Innovations In Clinical Neuroscience

ISCTM Supplement 2015

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

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Translational and Early Phase Strategies for Treatment Development: Report of ISCTM Autumn 2013 Symposium....................................................................................................................................5 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 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 c ompound 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) meeting in Philadelphia, Pennsylvania, September 30 to October 2, 2013, 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. Lessons Learned and Potentials for Improvement in CNS Drug Development: ISCTM Section on Designing the Right Series of Experiments..........................................................................................11 by Steven T. Szabo, MD, PhD; Bruce J. Kinon, MD; Stephen K. Brannan, MD; Andrew K. Krystal, MD, MSc; Joop M. A. van Gerven, MD, PhD; Atul Mahableshwarkar, MD; and Gary S. Sachs, MD ABSTRACT: Once a molecule has been characterized as engaging an identified target at the appropriate location (affinity and potency), the next step involves designing experiments that will determine its pharmacodynamic activities both for efficacy (on target) and safety-tolerability (on/off target). Two expert presentations focused on looking back at completed programs and two concentrated on looking forward at ongoing programs. Specific discussions pertain to assessment of pharmacologic agonists (mGluR2/3, k-opiate, peroxisome proliferator-activated receptor gamma) and antagonists (orexin and cannabinoid) in disorders of cognition, mood, and anxiety. Advanced experimental study designs using genetics to guide a treatment trial in Alzheimer's disease and neural target-based approaches as the primary outcome measure in the National Institute of Mental Health-sponsored Fast-Fail Trials (FAST)-Mood and Anxiety Spectrum Disorders (MAS) initiative for depression showcases novel methodological approaches. Of interest, some of these initiatives were successful, while others were not, and two are currently ongoing. In conclusion, methodologies that were utilized and are currently employed to reach a successful clinical drug trial outcome are appreciated, and in case of failure, approaches to reviewing programs to enable learning that would be helpful to future programs are brought forth. This article is based on proceedings from the "Designing the Right Series of Experiments" session, which was held during the International Society for Clinical Trials Meeting (ISCTM) in Philadelphia, Pennsylvania, September 30 to October 2, 2013. Taking Personalized Medicine Seriously: Biomarker Approaches in Phase IIb/III Studies in Major Depression and Schizophrenia.............................................................................................................26 by Harald Murck, MD, PhD; Thomas Laughren, MD; Femke Lamers, PhD; Rosalind Picard, ScD; Sebastian Walther, MD; Donald Goff, MD; and Stephen Sainati, MD, PhD ABSTRACT: The success rate in the development of psychopharmacological compounds is insufficient. Two main reasons for failure have been frequently identified: 1) treating the wrong patients and 2) using the wrong dose. This is potentially based on the known heterogeneity among patients, both on a syndromal and a biological level. A focus on personalized medicine through better characterization with biomarkers has been successful in other therapeutic areas. Nevertheless, obstacles toward this goal that exist are 1) the perception of a lack of validation, 2) the perception of an expensive and complicated enterprise, and 3) the perception of regulatory hurdles. The authors tackle these concerns and focus on the utilization of biomarkers as predictive markers for treatment outcome. The authors primarily cover examples from the areas of major depression and schizophrenia. Methodologies covered include salivary and plasma collection of neuroendocrine, metabolic, and inflammatory markers, which identified subgroups of patients in the Netherlands Study of Depression and Anxiety. A battery of vegetative markers, including sleep-electroencephalography parameters, heart rate variability, and bedside functional tests, can be utilized to characterize the activity of a functional system that is related to treatment refractoriness in depression (e.g., the renin-angiotensin-aldosterone system). Actigraphy and skin conductance can be utilized to classify patients with schizophrenia and provide objective readouts for vegetative activation as a functional marker of target engagement. Genetic markers, related to folate metabolism, or folate itself, has prognostic value for the treatment response in patients with schizophrenia. Already, several biomarkers are routinely collected in standard clinical trials (e.g., blood pressure and plasma electrolytes), and appear to be differentiating factors for treatment outcome. Given the availability of a wide variety of markers, the further development and integration of such markers into clinical research is both required and feasible in order to meet the benefit of personalized medicine. This article is based on proceedings from the "Taking Personalized Medicine Seriously—Biomarker Approaches in PhaseIIb/III Studies in Major Depression and Schizophrenia" session, which was held during the 10th Annual Scientific Meeting of the International Society for Clinical Trials Meeting (ISCTM) in Washington, DC, February 18 to 20, 2014. VOLUME 12 • NUMBER 3–4 MARCH–APRIL 2015 • SUPPLEMENT A THIS MONTH IN ANNOTATED TABLE OF CONTENTS 4S Innovations in CLINICAL NEUROSCIENCE [ 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 ] A SUPPLEMENT TO INNOVATIONS IN CLINICAL NEUROSCIENCE

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