Abstract 4140427: Potassium-sparing Diuresis and Natriuresis With a Novel Renal Outer Medullary Potassium Channel Inhibitor, in Healthy Adult Participants

Introduction: Persistent congestion and edema remain an unmet need in heart failure (HF). BMS-986308, a novel inhibitor of the Renal Outer Medullary Potassium Channel (ROMK), is predicted to enhance potassium-sparring diuresis and natriuresis in HF patients with persistent congestion and edema despite SOC treatment. We present pharmacodynamics and biomarkers of kidney function and injury from a first-in-human study of BMS-986308 (NCT04763226). Method: Thirty-two adult healthy participants were assigned to 1 of 4 dose cohorts (3, 10, 30, and 100 mg) and randomized (6:2) to receive a single dose of BMS-986308 oral solution or matching placebo. Diuresis and natriuresis were measured in intervals over 24 h post dose and baseline-adjusted using matching intervals at Day -1. Serum creatinine, cystatin C, electrolytes (K, Ca, Cl, Mg), aldosterone, renin activity; and urinary protein and albumin to creatinine ratios (UPCR, APCR); and biomarkers of kidney injury Kim1, NAGASE, OPN, CLUST were measured up to Day 5. Statistical significance between BMS-986308 treatment groups and placebo was assessed using unpaired t tests. Results are mean (±SD). ** P<0.01, *** P<0.001 Results: BMS-986308 increased natriuresis and diuresis in a dose-dependent manner starting at the 30 mg dose. The table below presents change from baseline (CFB). No significant change in kaliuresis was observed (mean placebo and 100mg dose respectively 0.08 ± 0.03 and 0.05 ± 0.01 mmol/min over 24h). Aldosterone and renin activity peaked at 24h at 30 mg and 100 mg (CFB 132 ± 102% and 405 ± 129%***, 121 ± 130% and 783 ± 282%** respectively). A transient rapid dose-dependent increase in serum creatinine was observed at the 100 mg dose (CFB 44 ± 12% at 6h***, 28 ± 13% at Day2***, 11 ± 9% at Day4**, 100 mg dose) as well as a less pronounced increase in serum cystatin C (peak at 30 ± 6% at 12h***, 100 mg dose). No meaningful change was observed for the other biomarkers tested. Conclusion: BMS-986308 significantly increased diuresis and natriuresis in healthy participants while sparing potassium. In line with the substantial natriuresis, activation of the RAAS pathway and transient elevations of serum creatinine and cystatin C (with no change in kidney injury markers) was observed.