Clinical trials with endothelin receptor antagonists: What went wrong and where can we improve?

Kohan, D. E., Cleland, J. G. , Rubin, L. J., Theodorescu, D. and Barton, M. (2012) Clinical trials with endothelin receptor antagonists: What went wrong and where can we improve? Life Sciences, 91(13-14), pp. 528-539. (doi: 10.1016/j.lfs.2012.07.034) (PMID:22967485)

Abstract

In the early 1990s, within three years of cloning of endothelin receptors, orally active endothelin receptor antagonists (ERAs) were tested in humans and the first clinical trial of ERA therapy in humans was published in 1995. ERAs were subsequently tested in clinical trials involving heart failure, pulmonary arterial hypertension, resistant arterial hypertension, stroke/subarachnoid hemorrhage and various forms of cancer. The results of most of these trials – except those for pulmonary arterial hypertension and scleroderma-related digital ulcers – were either negative or neutral. Problems with study design, patient selection, drug toxicity, and drug dosing have been used to explain or excuse failures. Currently, a number of pharmaceutical companies who had developed ERAs as drug candidates have discontinued clinical trials or further drug development. Given the problems with using ERAs in clinical medicine, at the Twelfth International Conference on Endothelin in Cambridge, UK, a panel discussion was held by clinicians actively involved in clinical development of ERA therapy in renal disease, systemic and pulmonary arterial hypertension, heart failure, and cancer. This article provides summaries from the panel discussion as well as personal perspectives of the panelists on how to proceed with further clinical testing of ERAs and guidance for researchers and decision makers in clinical drug development on where future research efforts might best be focused.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Cleland, Professor John
• Authors: Kohan, D. E., Cleland, J. G., Rubin, L. J., Theodorescu, D., and Barton, M.
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre
• Journal Name: Life Sciences
• Publisher: Elsevier
• ISSN: 0024-3205
• ISSN (Online): 1879-0631
• Published Online: 06 August 2012
• Copyright Holders: Copyright © 2012 Elsevier
• First Published: First published in Life Sciences 91:528-539
• Publisher Policy: Reproduced under a Creative Commons License