Inclusion Criteria:

• Male and female patients, English- or Spanish-speaking, aged ≥18 years and weighing ≥40 kg who have been fully informed and:

  • who have given voluntary written informed consent, or whose legally authorized representative(s) has/have been fully informed and has given voluntary written informed consent if applicable, and in compliance with local regulations OR

  • who have given oral informed consent witnessed in writing by an independent person and in compliance with local regulations for patients who are unable to write and/or read but who fully understand the oral information given by the Investigator (or nominated representative).

• Patients with confirmed disseminated coccidioidomycosis documented in medical records, involving extra-pulmonary sites with or without ongoing active disease in lungs, diagnosed as:

  • Histopathology or direct microscopy of specimens obtained from an affected site showing the distinctive form of the Coccidioides species OR

  • Recovery by culture of the Coccidioides species from a naturally sterile specimen from an affected site OR

  • Blood culture that yields Coccidioides species OR

  • All of the following:

    • evidence of environmental exposure to Coccidioides AND

    • a compatible clinical illness AND

    • positive serology testing defined as:

      • the presence of antibody to Coccidioides species in cerebrospinal fluid (CSF) OR

      • Coccidioides spp. serum antibodies titer 1:4 or higher

• Ongoing symptoms due to coccidioidomycosis are such that the risk benefit of treatment with an investigational agent with a hepatic risk requiring careful monitoring is judged favorable based on meeting criteria for progressive or refractory DCM:

  • The overall impact of all DCM-related symptoms at study entry results in a MZ PS score ≥1

  • AND

  • The patient’s DCM is either:

    • Progressive (worsening or new symptoms during the 28 days prior to start of study treatment despite a minimum of ≥43 days of SOC therapy immediately prior to start of study treatment) OR

    • Refractory (despite ≥85 days of SOC, symptoms are unchanged over the >28 days of SOC therapy immediately prior to start of study treatment).

• SOC therapy for DCM to date has included 2 different triazoles (with or without a course of IV amphotericin B), AND:

  • SOC therapy for DCM with a triazole (with or without concomitant IV amphotericin B) is ongoing AND

  • SOC therapy for DCM has continued for the 28 days prior to start of study treatment and meets the following criteria:

    • SOC triazole therapy has remained unchanged (except for dose changes to manage predicted drug-drug interactions [DDIs]¸ which are permitted) in the 28 days prior to start of study treatment, with adequate therapeutic drug levels (measured if TDM is performed as part of SOC at site).

    • If IV amphotericin B is to be continued after study entry as part of SOC, the patient must have been on IV amphotericin for at least 28 days prior to start of study treatment with dosing following local guidance. AND

  • Continued SOC therapy for DCM with the triazole is planned and acceptable for the next 24 weeks (discontinuation of IV amphotericin B is acceptable) AND

  • The patient has been compliant with SOC therapy for DCM and is willing to continue to be compliant with current SOC therapy.

• Ability and willingness to comply with the protocol.

• Female patients must be non-lactating and at no risk of pregnancy for one of the following reasons:

  • Postmenopausal for at least 1 year.

  • Post-hysterectomy and/or post-bilateral oophorectomy.

  • Of childbearing potential, with a negative urine or serum human chorionic gonadotropin pregnancy test at the Screening Visit and must be using one of listed below highly effective method of birth control throughout the course of the study period and up to and including 30 days after stopping study drug (and may not donate oocytes during this time):

    • Established use of oral, injected, transdermal, intravaginal, or implanted hormonal methods of contraception associated with inhibition of ovulation

    • Placement of an intrauterine device or intrauterine hormonereleasing system

    • Male sterilization

    • Bilateral tubal occlusion

    • Sexual abstinence (reliable sexual abstinence is acceptable but periodic abstinence [e.g., calendar, ovulation, symptom-thermal, or post-ovulation methods] and withdrawal are not acceptable).

• Male patients with female partners of childbearing potential must either totally abstain from sexual intercourse or use a highly effective means of contraception throughout study participation and agree to continue its use for 30 days after stopping study drug and may not donate semen during this time.

Exclusion Criteria:

• Patients who are unconscious.

• Patients who are pregnant or breastfeeding.

• Known history of allergy, hypersensitivity, or any serious reaction to any component of the study drug (olorofim or the olorofim-placebo tablets).

• Patients with or planned placement of indwelling CNS devices (e.g., reservoirs, shunts, ventriculostomies, or external drainage tubes).

• Patients receiving intrathecal (IT) amphotericin B at the time of study enrollment.

• Patients with coccidioidomycosis limited to fibro-cavitary pulmonary disease.

• All bothersome DCM-related symptoms at study entry are due to irreversible damage (e.g., neurologic deficits due to stroke).

• Patients with a second fungal infection requiring systemic antifungal treatment or prophylaxis, other than cutaneous fungal infections treated topically and Pneumocystis jirovecii infections.

• Patients with microbiological findings (e.g., bacteriological, virological) or other potential conditions that are temporally related and suggest a different than study indication etiology for the clinical features.

• Patients living with Human Immunodeficiency Virus (HIV) unless for at least 6 months prior to enrollment:

  • Are receiving antiretroviral therapy AND

  • Have no evidence of current clinical progression (e.g., no new or recent diagnosis of an opportunistic infection) resulting from HIV infection.

• Any known or suspected medical condition or social circumstance of the patient that may jeopardize adherence to the protocol requirements or impede the accurate measurement of efficacy.

• Patients with a concomitant medical condition or social circumstance that, in the opinion of the Investigator, may be an unacceptable additional risk to the patient should he/she participate in the study.

• Patients who have received prior treatment with olorofim/F901318.

• Treatment with any investigational drug within the 30 days prior to the first administration of study drug except for unblinded protocols (e.g., open label oncological regimen variations or biologic studies). Prior to enrolling patients who are on other open label studies, it is the site’s responsibility to ensure that the study criteria for that study allow for enrollment into this study.

• Patients receiving treatment limited to supportive care due to predicted short survival time.

• Patients with a baseline prolongation of QT using Fridericia’s Correction Formula (QTcF) ≥500 msec, or at high risk for QT/QTc prolongation, eg,

  • A family history of long QT syndrome

  • Other known pro-arrhythmic conditions

  • Risk factors for Torsade de Pointes (e.g., uncompensated heart failure, abnormal plasma potassium or magnesium levels that cannot be corrected, an unstable cardiac condition during the last 30 days).

• Evidence of hepatic dysfunction with any of the following abnormal laboratory parameters at screening:

  • Total bilirubin ≥2 × upper limit of the normal range (ULN), OR

  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥3× ULN, OR

  • Patients with known cirrhosis or chronic hepatic failure (regardless of ALT/AST/total bilirubin). Liver transplant recipients may be enrolled if their laboratory parameters do not meet the laboratory exclusions given above.

• Prohibited concomitant medications. Concomitant administration of inhibitors of human dihydro-orotate dehydrogenase (DHODH), teriflunomide, leflunomide, and use of cannabis/cannabinoid preparations (other than topical e.g. shampoos/creams), including tetrahydrocannabinol (THC) and cannabidiol (CBD) are prohibited. There are currently no other absolutely prohibited concomitant medications for olorofim but there are medications with potentially significant DDIs with olorofim or SOC and the management of potential interactions should be considered before study enrollment.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 03/16/2026. Questions regarding updates should be directed to the study team contact.