AVP-786 is an oral, investigational therapy being developed by Avanir Pharmaceuticals to treat agitation in Alzheimer’s disease patients. It is designed to be a second-generation version of Nuedexta, an approved treatment for Alzheimer’s and other neurological disorders also by Avanir.
How AVP-786 works
Dextromethorphan is an agent that affects signaling in the brain and triggers the cough reflex. It is usually used to treat coughing.
Quinidine affects the way the heart beats, and is used to help people with certain heart rhythm disorders. It also works by increasing the amount of dextromethorphan in the body.
The addition of deuterium into the dextromethorphan molecule, in conjunction with quinidine, is thought to reduce the metabolism of dextromethorphan in the liver, prolonging its exposure in the blood.
The exact mechanism of action by which AVP-786 reduces agitation in Alzheimer’s patients is not known. However, scientists think that its penetration into the brain leads to the activation and repression of certain neuronal pathways, which help to ease agitation.
AVP-786 in clinical trials
The safety, tolerability, and pharmacokinetics (how the drug is processed in the body) of AVP-786 were first assessed in a Phase 1 clinical trial (NCT01787747) in healthy volunteers. Although the results of the trial were not published, Avanir announced that the medicine successfully replicated the blood levels of Nuedexta, but with a substantially lower dose of quinidine.
Another Phase 1 trial (NCT02174835) compared the safety, tolerability, and pharmacokinetics of multiple doses of AVP-786 and Nuedexta in healthy volunteers. The study was completed in 2014, but results have not been published.
The effectiveness, safety, and tolerability of AVP-786, as an oral capsule, in treating moderate-to-severe agitation in Alzheimer’s patients were evaluated in a Phase 3 clinical trial called TRIAD-1 (NCT02442765). A second and similar Phase 3 study, called TRIAD-2, (NCT02442778) is not expected to end until October 2019.
The primary outcome for both trials is the Cohen Mansfield Agitation Inventory (CMAI), which assesses the frequency of agitated behaviors in patients.
TRIAD-1 enrolled 410 people with agitation secondary to Alzheimer’s dementia, and TRIAD-2 enrolled 522 patients with the same diagnosis. Avanir announced results of the TRIAD-1 trial in March 2019. This study investigated two different doses of AVP-786 using a Sequential Parallel Comparison Design (SPCD) and the CMAI. Only one dosage showed statistical improvement on the CMAI scale. The other showed improvement, but not enough to be scientifically significant. More detailed results are expected after further analysis of the data.
A long-term, Phase 3 extension study (NCT02446132) of AVP-786 is recruiting the roughly 700 people who took part in the TRIAD 1 and 2 studies, plus those from a Phase 2 trial (NCT01584440) investigating Nuedexta. In this 52-week extension trial, all patients will be given either a low or a high dose of AVP-786. The trial is enrolling at some 170 sites across the U.S., and in Canada and Hungary, and is expected to be completed in June 2022.
An international Phase 3 clinical trial (NCT03393520) is also recruiting 412 people with moderate-to-severe agitation secondary to Alzheimer’s dementia at locations across the U.S., Europe, Australia, and South Africa. (Enrollment sites and contact information are available here.) Like the TRIAD trials, patients will be assigned to one of two different AVP-786 doses, or placebo, but over a 12-week period. Its primary goal is changes in the CMAI composite score from baseline (study start) to week 12. It is expected to finish in June 2021.
AVP-786 was granted a fast track designation by the U.S. Food and Drug Administration (FDA) in 2015 as a potential treatment of agitation in Alzheimer’s patients. This designation works to speed the development and review of therapies for serious diseases with a high unmet medical need.
Last updated: August 17, 2019
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