this fungal infection," said Johan Maertens, MD, PhD, professor of hematology at University Hospitals Leuven in Belgium and the study's principal investigator, in a statement.²

Olorofim is investigational and not approved by any regulatory authority.² F2G anticipates resubmitting a New Drug Application to the FDA by the end of 2026, with Shionogi filing in Europe and Asia. The agent holds 2 FDA Breakthrough Therapy designations and orphan drug status for invasive aspergillosis.²

References

1. Rex JH, Maertens JA, Chayakulkeeree M, et al. Olorofim versus AmBisome-based standard of care (SOC) for treatment of invasive aspergillosis (IA) in patients for whom a mold-active azole antifungal (MAA) is inappropriate or ineffective (OASIS): a phase 3, randomized, controlled, adjudicator-blinded non-inferiority (NI) trial. Presented at: IDWeek 2026; October 21-24, 2026; Washington, DC.

2. Shionogi and F2G report data from global phase 3 OASIS study evaluating investigational oral olorofim versus AmBisome followed by standard of care in invasive aspergillosis in late-breaking oral presentation at IDWeek 2026. News release. Shionogi & Co, Ltd and F2G Ltd; October 21, 2026. Accessed October 23, 2026. https://www.shionogi.com/global/en/news/2026/10/e20261021_3.html