22 Sep 2015

In today’s JAMA Neurology, researchers led by Jeffrey Cummings at the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas formally published the results of a 10-week Phase 2 trial of Avanir Pharmaceuticals’ AVP-923 to treat agitation in Alzheimer’s disease. As previously reported at the 2014 meeting of the American Neurological Association in Baltimore, the drug met its endpoints, dampening agitation in the majority of the patients who took it (see Oct 2014 conference news).

The drug, trade named Nuedexta, is a combination of dextromethorphan hydrobromide and quinidine sulfate. The former is the active ingredient in cough syrup and acts on several neurotransmitter systems, including glutamate, serotonin, and norepinephrine, while the latter ingredient slows the metabolism of dextromethorphan, potentiating its effects. The drug is approved to treat pseudobulbar affect, a condition present in some neurodegenerative disorders that is marked by uncontrollable bouts of laughing or crying.

In an accompanying commentary, Clive Ballard, Samantha Sharp, and Anne Corbett at King’s College London expressed cautious optimism about the drug, though they noted that longer studies will be needed to confirm the results. “The magnitude of benefit for reducing agitation/aggression observed with dextromethorphan-quinidine compares favorably with previous studies … There is a reasonably strong case to prioritize dextromethorphan-quinidine as an off-label treatment for agitation,” they wrote.

In a multi-site study of 220 patients diagnosed with probable AD according to 2011 NIA-AA criteria, treatment roughly halved the severity of agitation as measured by the Neuropsychiatric Inventory Agitation/Aggression scale. Physicians agreed that patients had improved on Clinical Global Impression of Change scales, and caregivers rated their stress as lower. About two-thirds of patients responded to the drug, compared to less than half of the placebo group. Placebo responses occur commonly in treatment of neuropsychiatric symptoms.

The drug had side effects. Dizziness, falls, diarrhea, and urinary tract infections were the most common, occurring in 5 to 8 percent of participants. These effects match the known safety profile of the drug. According to the paper, treated participants exhibited no signs of sedation, cardiac problems, or declining cognition, which have plagued other medications tested for agitation (e.g. Feb 2014 news). According to Cummings, a Phase 3 study has begun enrolling.—Madolyn Bowman Rogers