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

Area of Science:

• Cardiovascular Medicine
• Pharmacology
• Clinical Trials

Background:

• Resistant hypertension poses a significant challenge, often requiring novel therapeutic approaches.
• Natriuretic peptide receptor-1 (NPR-1) agonism is a potential mechanism for blood pressure reduction.
• XXB750 is a human monoclonal antibody designed as a long-acting NPR-1 agonist.

Purpose of the Study:

• To evaluate the dose-response relationship of XXB750 in reducing 24-hour systolic blood pressure (SBP) in patients with resistant hypertension.
• To assess the effect of NPR-1 agonism on 24-hour ambulatory blood pressure.

Main Methods:

• A phase 2, multicenter, randomized, double-blind, placebo-controlled trial.
• 189 patients with resistant hypertension received placebo or one of four doses of XXB750 (30-240 mg) subcutaneously once monthly for 8 weeks.
• The primary endpoint was the change in mean 24-hour SBP from baseline to week 12.

Main Results:

• XXB750 demonstrated dose-dependent increases in plasma concentrations and cyclic guanosine monophosphate levels, indicating target engagement.
• No significant dose-dependent reduction in mean 24-hour SBP was observed at week 12 compared to placebo.
• Adverse events were numerically higher with XXB750 compared to placebo.

Conclusions:

• XXB750, an NPR-1 agonist, exhibited a neutral effect on 24-hour ambulatory SBP in patients with resistant hypertension.
• Despite evidence of target engagement, XXB750 did not provide a clinically meaningful blood pressure-lowering effect.
• Further investigation into NPR-1 agonism for resistant hypertension may require alternative strategies.