Effects of the renin inhibitor MK-8141 (ACT-077825) in patients with hypertension.
The renin inhibitor MK-8141 (ACT-077825) demonstrates substantial immunoreactive active renin (ir-AR) increase (sevenfold) without a persistent plasma renin activity (PRA) decrease. The present study assessed the antihypertensive efficacy of MK-8141 in hypertensive patients. In this double-blind, placebo- and active comparator-controlled study, 195 patients with hypertension (trough sitting diastolic blood pressure ≥92 to <105 mm Hg, trough sitting systolic blood pressure <170 mm Hg, and 24-hour mean diastolic blood pressure [DBP] ≥80 mm Hg) were randomized to one of four treatments (stratified by race, black versus others): MK-8141 250 mg, MK-8141 500 mg, enalapril 20 mg, or placebo. Blood pressure was measured at trough and as 24-hour ambulatory blood pressure monitoring. The primary end point was change from baseline in 24-hour mean ambulatory DBP measured after 4 weeks. At week 4, the change from baseline in 24-hour mean (95% CI) ambulatory DBP compared with placebo was -1.6 mm Hg (-4.2, 1.1), -1.1 mm Hg (-3.9, 1.6), and -4.9 (-7.5, -2.2) for MK-8141 250 mg, MK-8141 500 mg, and enalapril 20 mg, respectively. Only mean ambulatory DBP-lowering with enalapril 20 mg was statistically significant. Enalapril, but not MK-8141, also significantly lowered 24-hour mean ambulatory systolic blood pressure (SBP) compared with placebo (-6.7 mm Hg [-10.5, -2.8]). Neither enalapril nor MK-8141 significantly lowered trough DBP and SBP compared with placebo. MK-8141 was generally well tolerated. In patients with hypertension, MK-8141 (ACT-077825) did not produce significant blood pressure-lowering efficacy despite a demonstrated effect of the drug on ir-AR, in the absence of durable PRA suppression.
Jones-Burton
Charlotte
C
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA. charlotte_jones@merck.com
Rubino
Joseph
J
Roy
Sophie
S
Mai
Yabing
Y
Meehan
Alan
A
Bellet
Marc
M
Feig
Peter
P
D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D018660:Blood Pressure Monitoring, Ambulatory; D005260:Female; D006801:Humans; D006973:Hypertension / Q000175:diagnosis / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010919:Placebos; D011446:Prospective Studies; D012084:Renin-Angiotensin System / Q000187:drug effects*; D000092502:Renin Inhibitors
D000959:Antihypertensive Agents; D015415:Biomarkers; D010919:Placebos; D000092502:Renin Inhibitors