AVP-786 Relieves Agitation in Alzheimer’s Patients, Preliminary Trial Results Show

AVP-786, an investigational oral therapy, significantly relieved agitated behaviors among patients with Alzheimer’s dementia, according to preliminary data from a worldwide Phase 3 trial by Avanir Pharmaceuticals.

The treatment candidate was designed as a second-generation version of Nuedexta, a two-drug combo approved for pseudobulbar affect. AVP-786 is a combination of dextromethorphan and quinidine — like Nuedexta — but it also contains deuterium, an isotope of hydrogen.

Dextromethorphan is an over-the-counter cough suppressant which affects brain signals that trigger the cough reflex. Quinidine is a medicine that affects the way the heart beats and is used to treat abnormal heart rhythms. It also works by increasing the amount of dextromethorphan in the body. Deuterium is believed to leave a compound’s mechanism of action unchanged but can slow its processing in the liver, thereby prolonging its exposure in the blood and reducing side effects.

AVP-786 was granted Fast Track designation in 2015 by the U.S. Food and Drug Administration (FDA) for the treatment of agitation in patients with Alzheimer’s. Avanir is developing it for this indication, as well as for schizophrenia and other behavioral disorders.

The company has announced the initial results from the first study of four ongoing Phase 3 clinical trials involving Alzheimer’s patients. Three of the trials are currently recruiting patients.

The trial (NCT03393520), which is currently recruiting, assessed the efficacy, safety, and tolerability of AVP-786 to treat moderate-to-severe agitation associated with Alzheimer’s dementia. Approximately 412 participants are expected to enrol, from 50–90 years old, at about 90 centers in the U.S., Australia, South Africa, and Europe (Bulgaria, Hungary, Italy, Poland, Spain, and the U.K.). The study includes patients living in either community or institutional care settings.

In the first phase, participants are randomized to receive one of two doses of AVP-787 or a placebo. The treatment is administered orally twice-daily for six weeks.

In the second phase, those randomized to the therapy remain on the same regimen for six more weeks. Patients who received a placebo and did not respond to it are randomized again to either AVP-787 or a placebo, for an additional six weeks. Placebo responders are excluded from this stage.

The main goal will be to determine the change from baseline (the beginning of the study) to week 12 (total treatment period) in the Cohen-Mansfield Agitation Inventory, which is used to rate the frequency of a patient’s verbally and physically agitated behaviors, based on the caregiver’s observations.

One of the doses tested (its amount was not disclosed) led to a significant reduction in this score, reflecting diminished agitation in patients, according to Avanir.

The treatment’s most common side effects (prevalent in more than 5% of the patients) were falls, urinary tract infection, headache, and diarrhea. Overall mortality was low, and the casualties that occurred were not considered related to the treatment.

Two Phase 3 trials (NCT02442765, NCT02442778) are also currently ongoing, as well as a long-term extension study that is open to patients who participated in these two trials or in an earlier Phase 2 study (NCT01584440).

“These initial data from the first phase 3 study are encouraging and we look forward to continuing to evaluate AVP-786 for the treatment of moderate-to-severe agitation in patients with Alzheimer’s dementia as the clinical program progresses,” Sanjay Dubé, MD, Avanir’s vice president of research and development, and head of clinical development and scientific strategy, said in a press release.

As there are no FDA-approved treatments for agitation in patients with Alzheimer’s dementia yet, any advancement in the management of this problem “would help to bridge the treatment gap in these patients,” Dubé added. “We will continue to analyze the full set of data from this first study and plan to communicate more about the results at the time of publication in a peer-reviewed journal.”