First, some clinical background. In contrast to antibacterials, antifungals are often given for prolonged periods of time. Therefore, safety is important; drugs with significant toxicity are relegated to 2nd or 3rd tier roles. Think about aminoglycosides: still used but avoided as much as possible – mainly because of nephro- and ototoxicity with long-term use. We would not want to prescribe them for weeks and months on end.
Invasive fungal infections are rarely encountered except in immunocompromised patients, those with depressed numbers of protective neutrophils or lymphocytes. The occurrence of significant aspergillus or mucor infection demands treatment with a drug that is highly efficacious, as patient survival depends on it. Hence, antifungal efficacy becomes even more important than safety. Patients would otherwise die of an invasive fungal infection before succumbing to their underlying disease.
The rationale for prophylactic antibiotic regimens is to buy time from overwhelming bacterial or fungal infections during the times of severe immunosuppression. Therefore, most centers use fluconazole, a safe and effective drug to prevent invasive Candida yeast infections. However, after a period of time, organisms may emerge that are intrinsically resistant. Then we run into a dilemma as treatment of resistant fungi is often problematic, given the few choices available.
For some patients with Candida break-through infection, the new candin family of drugs may still be effective. However, for aspergillosis, the most dreaded fungal infection, the choice comes down to voriconazole, isavuconazole or amphotericin B (AMB). Isavuconazole is the preferred azole for invasive aspergillus or mucor infections, because it is better tolerated and lacks the many DDI issues associated with voriconazole use. Nobody likes to use AMB, the drug of last resort. It comes in several lipid formulations which are probably somewhat less toxic than the deoxycholate, but toxic it still is. There is a reason AMB is also known as “amphoterrible”. Now that’s the end of the road. It is obvious that we have a very limited antifungal tool chest.
With that said, let’s talk about the recently published Phase 2b olorofim study.[1]
Olorofim, a novel anti-aspergillosis drug, was tested in patients with intractable fungal disease: many patients were immunocompromised, all had proven or probable IFD and the fungus was either Aspergillus or some other rare or drug-resistant fungus. The list of study participants and authors reads like the Who Is Who of mycology experts around the world. The outcome endpoints were carefully chosen. It took 5 years to conduct this study which enrolled 202 patients at 22 international centers, a heroic effort for a small company like F2G. F2G partnered with Shionogi for X-US rights, but Shionogi is no Pfizer when it comes to antifungal expertise in drug development. So it came down to John Rex, a well-known mycologist and F2G’s CMO and his group of advisors to structure the study.
The key results came in as follows (excerpted from Table 2 – Ref 1)
Results were marginally better for the large subset of Aspergillus patients, but the total lack of activity against Coccidioides infections was disappointing as none of these patients benefited.
The Lancet article is a bit of a head-scratcher. How does one interpret such outcome results without the benefit of a comparator group? Historical comparisons and references were provided by the authors to frame the low response rates, but this approach just raises more questions.
A large element of this study dealt with dose adjustments and PK monitoring. This is unusual as the company had already run several PK studies in NHV. This reflects the fact that olorofim has significant PK issues that affect its efficacy (the need to stay above a trough of 0.7 μg/mL) and safety (the need to avoid hepatotoxicity).[2]
In essence, Phase 2b was a PK and safety study in the target population but too large for the purpose. Note it was initially conceived for a size of 100 patients, which should have sufficed.
Why was there a change of strategy leading to doubling the recruitment to 200 patients? Was it meant to convert it into a pivotal trial for early submission? It is obvious to us that, despite its enlarged size, this trial does not meet regulatory expectations for a ‘well-designed’ efficacy and safety study. One cannot assume that FDA would use its largesse and forego robust, contemporaneous, side-by-side comparative efficacy testing. We are not dealing with an Animal Rule situation or an LPAD indication, as similar studies in IFD have been done before.
Why, then, did F2G request approval so early, even before finishing the Ph2b trial? [3] Why risk FDA rejection and a public CRL telling the company and the world that ‘more data is needed’? F2G may have taken a calculated risk here, hoping to gain a few years on the competition. A rejection letter was probably anticipated.
In our opinion, this submission was premature. Regulatory reviewers have to be given the right kind of data to analyze and justify their approval decisions. We believe that FDA rejected the partial Phase 2b data mainly because the study was uncontrolled resulting in uninterpretable efficacy data.
Since the June 2023 rejection, F2G had “multiple productive meetings” with FDA. The company felt confident that they had “aligned on a plan for resubmission using the existing Phase 2 data”, planning a resubmission “towards the end of next year”.[4],[5] This would have been the end of 2024, presumably. But we are now in 2025 and are still waiting….
In any case, by the time of a resubmission F2G should have more preliminary data, this time from its large Phase 3 trial. Enrollment in the international Phase 3 OASIS trial already started in 2022, with results expected by the end of 2026.
This happens to be a well-controlled trial randomizing patients to either olorofim or liposomal AMB, now limited to treatment of invasive aspergillosis.
ABBREVIATIONS
AMB amphotericin B
CRL Complete Response Letter
IFD invasive fungal disease
LPAD limited population antibacterial & antifungal drugs
NHV normal healthy volunteer
REFERENCES
[1] Maertens J. 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, https://doi.org/10.1016/S1473-3099(25)00224-5
[2] Kennedy T. Multiple Dose Pharmacokinetics of an Immediate-Release Tablet Formulation of F901318 in Healthy Male and Female Subjects. ECCMID 2017, #P1710
[3] The submission was supported by data from the first 100 patients only
[4] https://f2g.com/press-release/f2g-receives-complete-response-letter-from-fda-for-new-drug-application-for-olorofim-for-the-treatment-of-invasive-fungal-infections-plans-resubmission-with-additional-data-and-analyses/ (accessed Sept 22, 2025)
[5] https://www.fiercebiotech.com/biotech/f2g-raises-100m-2nd-attempt-get-new-antifungal-class-market (accessed Sept 22, 2025)
