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

Abstract

Systemic infections caused by Candida species are an important cause of morbidity and mortality among immunocompromised and non-immunocompromised patients. In particular, Candida glabrata is an emerging species within the Candida family that causes infections ranging from superficial to life-threatening systemic disease. Echinocandins and azoles are typically the first-line therapies used to treat infections caused by C. glabrata, however, there is an increasing prevalence of resistance to these antifungal agents in patients. Thus, a need exists for novel therapies that demonstrate high efficacy against C. glabrata. Ibrexafungerp is a first-in-class glucan synthase inhibitor with oral availability developed to address this increasing antifungal resistance. Ibrexafungerp demonstrates broad in vitro activity against wild-type, azole-resistant, and echinocandin-resistant C. glabrata species. Furthermore, ibrexafungerp has shown efficacy in low pH environments, which suggests its potential effectiveness in treating vulvovaginal candidiasis. Additional preclinical and clinical studies are needed to further examine the mechanism(s) of ibrexafungerp, including acting as a promising new agent for treating C. glabrata infections.

Epidemiological Characterization of Clinical Fungal Isolates from Pauls Stradinš Clinical University Hospital, Latvia: A 4-Year Surveillance Report

“…The development of newer drug classes, including echinocandins, allylamines, etc., provides a viable alternative to these traditional antifungal agents. The development of ibrexafungerp (formerly known as SCY-078) has shown promising results for the treatment of echinocandin-resistant fungal isolates, especially C. glabrata -caused vulvovaginal candidiasis [ 117 ]. It is the first oral (1-3)-β-D-glucan synthase inhibitor (GSI) which works by hindering fungal cell wall synthesis [ 118 ].…”

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

“…Ibrexafungerp is currently available as an oral formulation (an intravenous formulation is still in phase I developments) and has a good oral absorption with a bioavailability rate of 35–50% and high protein binding of 99% [ 113 , 114 ]. Human data showed a peak plasma concentration within 4–6 h and a linear decline with a mean half-life of approximately 20–30 hours supporting a once-daily dosing strategy [ 115 ].…”

“…In ongoing studies, a once-daily dosage is used after 2 days of a twice-daily loading dose (FURI, NCT03059992). Although a high-fat meal increased the bioavailability, it delayed the median time to C max from 4 h (fasted state) to 6 h [ 114 ]. Based on data from animal models, ibrexafungerp shows a high tissue penetration with the following tissue-to-blood AUC ratios: spleen 54-fold; liver 50-fold; lung 31-fold; bone marrow 25-fold; kidney 20-fold; skin 12-fold to 18-fold; vaginal tissue nine-fold; and skeletal muscle four-fold, although tissue concentrations are known to not always infer site activity.…”

Candidemia: Evolution of Drug Resistance and Novel Therapeutic Approaches

“…57 Differently from echinocandins, ibrexafungerp can be administered both intravenously and orally and could be used in different fungal infections, from superficial to lifethreatening. 58 Several clinical trials studied the effectiveness of ibrexafungerp in invasive candidiasis, invasive pulmonary aspergillosis and vulvovaginal candidiasis (VVC). The recent Phase III trial VANISH 303 detected higher rate of clinical cure, mycological eradication and overall success of oral ibrexafungerp compared with placebo in VVC.…”