Small Molecule Inhibitor of Gut Microbial Choline Trimethylamine Lyase Reduces Serum Trimethylamine N-oxide and Slows the Loss of Kidney Function in a Rat Model of CKD

Background: Gut microbial choline trimethylamine (TMA) lyase (CutC) plays a key role in the formation of TMA, a precursor of trimethylamine N-oxide (TMAO) that is both a cause and driver of CKD. Here we describe the pharmacological effects of small molecule CutC inhibitor ZTx102 on serum TMAO level and kidney function in an adenine-induced rat model of CKD. Methods: CKD was induced and maintained in rats by adding 0.25% adenine to a standard chow diet supplemented with 0.5% choline in the drinking water. The small molecule CutC inhibitor, ZTx102, an orally administered colon directed formulation, was administered at doses of 1.25 and 12.5 mg/kg of body weight, once a day, during the maintenance phase. The controls received matching placebo, once a day. Serum TMAO was quantified using LC-MS/MS. Kidney function was assessed by serum levels of creatinine and eGFR. Results: Adenine and choline supplementation increased serum levels of TMAO and creatinine in rats. Oral administration of ZTx102 as a colon directed formulation resulted in rapid and sustained reduction of serum TMAO to the normal range during the maintenance phase of the study. ZTx102 significantly reduced serum levels of creatinine (0.8 mg/dL in 12.5 mg/kg ZTx102 vs. 1.5 mg/dL in placebo; P<0.001). ZTx102 significantly slowed eGFR decline (0.96 mL/min in 12.5 mg/kg ZTx102 vs. 0.64 mL/min in placebo; P<0.05). In addition, ZTx102 reduced serum N-terminal prohormone of brain natriuretic peptide (5.6 pg/mL in 12.5 mg/kg ZTx102 vs. 112.2 pg/mL in placebo; P<0.0001), a biomarker of myocardial stress and early heart failure. Conclusion: The small molecule CutC inhibitor ZTx102 is effective in normalizing elevated serum levels of TMAO and slowing the loss of kidney function in a rat model of CKD when administered as a colon directed formulation. Reduction of serum TMAO level by the CutC inhibitor ZTx102 may provide a potential new approach to slow disease progression in persons with CKD. Funding: Commercial Support - Zehna Therapeutics, Inc., Private Foundation Support