F2G’s oral antifungal clears Phase III hurdle

Azole antifungals remain the mainstay of treatment for invasive aspergillosis, but they are not suitable for every patient. Resistance to azoles is an increasing clinical problem, while drug–drug interactions, liver toxicity and tolerability issues can limit their use in the severely immunocompromised patients most at risk of the infection. In these cases, physicians often turn to alternative antifungals, including liposomal amphotericin B such as Gilead’s AmBisome, despite its need for intravenous administration and its own toxicity burden.

This is the treatment gap targeted by olorofim, F2G’s first-in-class oral antifungal. The drug belongs to the orotomide class and works through a mechanism distinct from azoles, giving it potential utility in invasive mould infections where existing options are inadequate or difficult to use.

UK antifungal specialist F2G and Japanese partner Shionogi have now announced positive topline results from the global Phase III OASIS trial, which evaluated oral olorofim against AmBisome followed by standard-of-care therapy in patients with invasive aspergillosis. The comparator is important: rather than testing olorofim against first-line azole therapy, the study compared it with a recognised non-azole treatment pathway used when azoles are unsuitable, poorly tolerated or clinically inappropriate.

The study met its primary endpoint of non-inferiority. All-cause mortality at Day 42 was 23.8% in the olorofim arm, compared with 24.3% for AmBisome followed by standard of care. In practical terms, the trial showed that mortality with oral olorofim was similar to that seen with the established amphotericin B-based regimen in this difficult-to-treat patient population.

The safety data also favour the logic behind developing a new non-azole option. F2G and Shionogi reported no new safety findings for olorofim. Drug-related treatment-emergent adverse events were reported in 35.8% of patients treated with olorofim, compared with 63.9% of those receiving AmBisome followed by standard of care. The difference was mainly driven by a higher rate of renal events in the AmBisome arm, consistent with the known kidney toxicity concerns associated with amphotericin B-based treatment.

The OASIS readout suggests that olorofim can deliver comparable survival while reducing drug-related adverse events, strengthening its regulatory case and potentially positioning the drug as a more convenient oral option.

An uncertain path to approval

The positive Phase III result follows a long and sometimes uncertain development path for olorofim. The drug received Breakthrough Therapy Designation from the US Food and Drug Administration in 2019, reflecting the need for new treatment options in serious invasive fungal infections. In 2022, Shionogi strengthened confidence in the programme by paying $100 million upfront to secure rights to olorofim in Europe and Asia through a partnership with F2G.

Momentum slowed in 2023 when F2G received a complete response letter from the FDA. The regulator requested additional data and analyses following the company’s Phase IIb study in a range of invasive fungal infections, delaying the drug’s regulatory progress and forcing the biotech to reassess its development strategy.

Despite the setback, F2G continued to back the programme. In 2024, the UK company raised $100 million to complete late-stage development and prepare for potential commercialisation. The OASIS trial was a key part of that effort, providing the confirmatory data needed to support the drug’s future regulatory filings.

The Phase III readout therefore represents more than a clinical milestone. It marks an important step in F2G’s attempt to bring the first member of the orotomide class to market after years of development, regulatory challenges and fundraising. Detailed OASIS data are expected to be presented at a future medical meeting and will likely form the basis of upcoming discussions with regulators.