Ibrexafungerp is efficacious in a neutropenic murine model of pulmonary mucormycosis as monotherapy and combined with liposomal amphotericin B

Abstract

ABSTRACT Ibrexafungerp (formerly SCY-078) is the first member of the triterpenoid class that prevents the synthesis of the fungal cell wall polymer β-(1,3)-D-glucan by inhibiting the enzyme glucan synthase. We evaluated the in vivo efficacy of ibrexafungerp against pulmonary mucormycosis using an established murine model. Neutropenic mice were intratracheally infected with either Rhizopus delemar or Mucor circinelloides . Treatment with placebo (diluent control), ibrexafungerp (30 mg/kg, PO BID), liposomal amphotericin B (LAMB 10 mg/kg IV QD), posaconazole (PSC 30 mg/kg PO QD), or a combination of ibrexafungerp plus LAMB or ibrexafungerp plus PSC began 16 h post-infection and continued for 7 days for ibrexafungerp or PSC and through day 4 for LAMB. Ibrexafungerp was as effective as LAMB or PSC in prolonging median survival (range: 15 days to >21 days) and enhancing overall survival (30%–65%) vs placebo (9 days and 0%; P < 0.001) in mice infected with R. delemar . Furthermore, median survival and overall percent survival resulting from the combination of ibrexafungerp plus LAMB were significantly greater compared to all monotherapies ( P ≤ 0.03). Similar survival results were observed in mice infected with M. circinelloides . Monotherapies also reduce the lung and brain fungal burden by ~0.5–1.0log 10 conidial equivalents (CE)/g of tissue vs placebo in mice infected with R. delemar ( P < 0.05), while a combination of ibrexafungerp plus LAMB lowered the fungal burden by ~0.5–1.5log 10 CE/g compared to placebo or any of the monotherapy groups ( P < 0.03). These results are promising and warrant continued investigation of ibrexafungerp as a novel treatment option against mucormycosis.