Review of the Novel Investigational Antifungal Olorofim
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1Fungus Testing Laboratory, Department of Pathology and Laboratory Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
Abstract:
The incidence of invasive fungal infections caused by molds and endemic fungi is increasing. There is also concern regarding increased rates of reduced susceptibility or frank resistance among Aspergillus and Coccidioides species, while Scedosporium species, Lomentospora prolificans, and Fusarium species are inherently less susceptible or intrinsically resistant to clinically available antifungals. Olorofim (formerly F901318) is the first member of the orotomide class of antifungals to be evaluated clinically for the treatment of invasive mold infections. This agent inhibits dihydroorotate dehydrogenase, a key enzyme in the biosynthesis of pyrimidines. Olorofim has activity against many molds and thermally dimorphic fungi, including species that are resistant to azoles and amphotericin B, but lacks activity against yeasts and the Mucorales. It is currently being developed for both oral and intravenous administration. Although published clinical outcome data have been limited to case reports to date, the results against invasive and refractory infections are promising. This review describes the mechanism of action of olorofim, its in vitro spectrum of activity, and what is currently known about its pharmacokinetic profile and clinical efficacy.
Insights
Olorofim, a novel antifungal, shows promise for treating invasive mold infections, including those resistant to existing therapies. Its unique mechanism targets pyrimidine biosynthesis, offering a new option for difficult-to-treat fungal diseases.
Area of Science:
- Mycology
- Infectious Diseases
- Pharmacology
Background:
- Increasing incidence of invasive fungal infections (IFIs) caused by molds and endemic fungi.
- Growing concern over antifungal resistance in key pathogens like Aspergillus and Coccidioides.
- Intrinsic resistance of Scedosporium, Lomentospora prolificans, and Fusarium species to current antifungals.
Purpose of the Study:
- To review the novel antifungal agent olorofim (orotomide class).
- To describe its mechanism of action, in vitro activity, pharmacokinetics, and clinical efficacy.
- To highlight its potential in treating invasive mold infections, particularly resistant cases.
Main Methods:
- Review of existing literature on olorofim, including preclinical data and early clinical case reports.
- Analysis of its mechanism targeting dihydroorotate dehydrogenase in pyrimidine biosynthesis.
- Evaluation of its in vitro spectrum of activity against various fungal species.
Main Results:
- Olorofim demonstrates activity against a broad range of molds and dimorphic fungi, including azole- and amphotericin B-resistant strains.
- It lacks activity against yeasts and Mucorales.
- Early clinical case reports suggest promising outcomes for invasive and refractory infections.
Conclusions:
- Olorofim represents a new class of antifungal (orotomides) with a unique mechanism of action.
- It shows potential for treating challenging invasive mold infections where other antifungals fail.
- Further clinical studies are needed to fully establish its role in patient care.
