Review of the Novel Investigational Antifungal Olorofim

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.

Roles for Structural Biology in the Discovery of Drugs and Agrochemicals Targeting Sterol 14α-Demethylases

“…In contrast, narrow spectrum antifungals require sufficiently large markets to meet the costs of their development. Olorofim, the recently discovered orotide antifungal that affects molds and thermally dimorphic species but not yeast, will be an important exception if it can circumvent this limitation [48,49]. Drug-related side effects should be minimal, both in host organisms and in the environment.…”

New Antimycotics in the Pipeline – For Ophthalmology Too?

“…Olorofim kann sowohl oral als auch intravenös appliziert werden; das Molekulargewicht beträgt 498,6 g/mol. Bei hoher Plasmaproteinbindung weist Olorofim Interaktionen mit CYP3A4 und CYP450 auf und dadurch mit vielen Medikamenten [26]. Es penetriert beim Mausmodell ins Hirn.…”

“…C. auris, gegen Aspergillus spp. und Cryptococcus neoformans, mäßig gegen Fusarium solani [20,26]. In einem Candidiasis-Augen-Maus-Modell war die Substanz der Kontrollgruppe überlegen und reduzierte den Candidabiofilm [27].…”

Coccidioidomycosis: Changing Concepts and Knowledge Gaps

“…Olorofim ( Table 2 ) is a member of a new class of antifungals, the orotomides, that reversibly inhibits fungal pyrimidine biosynthesis through the enzyme dihydroorotate dehydrogenase (DHODH) with little inhibition of the human enzyme [ 82 , 83 ]. It has demonstrated in vitro activity against Coccidioides [ 80 , 82 ].…”

“…In a murine model of coccidioidal meningitis, doses of 10 and 20 mg/kg appeared to confer a survival advantage over fluconazole at 25 mg/kg, although there were still deaths [ 84 ]. An intravenous formulation using a β-hydroxypropyl-cyclodextrin vehicle has been studied in human volunteers with a half-life between 20 and 30 h. An oral formulation is also being studied [ 83 ]. Human studies for coccidioidomycosis are being planned.…”