Phase IIb Trial of Oral Olorofim as Salvage Therapy for Advanced Valley Fever

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Summary of  Annals of Internal Medicine https://doi.org/10.7326/ANNALS-26-00103 
Dr. Fariba M. Donovan  et al.

Points

A Phase IIb multicenter study led by the University of Arizona evaluated the novel orotomide antifungal drug olorofim in 41 patients with refractory disseminated coccidioidomycosis.
Trial participants aged 16 and older received oral olorofim for 84 days after standard therapies failed due to drug resistance, clinical non-response, interactions, or intolerance.
Clinical evaluation showed that 76% of treated patients demonstrated measurable improvement by day 42, while 73% maintained clinical improvement through day 84 of the study.
Safety monitoring indicated that elevated liver enzymes were the primary adverse reaction, which clinicians successfully managed through regular laboratory tracking and drug dose adjustments.
Published in Annals of Internal Medicine, the findings highlight olorofim as a promising salvage option for severe extrapulmonary Valley Fever, warranting further controlled clinical investigation.

Summary

This study evaluated the efficacy, safety, and tolerability of olorofim, a novel first-in-class orotomide antifungal agent, in patients with refractory disseminated coccidioidomycosis (DCM). DCM is a severe, systemic extrapulmonary manifestation of Coccidioides infection, or Valley Fever, that presents critical therapeutic challenges when conventional azole or polyene treatments fail. The trial sought to determine whether targeting fungal dihydroorotate dehydrogenase via oral olorofim could provide effective salvage therapy for patients lacking standard treatment options.

In a single-group, open-label, Phase IIb subanalysis conducted between May 2019 and August 2022, researchers evaluated 41 participants aged 16 years and older presenting with refractory DCM. Enrolled individuals exhibited predicted or documented resistance to licensed antifungals, lack of clinical improvement, severe drug-drug interactions, or treatment-limiting drug intolerance. Participants received oral olorofim either as monotherapy or adjunctively with standard care over an 84-day treatment period. Clinical improvement was achieved in approximately 76% of patients at day 42 and 73% at day 84.

The safety profile revealed that olorofim was generally well tolerated, with transiently elevated liver transaminases representing the primary adverse effect, which was managed through routine laboratory monitoring or dose adjustments. While limited by its single-arm design without a formal control cohort, these results demonstrate that olorofim exhibits substantial efficacy in heavily pretreated DCM populations. These findings justify further comparative Phase III clinical trials to establish its role in treating severe, treatment-resistant fungal infections.

Link to the article: https://www.acpjournals.org/doi/10.7326/ANNALS-26-00103

References

Donovan, F. M., Johnson, R. H., Patterson, T. F., Hoenigl, M., Spec, A., Sikka, M. K., Holland, S. M., Shoham, S., Schaenman, J. M., Mehta, S. R., Kuran, R. A., Galgiani, J. N., Bresnik, M., Rex, J. H., & Thompson, G. R. (2026). Olorofim in treatment of patients with poorly controlled disseminated coccidioidomycosis: A single-group, open-label, phase 2b, multicenter study. Annals of Internal Medicine, ANNALS-26-00103. https://doi.org/10.7326/ANNALS-26-00103