Abstract
Alzheimer’s disease is an important condition with a considerable and unmet disease burden in large need of continued research and more treatment options. The 5HT6 antagonists are a new class of medications to be offered. Because they are pro-cholinergic, these medications are to be used as adjuncts to acetylcholinesterase inhibitors (such as donepezil), further increasing acetylcholine in the central nervous system (CNS). Early trials of the 5HT6 antagonists showed improvements in cognition and activities of daily living when used as adjuncts to current therapies for Alzheimer’s dementia. However, recent phase III trials have failed to show a statistically significant improvement in cognitive function. This article will provide a comprehensive review of 5HT6 antagonists in drug development, including some that have been recently discontinued. We will discuss both the successes and failures of this drug class and provide rationale for their continued research and development.
Highlights
Alzheimer’s disease is a progressive neurodegenerative disorder affecting over 40 million people worldwide [1]
The progression of Alzheimer’s disease is associated with the development of anxiety, depression, and sleep disorders, so AVN-101 may offer the additional benefit of symptomatic relief from these associated mood disorders
This study evaluated the use of intepirdine 35 mg daily in patients with Alzheimer’s disease already taking stable doses of donepezil [20]
Summary
Alzheimer’s disease is a progressive neurodegenerative disorder affecting over 40 million people worldwide [1]. These drugs block the 5HT6 receptor, which leads to a decrease in striatal GABA interneurons. The progression of Alzheimer’s disease is associated with the development of anxiety, depression, and sleep disorders, so AVN-101 may offer the additional benefit of symptomatic relief from these associated mood disorders This makes it a good drug candidate for further research into mood disorders [10]. Avineuro Pharmaceuticals has discussed plans to begin clinical trials for its use in Alzheimer’s disease after phase II trials for schizophrenia showed positive effects on cognition. SAM-760 (synonyms: PF-05212377, WYE103760) SAM-760 is a selective 5HT6 antagonist It was developed as a follow-up drug to cerlapirdine after cerlapirdine failed to show clinical efficacy at any dose in phase II trials [6]. This regime showed a significant improvement in cognitive function as measured by ADAS-cog, thereby meeting the phase II
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