The use of mechanistic biomarkers for evaluating investigational CNS compounds in early drug development.

Biomarkers serve as the fundamental building blocks of modern translational research strategies, and are widely implemented in current drug development. Biomarker techniques range from simple biofluid biochemical endpoints to more complex assessments, including imaging. Although biomarker usage is common throughout drug development, applications may vary depending on whether a drug candidate is in early- or late-stage testing. In early clinical drug development, biomarkers capable of providing proof of mechanism are considered critical tools in the management of attrition during phase II clinical trials. For CNS drugs, the ability to unequivocally demonstrate pharmacologically driven biological activity in the brain, as a result of the interaction of a drug with its intended target, ensures that proof-of-concept trials are designed in a manner that adequately tests the clinical efficacy hypothesis and that patients are not being exposed to inactive drugs. This review focuses on recent advances in proof-of-pharmacology biomarkers, with an emphasis on biochemical measures and simple circuit platforms used to demonstrate target engagement in central compartments.