Ibrexafungerp, a Novel Triterpenoid Antifungal in Development for the Treatment of Mold Infections

Molds are ubiquitous in the environment, and immunocompromised patients are at substantial risk of morbidity and mortality due to their underlying disease and the resistance of pathogenic molds to currently recommended antifungal therapies. This combination of weakened-host defense, with limited antifungal treatment options, and the opportunism of environmental molds renders patients at risk and especially vulnerable to invasive mold infections such as Aspergillus and members of the Order Mucorales. Currently, available antifungal drugs such as azoles and echinocandins, as well as combinations of the same, offer some degree of efficacy in the prevention and treatment of invasive mold infections, but their use is often limited by drug resistance mechanisms, toxicity, drug-drug interactions, and the relative paucity of oral treatment options. Clearly, there is a need for agents that are of a new class that provides adequate tissue penetration, can be administered orally, and have broad-spectrum efficacy against fungal infections, including those caused by invasive mold organisms. Ibrexafungerp, an orally bioavailable glucan synthase inhibitor, is the first in a new class of triterpenoid antifungals and shares a similar target to the well-established echinocandins. Ibrexafungerp has a very favorable pharmacokinetic profile for the treatment of fungal infections with excellent tissue penetration in organs targeted by molds, such as the lungs, liver, and skin. Ibrexafungerp has demonstrated in vitro activity against Aspergillus spp. as well as efficacy in animal models of invasive aspergillosis and mucormycosis. Furthermore, ibrexafungerp is approved for use in the USA for the treatment of women with vulvovaginal candidiasis. Ibrexafungerp is currently being evaluated in clinical trials as monotherapy or in combination with other antifungals for treating invasive fungal infections caused by yeasts and molds. Thus, ibrexafungerp offers promise as a new addition to the clinician’s armamentarium against these difficult-to-treat infections.


Introduction
Molds are ubiquitous in the environment and pose a serious and growing threat to public health, especially for patients who are immunocompromised [1][2][3]. Invasive fungal tory invasive aspergillosis [23]. Ibrexafungerp, an investigational agent in the treatment of invasive fungal disease, is the first member of the triterpenoid class of antifungals, and acts on the same target as the echinocandins, yet is orally available with evidence of good tissue penetration at many body sites [24].
On the basis of two large, randomized, double-blind, placebo-controlled Phase 3 clinical studies, ibrexafungerp was approved in the United States for the treatment of vulvovaginal candidiasis (VVC) in 2021. In both studies, ibrexafungerp 300 mg BID for 1 day was compared with a placebo. In both the VANISH 303 and VANISH 306 clinical trials, patients receiving ibrexafungerp had significantly higher rates of clinical cures. The cure rates were 50.5% for ibrexafungerp vs. 28.6% for placebo; p < 0.001 and 63.3% vs. 44.0%, p = 0.007 in VANISH 303 and VANISH 306; respectively, mycological eradication (49.5% for ibrexafungerp vs. 19.4% for placebo, p < 0.001 and 58.5% vs. 29.8%, p < 0.001 in VANISH 303 and VANISH 306, respectively), and overall therapeutic success (36.0% for ibrexafungerp vs. 12.6% for placebo, p < 0.001 and 46.1% vs. 28.4%, p = 0.022 in VANISH 303 and VANISH 306, respectively) [25,26]. Most importantly, symptom resolution was sustained, and symptoms improved further at follow-up with ibrexafungerp compared with the placebo. In both studies, ibrexafungerp was generally well tolerated. Adverse effects were primarily gastrointestinal and mild to moderate in severity.
Early evidence of ibrexafungerp in the treatment of invasive mold infections has shown promise, particularly in preclinical models of disease. We review here the potential use of ibrexafungerp for treating invasive infections caused by opportunistic molds.

Ibrexafungerp Mechanism of Action
Ibrexafungerp (previously MK-3118 and SCY-078; SCYNEXIS, Inc.; Jersey City, NJ, USA) disrupts fungal cell wall synthesis through the inhibition of (1,3)-β-D-glucan synthase [27]. Glucan synthase inhibition is also the mechanism of action of the echinocandins and has been demonstrated to result in a clinically meaningful effect in the treatment of yeast and mold infections. Because ibrexafungerp targets an enzymatic pathway that is not found in human cells, it has a low risk of off-target effects ( Figure 1).    Ibrexafungerp, a triterpenoid antifungal, is structurally distinct from the echniocandins ( Figure 2) and is a semisynthetic derivative of the naturally occurring hemiacetal triterpene glycoside enfumafungin that incorporates a pyridine triazole at position 15 of the core phenanthropyran carboxylic acid ring system and a 2-amino-2,3,3-trimethyl-butyl ether at position 14 to improve antifungal potency and pharmacokinetic properties [28]. Compared with echinocandins, ibrexafungerp has the advantages of oral bioavailability, a larger volume of distribution, and its binding to the glucan synthase appears distinct from that of echinocandins, leading to retention of activity against most echinocandin-resistant isolates of Candida spp., including those of C. auris [29].

Pharmacokinetics
In animals, ibrexafungerp is absorbed by the gastrointestinal tract after oral administration with a bioavailability of approximately 35-50%. Importantly, ibrexafungerp is widely distributed in tissues and demonstrates excellent tissue penetration in sites commonly associated with invasive fungal infection, including (but not limited to) the lung, liver, kidney, spleen, and skin. Ibrexafungerp has poor penetration into the central nervous system in uninfected animals [24] (Table 1).

Pharmacokinetics
In animals, ibrexafungerp is absorbed by the gastrointestinal tract after oral administration with a bioavailability of approximately 35-50%. Importantly, ibrexafungerp is widely distributed in tissues and demonstrates excellent tissue penetration in sites commonly associated with invasive fungal infection, including (but not limited to) the lung, liver, kidney, spleen, and skin. Ibrexafungerp has poor penetration into the central nervous system in uninfected animals [24] (Table 1). Ibrexafungerp is eliminated mainly via metabolism and biliary excretion with <2% of a dose recovered in urine. In vitro studies show that ibrexafungerp is metabolized via hydroxylation by CYP3A4 isoenzymes, followed by glucuronidation and sulfation of a hydroxylated inactive metabolite. Following oral administration of radio-labeled ibrexafungerp to healthy volunteers, a mean of 90% of the radioactive dose (51% as unchanged ibrexafungerp) was recovered in feces, and 1% was recovered in urine. The mean steady-state volume of distribution (V ss ) of ibrexafungerp in humans is approximately 600 L. Ibrexafungerp is highly protein-bound (greater than 99%), predominantly to albumin [30,31]. A dose-proportional increase in the mean area under the concentration-time curve (AUC 0-∞ ) and peak concentration (C max ) occurred with single doses of 10 mg to 1600 mg within 4 to 6 h, and the mean terminal half-life was 20 to 30 h [27]. The oral bioavailability of ibrexafungerp was increased with a high-fat meal, but absorption was delayed by administration with food [27]. No clinically meaningful effect was observed on the corrected QT interval (QTcF), heart rate, PR, or QRS intervals at plasma ibrexafungerp concentrations up to 4000 ng/mL [32]. Ibrexafungerp concentrations may be increased when administered with strong CYP3A4 inhibitors and dose adjustment may be needed. The coadministration of ibrexafungerp with CYP3A4 inducers is not recommended since it will decrease ibrexafungerp exposure [31].

In Vitro Activity against Aspergillus species
Ibrexafungerp has been extensively tested in vitro against a broad variety of fungal pathogens and has demonstrated potent activity against several isolates, with variable to weak activity against others ( Figure 3). state volume of distribution (Vss) of ibrexafungerp in humans is approximately 600 L. Ibrexafungerp is highly protein-bound (greater than 99%), predominantly to albumin [30,31]. A dose-proportional increase in the mean area under the concentration-time curve (AUC0-∞) and peak concentration (Cmax) occurred with single doses of 10 mg to 1600 mg within 4 to 6 h, and the mean terminal half-life was 20 to 30 h [27]. The oral bioavailability of ibrexafungerp was increased with a high-fat meal, but absorption was delayed by administration with food [27]. No clinically meaningful effect was observed on the corrected QT interval (QTcF), heart rate, PR, or QRS intervals at plasma ibrexafungerp concentrations up to 4000 ng/mL [32]. Ibrexafungerp concentrations may be increased when administered with strong CYP3A4 inhibitors and dose adjustment may be needed. The coadministration of ibrexafungerp with CYP3A4 inducers is not recommended since it will decrease ibrexafungerp exposure [31].

In Vitro Activity against Aspergillus species
Ibrexafungerp has been extensively tested in vitro against a broad variety of fungal pathogens and has demonstrated potent activity against several isolates, with variable to weak activity against others (Figure 3).   No in vitro activity, although in vivo activity has been reported in animal models.
Glucan synthase inhibitors exhibit a fungistatic effect against many molds [34,35], such as Aspergillus spp., despite a high proportion of β-(1,3)-D-glucan in the Aspergillus cell wall [34]. Because glucan synthase inhibitors exhibit a fungistatic effect against Aspergillus, MIC values are not accurate; thus, minimum effective concentrations (MEC; the lowest concentration at which abnormal hyphal growth occurs) are used for antifungal susceptibility testing in both CLSI and EUCAST methods [35].
In studies of in vitro susceptibility, ibrexafungerp demonstrated potent in vitro activity against Aspergillus spp. Complexes including azole-resistant strains [36][37][38][39]. The MEC of ibrexafungerp against a collection of Aspergillus spp. (n = 311) ranged from <0.06 µg/mL to 4 µg/mL [36]. The combinations of ibrexafungerp with voriconazole, amphotericin B, or isavuconazole were tested using a checkerboard combination test method against four strains of wild-type (WT) and two strains of azole-resistant Aspergillus strains. The combination of ibrexafungerp with voriconazole or isavuconazole showed in vitro synergy against WT Aspergillus spp. and was additive against azole-resistant strains. The combination of ibrexafungerp and amphotericin B were synergistic against both WT Aspergillus spp. and azole-resistant strains [36]. Similar results were observed in another study reporting that the combination of ibrexafungerp with isavuconazole resulted in a synergistic interaction in A. fumigatus, measured by Bliss independence drug interaction analysis [40].
The in vitro activity of ibrexafungerp combined with azole antifungals was evaluated against Aspergillus spp. isolates from patients undergoing lung transplantation [41]. The median MIC for azoles against all isolates was reduced by ≥4-fold when combined with ibrexafungerp, and the median MIC for ibrexafungerp also was reduced by ≥4-fold when combined with azoles against all isolated other than A. calidoustus. A synergistic effect was observed for ibrexafungerp combined with isavuconazole (62%), posaconazole (54%), and voriconazole (53%). Among isolates with an ibrexafungerp or azole MIC < 0.06 µg/mL, combinations remained beneficial with ≥4-fold reduction in MIC for 75%, 50%, and 75% of isolates for isavuconazole, posaconazole, and voriconazole, respectively.
Additionally, the in vitro activity of ibrexafungerp was examined against a selection of clinical isolates obtained from patients failing azole therapy for chronic pulmonary aspergillosis [45]. The MEC was determined for 22 A. fumigatus complex, 3 A. flavus complex, and 1 A. niger complex isolates with resistance to at least 1 azole antifungal. The MEC range for ibrexafungerp was from 0.008 to 0.25 µg/mL. The ibrexafungerp MEC among isolates considered resistant to all azoles ranged from 0.015 to 0.25 µg/L. One isolate that was resistant to all azoles and amphotericin B was susceptible to ibrexafungerp (MEC 0.125 µg/mL).

In Vivo Activity against Aspergillus spp. in Animal Models of Infection
In neutropenic mice, ibrexafungerp demonstrated potent in vivo efficacy against wildtype (WT) and azole-resistant strains of A. fumigatus when studied in a murine model of invasive aspergillosis [46]. Treatment with oral ibrexafungerp at 7.5 mg/kg/day and 10 mg/kg/day BID significantly increased the mean survival in all strains (p ≤ 0.003) and resulted in significant reductions in fungal kidney burden (p < 0.05) and serum galactomannan levels (p < 0.005). The exposure needed to achieve efficacy was similar to exposures reported in invasive candidiasis models.
The in vivo efficacy of ibrexafungerp combined with isavuconazole was examined in an experimental neutropenic rabbit model of invasive A. fumigatus pneumonia [40]. Ibrexafungerp 2.5 or 7.5 mg/kg/d IV or oral isavuconazole 40 mg/kg/d or their combination were administered. Ibrexafungerp and isavuconazole in combination demonstrated prolonged survival, decreased pulmonary injury, reduced residual fungal burden, and lower GMI and (1,3)-β-D-glucan levels in comparison to those of single therapy for the treatment of invasive pulmonary aspergillosis.
The in vitro interaction between ibrexafungerp and isavuconazole or amphotericin B was examined in a selection of molds [47]. Ibrexafungerp and isavuconazole exhibited synergistic effects in vitro against Cunninghamella bertholletiae, S. apiospermum, F. solani, and F. oxysporum with variable results against other molds.

In Vivo Activity against Other Molds
The in vivo efficacy of ibrexafungerp was examined alone and in combination against the clinical isolates of Rhizopus delemar and M. circinelloides causing mucormycosis [48]. Immunosuppressed mice were treated with a placebo, ibrexafungerp (30 mg/kg, po, BID), liposomal amphotericin B (LAMB, 10 mg/kg, IV, QD), posaconazole (POSA, 30 mg/kg, po, QD), a combination of ibrexafungerp + LAMB, or a combination of ibrexafungerp + POSA 24 h post-infection, and continued for 7 days for ibrexafungerp and POSA and 4 days for LAMB. The MEC for ibrexafungerp against the R. delemar isolate was >8 µg/mL, while the MICs for amphotericin B and posaconazole at 100% inhibition of growth were 0.06 and 0.5 µg/mL, respectively. Survival through Day 21 was the primary endpoint. All mice in the placebo group died by Day 16 post-infection. Following R. delemar infection, a significant (p < 0.002 for any treatment versus placebo) improvement in the median survival time and overall percent survival was observed with all treatments. In addition, ibrexafungerp + LAMB resulted in significantly (p < 0.04) improved overall survival versus any monotherapy. Thus, while ibrexafungerp lacked in vitro activity singly, ibrexafungerp monotherapy demonstrated in vivo efficacy against R. delemar infection and was equivalent to other antifungal drugs. The combination of ibrexafungerp + LAMB also demonstrated the highest survival among mice infected with M. circinelloides. Tissue burden determined by qPCR was also evaluated after infection with R. delemar, and ibrexafungerp mono-or combination-therapy reduced mice lung and brain fungal burden with the combination of ibrexafungerp + LAMB, resulting in the lowest fungal tissue burden when compared with placebo or monotherapy.

Ongoing Clinical Investigations with Ibrexafungerp for Invasive Mold Infections
There are two ongoing clinical studies evaluating the activity of ibrexafungerp against mold and fungal infections: an open-label study and a blinded phase 2 study. FURI is an open-label study of fungal diseases that are refractory to, or where, patients are intolerant of standard antifungal therapies (clinicaltrials.gov NCT03059992). Eligible patients have proven or probable severe mucocutaneous candidiasis, invasive candidiasis, invasive aspergillosis, or other fungal diseases such as coccidioidomycosis, histoplasmosis, and blastomycosis. In addition, patients must demonstrate treatment failure, intolerance or toxicity related to a currently approved standard-of-care antifungal treatment, or are unable to receive an approved oral antifungal drug (e.g., inadequate susceptibility of the organism), and a continued IV antifungal therapy is clinically undesirable or unfeasible. Most of the patients in this study have yeast infections, but data from some patients with mold infections are expected. Study completion is estimated by the end of 2022.
SCYNERGIA is a phase 2 study evaluating the safety and efficacy of ibrexafungerp co-administered with voriconazole in patients with IPA (ClinicalTrials.gov Identifier: NCT03672292). This is a multicenter, randomized, double-blind, two-arm study in male and female patients 18 years of age and older with a probable or proven IPA. Eligible patients are required to have a probable or proven infection that requires antifungal treatment and a diagnosis consistent with IPA. Patients are randomized to voriconazole alone or voriconazole combined with oral ibrexafungerp. Treatment is continued for a minimum of 6 weeks and up to 13 weeks. Outcomes include safety and tolerability, ibrexafungerp pharmacokinetics, and efficacy evaluated by a composite of clinical, radiological, and mycological response and mortality. Study completion is estimated by the end of 2022.

Summary
Invasive fungal infections, particularly mold infections, are associated with high mortality and often require prolonged antifungal therapy. Currently, available treatment options for mold infections are scarce and have limitations including increasing reports of resistance development. The increased incidence of Aspergillus spp. and Mucorales infections among COVID-19 patients have reminded us of the gaps in the available antifungal treatment armamentarium. Novel antifungals and treatment strategies are needed to improve the outcomes of these difficult-to-treat infections. The novel antifungal ibrexafungerp is a glucan synthase inhibitor with a spectrum of activity that includes several of the molds often involved in systemic diseases. Ibrexafungerp offers oral administration and has been found to be generally safe and well-tolerated. Ibrexafungerp is approved in the United States for treating acute episodic VVC, with approval for recurrent VVC anticipated, and is in development for the treatment of invasive fungal infections. The activity of ibrexafungerp includes the most prevalent fungal pathogens such as Candida spp., as well as Aspergillus spp. and other molds, and does not have cross-resistance with the azoles, which are the only oral antifungals available for many of these infections. The availability of a once-daily oral dosage form of ibrexafungerp offers the potential to reduce the need for IV administration and may decrease the frequency of prolonged hospitalization and complex dosing schedules, which may enhance the chances of treatment success. The evidence of the activity of ibrexafungerp against mold infections thus far is based on pre-clinical investigations, but these data provide a solid foundation for ongoing clinical development. For Aspergillus spp. infections, ibrexafungerp has shown in vitro and in vivo activity as monotherapy and synergetic activity in combination with other antifungals. For Mucorales infections, ibrexafungerp has shown evidence of activity in in vivo models despite the apparent lack of activity in traditional in vitro evaluation. The synergistic activity of ibrexafungerp noted in mice models of mucormycosis when combined with LAMB is particularly interesting considering the high mortality rate for these infections, representing a significant opportunity to improve outcomes for this devastating condition.
When reviewing new therapeutic options under development, it is important to understand their anticipated future role while taking into consideration their attributes and potential clinical implications. Additional clinical data are needed to better define ibrexafungerp's future role in mold infections; however, the pre-clinical data generated thus far are promising, justifying further development. Combination therapy appears to be an area of opportunity for ibrexafungerp, considering its inherent low risk for drug-todrug interactions, oral bioavailability, and preclinical data suggesting synergistic effects with other antifungals. The outcomes for many of these mold infections are still far from optimal, and novel therapeutic approaches including antifungal combinations may improve outcomes and warrant further investigation. The activity of ibrexafungerp against azoleresistant Aspergillus spp. is another feature of interest, particularly considering patients with chronic Aspergillus infections that often require long-term exposure to azoles, eventually developing resistance in geographic areas where azole-resistant Aspergillus spp. infections are more prevalent.
Another potential role of ibrexafungerp which will require further clinical demonstration could be its use in preventing fungal infections in patients at heightened risk. Its spectrum of activity, including the most prevalent fungal pathogens such as Candida spp. (including azole-resistant and most echinocandin-resistant), Aspergillus spp., Pneumocystis jirovecii, and Mucorales (based on animal models), together with its oral bioavailability, make ibrexafungerp a good candidate for evaluation as a prophylaxis agent. Based on the available preclinical data, other potential roles of ibrexafungerp include a salvage therapy for patients not responding to, or not tolerating, other antifungal options. As with any antimicrobial, the future role of this novel antifungal should consider the potential for drug resistance development and adequate surveillance and stewardship strategies.
Results from ongoing clinical trials are awaited to further define the efficacy of ibrexafungerp, alone or combined with other antifungals, for treating invasive fungal infections including those caused by Aspergillus spp. and other molds.