In 2016, the FDA approved the serotonin-boosting antipsychotic pimavanserin to treat hallucinations and delusions associated with Parkinson’s disease psychosis. Would the drug curb these symptoms in people with Alzheimer’s, a disease with a different underlying pathology?
- In Phase 2 AD trial, serotonin-targeted drug temporarily reduced psychosis.
- Pimavanserin appeared safer than other antipsychotic drugs.
- Experts question if the data is meaningful.
In the March Lancet Neurology, Clive Ballard and colleagues at the University of Exeter Medical School in the U.K. formally publish results from their double-blind, single-center Phase 2 study of pimavanserin in people with AD. They enrolled 181 nursing home residents with possible or probable AD who suffered delusions, hallucinations, or both, after dementia set in. Participants received pimavanserin or placebo for 12 weeks. Symptoms were measured using the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH) psychosis scale at two, four, six, nine, and 12 weeks of dosing. The primary outcome was the change from baseline to six weeks in the NPI-NH, where lower scores mean fewer symptoms.
As Ballard reported at the 2017 Clinical Trials on Alzheimer’s Disease meeting in Boston, both drug and placebo groups had fewer symptoms starting at two weeks. At six weeks, the treated group had a 39.5 percent reduction in NPI-NH scores, which was significantly greater than the 19.3 percent reduction in the placebo group. The drug showed no detriment on cognition or motor function measures (Dec 2017 conference news).
However, there was no benefit from pimavanserin after 12 weeks, at which point NPI-NH scores were down from baseline by about 40 percent in both treatment and control groups.
The absence of a drug effect at time points before and after six weeks casts doubt on the relevance of the outcome, wrote Lon Schneider, University of Southern California, in an accompanying editorial. “If the primary outcome had been specified for 12 weeks, typical of previous trials with antipsychotics, then pimavanserin would have been considered not effective,” Schneider wrote. He pointed out that the small drug effect seemed to be driven by a worsening of the placebo group at the six-week time point. Schneider believes that negative findings on most of the secondary outcomes and subgroup analyses, coupled with marginal symptom improvement, provides insufficient evidence to support a Phase 3 study.
At CTAD, Ballard had suggested two possible explanations for the results: Either pimavanserin was having a temporary effect, or the symptoms in the placebo group were remitting and recurring. He was optimistic about the results, and suggested a longer trial would provide more answers.
In September 2017, Acadia began a 26-week Phase 3, placebo-controlled trial to test pimavanserin’s ability to prevent relapse of psychosis in people with all-cause dementia who had stabilized after 12 weeks of the drug. The company is separately evaluating the drug for the treatment of agitation and aggression in people with AD in placebo-controlled and open-label Phase 2 studies.—Pat McCaffrey.
No Available Further Reading
- Ballard C, Banister C, Khan Z, Cummings J, Demos G, Coate B, Youakim JM, Owen R, Stankovic S, ADP Investigators. 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. Lancet Neurol. 2018 Mar;17(3):213-222. PubMed.
- Schneider LS. Pimavanserin for patients with Alzheimer's disease psychosis. Lancet Neurol. 2018 Mar;17(3):194-195. PubMed.