Improving and Accelerating Therapeutic Development for Nervous System Disorders Workshop Summary (2014) / Chapter Skim
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4 Target Validation
4 Target Validation
Pages 41-50
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From page 41... ...
If a target cannot be validated, then it will not proceed in the drug development process. Early validation of targets along with improved biomarkers were two opportunities discussed by Samuel Gandy, professor in the departments of neurology and psychiatry and associate director of Mount Sinai's Alzheimer's Disease Research Center, and Reisa Sperling, director of the Center for Alzheimer's Research and 41
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From page 42... ...
a biomarker for monitoring therapeutic efficacy or target modulation is not entirely perfected. However, Gandy noted that even though there is much interest in oligomeric β-amyloid because some experts believe it may be the toxin associated with many degenerative diseases, it is not a wellestablished drug target, and there are currently limited biomarkers for this peptide (Reitz, 2012)
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From page 43... ...
They found that an agonist for Group II metabotropic glutamate receptor also selectively produced β-amyloid42 in the synaptosomes. Having established the signaling pathway, they then sought to block β-amyloid42 production by pretreatment with a Group II metabotropic glutamate receptor antagonist, which was successful in inhibiting generation of β-amyloid42 (Kim et al., 2010)
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From page 44... ...
functional connectivity, or fc-MRI -- could be studied along with PET amyloid imaging to determine the benefits of anti-β-amyloid therapies. For example, fMRI and PET amyloid imaging were combined to study asymptomatic and minimally impaired older individuals to demonstrate that amyloid pathology was linked to neural dysfunction of the default network in cortical regions implicated in AD (Sperling et al., 2009)
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From page 45... ...
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.
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From page 46... ...
How can what is learned from tissue expression integrate with genetics and integrate with the clinic? Increasing Importance Clinical Translational experience endpoints Genetically Genetics engineered models Tissue expression Pharmacology Human Data Preclinical Data Target Validation Target Qualification FIGURE 4-1 Major components of target validation and qualification.
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From page 47... ...
TARGET VALIDATION 47 TABLE 4-1 Metrics of Target Validation Components of Metrics Target Validation Increasing Confidence Pharmacology Target protein Target mRNA Target protein is expressed or expression is expression is active in the altered by the altered in desired organ/ disease disease/tissue subregion/cell types Genetically Genetic Polygenic Monogenic Engineered association with association with association with Models disease occurs modest effect large effect size in small, under- size and known and known powered, or function of the function of gene non-replicated variant, or variant Increasing Importance studies without association with knowing the common, low function of the risk variant in a variant gene that also has rare variant associated with large effect size, or in the best case Translational Clinically Clinically At least one Endpoints relevant effica- relevant effica- ligand with an cy observed in cy is observed analogous mode a small trial, but with at least one of action on the knowledge of ligand with a target/target engagement of different mode pathway has specific target/ of target modu- "approvable" pathway is lation or with efficacy in the lacking two ligands on indication of biomarkers pre- interest and viously shown robust evidence to predict of target efficacy engagement NOTE: mRNA = messenger ribonucleic acid. SOURCE: Merchant presentation, April 9, 2013.
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From page 48... ...
However, Krystal said researchers cannot go directly into the patient population without knowing whether the biology of the animal models applies to healthy humans. The drug development process is exploratory; it is an iterative process of testing specific mechanistic hypotheses across cellular and animal studies, healthy human subjects, and clinical trials.
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From page 49... ...
SOURCE: Merchant presentation, April 9, 2013.
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