Improving and Accelerating Therapeutic Development for Nervous System Disorders: Workshop Summary by Sheena M. Posey Norris

Author:Sheena M. Posey Norris
Language: eng
Format: epub
Publisher: The National Academies Press
Published: 2014-01-23T00:00:00+00:00

• embed multiple biomarkers in Phase I/IIa trials in order to develop pharmacodynamic profiles quickly;

• develop synaptic and other biomarkers in humans that can give a functional readout in a short timeframe;

• test drugs aimed at upstream processes before irreversible downstream damage;

• find more potent drugs without dose-limiting toxicity; and

• use combination therapies and start them before symptoms appear.

In the case of psychiatric disorders and Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria, John Krystal, Robert L. McNeil, Jr., professor of translational research and chair of the department of psychiatry at Yale University School of Medicine, commented there needs to be a willingness to explore subgroups of patients with mechanistic homogeneity. Connecting genetic networks and quantitative traits might build the case for proof-of-concept studies; the studies would be based on quantitative information rather than behavioral readouts and could be tested in specific patient groups. In summary, Chas Bountra, head of the Structural Genomics Consortium and professor of translational medicine at the University of Oxford, noted that unless biomarkers are discovered, the field faces continued high failure rates in Phase IIa clinical trials. At this stage of drug development, the majority of novel compounds fail (Paul et al., 2010). As a result, target validation, or invalidation, is delayed.

PORTFOLIO ASSESSMENT TOOL FOR TARGET VALIDATION AND QUALIFICATION

Merchant provided her perspective on factors considered when making investment decisions in neuroscience portfolios. Merchant began by noting that attrition in drug development is very high in Phase II studies, with an approximate rate of 66 percent. Major causes of failure in Phase II are related to inadequacies in efficacy, safety, the overall strategic plan, and bioavailability and pharmacokinetic properties (Paul et al., 2010). High attrition underscores the need for better target validation and biomarkers to avoid selection of the wrong target, the wrong patient population, or the wrong dose. Merchant suggested that target validation is best accomplished in humans, while animal models are important for target qualification, which is a step in the process to determine the scientific validity and safety of a target (see Figure 4-1).

Target Validation

There are three major components of target validation using human data: tissue expression, genetics, and clinical experience. For each of these components, several metrics might guide decisions to invest in a particular therapy (see Figure 4-1). Merchant identified specific metrics that might apply in ascending order of priority (see Table 4-1).

Merchant noted that each step toward target validation provides an increasing level of importance on how to interpret data and build confidence in what projects to bring forward. All the components—tissue expression, genetics, and clinical experience—can inform disease pathways. It is an iterative learning problem. How can what is learned from tissue expression integrate with genetics and integrate with the clinic?

Download

Copyright Disclaimer:
This site does not store any files on its server. We only index and link to content provided by other sites. Please contact the content providers to delete copyright contents if any and email us, we'll remove relevant links or contents immediately.