Central nervous system drug development: an integrative biomarker approach toward individualized medicine

Abstract

Drug development for CNS disorders faces the same formidable hurdles as other therapeutic areas: escalating development costs; novel drug targets with unproven therapeutic potential; and health care systems and regulatory agencies demanding more compelling demonstrations of the value of new drug products. Extensive clinical testing remains the core of registration of new compounds; however, traditional clinical trial methods are falling short in overcoming these development hurdles. The most common CNS disorders targeted for drug treatment are chronic, slowly vitiating processes manifested by highly subjective and context dependent signs and symptoms. With the exception of a few rare familial degenerative disorders, they have ill-defined or undefined pathophysiology. Samples selected for treatment trials using clinical criteria are inevitably heterogeneous, and dependence on traditional endpoints results in early proof-of-concept trials being long and large, with very poor signal to noise. It is no wonder that pharmaceutical and biotechnology companies are looking to biomarkers as an integral part of decision-making process supported by new technologies such as genetics, genomics, proteomics, and imaging as a mean of rationalizing CNS drug development. The present review represent an effort to illustrate the integration of such technologies in drug development supporting the path of individualized medicine.

FIG. 1.

Toxicogenomics signatures of three hypothetical candidates for compound selection, showing clear toxicity for ZZZ003. This signature is observed in the GI tract after 1 day of treatment, and is reflected in the blood (see FIG. 2).

FIG. 2.

Hypothetical PCA analysis of blood samples showing a clear discrimination between the toxicological effect of ZZZ003 and the mechanistic effect of the two other compounds XXX001 and YYY002

FIG. 3.

Hypothetical PCA analysis of blood samples showing a clear dose effect between three different dosages of XXX001.

FIG. 4.

Dilution and correlation curve demonstrating the performance of Novachips at low RNA yields.

FIG. 5.

Pictures of scanned Novachips indicating the dilution of the fluorescent signals between 3 and 0.1 ng of input total RNA. However, the percentage of present genes with 0.1 ng is lower but not random.

FIG. 6.

Whole genome profiling of human CSF samples: Venn diagram showing the interindividual variability of three normal subjects, of whole genome profiling of human CSF samples.

FIG. 7.

A PET study with the NK₁ receptor-specific tracer ¹⁸F-SPARQ showing dose-dependent occupancy by the emesis drug aprepitant, a selective NK₁ antagonist. The first image on the left is pretreatment (baseline) showing highest uptake in striatum followed by cerebral cortex. With two increasing doses of aprepitant, a pronounced reduction in available NK₁ receptors is observed. The study suggested that over 90% receptor occupancy is required for a therapeutic effect.

FIG. 8.

The integrative approach. The sophisticated combination of clinical research, genetic, genomic, proteomic, imaging data, and information technologies is expected to revolutionize medical treatment allowing a better understanding of the molecular basis of neurological diseases, disease progression as well as patient stratification, increasing the chances of success of a given therapy and leading us toward personalized, or individualized medicine.