β3-Adrenoceptor agonists for overactive bladder syndrome: Role of translational pharmacology in a repositioning clinical drug development project

• Published in: Pharmacology & therapeutics (Oxford) Vol. 159; pp. 66 - 82
• Main Authors: Michel, Martin C, Korstanje, Cees
• Format: Journal Article
• Language: English
• Published: England 01.03.2016
• Subjects: Adrenergic beta-3 Receptor Agonists - pharmacology; Adrenergic beta-3 Receptor Agonists - therapeutic use; Adrenergic beta-3 Receptor Antagonists - pharmacology; Animals; Antibodies - pharmacology; Drug Repositioning; Humans; Ligands; Receptors, Adrenergic, beta-3 - genetics; Receptors, Adrenergic, beta-3 - physiology; Syndrome; Translational Medical Research; Urinary Bladder - physiology; Urinary Bladder, Overactive - drug therapy; Urinary Bladder, Overactive - physiopathology; Translational pharmacology; β-Adrenoceptor; Urinary bladder; Drug development; Mirabegron; Species differences
• ISSN: 1879-016X
• DOI: 10.1016/j.pharmthera.2016.01.007

β3-Adrenoceptor agonists were originally considered as a promising drug class for the treatment of obesity and/or type 2 diabetes. When these development efforts failed, they were repositioned for the treatment of the overactive bladder syndrome. Based on the example of the β3-adrenoceptor agonist mirabegron, but also taking into consideration evidence obtained with ritobegron and solabegron, we discuss challenges facing a translational pharmacology program accompanying clinical drug development for a first-in-class molecule. Challenges included generic ones such as ligand selectivity, species differences and drug target gene polymorphisms. Challenges that are more specific included changing concepts of the underlying pathophysiology of the target condition while clinical development was under way; moreover, a paucity of public domain tools for the study of the drug target and aspects of receptor agonists as drugs had to be addressed. Nonetheless, a successful first-in-class launch was accomplished. Looking back at this translational pharmacology program, we conclude that a specifically tailored and highly flexible approach is required. However, several of the lessons learned may also be applicable to translational pharmacology programs in other indications.