1386-P: XTL6001: A Novel Triple MasR/GCGR/GLP-1R Agonist for Chronic Kidney Disease/Diabetic Kidney Disease with Proteinuria and Hyperuricemia

Introduction and Objective: Although current 'four-pillar' therapies have made significant progress in slowing the progression of chronic kidney disease/diabetic nephropathy, no one drug can halt the progression of the diseases. Multireceptor agonists in development may provide approaches to fulfill this unmet medical need. XTL6001 is a novel triple agonist at the MasR (Mas receptor), GCGR, and GLP-1R.These studies aim to investigate its efficacy in chronic kidney disease (CKD) including diabetic kidney disease (DKD). Methods: Rats of DKD with proteinuria induced by oxymetholone combined with unilateral nephrectomy (model 1) and induced by STZ combined with unilateral nephrectomy (model 2), and rats of CKD with proteinuria and hyperuricemia (model 3) induced by oral administration of adenine combined with potassium oxonate, were dosed subcutaneously twice weekly for 4 weeks with XTL6001. Biochemical parameters in plasma and urine were analyzed. Results: In all the 3 rat models, XTL6001 dose-dependently reduced 24-hour urinary albumin and the urine albumin-to-creatinine ratio (UACR) (P<0.05, P<0.01, or P<0.001), improved glomerular filtration rate (GFR) and thus delayed the progression of kidney disease. Within the tested dose range, the 24-hour urinary albumin reduction rates of XTL6001 were 55.85% to 81.85% (vs. 38.64% for Finerenone) in Model 1, 54.72% (vs. 32.49% for Finerenone combined with Dulaglutide) in Model 2, and 71.44% to 86.26% in Model 3 (uric acid-lowering medication benzbromarone had no effect on reducing urinary albumin), respectively. XTL6001 also significantly reduced blood creatinine, blood urea nitrogen, and uric acid levels (P<0.05, P<0.01, or P<0.001), improving renal insufficiency. Conclusion: These findings indicated XTL6001 offers a multidimensional therapeutic solution for patients with CKD/DKD complicated by proteinuria and hyperuricemia by integrating renal protection and metabolic regulation. Thus, XTL6001 warrant further clinical assessment. Disclosure Y. Wang: Employee; Current; Shaanxi Micot Pharmaceutical Technology Co., Ltd. Y. Liu: Employee; Current; Shaanxi Micot Pharmaceutical Technology Co., Ltd. X. Wang: None. L. Wang: None. Z. Huang: Employee; Current; Shaanxi Micot Pharmaceutical Technology Co., Ltd.