Fosmanogepix (APX001) Is Effective in the Treatment of Pulmonary Murine Mucormycosis Due to Rhizopus arrhizus - PubMed (original) (raw)
Fosmanogepix (APX001) Is Effective in the Treatment of Pulmonary Murine Mucormycosis Due to Rhizopus arrhizus
Teclegiorgis Gebremariam et al. Antimicrob Agents Chemother. 2020.
Abstract
Mucormycosis is a life-threatening infection with high mortality that occurs predominantly in immunocompromised patients. Manogepix (MGX) is a novel antifungal that targets Gwt1, a protein involved in an early step in the conserved glycosylphosphotidyl inositol (GPI) posttranslational modification pathway of surface proteins in eukaryotic cells. Inhibition of fungal inositol acylation by MGX results in pleiotropic effects, including inhibition of maturation of GPI-anchored proteins necessary for growth and virulence. MGX has been previously shown to have in vitro activity against some strains of Mucorales. Here, we assessed the in vivo activity of the prodrug fosmanogepix, currently in clinical development for the treatment of invasive fungal infections, against two Rhizopus arrhizus strains with high (4.0 μg/ml) and low (0.25 μg/ml) minimum effective concentration (MEC) values. In both invasive pulmonary infection models, treatment of mice with 78 mg/kg or 104 mg/kg fosmanogepix, along with 1-aminobenzotriazole to enhance the serum half-life of MGX in mice, significantly increased median survival time and prolonged overall survival by day 21 postinfection compared to placebo. In addition, administration of fosmanogepix resulted in a 1 to 2 log reduction in both lung and brain fungal burden. For the 104 mg/kg fosmanogepix dose, tissue clearance and survival were comparable to clinically relevant doses of isavuconazole (ISA), which is FDA approved for the treatment of mucormycosis. These results support continued development of fosmanogepix as a first-in-class treatment for invasive mucormycosis.
Keywords: 1-aminobenzotriazole; APX001; APX001A; Gwt1; MGX; Rhizopus arrhizus; antifungal; antifungal agents; fosmanogepix; infection model; infectious disease; manogepix; mucormycosis.
Copyright © 2020 Gebremariam et al.
Figures
FIG 1
Survival of immunosuppressed mice infected with R. arrhizus var. delemar 99-880 (low MEC). Mice (n = 10/group) were infected intratracheally with R. arrhizus var. delemar (inhaled inoculum of 7 × 103 spores/mouse) and 16 h later treated with ISA 110 mg/kg TID p.o., or with fosmanogepix QD p.o. for 7 days. ABT was administered 2 h prior to each fosmanogepix treatment to enhance the half-life of MGX in mice. *, P = 0.001 for 78 mg/kg fosmanogepix and 110 ISA; **, P < 0.0001 for 104 mg/kg fosmanogepix versus placebo mice by log rank test. (A) Kaplan-Meier survival curve. (B) Median and percent survival at day 21.
FIG 2
Reduction in tissue fungal burden of immunosuppressed mice infected with R. arrhizus var. delemar 99-880. Mice (n = 10/group) infected intratracheally with R. arrhizus var. delemar (inhaled inoculum of 1.1 × 104 spores/mouse) and 16 h later treated with ISA 110 mg/kg TID p.o., or with fosmanogepix 104 mg/kg QD p.o. On day +4, organs were collected and processed for tissue fungal burden by qPCR. Data are presented as the median ± interquartile range and the y axis represents the lower limit of detection. Intergroup P values are shown as a dark line. All dosing groups resulted in a statistically significant reduction in brain and lung fungal burden versus placebo control using the Wilcoxon rank sum test.
FIG 3
Survival of immunosuppressed mice infected with R. arrhizus var. arrhizus 99-892 (high MEC). Mice (n = 10/group) infected intratracheally with R. arrhizus var. arrhizus (inhaled inoculum of 1.1 × 104 spores/mouse) and 16 h later treated with ISA 110 mg/kg TID p.o., or with fosmanogepix 104 mg/kg QD p.o. for 7 days. ABT was administered 2 h prior to fosmanogepix treatment to enhance the half-life of manogepix in mice. *, P = 0.01 for 104 mg/kg fosmanogepix; P = 0.02 for ISA 110 mg/kg, TID versus placebo mice by log rank test. (A) Kaplan-Meier survival curve. (B) Median and percent survival at day 21.
FIG 4
Reduction in tissue fungal burden of immunosuppressed mice infected with R. arrhizus var. arrhizus 99-892. Mice (n = 10/group) infected intratracheally with R. arrhizus var. arrhizus (inhaled inoculum of 6.4 × 103 spores/mouse) and 16 h later treated with ISA 110 mg/kg TID p.o., or with fosmanogepix 104 mg/kg QD p.o. On day +4, organs were collected and processed for tissue fungal burden by qPCR. Data are presented as the median ± interquartile range and the y axis represents the lower limit of detection. Intergroup P values are shown as a dark line. Both fosmanogepix and ISA resulted in a statistically significant reduction in brain and lung fungal burden versus placebo control using the Wilcoxon rank sum test.
References
- Warkentien T, Rodriguez C, Lloyd B, Wells J, Weintrob A, Dunne JR, Ganesan A, Li P, Bradley W, Gaskins LJ, Seillier-Moiseiwitsch F, Murray CK, Millar EV, Keenan B, Paolino K, Fleming M, Hospenthal DR, Wortmann GW, Landrum ML, Kortepeter MG, Tribble DR, Infectious Disease Clinical Research Program Trauma Infectious Disease Outcomes Study G . 2012. Invasive mold infections following combat-related injuries. Clin Infect Dis 55:1441–1449. doi: 10.1093/cid/cis749. -DOI -PMC -PubMed
- Sugar AM. 1995. Agent of mucormycosis and related species, p 2311–2321. In Mandell G, Bennett J, Dolin R (ed), Principles and practices of infectious diseases, 4th ed Churchill Livingstone, New, York, NY.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources