AVP-786 Relieves Agitation in Alzheimer’s Patients, Preliminary Phase 3 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 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.

AVP 786 is a combination product of deudextromethorphan hydrobromide and quinidine sulfate. Dextromethorphan is the component acting on the central nervous system (brain and spinal cord). It is also an over-the-counter cough suppressant that affects brain signals that trigger the cough reflex. Quinidine sulfate is a medicine that affects the way the heart beats and is used to treat abnormal heart rhythms. In this formulation, in a low dose, it helps increase the availability of dextromethorphan in the body by slowing its metabolism.

It was given Fast Track designation in 2015 by the U.S. Food and Drug Administration (FDA) to possibly treat agitation in patients with Alzheimer’s. Avanir is developing it for this indication, as well as for schizophrenia and other behavioral disorders.

These initial results are from the first of four Phase 3 clinical trials involving Alzheimer’s patients. The 12-week study, which involved 410 patients at 80 sites across the U.S., recently concluded.

The two-part trial (NCT02442765) assessed the efficacy, safety, and tolerability of AVP-786 to treat moderate-to-severe agitation associated with Alzheimer’s dementia. Enrolled patients, 50–90 years old, included those living in either community or institutional care settings.

In the first part, patients were randomized to one of two doses of AVP-787 or a placebo. The treatment was administered orally twice-daily for six weeks.

In the second, those randomized to the therapy remained on their assigned dose for six more weeks. Patients who received a placebo and did not respond to it were randomized again to either AVP-787 or a placebo for the additional six weeks. Placebo responders, which can be seen in clinical studies, were excluded from this stage so as not to impact analyses of treatment effects.

The main goal was 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 caregiver observations.

One of the doses tested (its amount was not disclosed) led to a significant reduction in this score, reflecting diminished agitation, Avanir reported. The other dose did not.

Most common side effects seen in treated patients (prevalent in more than 5%) were falls, urinary tract infection, headache, and diarrhea. Overall mortality was low and not considered related to the treatment.

Two other Phase 3 trials (NCT02442778, NCT03393520) are ongoing and enrolling eligible patients; one is at sites across the U.S. and in Canada, and the other is largely in Europe, with one site in Michigan. The third trial is a long-term extension study (NCT02446132) open to patients in North America who participated in previous Phase 3 studies, and 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.”