A Novel 1,3-Beta- d -Glucan Inhibitor, Ibrexafungerp (Formerly SCY-078), Shows Potent Activity in the Lower pH Environment of Vulvovaginitis

Abstract

Ibrexafungerp (IBX) (formerly SCY-078) is a novel glucan synthase inhibitor whose oral availability is being evaluated for efficacy against vulvovaginal candidiasis (VVC). Bioavailability and in vitro activity are important efficacy indicators, but accepted susceptibility methods do not always accurately predict activity in an acidic environment, such as the vagina. Studies were 3-fold, as follows: (i) pharmacokinetic study following oral administration in a murine model; (ii) susceptibility testing of isolates from a phase 2 VVC clinical trial by CLSI M27-A4 methodology; and (iii) susceptibility testing of Candida albicans and Candida glabrata isolates obtained from this trial group in RPMI 1640 adjusted to 3 different pH values, 7.0, 5.72, and 4.5, compared to susceptibility testing for micafungin and fluconazole. IBX readily accumulated in vaginal tissues and secretions following oral administration. Potent in vitro activity was demonstrated against Candida strains obtained at baseline and end of study visits. Moreover, the geometric mean (GM) values for IBX at pH 4.5 were dramatically lower than those at pH 7.0 and 5.72. The MIC90 values of micafungin remained the same regardless of pH value, while those of fluconazole tended to increase with lower pH values. IBX is able to reach target tissues following oral administration at pharmacologically meaningful levels. IBX demonstrated potent in vitro activity, with no development of resistance, following repeated exposure over the course of the clinical trial. Importantly, activity of IBX in an acidic medium suggests a therapeutic advantage of this novel antifungal in the treatment of vaginal Candida infections.

The Fungal Cell Wall: Candida, Cryptococcus, and Aspergillus Species

“…In addition, there is a novel drug called ibrexafungerp (SCY-078) that is a glucan synthase inhibitor belonging to the triterpenoid antifungal class and shows a broad in vitro and in vivo activity against a broad spectrum of Candida (Larkin et al, 2019). In vitro studies have demonstrated that this new drug has fungicidal activity against azole-resistant Candida spp.…”

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

“…Ibrexafungerp was shown to have activity against biofilms from different Candida species [ 28 ]. Consistent with clinical trials in treatment of vulvovaginal candidiasis, ibrexafungerp showed potent in vitro activity in the lower pH environment of vulvovaginitis [ 39 ].…”

Oral Ibrexafungerp: an investigational agent for the treatment of vulvovaginal candidiasis

“…as has been demonstrated previously [48]. Susceptibility testing was conducted with ibrexafungerp, micafungin, and fluconazole for C. albicans and C. glabrata isolates with test medium adjusted to pH values of 7.0, 5.7, and 4.5 [40]. The MIC 90 values for ibrexafungerp at pH 4.5 were dramatically lower than at pH 7.0 and 5.7.…”

“…In particular, with ibrexafungerp, vaginal tissue concentrations exceed plasma concentration and are higher than other antifungals, with a 9-fold higher concentration than what is seen with fluconazole [38][39][40][41]. Ibrexafungerp is extensively metabolized in the liver by cytochrome P450 3A4 isoenzymes, and <2% of a dose was recovered in urine [40].…”