ASP9726, A Unique 2nd Generation Echinocandin (3) -In Vitro and in vivo Activity against Aspergillus spp.-

Ref ID: 18682

Author:

S. Akamatsu, MS – Pharmacologist, S. Matsumoto, MS – Pharmacologist, S. Uchida, BS – Pharmacologist, T. Nakai, PhD – Pharmacologist, S. Takeda, PhD – Pharmacologist, K. Maki, MS – Pharmacologist, A. Okada, PhD – Chemist, N. Kayakiri, PhD – Chemist, D

Author address:

Astellas Pharma Inc.,, Tsukuba, Ibaraki, Japan.

Full conference title:

52nd Annual ICAAC

Date: 9 September 2014

Abstract:

Background: Therapeutic efficacy of 1st-generation echinocandins against invasive pulmonary aspergillosis (IPA) is not optimal. ASP9726 (ASP) is a new semi-synthetic echinocandin discovered by using a novel screening endpoint, the maximum inhibitory effect on A.fumigatus hypha (Emax). The objective of this study was to assess the activities of ASP against Aspergillus spp. Methods: MICs were determined according to CLSI M38-A2 using RPMI and human serum as broth media. Effects of ASP on Aspergillus hyphae in human serum at 4-fold MIC were compared with those of micafungin (MCFG) and caspofungin (CAS) under a light microscope. Therapeutic activities against IPA caused by A. fumigatus were studied in an immunosupressed mice model. Intravenous treatment of ASP, MCFG and CAS was initiated 1 day after infection and continued for 10 days QD, and survivals was monitored for 11 days. Results: MICs for Aspergillus spp. of ASP in human serum were superior or comparable to MCFG and CAS. ASP is fungistatic, as are the 1st generation echinocandins, however it demonstrated a remarkable potent inhibitory effect against Aspergillus hyphae. Microcolonies produced by exposure to ASP had severely stunted hypha, and were small, rounded and compact, whereas those under MCFG and CAS exposure were large and had hyphal elongation in all directions. In a murine model, ASP 1.5 or 3 mg/kg significantly prolonged the survival compared with control (p<0.025), whereas all mice died in the MCFG 12 mg/kg and CAS 3 mg/kg groups. Histopathology of lung tissue revealed a reduction in the size of lesions and intensive inhibition of hyphal invasion in ASP treated mice compared with MCFG and CAS, reflecting the potent inhibitory effect in vitro. Conclusions: ASP is a novel echinocandin with remarkably improved activity against Aspergillus spp. compared with 1st-generation echinocandins. ASP is a promising candidate for improving therapeutic efficacy of echinocandins against IPA.

Abstract Number: F-819

Conference Poster: y

Conference Year: 2012

Link to conference website: NULL

New link: NULL

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