Results from a Phase 2 clinical trial show that Nuplazid (pimavanserin) can safely treat, but possibly in the short-term only, symptoms of psychosis in Alzheimer’s patients, a study looking at data from that U.K. trial reports.
An accompanying commentary, however, raised concerns about the clinical meaningfulness of these results and findings of safety. More studies are now underway.
The research, “Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer’s disease psychosis: a phase 2, randomised, placebo-controlled, double-blind study,” appeared in the journal The Lancet Neurology.
Approximately 25 to 50 percent of Alzheimer’s patients develop psychotic symptoms over the course of their disease. If untreated, these symptoms may become more severe, taking on a pattern of recovery and relapse.
Psychosis in Alzheimer’s is associated with more rapid congitive decline, earlier institutionalization, greater caregiver burden, and greater treatment-related mortality.
Pimavanserin, being developed by Acadia Pharmaceuticals for dementia-related psychosis, is a selective serotonin inverse agonist that preferentially targets 5-HT2A serotonin receptors that work to transmit signals between nerve cells. In April 2016, Nuplazid became the first drug approved by the U.S. Food and Drug Administration (FDA) to treat hallucinations and delusions associated with Parkinson’s. However, no safe or effective therapy is available for psychosis in those with Alzheimer’s.
Most studies of antipsychotics in Alzheimer’s patients show no benefit against placebo and a significant risk of side effects, including cognitive decline. However, Nuplazid’s specific mechanism of action warrants its evaluation in these patients. Nuplazid does not bind to dopamine receptors, important to motor function, as many antipsychotics do.
Researchers conducted a double-blind Phase 2 study (NCT02035553) in 181 people (mean age, 86) with possible or probable Alzheimer’s and psychotic symptoms, such as visual or auditory hallucinations, delusions, or both. Patients, residents in one of 133 nursing homes in the London area, were randomly assigned to 12-week, oral treatment with Nuplazid (two 17 mg tablets daily) or placebo.
The trial’s main goal was to test the treatment’s antipsychotic efficacy, assessed by the mean change in the Neuropsychiatric Inventory-Nursing Home (NPI-NH) Psychosis score, which sums hallucinations and delusions scores, from study’s start to week six of treatment. Nuplazid’ cognition changes and safety were studied through week 12.
Results showed that treatment significantly improved psychosis scores at week six, particularly in patients with more severe symptoms, but no benefit in comparison with placebo was sustained at week 12. These results had been announced in a preliminary report.
Nuplazid’s use also improved irritability, but not agitation or occupational distress. Treatment and placebo groups did not show differences in change in activities of daily living or the use of rescue medications.
Nuplazid’s safety profile was consistent with prior research, the study reported. Falls, urinary tract infections, and agitation were the most common adverse events. Of note, the treatment did not negatively affect cognition or motor function, although the researchers noted that a 12-week treatment had limited sensitivity to evaluate these changes.
“The findings from this study suggest potential efficacy and acceptable tolerability of pimavanserin (Nuplazid) for psychosis in Alzheimer’s,” the investigators wrote.
An accompanying editorial comment in the same journal by Lon S. Schneider, MD, an Alzheimer’s expert at the Keck School of Medicine of the University of Southern California, however, argured that “the results of this trial cannot be considered to be positive or clinically meaningful.” He mentioned the small, short-term effect seen with Nuplazid, due to a transient worsening of those on placebo, rather than an improvement linked to treatment.
Schneider also questioned the safety of Nuplazid’s use, considering the occurrence among patients of edema, weight loss, agitation, aggression, and anxiety, which may counter any therapeutic effect. And, he noted that 12 weeks, not six, was the typical timeframe given to studying antipsychotics in clinical trials.
”If the primary outcome had been specified for 12 weeks, typical of previous trials with antipsychotics, then pimavanserin would have been considered as not effective,” Schneider wrote, adding that “it is unfortunate that in the current environment of drug development, experimental drugs often are advanced to larger phase 3 trials without evidence from phase 2 trials.”
Acadia is now conducting the multi-center HARMONY Phase 3 trial (NCT03325556) evaluating the efficacy of Nuplazid in preventing a relapse of psychotic symptoms in patients with dementia-related psychosis, including those with possible or probable Alzheimer’s or Parkinson’s. Patient recruitment is ongoing (more information is here).
Two other Phase 2 studies are also ongoing in Alzheimer’s patients. The first (NCT03118947) is now enrolling patients to assess the safety and tolerability of a 52-week treatment for agitation and aggression in more than 400 patients with probable Alzheimer’s at sites in the U.S., Europe and Chile. The second, SERENE (NCT02992132), compares the safety and efficacy of a 12-week treatment versus placebo for agitation and aggression in about 400 patients in those same countries.
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