#1942 Novel therapeutic for diabetic kidney disease through targeting Lp-PLA2 in immune cells and damaged renal parenchymal cell

Abstract Background and Aims Diabetic kidney disease (DKD), a highly prevalent form of chronic kidney injury, is characterized by intricate mechanisms involving inflammation, metabolism and haemodynamics. Currently, the available therapeutic interventions fall short of effectively halting the progression of patients towards end-stage renal disease (ESRD). Lp-PLA2 (Lipoprotein-associated phospholipase A2) is an enzyme that participates in regulating the immune response, cellular senescence and metabolism. Under the pathological conditions of DKD, significantly elevated levels of Lp-PLA2 have been detected in the blood, and these levels are positively correlated with the urine albumin-to-creatinine ratio (UACR). In this study, we provide a series of comprehensive evidence supporting Lp-PLA2 as a promising potential therapeutic target for DKD. Our analysis draws upon three distinct perspectives including preclinical studies using animal models, renal biopsy section analysis, and an investigator-initiated clinical trial. Methods The efficacy of the proprietary Lp-PLA2 inhibitor SR1375 on renal function were tested in a mice model of diabetic nephropathy (HFD-Unx-STZ-DKD model) and a rat model of hypertensive nephropathy (DOCA-salt-HTN model). Localization and quantification of Lp-PLA2 were analyzed in renal biopsy samples (n = 6) from DKD patients. The results were then correlated with renal function indices. A randomized, double-blind, placebo-controlled investigator-initiated trial (IIT) involving 3 multiple dosing cohorts (1, 3, 10 mg) of SR1375 for patients with DKD is currently underway in Huashan Hospital in China. An interim analysis was conducted in 12 subjects who completed 12 weeks of drug administration and data collection. Results In the animal models of both diabetic nephropathy and hypertensive nephropathy, elevated plasma Lp-PLA2 enzyme activity was detected. After administration of SR1375, a significant inhibition of plasma Lp-PLA2 enzyme activity was achieved. Concurrently, the UACR and UAE were substantially reduced in both models, with the highest remission rate reaching up to 65.5%. In the kidneys of DKD patients, the mRNA levels of renal PLA2G7(Lp-PLA2) were elevated. PLA2G7 was localized not only in infiltrating immune cells but also in damaged renal parenchymal cells. Moreover, the levels of PLA2G7 in the kidney showed a positive correlation with UACR. The interim analyses of the IIT revealed the following key findings: SR1375 demonstrated a favorable safety and PK profile in DKD patients, and in subjects with UACR >100 mg/g*Cr at baseline, those who received SR1375 treatment for 12 weeks showed an average 49.7% reduction in UACR (n = 5). In contrast, only an average 17.5% reduction was observed in the placebo group (n = 2). Conclusions Our results suggest a functional role for Lp-PLA2 in the pathogenesis of DKD, providing preclinical and clinical proof-of-concept for Lp-PLA2 inhibitors as a novel therapeutic approach for patients with DKD. A Phase 2 clinical trial in DKD patients is scheduled to be conducted in the second half of 2025.