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By Steven W. Louie

The brain retains a nearly impenetrable wall against any potential central nervous system (CNS) therapeutic agents attempting to invade its fortress. Due to the complexity of the brain, developing CNS therapeutic drugs remains a formidable challenge for all pharmaceutical companies. In 2014, the Tufts Center for the Study of Drug Development reported that drugs developed between 1999 and 2013 that were designed to target CNS diseases took more than one year longer (12.8 months, 18 percent longer) to develop than non-CNS drugs. This analysis included 42 CNS and 345 non-CNS therapeutic compounds approved by the Food and Drug Administration (FDA). Additionally, CNS drugs were less likely to obtain marketing approval than non-CNS drugs based on development and approval histories of 274 CNS and 1,168 non-CNS investigational drugs.

An example of the complexities of both the brain and CNS drug development is highlighted in the recent failure of the Alzheimer disease (AD) drug solanezumab in clinical trials. In 2012, Eli Lilly reported promising results from patients with mild AD; however, the most recent large-scale clinical trial failed to replicate those earlier findings. This clinical trial also highlights that the reduction of amyloid-β protein levels does not necessarily reduce Aβ-plaque formation, further adding to the complexity of CNS drug development.

The European Medicines Agency (EMA) recently published a report highlighting the higher rate of failure during the clinical development of CNS drugs compared to non-CNS drugs. EMA staff reviewed 103 new drug applications submitted between 1995 and 2014 for various CNS targets. They focused on major objections raised by the Committee for Medicinal Products for Human Use during the review process for neurological and psychiatric drugs. According to the agency, more than a third of the applications had issues related to clinical efficacy and safety in late stage studies.

Despite the higher failure rate of CNS drugs in clinical development, the rate of CNS drug discovery and development remains consistent over time. Many strategies have been developed to deliver therapeutic drugs to the brain, including hydrophilic and hydrophobic small molecules, peptides, RNA, antibodies, and others by liposomes, nanoparticles, carrier-mediated, receptor-mediated, transporter-mediated approaches, and many more. Some exciting new technologies and innovative approaches to classical methods have provided some interesting advancements to the field. Read more about these advancements in the April AAPS Newsmagazine  cover story Hitting the BBB: Technological Advancements in CNS Research and Drug Targeting, and share your thoughts on the topic in the comments below.

Steven W. Louie is a senior scientist in the Department of Pharmacokinetics and Drug Metabolism at Amgen, Cambridge, Mass. He is the current chair of the AAPS Drug Transport focus group and had the honor of co-organizing the newly launched AAPS ecourse Transporter Knowledge for New Frontiers and will be organizing the 2018 AAPS transporter workshop: NexGen Transporters: Next Generation of New Transporters and Transport Mechanisms.