Efficacy assessments of EL219, a next-generation polyene antifungal, in immunosuppressed mice infected with drug-sensitive and drug-resistant Aspergillus isolates

TL;DR

A new antifungal drug, EL219, shows improved effectiveness and safety in treating a dangerous lung fungal infection in mice.

Contribution

EL219 demonstrates superior efficacy against drug-resistant Aspergillus species compared to existing treatments in mouse models.

Findings

EL219 improved survival in a dose-dependent manner, with 30 mg/kg outperforming LAMB.

EL219 reduced lung fungal burden by more than 5 logs in A. fumigatus-infected mice.

EL219 showed enhanced in vitro activity against A. lentulus and A. calidoustus compared to LAMB.

Abstract

Invasive pulmonary aspergillosis (IPA), mainly caused by A. fumigatus, remains a life-threatening fungal infection, with rising reports of infections caused by resistant species such as Aspergillus lentulus and Aspergillus calidoustus. EL219 (formerly known as SF001) is a novel, next-generation polyene with enhanced ergosterol selectivity and reduced nephrotoxicity. We evaluated the efficacy of EL219 compared to liposomal amphotericin B (LAMB) in vitro using the Clinical Laboratory and Standards Institute M38 methodology and in immunosuppressed murine models of IPA caused by A. fumigatus, A. lentulus, and A. calidoustus. Immunosuppressed ICR mice were infected via inhalation (A. fumigatus) or via intratracheal instillation (A. lentulus and A. calidoustus), then treated intravenously once daily with placebo, EL219 (0.3, 1.5, 7.5, and 30 mg/kg), or LAMB (5 mg/kg) starting 16 h post-infection. Treatment lasted 4 days (A. fumigatus and A. lentulus) or 7 days (A. calidoustus). Survival through Day 21 and lung fungal burden at Day 4 were assessed. EL219 showed enhanced in vitro activity against A. lentulus and A. calidoustus compared to LAMB. EL219 significantly improved survival in a dose-dependent manner, with 30 mg/kg outperforming LAMB. EL219 also resulted in >5-log fungal burden reductions in A. fumigatus-infected lungs. EL219 demonstrated broad-spectrum efficacy, improved survival, and reduced lung fungal burden, supporting its potential as a novel therapy for IPA.

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