A New Drug to Calm Agitation, Uncontrollable Laughing and Crying, in Alzheimer’s?

Scientists do not know exactly how AVP-923 works for agitation. It is a stable combination of two old drugs: dextromethorphan hydrobromide, the active ingredient in cough medicines such as Robitussin, and the arrhythmia drug quinidine sulfate. The former is an uncompetitive antagonist of NMDA-type glutamate receptors and an agonist of the sigma-1 receptor, a protein chaperone that resides in the endoplasmic reticulum membranes. The latter blocks cytochrome P450 2D6, a liver enzyme that metabolizes dextromethorphan hydrobromide, increasing its plasma concentration (Cruz, 2013).

A previous Phase 3 trial reported that AVP-923 improved pseudobulbar affect in people with amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) (see Pioro et al., 2010). Trials are ongoing for neuropathic pain and for levodopa-induced movements in Parkinson’s, as well as for autism, migraine, and depression.

To see if AVP-923 treated agitation in Alzheimer’s, researchers at 44 sites, including Jeffrey Cummings of the Cleveland Clinic, Luo Ruvo Center for Brain Health in Las Vegas, enrolled 220 adults aged 50 to 90, all of whom had probable AD with clinical agitation. The researchers used a sequential, parallel comparison design developed for indications that are particularly prone to placebo effects (see Ivanova et al., 2011). These trials have two stages. Scientists first randomize subjects to receive drug or placebo. After some time, they separate the placebo group into those who improve and those who did not, and re-randomize them to receive either drug or placebo. This allows researchers to compare the two treatments among people who exhibit a minimal placebo response.

The researchers divided the double-blind trial into two five-week periods. For the first, 93 people were randomized to receive AVP-923 twice daily; 127 got placebo. Because this drug combination has known side effects, doses started at 20 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate, and then rose to 30 mg and 10 mg, respectively. For the second stage, people already on the drug stayed on it, but the placebo group was re-randomized such that 15 of the 30 who had had a strong placebo response were switched to the drug and 15 stayed on placebo. Of the 89 placebo participants whose scores stayed stable, 44 now got the drug and 45 stayed on placebo. This brought the total number of people who received the drug to 152.

The agitation/aggression domain of the neuropsychiatric inventory (NPI) served as the primary outcome measure; secondary outcomes included the other subdomains and the total NPI score. As an exploratory outcome, the researchers measured change in the Alzheimer’s Disease Assessment Scale-Cognition (ADAS-Cog).

At the end of the first stage, AVP-923 improved the NPI agitation score by 3.3 points, compared with 1.7 points in the placebo group. At the end of the second stage, the researchers assessed the 44 people in the initial placebo group who had demonstrated no strong placebo effect and began taking AVP-923 after five weeks. In them, the drug reduced agitation and aggression. Scores fell by 2 points, compared with 0.8 points for the 45 people still on placebo. Overall, NPI total and subdomain scores also improved more for the drug treatment group. In both stages, caregivers reported that their own stress abated, and both they and clinicians reported that the patient was less agitated.

Adverse events occurred in 61 percent of people taking AVP-923, versus 43 percent on placebo. They included falls, diarrhea, urinary-tract infections, dizziness, agitation, contusion, back pain, and peripheral edema, and are in line with the drug’s known safety profile, said co-author Joao Siffert of Avanir. Serious adverse events occurred in 12 people on the drug and six on placebo. Twenty-six people dropped out of the trial; 17 from the AVP-923 group, nine from placebo. Eight and four, respectively, stopped because of adverse events. No one died during the trial.

AVP-923’s safety profile is not benign. It is contraindicated for people with heart problems such as prolonged QT interval, atrioventricular block, and others, as well as people with a history of thrombocytopenia, hepatitis, bone-marrow depression, or lupus-like syndrome. People who are overly sensitive to dextromethorphan-containing common cough medicines also should not take AVP-923. Drug interactions with other CNS drugs, such as monoamine oxidase inhibitors (MAOs) and serotonin reuptake inhibitors (SSRIs) are also known (see Cruz, 2013; Schoedel et al., 2014).

Still, Siffert interpreted the latest trial results to mean that overall, AVP-923 was well-tolerated. The researchers found no evidence of treatment-related cognitive decline on the MMSE or ADAS-cog. This is important, he said, because other drugs aimed at treating agitation have been associated with cognitive decline (see Feb 2014 news story).

The results justify larger Phase 3 trials, claimed Siffert, who said that the company would begin talks with the FDA early next year. “The study shows potential for this drug to be helpful,” agreed Lon Schneider, University of Southern California, Los Angeles, who was not involved in this trial but saw the poster. Schneider noted that the relatively small sample was heterogeneous in age, MMSE score, and both level and type of agitation. Patients also differed on the drugs they were already taking, such as acetylcholinesterase inhibitors, memantine, antidepressants, and antipsychotics. Since quinidine sulfate is a potent inhibitor of cytochrome P450 2D6 and slows the metabolism of several drugs, it may affect other drugs, and that could contribute to efficacy as well as adverse events, he told Alzforum. Schneider noted that larger trials will be needed to discern how well the drug works in which type of patient.

A second AVP-923 study was also presented on a poster at the AAN conference. This study followed 134 patients with AD, vascular or frontotemporal dementia, or dementia with Lewy bodies who took AVP-923. They constituted the dementia cohort, led by Rachelle Doody, Baylor College of Medicine, Houston, of the larger PRISM-II study. Conducted at more than 100 centers in the United States, PRISM-II used no placebo control, but simply evaluated safety, tolerability, and the effect of AVP-923 in 750 people whose PBA accompanied primary conditions such as stroke or a traumatic brain injury. “The purpose of this investigation was to gain more experience with the use of AVP-923 in patients whose PBA was related to disorders that were not well-represented in the trials used for regulatory approval,” Doody wrote to Alzforum.

Participants received the 20 mg/10 mg combination twice daily for 12 weeks, and were assessed for change in the Center for Neurologic Study-Lability Scale (CNS-LS). The Center for Neurologic Study is the not-for-profit organization in La Jolla, California, that originally developed this drug combination. CNS-LS is a questionnaire to measure uncontrollable tearfulness or laughter (see Moore et al., 1997). Other endpoints included how often participants had such episodes, their MMSE score, and clinicians’ and caregivers’ global impression of change.

Patients improved on the CNS-LS. Episodes dropped by half at day 30 compared to baseline, by two-thirds at day 60, and three-quarters of clinicians and caregivers reported that symptoms improved at day 90. Overall, MMSE scores remained steady.

Forty-nine patients had mild to moderate adverse events, such as headache, urinary-tract infection, diarrhea, nausea, falls, dizziness, and sleepiness; a third were considered possibly related to AVP-923. Fourteen people had serious side effects, but Doody and colleagues considered these unrelated to the drug. Seventeen patients dropped out because of adverse events. The authors wrote that the results suggest that AVP-923 treats PBA regardless of the underlying neurological condition.

John (Wes) Ashford of Stanford University Medical Center in California wrote to Alzforum that PBA is uncommon in Alzheimer’s. Ashford suggested that other off-patent drugs could work as well or better than AVP-923 if they were competitively tested against one another. As examples, he mentioned the antidepressants nortriptyline and citalopram, the antipsychotic olanzapine, and the anticonvulsants lamotrigine, valproic acid, and topiramate. The study was funded by Avanir; both Cummings and Doody have consulted for this company.


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