SAN FRANCISCO—Aimed at curbing the aggression of Alzheimer’s disease patients, biotech Amarantus Bioscience Holdings Inc. has announced positive data for eltoprazine in a Phase 2 clinical trial of elderly patients with Alzheimer’s dementia with a history of aggressive behavior. Eltoprazine is a selective 5HT1a/1b partial agonist in development by Amarantus for the treatment of Parkinson's disease levodopa-induced dyskinesia, and is now poised for further clinical development as a symptomatic treatment in adult ADHD and Alzheimer's aggression.
“Verbal and physical agitation and aggression symptoms are commonly associated with Alzheimer's disease as the disease progresses into the dementia phase,” stated Dr. Paula T. Trzepacz, clinical professor of psychiatry at the Indiana University School of Medicine. “Caregivers find these symptoms to be very distressing, leading to significant caregiver distress, health problems and burnout, as well as a high likelihood of patient institutionalization. There are currently no medications specifically indicated for these symptoms, though many types have been studied in clinical trials, including neuroleptics, antidepressants, anticonvulsants, anxiolytics, sedative/hypnotics, cholinesterase inhibitors and glutamate system agents.”
Clinically, a variety of psychoactive medications are used off-label to attempt to manage these symptoms, but none have proven efficacy. Further, many carry problematic adverse effects such as excess sedation or even more serious ones such as stroke and death, she said.
The four primary study objectives were to collect data on safety on tolerability of multiple dose treatment of eltoprazine in elderly subjects, to evaluate the feasibility of the assessment methods, to obtain information on the effects of eltoprazine on hostile or disruptive behavior in hospitalized demented elderly and to obtain preliminary information on possible relations between plasma concentrations and eventual side effects. Twenty-nine subjects entered the study, 20 of whom were randomized to receive eltoprazine, while nine subjects were randomized to receive placebo. The data from the study demonstrated a significant improvement in eltoprazine-treated patients in the severely aggressive eltoprazine-treated population as measured by the Social Dysfunction and Aggression Scale at the end of the four-week treatment regimen, which followed a washout from previous psychoactive treatments and a three-week placebo-lead-in period, Amarantus reported. Further evaluation of the complete data package is underway prior to submission for publication.
In a Chairman’s Blog dated July 2015, Trzepacz penned a guest column, providing a bit of background and history of Alzheimer’s disease (AD), which “has become a household word because it afflicts approximately 5 million older Americans with projections to afflict over 7 million by 2030. AD causes gradual disability through progressive deterioration of the brain. It is often not detected in its earlier stages when lifestyle changes and some medications could be started and can have some impact.”
“Aggression associated with Alzheimer’s disease or dementia represents a massive unmet medical need that disrupts the normal course of activity throughout the lifespan of nursing home facilities and the homes of Alzheimer's patients, putting a tremendous strain on caregivers,” Gerald E. Commissiong, president and CEO of Amarantus, has noted in comments about his company’s work in the AD realm.
“Amarantus is committed to improving the lives of patients with Alzheimer's disease and their caregivers,” Commissiong added. “Through our work in both the diagnostic and therapeutic arenas, we believe we can ultimately have a meaningful positive impact on the management of this devastating international conundrum, which represents a looming $2-plus trillion cost to the world's healthcare systems by 2050.”
In general, eltorpazine was reasonably well tolerated. Treatment emergent signs and symptoms were confusion (four subjects), insomnia (two), somnolence (three) and anxiety (two). One male experienced delusions, which spontaneously disappeared within one week. Using a dosing regimen with phases of gradual dose increase followed by reduction, eltorpazine appeared safe and reasonably well tolerated in a population of demented elderly subjects with aggressive behavior. There are clear hints of antiaggressive efficacy in more severely aggressive subjects which merit further research, the company reported.
An estimated 6 million Americans have Alzheimer's disease, a number that has doubled since 1980 and is expected to be as high as 16 million by 2050. According to the Alzheimer's Association, over 500,000 patients are diagnosed annually, with nearly one in eight older Americans affected by the disease. Alzheimer's disease is the third leading cause of death in the U.S., and the cost of unpaid care is estimated at over $210 billion annually. Worldwide, about 35.6 million individuals have the disease, and, according to the World Health Organization, the number will double every 20 years to 115.4 million people with Alzheimer's by 2050.