Ibrexafungerp: Mechanism of Action, Clinical, and Translational Science

Abstract

Ibrexafungerp is a first-in-class triterpenoid antifungal that targets β-(1,3)-glucan synthase in fungal cell wall development. It is indicated for vulvovaginal candidiasis (VVC) and recurrent vulvovaginal candidiasis (RVVC) in adult and post-menarchal pediatric females. The drug was approved in 2021 and 2022 for VVC and RVVC, respectively. Research is ongoing to evaluate the safety of ibrexafungerp in pregnancy and lactation as well as to explore intravenous and oral formulations for invasive candidiasis and invasive aspergillosis. Ibrexafungerp binds and inhibits β-(1,3)-glucan synthase that is essential for the synthesis of β-(1,3)-D-glucan, a key polymer in the fungal cell wall, leading to cell lysis and death. This mechanism of action varies from that of the current VVC therapy, fluconazole, which makes ibrexafungerp a primary candidate for treating fluconazole-resistant patient cases. The drug is distributed into vaginal tissue at higher concentrations and has increased efficacy at lower pH compared to fluconazole, indicating a therapeutic advantage for VVC. Ibrexafungerp was generally well-tolerated in most participants throughout clinical trials. The most commonly reported treatment-emergent adverse events were headache, dizziness, and gastrointestinal-related effects. The efficacy of ibrexafungerp was found to be comparable to fluconazole and superior to placebo as seen in key clinical trials: DOVE (NCT03253094) and VANISH303 (NCT03734991). We reviewed the regulatory approval process of ibrexafungerp, including key clinical trials and in-depth analyses of pivotal studies related to the drug's clinical efficacy and safety. Additionally, we reviewed the drug's unique mechanism of action and the pharmacokinetic and pharmacodynamic characteristics essential for its use in VVC and RVVC.