Translational Medicine Strategies in Alzheimer's Disease Drug Development

Alzheimer's disease (AD) represents a slowly progressing neurodegenerative disorder with complicated, multifactorial pathophysiology that remains poorly understood. The past two decades of AD research have been marked by numerous attempts at developing therapies, which have resulted in five approved agents and multiple failures. All of the five agents represent symptomatic treatments. Disease-modifying drugs that slow down neurodegeneration and clinical progression have been an area of particular interest and active research but have been associated with uniform failure. The last 16 putative disease-modifying agents failed to meet the primary efficacy objective in Phase 3 trials, the most resource intense and expensive stage of development. While these failures in part are due to our incomplete understanding of the underlying pathophysiology of the disease, they also reflect many challenges with designing and executing clinical development programs for such potential disease-modifying therapies. In the disease modification area, the interest has moved to patients with early stages of AD, such as mild cognitive impairment (MCI) due to AD or prodromal AD and mild AD dementia, when neuronal damage is still limited and a clinical meaningful change in the underlying neurodegenerative process and the corresponding clinical state is still possible. At the same time, these early disease stages are characterized by difficult to identify heterogeneous target populations, slow disease progression, and uncertain outcome measures that often lack the necessary sensitivity to establish clinical efficacy. Putative disease-modifying agents have been moving from small Phase 1 studies to large and long Phase 2b/3 trials in which failure is particularly costly and may be due to deficiencies in designs and not necessarily inherent lack of efficacy for an investigational agent. In this chapter, we address issues of trial efficiency that have become key to the development of AD therapies and, particularly, disease-modifying therapies. We review innovative trial designs and new clinical outcomes, which the AD field is bringing forward. We examine each of these components by focusing on select examples from recently completed or ongoing development programs, including more flexible adaptive trial designs and new clinical outcomes, such as composite scores and performance-based functional tools. These new methodologies hold the promise for trials that are likely to obtain evidence of success or failure earlier in a development program and to provide more robust investigations of putative therapeutic agents.