Novel NPR-1 agonist no better than placebo for treatment of resistant hypertension

Treatment with the novel natriuretic peptide receptor-1 (NPR-1) agonist XXB750 demonstrates a neutral effect on 24-h ambulatory systolic blood pressure (SBP) in patients with resistant hypertension, as shown by the results of a phase II trial.

In this multicentre, randomized, double-blind, placebo-controlled trial, the investigators assessed four once-monthly subcutaneous doses of XXB750 (30, 60, 120, and 240 mg) administered at baseline, week 4, and week 8 in patients with resistant hypertension. The dose-response relationship of XXB750 vs placebo in reducing the mean 24-h SBP from baseline to week 12 was the primary endpoint.

Resistant hypertension was characterized by 24-h SBP ≥135 despite treatment with three or four guideline-directed antihypertensive medications.

One hundred eighty-nine patients (mean age 61 years, 69 percent male, 20 percent Asian) who had a baseline mean 24-h ambulatory BP of 148/81 mm Hg were enrolled in this phase II trial.

A dose-dependent increase in plasma concentrations was observed in the XXB750 groups, specifically increasing plasma, and urine cyclic guanosine monophosphate concentrations by week 12. However, no significant dose-dependent change from baseline was noted in mean 24-h SBP at week 12.

“In fact, none of the doses of XXB750 had a greater BP-lowering effect than placebo,” the investigators said. “Changes in ambulatory BP were not affected by the development of antidrug antibodies.”

There were also no changes from baseline seen in urinary sodium excretion, but small increases were noted in plasma renin levels with XXB750 treatment. Furthermore, adverse events occurred more frequently in the XXB750 groups than in the placebo group.

Adherence to background antihypertensive medications, assessed by drug assays in 88 patients, was consistent across treatment groups at baseline and week 12.

“XXB750, an NPR-1 agonist, had a neutral effect on 24-h 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,” the investigators said.