olorofim

Olorofim is an investigational, first-in-class orotomide antifungal agent (1,2)

• targets severe, invasive mold infections that are often resistant to current therapies.

Mechanism of Action

• inhibits dihydroorotate dehydrogenase (DHODH), a key enzyme in the fungal pyrimidine synthesis pathway
• arrests DNA and RNA synthesis, leading to cell death
• distinct from azoles (ergosterol synthesis) and echinocandins (cell wall synthesis), meaning no cross-resistance exists

Spectrum of activity

• highly active against Aspergillus species, including azole-resistant strains
• exhibits potent activity against difficult-to-treat molds such as Lomentospora prolificans and Scedosporium species
• covers dimorphic fungi, including Coccidioides immitis
• possesses no activity against yeasts, such as Candida or Cryptococcus species
• entirely inactive against Mucorales (such as Rhizopus) and Fusarium species

Clinical Indications and Administration

• targeted at patients with invasive aspergillosis or rare mold infections who have limited or no alternative treatment options due to resistance or intolerance
• formulated for both intravenous and oral administration, facilitating step-down outpatient therapy
• received FDA Breakthrough Therapy designation, with positive Phase 3 OASIS trial results announced in mid-2026

Key Practice Points

• fungal identification is vital before use, as it is entirely inactive against common Candida infections
• monitoring of liver function tests (LFTs) is required as transient elevations can occur

Notes:

• study evidence showed that olorofim, a first-in-class antifungal agent, demonstrated clinical success in patients with limited or no therapeutic options (clinical success rate 75.6% [95% CI, 59.7% to 87.6%] at day 42, 73.2% [57.1% to 85.8%] at day 84) (3)

Reference:

1. Vanbiervliet Y et al. Review of the novel antifungal drug olorofim (F901318). BMC Infect Dis. 2024 Nov 7;24(1):1256. doi: 10.1186/s12879-024-10143-3. Erratum in: BMC Infect Dis. 2024 Dec 12;24(1):1395.
2. Maertens JA et al. 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 Nov;25(11):1177-1188. doi: 10.1016/S1473-3099(25)00224-5.
3. Fariba M. Donovan, Royce H. Johnson, Thomas F. Patterson, et al. Olorofim in Treatment of Patients With Poorly Controlled Disseminated Coccidioidomycosis (https://www.acpjournals.org/doi/abs/10.7326/ANNALS-26-00103): A Single-Group, Open-Label, Phase 2b, Multicenter Study. Ann Intern Med.[Epub 21 July 2026].