Alzheimer’s Agitation Drug AVP-923 Clears Next Hurdle

Agitation and aggression are among the most disruptive symptoms of Alzheimer’s. They effect 60% of people living at home and 80% of people in care facilities. Learn about AVP-923 as it gets one step closer to availability.

ALISO VIEJO, Calif. — Avanir Pharmaceuticals, Inc. announced that results from the Phase II study evaluating AVP-923 for the treatment of agitation in patients with Alzheimer’s disease were presented at the 2014 American Neurological Association Meeting.

In this study, AVP-923 showed a clinically meaningful and statistically significant improvement in agitation on the primary endpoint and a majority of the secondary endpoints.

Why Is This Important?

“Agitation and aggression in Alzheimer’s disease are among the most disruptive of dementia-related neuropsychiatric symptoms and leading causes of institutionalization,” said Jeffrey Cummings, MD, director of theCleveland Clinic Lou Ruvo Center for Brain Health, chair of the study steering committee and a paid member of Avanir Pharmaceuticals Advisory Board, Inc. “These study results are encouraging for Alzheimer’s patients suffering from agitation and their caregivers.” 

How Big is the Breakthrough?

“We are highly encouraged by these data showing a nearly 50 percent reduction in agitation for patients treated with AVP-923. In addition, clear improvements in global measures of agitation, as assessed by both clinicians and patients/caregivers, indicate the improvement was deemed clinically meaningful,” said Joao Siffert, MD, chief medical officer for Avanir. “We are committed to working with regulatory agencies in the United States and the EU with the goal to advance the program and make the treatment available as early as possible, upon approval, for patients with Alzheimer’s disease who have agitation.”

How was the Study Designed?

The 10-week randomized, double-blind, placebo-controlled, multicenter Phase II study evaluated the efficacy, safety and tolerability of AVP-923 for the treatment of agitation in Alzheimer’s patients. A total of 220 Alzheimer’s patients in the United States were enrolled. Eligible patients were initially randomized in a 3:4 ratio to receive either AVP-923 (dose escalated from DM 20mg/Q 10mg to DM 30mg/Q 10mg) or placebo.

The main efficacy measure was the agitation/aggression domain of the Neuropsychiatric Inventory (NPI). Secondary outcome measures included global assessments of disease severity, other neuropsychiatric symptoms, cognition, activities of daily living, quality of life and caregiver strain. Standard safety assessments were also conducted.

Who is Effected by Agitation in Alzheimer’s Disease?

An estimated 6 million Americans have Alzheimer’s, a number that has doubled since 1980 and is expected to be as high as 16 million by 2050. Alzheimer’s disease is generally characterized by cognitive decline, impaired performance of daily activities, and behavioral disturbances. Behavioral and psychiatric symptoms develop in as many as 60% of community-dwelling dementia patients and in more than 80 percent of patients with dementia living in nursing homes. Dementia-related behavioral symptoms, including agitation, can be extremely distressing to the individual, the family and caregivers. These behavioral disturbances have been associated with more rapid cognitive decline, institutionalization and increased caregiver burden.

Details About the Agitation Drug AVP-923

AVP-923 is a combination of two well-characterized compounds, the active CNS ingredient dextromethorphan hydrobromide (an uncompetitive NMDA receptor antagonist, sigma-1 receptor agonist and inhibitor of the serotonin transporter [SERT] and norepinephrine transporter [NET]) plus low-dose quinidine sulfate (a CYP2D6 enzyme inhibitor), which serves to increase the bioavailability of dextromethorphan. AVP-923 is known to have certain cardiovascular risks and drug-drug interactions. Patients with history of certain cardiovascular risks and on certain drugs were excluded from the study. AVP-923 is an investigational drug not approved by the FDA for the treatment of agitation in Alzheimer’s disease.

Study Details

Key highlights from the poster were:

• AVP-923 showed a statistically significant benefit on the agitation/aggression domain of the Neuropsychiatric Inventory (NPI) (primary endpoint; p=0.00008) 
• The NPI agitation/aggression score was reduced by 3.3 points from baseline in AVP-923 treated patients at week five (stage 1; p=0.0002 v. placebo) and was reduced by 2.0 points in stage 2 (p=0.021)
• The change in the NPI agitation/aggression score corresponds to a mean (SD) reduction from baseline of 47 percent (43.1 percent) for AVP-923 vs. 22 percent (50.8 percent) for placebo in Stage 1, and 26 percent (67.5 percent) for AVP-923 vs. 6.7 percent (77.9 percent) for placebo in Stage 2.
• Treatment benefit with AVP-923 was evident at week one and was sustained for the duration of the 10-week study
• AVP-923 also demonstrated significant improvements versus placebo on the following outcomes: NPI total score (p=0.014), NPI4A (p=0.001), NPI4D (p<0.001), clinical global impression of change-agitation (p=0.0003), patient global impression of change (p=0.001) and measures of caregiver burden (p≤0.05)
• AVP-923 was generally safe and well-tolerated and associated with a low rate of discontinuation from the study (11.8 percent)
• Treatment with AVP-923 was not associated with cognitive decline or somnolence