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Abstract: FR-PO334

Preclinical Efficacy of CHK-336: A First in Class, Liver-Targeted, Small Molecule Inhibitor of Lactate Dehydrogenase for the Treatment of Primary Hyperoxalurias

Session Information

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Cox, Jennifer H., Chinook Therapeutics Inc, Seattle, Washington, United States
  • Boily, Marc-Olivier, Chinook Therapeutics Inc, Seattle, Washington, United States
  • Caron, Alex, Chinook Therapeutics Inc, Seattle, Washington, United States
  • Chong, Oliver, Chinook Therapeutics Inc, Seattle, Washington, United States
  • Ding, Jim, Chinook Therapeutics Inc, Seattle, Washington, United States
  • Gaudreault, Samuel, Chinook Therapeutics Inc, Seattle, Washington, United States
  • Gomez, Robert, Chinook Therapeutics Inc, Seattle, Washington, United States
  • Knight, John, The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Lester, Jeff, Chinook Therapeutics Inc, Seattle, Washington, United States
  • Li, Xingsheng, The University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Lowther, W. Todd, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
  • Oballa, Renata, Chinook Therapeutics Inc, Seattle, Washington, United States
  • Powell, David A., Chinook Therapeutics Inc, Seattle, Washington, United States
  • Sheng, Tao, Chinook Therapeutics Inc, Seattle, Washington, United States
  • Surendradoss, Jayakumar, Chinook Therapeutics Inc, Seattle, Washington, United States
  • Tong, Vincent, Chinook Therapeutics Inc, Seattle, Washington, United States
  • Wu, Joyce, Chinook Therapeutics Inc, Seattle, Washington, United States
  • King, Andrew J., Chinook Therapeutics Inc, Seattle, Washington, United States
Background

Primary hyperoxalurias (PH) 1-3 are disorders involving excess hepatic oxalate production, resulting in calcium oxalate kidney stones, progressive CKD, and potentially ESKD. There are limited therapeutic options, with only one approved agent for PH1, and no approved therapies for PH2-3. Lactate dehydrogenase (LDH) catalyzes the final step in hepatic oxalate synthesis and represents a potential therapeutic target for all forms of PH and other forms of hyperoxaluria driven by increased oxalate production. Herein we describe the preclinical efficacy profile of CHK-336, a potent and selective LDH inhibitor currently in development.

Methods

CHK-336 was evaluated in biochemical and cellular LDH activity assays, a 13C2-glycolate stable isotope tracer pharmacodynamic model, an Agxt knockout PH1 mouse model, and a Grhpr knockout PH2 mouse model.

Results

CHK-336 demonstrates potent and selective inhibition of LDH in human enzyme assays and hepatocyte assays across multiple species, including hepatocytes isolated from PH1 mice. A liver-targeted tissue distribution profile was engineered into the molecule; CHK-336 demonstrates effective liver-targeting across species. In a rat pharmacodynamic model, CHK-336 inhibited the conversion of 13C2-glycolate to 13C2-oxalate in a dose-dependent manner. In a novel PH1 mouse model, low once-daily oral doses of CHK-336 produced robust and dose-dependent reductions in urinary oxalate to the normal range. The magnitude of effect was comparable, but with a more rapid onset than a GO-targeting siRNA. Seven days of CHK-336 treatment resulted in a statistically significant reduction in urinary oxalate in a PH2 mouse model.

Conclusion

By potently blocking LDH, the final step in hepatic oxalate synthesis, along with a liver-targeted tissue distribution profile, CHK-336 is a novel oral small molecule with the potential to treat all types of primary hyperoxaluria and other disorders resulting in increased oxalate production. The human safety, pharmacokinetic and pharmacodynamic profile of CHK-336 are currently under investigation in a healthy volunteer SAD/MAD study (NCT05367661).

Funding

  • Commercial Support