Efficacy assessment of SF001, A 3rd generation polyene antifungal, in the neutropenic mouse model of invasive pulmonary aspergillosis and mucormycosis

Author:

Teclegiorgis Gebremariam, Yiyou Gu, Eman Youssef, Sondus Alkhazraji, Joshua Quran, Nathan P. Wiederhold, Ashraf S. Ibrahim

Abstract:

Objective: Invasive pulmonary aspergillosis (IPA) and invasive mucormycosis (IM) are associated with high mortality and morbidity. SF001 is a 3rd generation polyene structurally designed to have increased specificity to ergosterol and not cholesterol, resulting in less renal toxicity and improved therapeutic index compared to amphotericin (AMB). In vitro studies show increased potency to some organisms classically resistant to AMB. We sought to evaluate the efficacy of SF001 monotherapy and compare it to liposomal amphotericin B (LAMB) in immunosuppressed mouse models of IPA and IM.

 

Methods: In vitro susceptibility was determined by the CLSI M38 method using clinical isolates of Aspergilus fumigatus, A. lentulus, A. calidoustus, Rhizopus delemar, and Mucor circinelloides. ICR mice were immunosuppressed with cyclophosphamide and cortisone acetate on Days -2 and +3, respectively, relative to infection with intranasal inhalation with A. fumigatus or by intratracheal instillation for A. lentulus, A. calidoustus, R. delemar, and M. circinelloides. Treatment with placebo (diluent control), SF001 (0.3, 1.5, 5.0, 7.5, or 30 mg/kg, iv, qd), or LAMB (5 or 10 mg/kg, iv, qd), began 16 h post infection and continued for 4 days for A. fumigatus, A. lentulus, R. delemar, or M. circinelloides and for 7 days for A. calidoustus. Survival (n= 10 or 20/group from 1 or 2 experiments) through Day +21 and tissue fungal burden (n=10/group) on Day +4 (qPCR) served as primary and secondary endpoints, respectively.

 

Results: The MIC100 values defined as the concentration that resulted in 100% growth inhibition for SF001 were 0.5 µg/mL for A. fumigatus, 2 µg/mL for A. lentulus, 1 µg/mL for A. calidoustus, and 0.25-1.0 µg/mL for R. delemar, and M. circinelloides. In contrast, the MIC100 values for LAMB were 0.06 µg/mL for A. fumigatus and >16 µg/mL for both A. lentulus and A. calidoustus, and  £0.03 µg/mL for R. delemar and M. circinelloides. All placebo-treated mice had 95%-100% mortality by Day 21. Doses of SF001 ³1.5 mg/kg significantly prolonged median survival and enhanced overall survival vs. placebo-treated mice (Table 1, *P <0.05 vs. placebo, **P <0.05 vs. LAMB). LAMB at 5 mg/kg for IPA and 10 mg/kg for IM also improved survival of mice when compared to placebo. Importantly, SF001 doses of 5.0 and 7.5 mg/kg were as effective as LAMB treatment and the higher dose of 30 mg/kg was superior to LAMB in the A. fumigatus infection model and was well-tolerated in each infection model. The survival data was mirrored in the tissue fungal burden results and histopathological examination of lungs.

 

Conclusions: SF001 is a 3rd generation polyene that has more potent in vitro activity compared to LAMB against Aspergillus species and Mucorales fungi. SF001 demonstrated dose-dependent efficacy, was well-tolerated, and improved survival in mouse models of IPA and IM caused by hard-to-treat Aspergillus species and Mucorales fungi. Continued investigation and development of SF001 as a novel agent against IPA and IM is warranted.

Abstract Number: 86

Conference Year: 2024

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