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

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.

Keywords: Aspergillus; EL219; SF001; antifungal agents; infection model; liposomal amphotericin B; murine; polyene.

Fig 1

Survival of immunosuppressed mice infected with A. fumigatus Af293 and treated with either EL219 or LAMB. Mice (n = 10/group) were rendered immunosuppressed and infected via inhalation with an inoculum of 2.4×10⁴ conidia. Treatment began 16 h post-infection and continued once daily for four consecutive days. EL219 at doses of 1.5, 7.5, or 30 mg/kg prolonged median survival compared to placebo. Doses of 7.5 or 30 mg/kg EL219, as well as LAMB at 5 mg/kg, improved overall survival compared to placebo (20%, 50%, 10%, and 0% survival for 7.5, 30 mg/kg EL219, LAMB, and placebo, respectively). Numbers on the figure represent P values compared to placebo or as stated in the figure. The accompanying table presents median survival times and overall survival percentages through Day 21 post-infection.

Fig 2

Reduction in lungs tissue fungal burden and histological examination of lung sections of immunosuppressed mice infected with A. fumigatus. (A) Mice (n = 10/group) infected with A. fumigatus via inhalation and treated daily with EL219 or LAMB were euthanized on Day +4 post-infection ~6 h after last treatment. EL219 at 7.5 or 30 mg/kg resulted in 1.5-log and 5-log reduction, respectively. * or ** P = 0.04 and <0.0001 versus placebo, respectively, and # P <0.0001 = versus LAMB. (B) Lung sections stained with GMS show that mice treated with EL219 had reduced fungal abscesses with shorter damaged hyphae in the lung tissues versus placebo-treated or LAMB-treated mice. Black bar is 100 µm.

Fig 3

Survival of immunosuppressed mice infected with A. lentulus (Al-1) and treated with varying doses of EL219. Immunosuppressed mice (n = 10/group) were infected via intratracheal instillation with a verified inoculum of 1.0×10⁴ conidia delivered to the lungs. Treatment was administered once daily for four consecutive days, starting 16 h post-infection. P values shown on the graph represent statistical comparisons versus placebo-treated mice. The accompanying table summarizes median survival times and overall survival percentages for each treatment group.

Fig 4

Survival of immunosuppressed mice infected with A. calidoustus (Ac-6) and treated with different doses of EL219. Immunosuppressed mice (n = 10/group) were infected via intratracheal instillation with a verified inoculum of 2.8×10⁴ conidia per mouse. Treatment was initiated 16 h post-infection and administered once daily for seven consecutive days. P values shown on the graph indicate statistical comparisons versus placebo-treated mice. The accompanying table presents median survival times and overall survival percentages through Day 21 post-infection.