Ibrexafungerp: A Novel Oral Triterpenoid Antifungal in Development for the Treatment of Candida auris Infections

Abstract

Candida auris is an emerging multidrug-resistant fungal pathogen reported worldwide. Infections due to C. auris are usually nosocomial and associated with high rates of fluconazole resistance and mortality. Echinocandins are utilized as the first-line treatment. However, echinocandins are only available intravenously and are associated with increasingly higher rates of resistance by C. auris. Thus, a need exists for novel treatments that demonstrate potent activity against C. auris. Ibrexafungerp is a first-in-class triterpenoid antifungal agent. Similar to echinocandins, ibrexafungerp inhibits (1→3)-β-D-glucan synthase, a key component of the fungal cell wall, resulting in fungicidal activity against Candida spp. Ibrexafungerp demonstrates broad in vitro activity against various Candida spp. including C. auris and C. auris isolates with fks mutations. Minimum inhibitory concentration (MIC50 and MIC90) values in >400 C. auris isolates were 0.5 μg/mL and 1.0 μg/mL, respectively. Clinical results were reported for two patients with invasive candidiasis or candidemia due to C. auris treated during the CARES (Candidiasis Caused by Candida Auris) trial, an ongoing open-label study. These patients experienced a complete response after treatment with ibrexafungerp. Thus, ibrexafungerp represents a promising new antifungal agent for treating C. auris infections.

Ibrexafungerp, a Novel Oral Triterpenoid Antifungal in Development: Overview of Antifungal Activity Against Candida glabrata

“…It also showed consistent activity against C. glabrata with fks mutations, which confer resistance to echinocandins, with MIC values ranging from <0.03 to 4 μg/ml ( Nunnally et al., 2019 ). Additionally, ibrexafungerp has uniform and potent activity against C. auris , an emerging multidrug-resistant fungus, which was demonstrated in several studies ( Berkow et al., 2017 ; Arendrup et al., 2020 ; Barat SB-E, 2020 ; Ghannoum et al., 2020a ). Furthermore, ibrexafungerp has also shown the ability to reduce C. auris tissue fungal burden in an in vivo guinea pig model ( Ghannoum et al., 2020b ).…”

“…Ibrexafungerp (formerly SCY-078) is the first compound of the enfumafungin-derived triterpenoid class of antifungals and the first oral (1-3)-β-D-glucan synthase inhibitor (GSIs) ( Ghannoum et al., 2020a ). GSIs are a group of drugs that act by inhibition of β-1,3-D-glucan synthase, a key enzyme in the biosynthesis of ß-(1,3)-D-glucan, a major component of the fungal cell wall.…”

“…Derivatives of enfumafungin were found to be potent inhibitors of β-1,3-D-glucan synthase and are structurally different from the echinocandins. Semi-synthetic modification of these derivatives resulted in improvement of oral bioavailability and PK properties thereby leading to the discovery of ibrexafungerp ( Ghannoum et al., 2020a ).…”

Promising Drug Candidates and New Strategies for Fighting against the Emerging Superbug Candida auris

“…In parallel, Chaturvedi et al reported that Ibrexafungerp was efficient against pan-resistant (defined as in vitro resistance to two or more azoles, all echinocandins and amphotericin B) C. auris isolates from the outbreak in New-York [98] and Ghannoum et al demonstrated that it was active to control skin infection and colonization of hospitalized patients [99]. Recently, a review compiled data on Ibrexafungerp, established it is a promising, new antifungal agent to treat C. auris infections, as patients experienced a complete response after treatment [100]. From a chemical point of view, SCY-078 is based on a lipophilic tetracyclic-fused core with addition of protonable nitrogen moieties (pyridine, triazole and primary amine).…”

Antifungal Pipeline

“…In Vitro studies demonstrate significant activity against most common Candida species including several resistant strains such as Candida glabrata and Candida auris ( Schell et al., 2017a ; Ghannoum et al., 2020 ). Moreover, it demonstrates excellent in vitro activity versus both wild-type and azole-resistant strains of Aspergillus ( Lamoth and Alexander, 2015 ).…”