1529. Efficacy of Oral APX001 in a Murine Model of Cryptococcal Meningitis
Session: Poster Abstract Session: Preclinical Study with New Antibiotics and Antifungals
Friday, October 6, 2017
Room: Poster Hall CD
Posters
  • Schell APX001 poster draft powerpoint ver final revised for PhD posters.pdf (511.8 kB)
  • Background:

    APX001 is a first-in-class intravenous and orally available broad spectrum antifungal inhibitor of Gwt1, a protein involved in glycosylphosphatidylinositol anchor biosynthesis.  This study evaluated efficacy of APX001, alone and in combination with fluconazole (FCN), in a mouse model of cryptococcal meningitis. 

    Methods:

    Mice (10/group) infected via tail vein with Cryptococcus neoformans received APX001, FCN, both, or neither, for 7 days.  APX001 was given orally as 390mg/kg thrice daily. FCN was given intraperitoneally as 80mg/kg/day. Brain and lung were cultured to determine tissue burden.   Data were evaluated by unpaired t-test.

     

    Results:

    In brain, the burden of C. neoformans in mice receiving combined therapy was 3.52 log lower than in untreated control mice.  The burden in mice receiving APX001 alone was 0.78 log lower than in untreated mice.  The burden in mice receiving FCN alone was 1.04 log lower than in untreated mice.

    In lung, the burden in mice receiving combined therapy was 1.84 log lower than in untreated control mice.  The tissue burden for mice receiving APX001 alone was 1.58 log lower than in untreated mice.  The tissue burden in mice receiving FCN alone was 1.3 log lower than untreated mice.

    Conclusion:

    Activity in murine brain

    o   Combined therapy of APX001 with FCN significantly inhibited growth of C. neoformans H99 compared to untreated control mice (p<0.0001), and was significantly more active than monotherapy with APX001 or FCN (p<0.0001 and p<0.0003, respectively). 

    o   APX001 and FCN each, alone, significantly inhibited growth of C. neoformans H99 in brain tissue compared to untreated control mice (p<0.0001).

    Activity in murine lung

    o   Combined therapy of APX001 with FCN performed somewhat better than FCN alone (p=0.0297), but no better than APX001 alone (p=0.2500).

    o   APX001 and FCN each, alone, significantly inhibited growth of C. neformans H99 in lung tissue compared to untreated control mice (p<0.0001).

    o   Significant potentiation of APX001 in combination with FCN in this model with C. neoformans H99 was observed within the brain, and further investigation is warranted to determine whether APX001 in combination with FCN has potential to be an effective oral regimen for treating cryptococcal meningitis.

     

    Wiley A. Schell, MS, Medicine, Duke University Medical Center, Durham, NC, Charles Giamberardino, M.R., Infectious Diseases, Duke University Medical Center, Durham, NC, Karen J. Shaw, PhD, Amplyx Pharmaceuticals Inc., San Diego, CA and John R Perfect, M.D., FIDSA, Medicine, Duke University School of Medicine, Durham, NC

    Disclosures:

    W. A. Schell, None

    C. Giamberardino, None

    K. J. Shaw, Amplyx Pharmaceuticals Inc.: Employee , Salary

    J. R. Perfect, None

    Findings in the abstracts are embargoed until 12:01 a.m. PDT, Wednesday Oct. 4th with the exception of research findings presented at the IDWeek press conferences.