The Antifungal Pipeline: Fosmanogepix, Ibrexafungerp, Olorofim, Opelconazole, and Rezafungin

Abstract

The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug–drug interactions, toxicity, and constraints in administration routes. Despite the need for more antifungal drug options, no new classes of antifungal drugs have become available over the last 2 decades, and only one single new agent from a known antifungal class has been approved in the last decade. Nevertheless, there is hope on the horizon, with a number of new antifungal classes in late-stage clinical development. In this review, we describe the mechanisms of drug resistance employed by fungi and extensively discuss the most promising drugs in development, including fosmanogepix (a novel Gwt1 enzyme inhibitor), ibrexafungerp (a first-in-class triterpenoid), olorofim (a novel dihyroorotate dehydrogenase enzyme inhibitor), opelconazole (a novel triazole optimized for inhalation), and rezafungin (an echinocandin designed to be dosed once weekly). We focus on the mechanism of action and pharmacokinetics, as well as the spectrum of activity and stages of clinical development. We also highlight the potential future role of these drugs and unmet needs. Supplementary Information The online version contains supplementary material available at 10.1007/s40265-021-01611-0.

A Visual and Comprehensive Review on COVID-19-Associated Pulmonary Aspergillosis (CAPA)

“…New antifungals, such as opelconazole, fosmanogepix, ibrexafungerp, olorofim and rezafungin are currently being evaluated and may be added to the therapeutic armamentarium in the future [7,111].…”

Inhaled Antifungal Agents for Treatment and Prophylaxis of Bronchopulmonary Invasive Mold Infections

“…A new triazole drug, named PC945 (opelconazole), was developed to optimize topical treatment with tissue retention and physicochemical properties adapted to inhalation [ 163 , 164 ]. Opelconazole inhalation resulted in high local concentrations, prolonged lung retention, slow absorption from the lung, and low plasma concentrations [ 165 ].…”

“…Phase I and IIa were recently performed and showed only mild-to-moderate AEs in 29 subjects. Opelconazole was used in a compassionate program on nine patients and positive clinical results were observed in eight [ 164 ]. Since opelconazole was poorly absorbed, the drug should not be used alone in disseminated forms of IMI but could represent a new option of great value in combination with systemic treatment or in prophylaxis.…”

“…New drugs, some belonging to new families, are actually under development. These new drugs include fosmanogepix (a novel Gwt1 enzyme inhibitor), ibrexafungerp (a first-in-class triterpenoid), and olorofim (a novel dihydroorotate dehydrogenase enzyme inhibitor) [ 164 ]. The use of these drugs by nebulized routes should be evaluated to bring new families of inhaled drugs.…”

Nebulized Amphotericin B in Mechanically Ventilated COVID-19 Patients to Prevent Invasive Pulmonary Aspergillosis: A Retrospective Cohort Study

“…For nebulized antifungals, little is known regarding drug deposition in the lung and airways in ventilated individuals, optimal particle size, dose, and dosing frequency. Although most studies have used a formulation of AmB, new azole drugs, such as opelconazole, are in clinical development for inhalation, which may also be considered for this indication ( 28 ). The benefit of antifungal prophylaxis will further depend on the frequency of CAPA and characteristics of critically ill COVID-19 cases, which depends on evolution of the COVID, vaccination coverages, and efficacy of SARS-CoV-2 treatments.…”