Olorofim met the Phase 3 OASIS non-inferiority endpoint against AmBisome-based therapy, with similar Day 42 mortality and fewer renal adverse events.
Written By: Anamika Koshti, PharmD
Reviewed By: Pharmacally Editorial Team
Shionogi and F2G reported that investigational oral antifungal olorofim met the primary endpoint of non-inferiority to intravenous AmBisome (liposomal amphotericin B) followed by standard of care (SOC) in the Phase 3 OASIS study (NCT05101187). The results will be presented at IDWeek 2026 on October 22. F2G anticipates resubmitting its US New Drug Application (NDA) by the end of 2026, while Shionogi plans regulatory submissions in Europe and Asia.
A High-Risk Population Without Suitable Azole Options
OASIS was a global, randomized, adjudicator-blinded study involving 225 adults with proven invasive aspergillosis or probable pulmonary disease for whom mould-active azole therapy was unsuitable or ineffective. Reasons included known or suspected azole resistance, intolerance, drug interactions, breakthrough infection during azole prophylaxis or prior treatment failure.
Patients were randomized 2:1 to oral olorofim (151 patients) or AmBisome-based therapy (74 patients), for up to 84 days. Approximately 79% had a hematologic malignancy or history of stem cell transplantation, around 11% had received a solid-organ transplant, and approximately 40% were neutropenic at enrollment or during the preceding four calendar days.
Olorofim was administered at 150 mg twice daily on Day 1, followed by 90 mg twice daily, with dose adjustments permitted according to concomitant medications and clinical circumstances. The comparator received intravenous AmBisome at 3 mg/kg daily for at least 10 days, unless stopped earlier because of toxicity, followed by continued AmBisome or another SOC antifungal.
Day 42 Mortality Meets the Non-Inferiority Criterion
The primary endpoint was all-cause mortality at Day 42 in the intention-to-treat population. Olorofim achieved a mortality rate of 23.8% (36/151), compared with 24.3% (18/74) with AmBisome-based therapy. The between-group difference was −0.5 percentage points (95% confidence interval [CI], −13.1 to 10.8), meeting the prespecified non-inferiority margin of 20 percentage points agreed with the FDA and the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).
The result supports olorofim as an oral treatment alternative in this population, but it does not establish superiority or equivalent efficacy. The confidence interval remains compatible with a potentially mea ningful mortality disadvantage, although the upper bound falls within the trial’s prespecified non-inferiority margin.
At Day 84, mortality was 32.5% (49/151) with olorofim and 29.7% (22/74) with AmBisome-based therapy, a difference of 2.7 percentage points (95% CI, −10.6 to 15.0). Independently assessed global response rates, requiring improvement in clinical, radiological and mycological components, were 26.5% versus 31.1% at Day 42 and 30.5% versus 28.4% at Day 84, respectively.
These secondary results do not establish a consistent efficacy advantage for either treatment. The available company announcement does not report formal superiority findings for these endpoints.
Fewer Renal Events, but Liver Injury Remains Relevant
Drug-related adverse events occurred in 35.8% of olorofim recipients (54/151), compared with 63.9% of patients receiving AmBisome-based therapy (46/72). Serious drug-related adverse events occurred in 4.0% versus 18.1%, respectively. Renal adverse events accounted for much of the difference, affecting 1.3% (2/151) of olorofim recipients and 22.2% (16/72) of comparator patients.
The safety denominators differ from the randomized efficacy population because the reported comparator safety analyses included 72 patients. These findings suggest a potential renal safety advantage for the olorofim treatment strategy, although the comparison should not be interpreted as proof of an overall net clinical benefit.
Drug-induced liver injury adjudicated as at least possibly related to treatment occurred at similar rates: 4.6% (7/151) with olorofim and 4.2% (3/72) with AmBisome-based therapy. Liver safety therefore remains an important consideration.
Mean hospital stay was also shorter in the olorofim arm, at 17±15 days versus 28±25 days. This is a potentially relevant finding, but the announced data do not establish that oral administration alone caused the difference.
Regulatory Resubmission Follows the 2023 FDA Setback
In June 2023, the FDA issued a Complete Response Letter for F2G’s initial olorofim NDA, which relied on data from the first 100 patients in the Phase 2b Study 32 (NCT03583164). The agency requested additional data and analyses. OASIS subsequently provided randomized Phase 3 evidence in invasive aspergillosis.
Olorofim belongs to the orotomide class of antifungals and has a novel mechanism of action, with activity against Aspergillus species, including azole-resistant strains. It has received FDA Breakthrough Therapy designations, orphan drug status and Qualified Infectious Disease Product designation for specified indications. These designations do not constitute marketing approval.
Clinical Interpretation
OASIS supports olorofim as a potential oral option for adults with invasive aspergillosis who cannot receive effective azole therapy. Its primary endpoint result and lower frequency of renal adverse events are clinically relevant, particularly in a population with limited treatment options.
However, Day 84 mortality was numerically higher with olorofim, global response rates did not consistently favor the investigational drug, and liver injury occurred at similar rates. The comparator also allowed different SOC antifungal regimens after initial AmBisome treatment, limiting drug-to-drug interpretation of the findings.
The results strengthen the evidence package for planned regulatory submissions but do not establish superiority or guarantee approval. Olorofim remains investigational, and its benefit-risk profile will require regulatory assessment of the complete clinical dataset.
Reference
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, Shionogi, 21 October 2026
Olorofim Aspergillus Infection Study (OASIS), ClinicalTrials.gov ID NCT05101187
About the Writer
Anamika Koshti (LinkedIn) is a PharmD professional and healthcare writer with interests in clinical research, pharmacovigilance, and evidence-based medicine. She has authored peer-reviewed publications on Alzheimer’s disease and PCOS, presented research at national conferences, and gained hands-on experience in medical content development and clinical data interpretation. She is committed to translating complex medical research into accurate, accessible content for healthcare professionals and patients.