18 Sep 2019

A Phase 3 trial of pimavanserin was halted early when the study met its primary endpoint of delaying relapse to psychosis in people with dementia, according to a press release by its sponsor, Acadia Pharmaceuticals. Pimavanserin—a selective serotonin inverse agonist—is approved to treat psychosis in Parkinson’s, and the company is gunning for approval in people who suffer from psychosis associated with all-cause dementia. Trial data have yet to be released.

Phase 3 trial of pimavanserin stopped early when primary endpoint reached.

Drug delayed relapse of psychosis in patients who were responding to treatment.

Results of the trial have yet to be released.

The announcement comes nearly two years after a Phase 2 study left researchers scratching their heads. In a parallel design that tested pimavanserin’s efficacy at reducing dementia-related psychosis over 12 weeks, both treatment and placebo groups improved throughout the trial. Only at the six-week time point did the treatment group appear to benefit (Dec 2017 conference news; Feb 2018 news).

The Phase 3 study took a different approach. It tested how patients fared when they came off the drug, rather than when they were on it. It started with 12 weeks of “stabilization,” during which time participants took 34 mg per day of pimavanserin, open label, with the option to reduce the dosage to 20 mg. The study aimed to enroll 356 participants with all-cause dementia who had had symptoms of psychosis for at least two months. Those who responded to the drug during the open-label phase then continued on to a 26-week, placebo-controlled, double-blind period, in which half were randomized to continue pimavanserin, and half to placebo. The primary endpoint was delay in psychosis relapse with a p value of less than 0.0033. According to an interim analysis, the trial met its primary endpoint early.

Relapse was defined as hospitalization due to dementia-related psychosis, significant deterioration of dementia-related symptoms on clinical scales, withdrawal from the study due to lack of efficacy, or the use of an off-label antipsychotic medication. Patients were only followed until relapse occurred.

Lon Schneider of the University of Southern California, Los Angeles, pointed out that the press release included no meaningful trial data, such as how many participants continued to the placebo-controlled portion, how many relapsed in each group, or the treatment effect size. He noted that a p value is not an effect size, and that the most efficient and straightforward test of efficacy would have been a parallel group design. “There will be much to unpack when a full report of the data is produced,” he wrote.

Jeffrey Cummings of the Lou Ruvo Center for Brain Health in Las Vegas considers the trial design to be a patient-centric means of gathering critically important information about a drug, and one that enables recruitment. “All patients are on drug, and this diminishes the fears of families that their loved one with psychosis will go on placebo,” he wrote. Cummings believes the design will help expose any treatment effect. “Only responders are moved on to the placebo-controlled phase, and this further increases the likelihood of seeing a drug-placebo difference in the withdrawal period of the trial,” he said.

Even so, that all participants know they are receiving the drug for the first 12 weeks of the trial complicates interpretation of the results. Suzanne Hendrix of Pentara Corporation, a biostatistician, compared the results of the Phase 2 study, in which people in the placebo group had a reduction in psychosis, with those of the new Phase 3 study. “In both cases, the pimavanserin effect is not by chance, but may not be much larger than the relatively large placebo effect,” she wrote.

As with many anti-psychotic drugs, pimavanserin, marketed as Nuplazid, comes with a black box warning against use in elderly people with dementia, owing to increased mortality.—Jessica Shugart