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

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 ~0.5-1.0log₁₀ 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 ~0.5-1.5log₁₀ 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.

Keywords: Ibrexafungerp; Rhizopus; combination therapy; infection model; liposomal amphotericin B; mouse; mucor; mucormycosis; posaconazole.

Fig 1

Survival curves in mice with R. delemar pulmonary infection. Mice (n = 20/group from two independent experiments with similar results) were infected intratracheally and treated with (A) monotherapy [placebo, ibrexafungerp (IBX), liposomal amphotericin B (LAMB), or posaconazole (PSC)] or (B) combination therapy with IBX plus LAMB or IBX plus PSC. *P < 0.002 vs placebo-treated mice; §P = 0.03 vs IBX monotherapy; and ¶P = 0.008 vs LAMB monotherapy.

Fig 2

Tissue fungal burden in lungs and brain in mice with R. delemar pulmonary mucormycosis. Mice (n = 10/group) were infected intratracheally and treated with (A) monotherapy [placebo, ibrexafungerp (IBX), liposomal amphotericin B (LAMB), or posaconazole (PSC)] or (B) combination therapy with IBX plus LAMB or IBX plus PSC. Lungs and brains were collected on day 4 post-inoculation, and fungal burden was measured by quantitative real-time PCR and reported as conidial equivalents per gram of tissue. *P ≤ 0.05 vs placebo-treated mice; §P ≤ 0.006 vs IBX monotherapy; and ¶P ≤ 0.03 vs LAMB monotherapy.

Fig 3

Survival curves in mice with M. circinelloides pulmonary mucormycosis. Mice (n = 10/group) were infected intratracheally and treated with (A) monotherapy [placebo, ibrexafungerp (IBX), liposomal amphotericin B (LAMB), or posaconazole (PSC)] or (B) combination therapy with IBX plus LAMB or IBX plus PSC. *P ≤ 0.02 vs placebo-treated mice.