Drug discovery and development: Biomarkers of neurotoxicity and neurodegeneration

Abstract

The discovery and development of new drugs are vital if we are to improve and expand treatment options available to improve outcomes for patients. Overall, therapeutic strategies fall into two broad categories: small molecules and biologics, although more recently there has been a growth in novel platforms such as miRNAs and oligonucleotides. On average, the development of a small molecule drug takes around 12 years and costs around $50m. Despite this huge investment of time and money, attrition remains a major challenge and very few molecules actually make it through to the market. Here, we look at reasons for attrition in the small molecule field with a focus on neurotoxicology and efforts being made to improve success via the development of imaging and fluidic biomarkers. We also look at learnings from other models of CNS damage and degeneration such as Parkinson’s disease, traumatic brain injury, and multiple sclerosis since these may offer the opportunity to improve tools available to nonclinical toxicologists in the early detection of potential neurotoxicity. Reciprocally, learnings from studies of animal neurotoxicity may offer better ways to potentially monitor patients during clinical development of new drugs for neurodegeneration. Impact statement: Attrition in drug discovery and development remains a major challenge. Safety/toxicity is the most prevalent reason for failure with cardiovascular and CNS toxicities predominating. Non-invasive biomarkers of neurotoxicity would provide significant advantage by allowing earlier prediction of likely neurotoxicity in preclinical studies as well as facilitating clinical trials of new therapies for neurodegenerative conditions such as Parkinson’s disease (PD) and multiple sclerosis (MS).