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A1629 - Demonstration of Preclinical Efficacy in Pulmonary Fibrosis Models and of Clinical Safety, Tolerability, and Pharmacodynamic Effects of the First-in-Class Angiotensin AT2-Receptor Agonist Compound 21 (C21)
Author Block: U. M. Steckelings1, L. Lindblad1, P. Vainio2, J. Graens1, B. Dahloef3, P. Jansson1, T. Unger4, P. Korhonen5, A. Wiksten5, E. Bruce6, A. Rathinasabapathy7, V. Shenoy8, C. Sumners6, M. Katovich6, M. Scheinin2; 1Vicore Pharma, Mölndal, Sweden, 2University of Turku, Turku, Finland, 3Sahlgrenska University, Gothenburg, Sweden, 4CARIM - Maastricht University, Maastricht, Netherlands, 5StatFinn, Espoo, Finland, 6University of Florida, Gainesville, FL, United States, 7Vanderbilt University, Nashville, TN, United States, 8Pharmaceutical and Biomedical Sciences, California Health Sciences University, Clovis, CA, United States.
The angiotensin AT2-receptor (AT2R) is a main receptor of the protective arm of the renin-angiotensin system, mediating anti-fibrosis and anti-inflammation. C21 is a first-in-class AT2R-agonist in early clinical development for the treatment of idiopathic pulmonary fibrosis (IPF) and other fibrotic diseases. For preclinical proof-of-concept, C21 (0.03 mg/kg/day i.p.) or vehicle were applied to Sprague-Dawley rats, in which pulmonary fibrosis was induced either by a single s.c. injection of 50 mg/kg monocrotalin (MCT) or by a single intra-tracheal injection of 4 U/kg bleomycin (Bleo). MCT animals were treated from week 2 to 4 after MCT dosing and Bleo animals from day 3 to 14 after Bleo. For evaluation of safety, tolerability and pharmacokinetics, two Phase I, randomised, double-blind studies were performed in healthy male volunteers, aged 18-45, BMI 18-30 kg/m2. In the single ascending dose (SAD) study, subjects received either single oral doses of C21 (6 subjects/dose: 0.3, 1, 3, 10, 30 or 100 mg) or placebo (12 subjects). In the multiple ascending dose (MAD) study, either C21 (6 subjects/dose: 25, 50 or 100 mg) or placebo (6 subjects) were given once daily on 8 consecutive days. Safety was monitored by vital signs, ECG and safety laboratory parameters. For demonstration of pharmacodynamic effects of C21, an extension of the MAD study was performed in overweight (BMI 30-35 kg/m2, waist/hip >0.90) male volunteers, receiving C21 (100 mg) or placebo once daily for 8 days. Routine laboratory parameters were determined and plasma samples analysed for metabolic markers by NMR. In rats, C21 either reversed pulmonary fibrosis (MCT model) or significantly prevented its progression (Bleo model) as determined by histological analysis. This therapeutic effect was associated with lowering of pulmonary blood pressure (BP) (without systemic BP changes) and with lowering of markers of inflammation (TNFα, IL1β) and fibrosis (TGF-β). In the SAD and MAD studies, C21 was well tolerated with no severe adverse effects and no major abnormalities in the laboratory safety parameters. In the overweight subjects, C21 application resulted in changes in the pattern of lipoproteins (mainly LDL and HDL fractions) strongly suggesting a pharmacodynamic, beneficial effect of C21 on lipid metabolism. In conclusion, C21 shows anti-fibrotic efficacy in rats and is safe in humans at daily doses up to 100 mg. This dose was associated with pharmacodynamic effects in humans. C21 will be tested in a Phase IIa study in patients with IPF, planned to start in Q2/2018.