Combination Therapy with Ibrexafungerp (Formerly SCY-078), a First-in-Class Triterpenoid Inhibitor of (1→3)-β- d -Glucan Synthesis, and Isavuconazole for Treatment of Experimental Invasive Pulmonary Aspergillosis

Abstract

Ibrexafungerp (formerly SCY-078) is a semisynthetic triterpenoid and potent (1→3)-β-d-glucan synthase inhibitor. We investigated the in vitro activity, pharmacokinetics, and in vivo efficacy of ibrexafungerp (SCY) alone and in combination with antimold triazole isavuconazole (ISA) against invasive pulmonary aspergillosis (IPA). The combination of ibrexafungerp and isavuconazole in in vitro studies resulted in additive and synergistic interactions against Aspergillus spp. Plasma concentration-time curves of ibrexafungerp were compatible with linear dose proportional profile. In vivo efficacy was studied in a well-established persistently neutropenic New Zealand White (NZW) rabbit model of experimental IPA. Treatment groups included untreated control (UC) rabbits and rabbits receiving ibrexafungerp at 2.5 (SCY2.5) and 7.5 (SCY7.5) mg/kg of body weight/day, isavuconazole at 40 (ISA40) mg/kg/day, or combinations of SCY2.5+ISA40 and SCY7.5+ISA40. The combination of SCY+ISA produced an in vitro synergistic interaction. There were significant in vivo reductions of residual fungal burden, lung weights, and pulmonary infarct scores in SCY2.5+ISA40, SCY7.5+ISA40, and ISA40 treatment groups versus those of the SCY2.5-treated, SCY7.5-treated, and UC (P < 0.01) groups. Rabbits treated with SCY2.5+ISA40 and SCY7.5+ISA40 had prolonged survival in comparison to that of the SCY2.5-, SCY7.5-, ISA40-treated, or UC (P < 0.05) groups. Serum galactomannan index (GMI) and (1→3)-β-d-glucan levels significantly declined in animals treated with the combination of SCY7.5+ISA40 in comparison to those of animals treated with SCY7.5 or ISA40 (P < 0.05). Ibrexafungerp and isavuconazole 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 treatment of IPA. These findings provide an experimental foundation for clinical evaluation of the combination of ibrexafungerp and an antimold triazole for treatment of IPA.

In Vitro Activity of Ibrexafungerp against a Collection of Clinical Isolates of Aspergillus, Including Cryptic Species and Cyp51A Mutants, Using EUCAST and CLSI Methodologies

“…While MIC 50 values for voriconazole were 2 mg/L by EUCAST and 0.5 mg/L by CLSI for the susceptible ones and 4 mg/L by both testing methodologies for the resistant strains, MEC 50 s for ibrexafungerp were 0.03 mg/L (EUCAST) and 0.06 mg/L (CLSI). These results are in agreement with those previously reported after in vitro testing [ 14 , 15 , 16 , 17 ] and after assessing in vivo activity when administered orally or intravenously in murine models of infection of invasive aspergillosis caused by A. fumigatus [ 20 , 22 ].…”

“…However, ibrexafungerp has a longer half-life and is available as an oral formulation due to its improved pharmacokinetics and pharmacodynamics [ 35 ]. In addition to its good in vitro activity against susceptible and azole resistant Aspergillus spp., ibrexafungerp has proven to be effective against a caspofungin resistant A. fumigatus isolate [ 15 ] and has also yielded good results in neutropenic mice with invasive aspergillosis caused by azole susceptible and resistant A. fumigatus [ 20 , 22 ]. Therefore, this drug is currently undergoing phase II as an oral formulation for the treatment of invasive aspergillosis, as well as being in phase III for the treatment of vulvovaginal and invasive candidiasis.…”

“…or the Mucorales order [ 18 ]. The in vivo activity of this compound has been positively demonstrated when orally or intravenously administered to murine models of invasive candidiasis, invasive aspergillosis, and pneumocystosis [ 9 , 14 , 19 , 20 , 21 , 22 , 23 ].…”

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

“…Animal studies looking at the tissue distribution of ibrexafungerp achieved high concentrations in the skin, an attribute that may be of importance to limit C. auris skin colonization, with a potential impact of limiting transmission. Ibrexafungerp demonstrates activity across a range of invasive fungal diseases as a monotherapy but also in combination [ 58 , 59 ]. Early clinical evidence from an emergency-use Phase 3 study of ibrexafungerp for invasive candidiasis due to C. auris is promising.…”

Modeling Invasive Aspergillosis: How Close Are Predicted Antifungal Targets?

“…Olorofim, a first-in-class orotomide inhibitor of dihydroorotate dehydrogenase in the pyrimidine salvage pathway, was studied in the rabbit model of acute IPA [ 69 ]. Using serum galactomannan as the primary pharmacodynamic endpoint, the authors found that C min and C min /MIC targets of 0.1 and 3.3, respectively, produced in vivo effects similar to those reported for isavuconazole administered in human exposures.…”