Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Proof-of-Mechanism of MZE782, a Specific Inhibitor of SLC6A19 for the Treatment of CKD: Phase 1 Study in Healthy Adults

Background: SLC6A19, also known as BoAT1, is a neutral amino acid transporter expressed in the proximal tubule and small intestine that is involved in the reabsorption of amino acids from the urine and the uptake of free amino acids from the diet. Genetic data suggest that loss of SLC6A19 function in humans and mice may be protective against chronic kidney disease (CKD). MZE782 is a selective, small molecule inhibitor of SLC6A19 currently in development for the treatment of CKD. We conducted a first-in-human trial to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of MZE782 in healthy participants. Methods: The randomized, blinded, placebo-controlled Phase 1 trial evaluated single and multiple ascending doses of MZE782 in healthy participants aged 18 years and older. Safety and tolerability were evaluated through the assessment of multiple primary endpoints including the incidence and severity of adverse events, clinically significant abnormalities in laboratory assessments, physical examinations, vital signs, and 12-lead ECGs. Excretion of urinary amino acids was assessed as a pharmacodynamic marker of SLC6A19 inhibition. Plasma pharmacokinetics and excretion of urinary amino acids were evaluated using noncompartmental analysis to inform dose selection for patient studies. Results: The study is in progress. Final safety, pharmacokinetic, and pharmacodynamic results will be presented. Conclusion: MZE782 is a selective, small molecule inhibitor of SLC6A19. Phase 1 evaluation in healthy adult participants through the projected efficacious exposure range supports further assessment of MZE782 in proof-of-concept trials for the treatment of CKD. Funding: Commercial Support - Maze Therapeutics