Entry-into-humans study with a new direct renin inhibitor

Area of Science:

• Pharmacology
• Clinical Pharmacology
• Cardiovascular Research

Background:

• Hypertension remains a significant global health concern, necessitating novel therapeutic agents.
• Renin inhibition is a validated strategy for blood pressure management.
• Orally active renin inhibitors offer potential advantages in patient compliance and administration.

Purpose of the Study:

• To assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of escalating single oral doses of ACT-077825.
• To evaluate ACT-077825 as a novel orally active renin inhibitor in healthy male subjects.
• To establish the safety and tolerability profile of ACT-077825 across a range of doses.

Main Methods:

• A single-center, double-blind, placebo- and active-controlled (enalapril) randomized study.
• 70 healthy male subjects received single oral doses of ACT-077825 (1-1,000 mg), placebo, or enalapril 20 mg.
• Key endpoints included pharmacokinetic parameters (AUC, t(1/2)), pharmacodynamic markers (iAR, PRA), and safety assessments.

Main Results:

• ACT-077825 exhibited dose-proportional pharmacokinetics from 100 to 1,000 mg.
• The terminal half-life (t(1/2)) was approximately 41.6 hours with a Tmax of 4-5 hours.
• Dose-dependent increases in immunoactive renin (iAR) and decreases in plasma renin activity (PRA) were observed, accompanied by blood pressure reduction at 1,000 mg.

Conclusions:

• ACT-077825 demonstrated a favorable pharmacokinetic profile suitable for once-daily dosing.
• The observed effects on renin and blood pressure suggest potential as an antihypertensive agent.
• These findings support further investigation in a multiple-ascending dose study.