Phase Ib study of intravenous HRS-9057, an arginine vasopressin V2 receptor antagonist, versus oral tolvaptan in congestive heart failure with volume overload despite prior diuretic therapy

Background Arginine vasopressin (AVP) contributes to fluid retention in heart failure (HF). HRS-9057 is an AVP V2 receptor antagonist that promotes aquaresis with minimal electrolyte loss. Preclinical and early-phase studies have indicated a diuretic effect and favorable safety profile. Purpose This Phase 1b study aimed to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of intravenous HRS-9057 versus oral tolvaptan in congestive heart failure (CHF) patients with persistent volume overload despite prior non-V2 antagonist diuretic therapy. Methods In this open-label, active-controlled, dose-escalation Phase 1b study, two dose cohorts were planned. For each cohort, 12 CHF patients with persistent volume overload despite prior non-V2 antagonist diuretic therapy were randomized (9:3) to receive once-daily intravenous infusion of HRS-9057 administered over 1 hour (15 mg or 30 mg) or oral tolvaptan 15 mg for 7 days. The primary endpoints were safety and tolerability. Results Twenty-five patients were enrolled and treated (HRS-9057 15 mg, n = 9; 30 mg, n = 10; tolvaptan 15 mg, n = 6). Mean body weight reductions from baseline at Day 8 were -1.81 and -2.82 kg with HRS-9057 at 15 and 30 mg, compared to -1.40 kg with tolvaptan. An earlier onset of weight reduction was observed in both HRS-9057 groups compared to tolvaptan (Figure 1). By Day 8, lower limb edema resolved in 9/9 (100%), 8/9 (88.9%), and 3/5 (60.0%) of patients in the HRS-9057 15 mg, 30 mg, and tolvaptan groups, respectively. Pulmonary rales resolution was observed in 1/2 (50.0%), 3/3 (100%), and 3/4 (75.0%), respectively. Treatment-emergent adverse events (TEAEs) were reported in 9 (100%), 8 (80.0%) and 6 (100%) of patients in the HRS-9057 15 mg, 30 mg, and tolvaptan groups, respectively. Most TEAEs were mild in severity, and no serious adverse events occurred. The most common treatment-related adverse events (TRAEs) included dry mouth (66.7%, 40.0%, 33.3%), increased alanine aminotransferase (33.3%, 10.0%, 0.0%), increased aspartate aminotransferase (22.2%, 10.0%, 0.0%), electrocardiogram QT prolonged (33.3%, 0.0%, 16.7%) and hypernatremia (0.0%, 20.0%, 0.0%). Following 1-hour intravenous infusion, median Tmax of HRS-9057 was 1 hour, and geometric mean t1/2 was 2–3 hours. The plasma exposure increased approximately proportionally from 15 to 30 mg doses. Steady state was achieved after 3 days of dosing, with minimal accumulation. Both HRS-9057 groups maintained a negative fluid balance throughout the 7-day treatment, whereas the tolvaptan group exhibited a negative balance only on Day 1 (Figure 2). Comparable elevations in serum sodium were observed across all groups, with values remaining within the normal range. Conclusion In CHF patients with persistent volume overload, intravenous HRS-9057 showed a trend toward greater body weight reduction and decongestive effects compared with oral tolvaptan, with no new safety concerns.Figure 1Figure 2