Preclinical and Early Clinical Profile of a Highly Selective and Potent Oral Inhibitor of Aldosterone Synthase (CYP11B2)

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 2017-01, Vol.69 (1), p.189-196
• Main Authors: Bogman, Katrijn, Schwab, Dietmar, Delporte, Marie-Laure, Palermo, Giuseppe, Amrein, Kurt, Mohr, Susanne, De Vera Mudry, Maria Cristina, Brown, Morris J, Ferber, Philippe
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Blood Pressure - drug effects; Blood Pressure - physiology; Cytochrome P-450 CYP11B2 - antagonists & inhibitors; Cytochrome P-450 CYP11B2 - metabolism; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacokinetics; Humans; Hyperaldosteronism - complications; Hyperaldosteronism - drug therapy; Hyperaldosteronism - metabolism; Hypertension - drug therapy; Hypertension - etiology; Hypertension - physiopathology; Macaca fascicularis; Original
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.116.07716

Primary hyperaldosteronism is a common cause of resistant hypertension. Aldosterone is produced in the adrenal by aldosterone synthase (AS, encoded by the gene CYP11B2). AS shares 93% homology to 11β-hydroxylase (encoded by the gene CYP11B1), responsible for cortisol production. This homology has hitherto impeded the development of a drug, which selectively suppresses aldosterone but not cortisol production, as a new treatment for primary hyperaldosteronism. We now report the development of RO6836191 as a potent (Ki 13 nmol/L) competitive inhibitor of AS, with in vitro selectivity >100-fold over 11β-hydroxylase. In cynomolgus monkeys challenged with synthetic adrenocorticotropic hormone, single doses of RO6836191 inhibited aldosterone synthesis without affecting the adrenocorticotropic hormone–induced rise in cortisol. In repeat-dose toxicity studies in monkeys, RO6836191 reproduced the adrenal changes of the AS mouseexpansion of the zona glomerulosa; increased expression of AS (or disrupted green fluorescent protein gene in the AS mouse); hypertrophy, proliferation, and apoptosis of zona glomerulosa cells. These changes in the monkey were partially reversible and partially preventable by electrolyte supplementation and treatment with an angiotensin-converting enzyme inhibitor. In healthy subjects, single doses of RO6836191, across a 360-fold dose range, reduced plasma and urine aldosterone levels with maximum suppression at a dose of 10 mg, but unchanged cortisol, on adrenocorticotropic hormone challenge, up to 360 mg, and increase in the precursors 11-deoxycorticosterone and 11-deoxycortisol only at or >90 mg. In conclusion, RO6836191 demonstrates that it is possible to suppress aldosterone production completely in humans without affecting cortisol production. CLINICAL TRIAL REGISTRATION—URLhttp://www.clinicaltrials.gov. Unique identifierNCT01995383.