True alignment of preclinical and clinical research to enhance success in CNS drug development: a review of the current evidence

Abstract

Central nervous system pharmacological research and development has reached a critical turning point. Patients suffering from disorders afflicting the central nervous system are numerous and command significant attention from the pharmaceutical industry. However, given the numerous failures of promising drugs, many companies are no longer investing in or, indeed, are divesting from this therapeutic area. Central nervous system drug development must change in order to develop effective therapies to treat these patients. Preclinical research is a cornerstone of drug development; however, it is frequently criticised for its lack of predictive validity. Animal models and assays can be shown to be more predictive than reported and, on many occasions, the lack of thorough preclinical testing is potentially to blame for some of the clinical failures. Important factors such as translational aspects, nature of animal models, variances in acute versus chronic dosing, development of add-on therapies and understanding of the full dose-response relationship are too often neglected. Reducing the attrition rate in central nervous system drug development could be achieved by addressing these important questions before novel compounds enter the clinical phase. This review illustrates the relevance of employing these criteria to translational central nervous system research, better to ensure success in developing new drugs in this therapeutic area.

Comparative Pro-cognitive and Neurochemical Profiles of Glycine Modulatory Site Agonists and Glycine Reuptake Inhibitors in the Rat: Potential Relevance to Cognitive Dysfunction and Its Management

“…Taken together, this study provides extensive, consistent complimentary and neurochemical evidence that pharmacological modulation of glycine site activity on NMDA receptors can improve cognitive dysfunction in rats, but similar robust positive observations have not been reported in schizophrenia trials using glycine site agonists [17,26]. Poor translation may result from desensitisation of the glycine site as seen with repeated D-cycloserine [102], producing NMDA receptor internalisation [103] which might not occur with acute administration used in most animal studies. Second, the glycine full and partial agonists appear to have differential affinity for the different NMDA receptor subunit compositions found at pre-and post-synaptic sites in the cortex [104] that could affect their relative clinical effectiveness.…”

“…As a note of caution both social recognition and NOR tasks rely on spontaneous preference for novelty and their predictive validity to cognitive impairment in schizophrenia requires further confirmation [39,100,101]. For instance, drugs with different pharmacological mechanisms, such as α7-nicotinic agonists and 5-HT 6 receptor antagonists produced much smaller improvements in cognition in schizophrenia clinical trials than would have been predicted from preclinical data, even in studies using disease models rather than normal animals.…”

Longitudinal changes in EEG power, sleep cycles and behaviour in a tau model of neurodegeneration.

“…The changes in open field locomotor activity and T-maze performance we observe are similar to those previously reported (19) (35). Data from this study provides further evidence that the rTg4510 tauopathy model can be useful in the investigation of tau related functional deficits.…”

Bundling arrows: improving translational CNS drug development by integrated PK/PD-metabolomics

“…Metabolomics was found useful to understand species differences with regard to pathology [72]. As such, it has potential to translate the pathology-dependent pharmacology from animal to men [106].…”