The "five-star matrix" for patient-centric drug discovery and development in neuroscience

Progress in understanding human biology has revealed potential therapeutic targets for brain disorders. Yet, the discovery of new neuroscience drugs is often hampered by the lack of precise translation tools and disease models, resulting in high preclinical and clinical failure rates. To improve success, robust translational foundations linking pharmacological targets to disease phenotypes are essential. The "five-star matrix" offers a comprehensive framework for translational drug discovery, consisting of five "dimensions" (biodistribution, target binding/occupancy, proximal effect, biological effect, and disease effect) and five "systems" (biochemical, cellular, ex vivo, preclinical, and clinical). By identifying translatable biomarkers across these dimensions and systems, researchers can test hypotheses from early target assessments to clinical studies. Although linking pathogenic processes to disease-relevant endpoints is challenging, applying the five-star matrix across neuroscience projects fosters collaboration to develop holistic, patient-centric strategies with clear deliverables toward clinical proof of concept. Case studies illustrate the rationale for the five-star matrix in creating a translational continuum from bench to bedside.