AXS-05: an investigational treatment for Alzheimer’s disease-associated agitation

ABSTRACT

Introduction

Agitation is common in patients with Alzheimer’s disease (AD). Although nonpharmacologic de-escalation strategies are recommended as first-line treatment, medication is often needed to treat agitation. Currently, there are no FDA-approved medications for this indication. Psychotropics used to treat agitation include antipsychotics, which are notable for their efficacy but also their potential to cause serious side effects. AXS-05, a combination of dextromethorphan and bupropion, is currently being investigated for this indication.

Areas covered

This review will discuss the pharmacology of AXS-05 and available clinical trial results from completed Phase I and Phase II/III studies assessing the potential for this compound to treat agitation in patients with AD. Ongoing research investigating AXS-05 for this indication will also be highlighted. Resources used for this review include PubMed, Embase, clinicaltrials.gov, and literature available on the manufacturer’s website.

Expert opinion

Early released clinical trial data indicate that AXS-05 may be a useful option to treat agitation in patients with AD and that it appears to be generally well tolerated. AXS-05 may be especially helpful for patients with comorbid depression, when considering available data from separate phase III studies assessing the efficacy and safety of this compound in the treatment of depression.

KEYWORDS:

• Agitation
• aggression
• Alzheimer’s disease
• bupropion
• dextromethorphan
• pharmacodynamics
• pharmacokinetics

Article highlights

• Agitation is common in patients with Alzheimer’s Disease, and although non-pharmacologic de-escalation techniques are recommended as first-line treatment, they can be inadequate when used alone.

• Current medications used for the treatment of agitation in patients with Alzheimer’s disease include antipsychotics, antidepressants, and benzodiazepines, but none have been FDA-approved for this specific purpose, and there is an unmet need for development of safer alternatives.

• AXS-05 is a novel formulation of dextromethorphan and bupropion, to be dosed twice daily, that is being investigated for the treatment of agitation in patients with Alzheimer’s Disease.

• Bupropion is used in this compound primarily as a CYP 2D6 inhibitor to boost concentrations of dextromethorphan, which has multiple actions such as sigma-1 agonism, uncompetitive antagonism of N-methyl-D-aspartate (NMDA) receptors, and serotonin transporter inhibition.

• Available results from clinical trials suggest that AXS-05 is effective in reducing agitation and it is generally well tolerated, with somnolence and dizziness being the side effects reported in at least 5% of study participants.

• Pending the results of ongoing phase III clinical trials, AXS-05 may be an option for patients with Alzheimer’s Disease and agitation.

Declaration of interest

L Citrome is a consultant to AbbVie/Allergan, Acadia, Adamas, Alkermes, Angelini, Astellas, Avanir, Axsome, BioXcel, Boehringer Ingelheim, Cadent Therapeutics, Cerevel, COMPASS, Eisai, Enteris BioPharma, HLS Therapeutics, INmune Bio, Impel, Intra-Cellular Therapies, Janssen, Karuna, Lundbeck, Lyndra, Medavante-ProPhase, Merck, Neurocrine, Novartis, Noven, Otsuka, Ovid, Praxis, Relmada, Reviva, Sage, Sunovion, Supernus, Teva, University of Arizona, and one-off ad hoc consulting for individuals/entities conducting marketing, commercial, or scientific scoping research; speaker for AbbVie/Allergan, Acadia, Alkermes, Angelini, Eisai, Intra-Cellular Therapies, Janssen, Lundbeck, Neurocrine, Noven, Otsuka, Sage, Sunovion, Takeda, Teva, and CME activities organized by medical education companies such as Medscape, NACCME, NEI, Vindico, and Universities and Professional Organizations/Societies; owns stocks (small number of shares of common stock) in Bristol-Myers Squibb, Eli Lilly, J & J, Merck, Pfizer purchased >10 years ago, and stock options in Reviva; and receives royalties from Wiley (Editor-in-Chief, International Journal of Clinical Practice, through end 2019), UpToDate (reviewer), Springer Healthcare (book), and Elsevier (Topic Editor, Psychiatry, Clinical Therapeutics). K Ward has participated in an advisory board for BioXcel.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This review was not funded.