Session Type: 1,5-hour Oral Session
Session Title: 1,5-hour Oral Session
Authors(s): T. Gebremariam (1), Y. Gu (1), S. Alkhazraji (1), E. Youssef (1, 2), K. Shaw (3), A. Ibrahim (1, 4)
Authors Affiliations(s): (1) The Lundquist Institute at Harbor-UCLA Med Ctr, United States, (2) Beni-Suef University,, Egypt, (3) Hearts Consulting Group, LLC,, United States, (4) David Geffen School of Medicine at UCLA, United States
Background:
Invasive pulmonary aspergillosis (IPA) and invasive mucormycosis (IM) are associated with high mortality and morbidity. Fosmanogepix (FMGX) is a first-in-class antifungal in development with demonstrated broad spectrum activity in animal models of infections, including IPA and IM. We sought to evaluate the benefit of combination therapy of FMGX + liposomal amphotericin B (LAMB) in a very severe delayed treatment model of murine IPA or IM.
Methods:ICR mice were immunosuppressed with cyclophosphamide and cortisone acetate on days -2, and +3 for IPA and on days -2, +3, and +8 for IM, relative to infection with inhaled Aspergillus fumigatus or intratracheally instilled Rhizopus delemar. Treatment with placebo (diluent control), FMGX (78 mg/kg, po), or LAMB (5 mg/kg for IPA, 10 mg/kg for IM, iv) began 48 h post infection and continued for 8 days for FMGX and 4 days for LAMB. Mice survival through Day +21 and tissue fungal burden on Day +4 (conidial equivalents using qPCR) served as primary and secondary endpoints, respectively.
Results:For mice (n=10) infected with A. fumigatus, as expected in this severe model of infection, neither LAMB nor FMGX monotherapies significantly prolonged median survival or enhanced overall survival vs. placebo. However, combination treatment resulted in increased median survival (>21 days) and overall survival (70%) vs. all other treatments (10%, 30% and 20% survival for placebo, FMGX, and LAMB, respectivly, P <0.05, Log Rank). Combination treatment also resulted in reducing lung fungal burden (n=10 mice) by ~4.0 log vs. all other treatments (P <0.0001, Wilcoxon Rank Sum). For mice (n=10) with IM, again only combination therapy significantly increased median survival (>21 days) and overall survival (80%) (10% survival for placebo and 30% survival for FMGX or LAMB, P <0.05) and reduced lung fungal burden by ~2.0 log vs. all other treatments (P <0.0005).
Conclusions:Combination of FMGX plus LAMB demonstrated high survival and fungal burden reduction in severe animal models of invasive mold infections, at drug exposures in mice similar to those achieved clinically. These impressive results warrant further investigation of FMGX plus LAMB combination treatment for severely ill patients with IPA and IM.
Keyword(s): Fosmanogepix, Aspergillosis, MucormycosisSession Type: 1,5-hour Oral Session
Session Title: 1,5-hour Oral Session
Authors(s): T. Gebremariam (1), Y. Gu (1), S. Alkhazraji (1), E. Youssef (1, 2), K. Shaw (3), A. Ibrahim (1, 4)
Authors Affiliations(s): (1) The Lundquist Institute at Harbor-UCLA Med Ctr, United States, (2) Beni-Suef University,, Egypt, (3) Hearts Consulting Group, LLC,, United States, (4) David Geffen School of Medicine at UCLA, United States
Background:
Invasive pulmonary aspergillosis (IPA) and invasive mucormycosis (IM) are associated with high mortality and morbidity. Fosmanogepix (FMGX) is a first-in-class antifungal in development with demonstrated broad spectrum activity in animal models of infections, including IPA and IM. We sought to evaluate the benefit of combination therapy of FMGX + liposomal amphotericin B (LAMB) in a very severe delayed treatment model of murine IPA or IM.
Methods:ICR mice were immunosuppressed with cyclophosphamide and cortisone acetate on days -2, and +3 for IPA and on days -2, +3, and +8 for IM, relative to infection with inhaled Aspergillus fumigatus or intratracheally instilled Rhizopus delemar. Treatment with placebo (diluent control), FMGX (78 mg/kg, po), or LAMB (5 mg/kg for IPA, 10 mg/kg for IM, iv) began 48 h post infection and continued for 8 days for FMGX and 4 days for LAMB. Mice survival through Day +21 and tissue fungal burden on Day +4 (conidial equivalents using qPCR) served as primary and secondary endpoints, respectively.
Results:For mice (n=10) infected with A. fumigatus, as expected in this severe model of infection, neither LAMB nor FMGX monotherapies significantly prolonged median survival or enhanced overall survival vs. placebo. However, combination treatment resulted in increased median survival (>21 days) and overall survival (70%) vs. all other treatments (10%, 30% and 20% survival for placebo, FMGX, and LAMB, respectivly, P <0.05, Log Rank). Combination treatment also resulted in reducing lung fungal burden (n=10 mice) by ~4.0 log vs. all other treatments (P <0.0001, Wilcoxon Rank Sum). For mice (n=10) with IM, again only combination therapy significantly increased median survival (>21 days) and overall survival (80%) (10% survival for placebo and 30% survival for FMGX or LAMB, P <0.05) and reduced lung fungal burden by ~2.0 log vs. all other treatments (P <0.0005).
Conclusions:Combination of FMGX plus LAMB demonstrated high survival and fungal burden reduction in severe animal models of invasive mold infections, at drug exposures in mice similar to those achieved clinically. These impressive results warrant further investigation of FMGX plus LAMB combination treatment for severely ill patients with IPA and IM.
Keyword(s): Fosmanogepix, Aspergillosis, Mucormycosis