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
L Wang, W Ou, Z Xie, L Liu, Y Zhang, Z Zhang, J Feng, Y Ling, C Liu, G Chen, S Jiang, J Yu, Y WangAbstract
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