Development of a disease‐modifying treatment for Alzheimer's disease: Alzhemed

e n Alzheimer’s disease (AD) treatments currently available n the United States are neurotransmitter-based intervenions, targeting cholinergic or glutamatergic synaptic activty. They are generally assumed to provide symptomatic enefits without altering the underlying pathophysiology of he disease. Recently, there have been growing efforts to evelop treatments directed not at neurotransmitter systems, ut rather at the amyloid and tau cascades that are believed o represent the key pathophysiology of AD. Several such nterventions are now in Phase II and III clinical testing [1]. ecause, in general, such interventions do not provide hort-term symptomatic benefits, trial design must be based n demonstration of a slowed rate of cognitive and clinical ecline; this has significant implications for the number of ubjects, duration of treatment, and selection of outcome easures. For example, a trial duration of 12 to 26 weeks, enerally sufficient to demonstrate the impact of a cholineserase inhibitor or N-methyl-D-aspartate (NMDA) antagoist that improves cognition, is not likely to be sufficient to emonstrate a reduced rate of cognitive decline as a result of n anti-amyloid intervention. Thus, most trials of anti-amyoid and anti-tau agents last at least 12 months and often 18 o 24 months. Demonstration of clinical efficacy in a Phase I study of limited duration may not be feasible; use of urrogate markers of efficacy in Phase II studies may be ecessary. If treatment with a putative disease-modifying gent shows a beneficial effect on cognition and function or lobal clinical status in a long term trial, can the sponsor laim that the treatment modifies the course of AD? Prior uidance from the US Food and Drug Administration FDA) has indicated that trials should be designed to show n impact on the disease process; that is, a second randomzation should be used to show that placebo-treated subjects ater given active treatment do not “catch up” to those