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Abstract: FR-PO498

Stronger Phosphate Lowering Effects of a Novel PiT-1/PiT-2/NaPi-IIb Triple Inhibitor EOS789 in Hyperphosphatemia Than a NaPi-IIb Inhibitor

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Ohtomo, Shuichi, Chugai Pharmaceutical Co. Ltd., Gotemba, Shizuoka, Japan
  • Tsuboi, Yoshinori, Chugai Pharmaceutical Co. Ltd., Gotemba, Shizuoka, Japan
  • Ichida, Yasuhiro, Chugai Pharmaceutical Co. Ltd., Gotemba, Shizuoka, Japan
  • Hagita, Hitoshi, Chugai Research Institute for Medical Science, Inc., Gotemba, Shizuoka, Japan
  • Iida, Manami, Chugai Pharmaceutical Co. Ltd., Gotemba, Shizuoka, Japan
  • Horiba, Naoshi, Chugai Pharmaceutical Co. Ltd., Gotemba, Shizuoka, Japan
Background

EOS789 is a novel inhibitor of the sodium-dependent phosphate co-transporters PiT-1, PiT-2, and NaPi-IIb, which play central roles in intestinal phosphate absorption.

Methods

The in vitro inhibitory activity and the in vivo potency of EOS789 were evaluated.

Results

The in vitro IC50 values of EOS789 on human or rat NaPi-IIa, NaPi-IIb, NaPi-IIc, PiT-1, and PiT-2 were between 1 and 10 μM, and its IC50 value on sodium-dependent phosphate uptake in rat small intestinal brush border membrane vesicles was 3.1 μM. The inhibitory effect of EOS789 on intestinal phosphorus uptake was evaluated in healthy rats by fecal phosphorus excretion rate. EOS789 dose-dependently increased the fecal phosphorus excretion rate and inversely decreased the urinary phosphorus excretion rate.
The effects of EOS789 on serum phosphorus, FGF23, and intact PTH concentrations were evaluated in a hyperphosphatemia model of adenine-induced nephritis rats. After 14 days food admixture dosing of EOS789 with a dose between 0.015% and 0.5%, the serum phosphorus, FGF23, and intact PTH concentrations were decreased dose-dependently. Notably, EOS789 at the highest dose decreased these serum parameters to below their values in normal control rats. In addition, EOS789 exhibited a more potent effect on serum phosphorus than a NaPi-IIb-selective inhibitor in hyperphosphatemia rats.
The effect of EOS789 on the progression of chronic kidney disease was also evaluated in chronic anti-Thy1.1 nephritis rats. During the experimental period, dietary dosing of EOS789 provided a sustained suppression of serum phosphorus, FGF23, and intact PTH. After 16 weeks of dosing, EOS789 significantly decreased serum creatinine concentration in parallel with suppression of fibrosis-related mRNA and pro-inflammatory cytokine mRNA expressions. In addition, EOS789 significantly ameliorated ectopic calcification of the thoracic aorta.

Conclusion

This series of data suggests that EOS789 has a robust lowering effect on serum phosphorus under hyperphosphatemic conditions, and that EOS789 treatment can ameliorate renal function deterioration and protect the cardiovascular system from ectopic calcification.