[PP.02.17] SUCCESSFUL COMPLETION OF A PHASE I, RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED, SINGLE ASCENDING DOSE TRIAL FOR THE FIRST IN CLASS ANGIOTENSIN AT2-RECEPTOR AGONIST COMPOUND 21

Objective: The angiotensin AT2-receptor (AT2R) is a main receptor of the protective arm of the renin-angiotensin system (RAS), mediating tissue protective effects such as anti-fibrosis and anti-inflammation. A number of drug development projects are currently ongoing, which aim at making therapeutic use of the protective RAS by targeting the receptors AT2 and MAS with selective agonists. This phase I, randomised, double-blind study was designed to test the first-in-class, selective, non-peptide AT2R-agonist “Compound 21” (C21) for safety, tolerability and pharmacokinetic properties in healthy, young men. Design and method: Male, healthy volunteers, aged 18–45 years and with a BMI of 18–30 kg/m2 were randomised and treated with escalating, single oral doses of C21 in cohorts of 8 (6 receiving C21 and 2 receiving placebo). Six dose levels were tested: 0.3, 1, 3, 10, 30 and 100 mg. Subjects were retained in the phase 1 clinic for 24 hours after dosing and further followed up for one week. A total of 17 blood samples were taken for pharmacokinetics from prior to up to 72 hours after drug intake. Safety was monitored by physical exams, blood pressure measurements, 12-lead ECG and clinical safety laboratory parameters. Potential adverse effects were documented. Results: C21 was rapidly absorbed with median Tmax at 40 min. C21 exposure increased supraproportionally to dose. with Cmax increasing from 1.8 to 2004 ng/ml, and AUC (0–24) from 2.2 to 2438 h*ng/ml. T1/2 was 5.4 h on average at the 100 mg dose level. C21 was generally well tolerated with no serious or severe adverse events being recorded and no major abnormalities in the laboratory safety parameters related to drug intake. In one subject's ECG, transient PR prolongation was noted 1 hour after intake of 3 mg of C21. PR prolongation did not occur at higher doses. Conclusions: From these data it can be concluded that orally applied C21 at doses from 0.3 to 100 mg is safe and well-tolerated and has favorable pharmacokinetic properties for further clinical development of this first-in-class AT2-receptor agonist in a multiple ascending dose study. Trial registration: EudraCT 2015-005718-32