Innovations In Clinical Neuroscience

ISCTM Supplement 2015

A peer-reviewed, evidence-based journal for clinicians in the field of neuroscience

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[ V O L U M E 1 2 , N U M B E R 3 – 4 , S U P P L E M E N T A , M A R C H – A P R I L 2 0 1 5 ] Innovations in CLINICAL NEUROSCIENCE 5S ABSTRACT For decades, there has been a distinct disconnect translating a compound's effects from basic neuroscience into clinical efficacy. This disconnect has not only been in terms of generating approved compounds, but also in rejecting targets. During the drug discovery process there are key points to be adhered to that would strengthen the likelihood of a compound being translated to the clinic. These points include 1) the importance of translational pharmacology whereby preclinical pharmacological data should predict clinical efficacy; 2) rigorous early phase drug evaluation to enhance early go/no-go decision- making; 3) using exposure response modeling to predict drug efficacy during proof-of-concept trials; 4) designing and conducting the appropriate proof-of-concept study; and 5) optimizing Phase II studies to set the stage for success in Phase III trials. These topics were covered in The International Society for CNS Clinical Trials and Methodology (ISCTM) Autumn 2013 meeting on the topic of translational and early development strategies and tools led by Drs. Potter and Feltner. This report comprises a review of those proceedings with a concluding summary to advance future clinical trials. INTRODUCTION Within translational medicine, there remains a critical need for the successful translation of the effects of compounds developed from basic neuroscience to their effects in the clinic. This gap in translation is not only in terms of generating United States Food Drug Administration (FDA) approval, thus validating the target in the marketplace, but also in terms of difficulty in target rejection—giving up on a target despite clinical evidence. For example, in recent years there have been more than 75 targets for antidepressants, and while three have been validated, only three have been rejected, leaving many still being pursued because of lack of ability to finalize rejecting a target. For psychosis, including cognition in schizophrenia, a similar pattern emerges where, in more than 50 targets, only one has been validated and only three have been rejected. For Alzheimer's disease, this situation is even more pronounced: in more than 150 targets, only one has been validated and none have been Translational and Early Phase Strategies for Treatment Development: Report of ISCTM Autumn 2013 Symposium by JARED W. YOUNG, PhD; WILLIAM Z. POTTER, MD, PhD; STEVE RILEY, PharmD, PhD; GEERT J. GROENEVELD, MD, PhD; BRUCE J. KINON, MD; MIKE F. EGAN, MD; and DOUGLAS E. FELTNER, MD Dr. Young is with the Department of Psychiatry, University of California San Diego, La Jolla, California, and Research Service, VA San Diego Healthcare System, San Diego, California; Dr. Potter is with the National Institute of Mental Health, Rockville, Maryland; Dr. Riley is with the Department of Clinical Pharmacology, Global Innovative Pharma Business, Pfizer, Inc., Groton, Connecticut; Dr. Groeneveld is with Center for Human Drug Research, The Netherlands; Dr. Kinon is with Lundbeck LLC, Deerfield, Illinois (Dr. Kinon was with Eli Lilly and Company, Indianapolis, Indiana, when this material was presented); Dr. Egan is with Clinical Neuroscience, Merck & Co, Inc, North Wales, Pennsylvania; and Dr. Feltner is with AbbVie Inc. Pharmaceuticals, Chicago, Illinois. Innov Clin Neurosci 2015;12(1–2 Suppl A):5S–10S FUNDING: No funding was provided for the preparation of this article. FINANCIAL DISCLOSURES: In the past three years, Dr. Young's work has been funded by NIDA and NIMH, as well as the US Veteran's Administration VISN 22 Mental Illness, Research, Education, and Clinical Center, Cerca Insights, Lundbeck Ltd, and Omeros; Dr. Young has also received consulting compensation for Amgen. Dr. Potter reports consulting fees for Amgen, Lilly, Ironside, Takeda, and Taisho. Dr. Riley is an employee of Pfizer, Inc. Dr. Groeneveld reports no financial disclosures relevant to the content of this article. Dr. Kinon is an employee of Lundbeck LLC (was an employee of Eli Lilly and Co. when this material was presented). Dr. Egan is an employee of Merck. Dr. Feltner is an employee of AbbVie Pharmaceuticals. ADDRESS CORRESPONDENCE TO: Jared W. Young, Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, MC 0804, La Jolla, CA 92093- 0804; E-mail: KEY WORDS: Drug discovery, pharmacology, FDA, pharmacokinetics, decision-making, proof of concept, target rejection P R O C E E D I N G S

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