Standard of care treatments for neurological disorders like Parkinson’s still rely on therapeutic principles established over 50 years ago,¹² and these treatments are largely not curative. This calls for examination of the paradigms in which drug discovery operates. We cannot answer questions that have not been asked in the first place, and drug discovery cannot identify targets that its biological paradigm does not recognise. The limited emergence of disease-modifying neurological therapies despite decades of intensive research and ever more advanced technology suggests that expanding the biological framework underpinning target discovery may be warranted.

Translational Bottleneck in Neurology

Every year, the pharmaceutical industry invests billions of dollars in discovering and developing treatments for disorders of the central nervous system (CNS)³. Yet, unlike oncology or cardiometabolic medicine, where new biological paradigms have repeatedly translated into first-in-class therapies, the neurodegenerative field has delivered remarkably few disease-modifying medicines. Only two novel disease-modifying treatments for Alzheimer’s disease have received traditional FDA approval in recent years, and both offer modest slowing of disease progression rather than truly halting or reversing the disease.⁴⁵ This suggests that the amyloid theory may not be wrong, but it may not be sufficient. The question therefore is not simply why drug candidates fail, but whether the biological frameworks used to identify therapeutic targets have become unnecessarily constrained.

Neurological drug discovery continually focuses on a limited number of targets. Take Parkinson’s for example, drug discovery in this indication has largely revolved around a relatively limited set of biological pathways, with successive programmes often refining rather than fundamentally expanding the therapeutic target landscape.⁶ While hundreds of compounds have entered development, many have converged on a comparatively small number of mechanistic hypotheses. Paradoxically, an over-reliance on established, albeit not necessarily most effective, biological pathways may increase rather than reduce risk across the field. As drug discovery efforts converge on a relatively narrow set of mechanisms, the failure of even a small number of these approaches can leave therapeutic pipelines with few fundamentally different alternatives.