CNS Drug Development, Lessons Learned, Part 4: The Role of Brain Circuitry and Genes—Tasimelteon as an Example
This is the fourth in a series of columns discussing the rational and targeted development of drugs to affect specific central nervous system (CNS) circuits in specific ways based on knowledge gained by molecular biology and the human genome project. The first column in this series described 6 CNS drugs with novel mechanisms of action developed over the last 25 years. The second column discussed differences between syndromic diagnoses as exemplified by the third through the fifth editions of the Diagnostic and Statistical Manual of Mental Disorders (DSM III through DSM-5) and the new approach to psychiatric diagnoses championed by the National Institute of Mental Health in their Research Domain Criteria Initiative. The third column reviewed the last 9 years of drug development contrasting the development of drugs in other therapeutic areas (eg, cancer) with psychiatric and related CNS-active drugs. This column extends the discussion of modern drug development for psychiatric and other CNS-related indications, using the development of tasimelteon as an example of how modern drug development focuses rationally on novel targets of interest while simultaneously achieving “specificity.” Tasimelteon, which is indicated for the treatment of non-24-hour sleep-wake disorder, was developed to be a selective agonist at the melatonin MT1 and MT2 receptors, with limited or no effects at other pharmacologically relevant receptors and enzymes to minimize the potential for off-target effects (eg, nuisance side effects), toxicity, drug-drug interactions, and effects on oxidative drug metabolizing enzymes. The next column in this series will continue the discussion of the development of CNS drugs with novel mechanisms of action, using suvorexant, which targets orexin-1 and orexin-2 receptors, to illustrate the preclinical and human studies that were carried out to assess its safety as part of a successful new drug application.