Non-clinical toxicology evaluation of BIA 10-2474

Abstract

In 2016, one subject died and four were hospitalized with neurological symptoms during a clinical trial with the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474. The present paper reviews the regulatory toxicology studies that were carried out to support the clinical trial application for BIA 10-2474. Animal studies complied with national and international standards including European regulatory guidelines (e.g. EEC Council Directive 75/318/EEC and subsequent amendments). The CNS effects seen in the rat and mouse appear to be common in rodents in such studies and do not in principle seem to be of the type to generate a signal. In the same way in non-human primates, insignificant alterations in the mesencephalon, and especially of the autonomic nervous system (Meissner’s plexus in the bowel) in rodents and monkeys were observed in some animals treated with a high dose. Overall, these data, as well as the extensive additional data generated since the accident, support the conclusion that the tragic fatality that occurred during the clinical trial with BIA 10-2474 was unpredictable and that the mechanism responsible remains unknown, from a non-clinical toxicological perspective.

Keywords:

• BIA 10-2474
• FAAH
• safety pharmacology
• toxicology
• DART
• genotoxicity

Acknowledgments

The manuscript was written by the authors and reviewed by Bial-Portela & C^a S.A. (São Mamede do Coronado, Portugal); however, the work product and conclusions are those of the authors. The authors thank the editor and his reviewers (Who remain unknown to us.) for their most helpful comments and suggestions that greatly improved the scientific basis and readability of the manuscript.

Declaration of interest

These studies were funded by Bial-Portela & C^a S.A. (São Mamede do Coronado, Portugal). A. Wallace Hayes and Klaus Weber were paid consultants of Bial-Portela & C^a. S. A. Paul Moser and Patrício Soares-da-Silva are employees of Bial Portela & Companhia. S. A. BIA 10-2474 has been the subject of a Phase 1 clinical trial in France (Rennes) which was interrupted because of the occurrence of adverse reactions and is currently the subject of pending proceedings in France.