Kidney Week

Abstract: PO1620

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

Session Information

• Genetic Diseases of the Kidneys: Non-Cystic - 1
  October 22, 2020 | Location: On-Demand
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Cox, Jennifer H., Chinook Therapeutics Inc., Vancouver, British Columbia, Canada

Jennifer H. Cox,

• Boily, Marc-Olivier, Chinook Therapeutics Inc., Vancouver, British Columbia, Canada

Marc-Olivier Boily,

• Caron, Alex, Chinook Therapeutics Inc., Vancouver, British Columbia, Canada

Alex Caron,

• Chefson, Amandine, Chinook Therapeutics Inc., Vancouver, British Columbia, Canada

Amandine Chefson,

• Chong, Oliver, Chinook Therapeutics Inc., Vancouver, British Columbia, Canada

Oliver Chong,

• Ding, Jim, Chinook Therapeutics Inc., Vancouver, British Columbia, Canada

Jim Ding,

• Dumais, Valerie, Chinook Therapeutics Inc., Vancouver, British Columbia, Canada

Valerie Dumais,

• Gaudreault, Samuel, Chinook Therapeutics Inc., Vancouver, British Columbia, Canada

Samuel Gaudreault,

• Gomez, Robert, Chinook Therapeutics Inc., Vancouver, British Columbia, Canada

Robert Gomez,

• Guthrie, James, Chinook Therapeutics Inc., Vancouver, British Columbia, Canada

James Guthrie,

• Holmes, Ross P., University of Alabama at Birmingham, Birmingham, Alabama, United States

Ross P. Holmes,

• King, Andrew J., Chinook Therapeutics Inc., Vancouver, British Columbia, Canada

Andrew J. King,

• Knight, John, University of Alabama at Birmingham, Birmingham, Alabama, United States

John Knight,

• Lester, Jeff, Chinook Therapeutics Inc., Vancouver, British Columbia, Canada

Jeff Lester,

• Lowther, W. Todd, Wake Forest University, Winston-Salem, North Carolina, United States

W. Todd Lowther,

• Oballa, Renata, Chinook Therapeutics Inc., Vancouver, British Columbia, Canada

Renata Oballa,

• Percival, Michael David, Chinook Therapeutics Inc., Vancouver, British Columbia, Canada

Michael David Percival,

• Sheng, Tao, Chinook Therapeutics Inc., Vancouver, British Columbia, Canada

Tao Sheng,

• Surendradoss, Jayakumar, Chinook Therapeutics Inc., Vancouver, British Columbia, Canada

Jayakumar Surendradoss,

• Wu, Joyce, Chinook Therapeutics Inc., Vancouver, British Columbia, Canada

Joyce Wu,

• Powell, David A., Chinook Therapeutics Inc., Vancouver, British Columbia, Canada

David A. Powell,

Background

Primary hyperoxalurias (PH) 1-3 are autosomal recessive disorders involving excess hepatic oxalate production resulting in frequent kidney stones, progressive CKD and ESRD. Few therapeutic options currently exist for these patients. Lactate dehydrogenase (LDH) catalyzes the final and only committed step in hepatic oxalate synthesis and represents a potential therapeutic target for all forms of PH. Herein we describe the profile of a potent and selective LDH inhibitor.

Methods

CHK-336 was evaluated in LDH activity assays and in an AGXT knockout PH1 mouse model. Additional characterization of drug properties was performed.

Results

CHK-336 demonstrates potent and selective inhibition of LDH in enzyme assays (IC₅₀ = 0.4 nM) and hepatocyte assays (IC₅₀ = 80-142 nM). To minimize the potential for extra-hepatic LDH inhibition, a liver-targeted tissue distribution profile was engineered into the molecule. CHK-336 demonstrates exceptional liver-targeting across species mediated by OATP-uptake into hepatocytes and tight binding to LDH resulting in a long liver half-life that supports once-daily oral dosing. In a PH1 mouse model, CHK-336 produced significant and dose-dependent reductions in urinary oxalate to levels observed in wild-type mice. Wide safety margins were established in rodent toxicity studies to support continued development of CHK-336.

Conclusion

By potently blocking LDH, the terminal step in hepatic oxalate synthesis, along with engineering of liver-targeted tissue distribution, CHK-336 is a promising oral small molecule development candidate with the potential to treat patients with hyperoxaluria.

CHK-336 reduces UOx in AGXT-KO mice

Funding

• Commercial Support – Chinook Therapeutics Inc.