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

Invasive pulmonary aspergillosis (IPA), mainly caused by <i>A. fumigatus,</i> remains a life-threatening fungal infection, with rising reports of infections caused by resistant species such as <i>Aspergillus lentulus</i> and <i>Aspergillus calidoustus</i>. 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) <i>in vitro</i> using the Clinical Laboratory and Standards Institute M38 methodology and in immunosuppressed murine models of IPA caused by <i>A. fumigatus</i>, <i>A. lentulus</i>, and <i>A. calidoustus</i>. Immunosuppressed ICR mice were infected via inhalation (<i>A. fumigatus</i>) or via intratracheal instillation (<i>A. lentulus</i> and <i>A. calidoustus</i>), 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 (<i>A. fumigatus</i> and <i>A. lentulus</i>) or 7 days (<i>A. calidoustus</i>). Survival through Day 21 and lung fungal burden at Day 4 were assessed. EL219 showed enhanced <i>in vitro</i> activity against <i>A. lentulus</i> and <i>A. calidoustus</i> 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 <i>A. fumigatus</i>-infected lungs. EL219 demonstrated broad-spectrum efficacy, improved survival, and reduced lung fungal burden, supporting its potential as a novel therapy for IPA.