AVP-786 as a promising treatment option for Alzheimer’s Disease including agitation

ABSTRACT

Introduction

To date, there is no FDA-approved treatment for agitation in Alzheimer’s disease (AD). Medications currently used off-label have modest clinical efficacy and serious side effects.

Areas covered

The authors review the pharmacology, mechanism of action, pharmacokinetics, efficacy, safety and tolerability data of AVP-786, for the treatment of agitation in AD.

Expert opinion

AVP-786, the deuterated form of dextromethorphan/quinidine (AVP-923) which is an approved treatment for Pseudo-Bulbar Affect, emerges as a promising and safe treatment for agitation in AD. Deuteration is an innovative technology that accelerates drug development by conducting faster and less costly clinical trials. No phase II trial was conducted with AVP-786 for the treatment of agitation in AD; the decision to expedite the development of this drug was based on a successful phase II study with AVP-923. Phase III trials with AVP-786 (TRIAD-1 and TRIAD-2) showed mixed findings probably due to the difference in study design. Future phase III studies should use innovative study designs such as the Sequential Parallel Comparison Design to mitigate high placebo response, and the Cohen-Mansfield Agitation Inventory for agitation assessment. They should also include positron emission tomography studies to assess occupancy of various receptors in the brain after AVP-786 is administered.

KEYWORDS:

• Agitation
• alzheimer’s Disease
• avp-786
• deuteration
• dextromethorphan
• efficacy
• pharmacology
• quinidine
• safety
• tolerability

Declaration of interest

G Grossberg is a consultant for Acadia, Alkahest, Allergan, Avanir, Axsome, Bioxcel, GE Healthcare, Genentech, Karuna, Lundbeck, Novartis, Otsuka, Roche and Takeda. He is also on the safety monitoring committee of Avanex, Erydel and Newron as well as the dating monitoring committee of ITI Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

One referee is an employee of Chiesi Farmaceutici while another referee declares having colleagues who work directly on a clinical trial of this drug. Another referee is an employee of TaurRx Therapeutics Ltd. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Box 1. Drug summary

Article highlights

• Symptomatic medications used off-label to treat agitation in Alzheimer’s disease including antipsychotics and antidepressants have a modest efficacy profile and serious side effects.

• AVP-786, the deuterated form of dextromethorphan/quinidine emerges as a promising and relatively safe treatment option for agitation in Alzheimer’s disease.

• There has been only one successful phase III randomized controlled trial with this compound. Further phase III studies are thus required to replicate these positive findings.

• More research is needed to better understand the pharmacodynamics of this compound as well as optimal doses to be used in human clinical trials.

• There is a need to critically review clinical trial data on this compound after the full set of data or results are published in a peer-reviewed journal.