Natriuretic Peptide Receptor-1 Agonist for Resistant Hypertension: A Randomized Phase 2 Trial

Clinical Snapshot

Key Findings

• P Value: Not reported for primary endpoint

• Effect Size: Neutral effect - no XXB750 dose superior to placebo

• Primary Outcome: No significant dose-dependent reduction in 24-hour systolic BP at week 12

• Nnt Or Sensitivity: Not applicable - no therapeutic benefit demonstrated

• Confidence Interval: Not reported

Clinical Application

Monthly subcutaneous injections feasible but no clinical benefit demonstrated Results relevant to Australian resistant hypertension management; would not support TGA approval or PBS listing given lack of efficacy Limited applicability - results suggest NPR-1 agonism ineffective for resistant hypertension despite theoretical rationale

Abstract

BACKGROUND: XXB750 is a potent and long-acting human monoclonal antibody agonist of the natriuretic peptide receptor-1 (NPR-1), the receptor for atrial natriuretic peptide and B-type natriuretic peptide. Activation of NPR-1 may lower blood pressure (BP) in patients with resistant hypertension through increases in the second messenger cyclic guanosine monophosphate. OBJECTIVES: The aim of this study was to determine the effect of NPR-1 agonism on 24-hour BP. METHODS: This phase 2, multicenter, randomized, double-blind, placebo-controlled trial evaluated 4 once-monthly subcutaneous doses of XXB750 (30 mg, 60 mg, 120 mg, and 240 mg) administered at baseline, week 4, and week 8 in patients with resistant hypertension. Resistant hypertension was defined as 24-hour systolic BP (SBP) ≥135 mm Hg despite treatment with 3 or 4 guideline-directed antihypertensive agents. The primary endpoint was the dose-response relationship of XXB750 vs placebo in reducing the mean 24-hour SBP from baseline to week 12. RESULTS: The study population (N = 189) had a mean age of 61 years, was 69% male, 61% White, 20% Asian, and 14% Black/African American, and had a baseline mean 24-hour ambulatory BP of 148/81 ± 11/10 mm Hg. Plasma concentrations of XXB750 dose-dependently increased in the XXB750 groups, and XXB750 dose-dependently increased plasma and urine cyclic guanosine monophosphate concentrations by week 12. However, paradoxically, there was no significant dose-dependent change from baseline in mean 24-hour SBP at week 12. In fact, none of the doses of XXB750 had a greater BP-lowering effect than placebo. Changes in ambulatory BP were not affected by the development of anti-drug antibodies. Although there were no changes from baseline in urinary sodium excretion, there were small increases in plasma renin levels in the XXB750 groups. Adverse events with XXB750 were numerically higher than with placebo. Adherence to background antihypertensive medications, assessed by drug assays in 88 patients with available plasma samples, was consistent across all treatment groups at both baseline and week 12. CONCLUSIONS: XXB750, an NPR-1 agonist, had a neutral effect on 24-hour ambulatory SBP in patients with resistant hypertension, despite showing a robust dose-response relationship for engagement of the target of pharmacologic action as indicated by increases in cyclic guanosine monophosphate levels. (An Efficacy, Safety, Tolerability and Dose Finding Study of XXB750 in Resistant Hypertension Patients; NCT05562934).

References

1. 1.White, W. B., Azizi, M., Ferdinand, K., Cohen, D. L., Nührenberg, T., Lefkowitz, M., Jiao, R., Rizkala, A. R., Maboudian, M., & Williams, B. (2026). Natriuretic peptide receptor-1 agonist for resistant hypertension: A randomized phase 2 trial. Journal of the American College of Cardiology. https://doi.org/10.1016/j.jacc.2025.11.045