168 - Efficacy of the Novel gwt1 Inhibitor APX2039 in a Rabbit Model of cryptococcus Meningitis

Background: Cryptococcal meningitis (CM), caused primarily by Cryptococcus neoformans, is uniformly fatal if not treated. Treatment options are limited especially in resource-poor geographical regions, and mortality rates remain high despite current therapies.  New oral treatment options are needed that demonstrate rapid reductions in CFU in CSF and brain tissue.
 
APX2039 is a novel inhibitor of the fungal Gwt1 enzyme, which catalyzes an early step in glycosylphosphatidyl inositol (GPI) anchor biosynthesis.  It is highly active against both C. neoformans and C. gattii and has previously demonstrated significant efficacy in a mouse delayed-treatment model of CM.CSF Fungal Burden in Rabbits


Methods: Male New Zealand White rabbits were inoculated with C. neoformans H99 (1.4 ×10⁶ CFU) directly into the cisterna magna. Rabbits were immunosuppressed with cortisone acetate at 7.5 mg/kg (i.m.), starting on Day -1 relative to inoculation and then administered drug daily throughout the 14-day experimental period. Treatment was initiated on Day 2 postinfection and continued through Day 14 consisting of: 50 mg/kg APX2039 PO (BID), 80 mg/kg fluconazole (FLU) PO (QD), c) 1 mg/kg amphotericin B deoxycholate (AMB) IV (QD); and vehicle control. CSF was removed via an intracisternal tap on Days 2, 7, 10 and 14 post-infection and CFU/ml was assessed. Animals were sacrificed on Day 14 and CFU/g brain tissue was assessed.

Results: APX2039 demonstrated rapid reduction in CFU in both CSF and brain tissue. The range in CFU values in rabbit CSF is shown (Figure).  Reductions in CFU were statistically different from the control group for all treatment groups.  APX2039 was also different from both FLU and AMB and resulted in sterilization in CSF by Day 10.  Brain harvested on Day 14 demonstrated a reduction in CFU/g tissue vs control of 1.8 log₁₀ and 3.4 log₁₀ for FLU and AMB, respectively, while a > 6 log₁₀ reduction (tissue sterilization) was observed for APX2039.

Conclusion: APX2039 demonstrated potent efficacy in a rabbit model of CM.  The more rapid clearance in CSF than either AMB or FLU, as well as  > 6 log₁₀ reduction in brain CFU highlights the unique properties of this drug, warranting further investigation of this molecule for the treatment of CM.

Presenting Author(s)

• 

  Charles D. Giamberardino, Jr., MR

  Associate in Research
  Duke University
  Durham, NC

  Disclosure: Box: Shareholder

  Slides Slides and Audio

Co-Author(s)

• QS

  Quinlyn A. Soltow, PhD

  Sr Manager, Analytical Science
  Amplyx Pharmaceuticals
  San Diego, California

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• JT

  Jennifer Tenor, PhD

  PhD
  Duke University
  Durham, North Carolina

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• DT

  Dena Toffaletti, PhD

  PhD
  Duke University
  Durham, North Carolina

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• JB

  Jane-Valeriane Boua, BS

  research aid
  Duke University
  Durham, North Carolina

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• CM

  Choiselle Marius, n/a

  Research Technician
  Duke University
  Durham, North Carolina

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• JP

  Julia R. Palmucci, n/a

  PhD Student
  Duke University
  Durham, North Carolina

  Disclosure: I do not have any relevant financial / non-financial relationships with any proprietary interests.
• 

  John R. Perfect, MD

  Professor of Medicine
  Duke University
  Durham, North Carolina

  Disclosure: amplyx (Grant/Research Support)astellas (Grant/Research Support)astellas (Grant/Research Support)