Background

Pimavanserin is a serotonergic agent, specifically a selective serotonin (5-HT) 2A receptor inverse agonist. In April 2016, the FDA approved this once-daily atypical antipsychotic to treat the delusions and hallucinations that are a feature of psychosis in Parkinson's disease, and it came on the market in the United States in June (Apr 2016 news; prescribing information). Pimavanserin is thought to have fewer adverse effects than older antipsychotic agents used to treat Parkinson's psychosis, but evidence remains limited (e.g., Sarva and Henchcliffe, 2016; Tampi et al., 2019).

The drug carries a black-box warning of increased mortality in elderly people. One large retrospective study reported a higher risk of death in nursing home residents with PD who were prescribed pimavanserin (Hwang et al., 2021), while other analyses found no extra risk (Moreno et al., 2018; FDA analysis). Debate continues regarding these results, and regarding the safety of pimavanserin in real-world use (e.g., see Ganesh and Galetta, 2022; Subbiah et al., 2022; Hwang et al., 2022). A meta-analysis of clinical trials involving 680 patients found significant reduction in hallucinations and delusions, with no change in other symptoms. Adverse events were similar to placebo, except that the pimavanserin group had less orthostatic hypotension (Mansuri et al., 2022). In a small retrospective study of 54 patients, half of patients showed initial improvement in psychosis, but only 15 percent maintained the benefit after a year of treatment (Akbar and Friedman, 2022). An analysis of Medicare beneficiaries with PD who were starting pimavanserin or an atypical antipsychotic indicated lower mortality with pimavanserin, but only during the first 180 days of treatment and only in community-dwelling, not nursing home, patients (Mosholder et al., 2022).

Pimavanserin affects heart rhythms and should not be used by people with arrhythmia or those who take drugs that prolong the QT interval. The most common adverse events seen in trials were peripheral edema, nausea, confusion, hallucinations, constipation, and gait disturbance, though Acadia argues that PD with psychoses itself is associated with a higher risk of falls (Forns et al., 2021). Phase 4/real-world trials in Parkinson's psychosis are ongoing (Dashtipour et al., 2021; Cusick and Gupta, 2021).

Pimavanserin is in development for psychosis, agitation, and aggression in Alzheimer's disease. It is also in development for schizophrenia, insomnia, PTSD, and for psychosis related to all-cause dementia. Development for depression was discontinued. A different serotonin 2A receptor inverse agonist, nelotanserin, was in Phase 2 development for dementia with Lewy bodies (DLB) but has been discontinued.

Serotonin receptor activation is known to inhibit brain Aβ peptide production by altering the cleavage of amyloid precursor protein (Sheline et al., 2014). In recent preclinical work, pimavanserin or another 5HT2A agonist, M100907, acutely reduced Aβ concentrations in brain interstitial fluid of APP/PS1 transgenic mice. Chronic administration to aged APP/PS1 mice decreased CSF Aβ and brain plaque pathology, and improved cognition (Yuede et al., 2021; Gründer and Cumming, 2021).

Findings

Between November 2013 and November 2016, Acadia conducted a Phase 2 study of pimavanserin in 181 nursing home residents in London, who had psychosis along with their clinical diagnosis of AD. Participants received a 12-week course of 40 mg pimavanserin or placebo, and were evaluated on the nursing home version of the neuropsychiatric inventory (NPI), the short form of the Cohen-Mansfield Agitation Inventory (CMAI-SF), and the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). The primary outcome was change from baseline to six weeks in the NPI-NH, on which lower scores mean fewer symptoms. By two weeks, both the placebo and pimavanserin groups had improved on the test. At six weeks, those taking the drug had a 39.5 percent reduction in NPI-NH scores, compared to 19.3 percent reduction in the placebo group. However, by 12 weeks, scores were down 40 percent from baseline in both groups. These results were presented at CTAD, and later formally published (Dec 2017 conference news; Ballard et al., 2018). A subsequent subgroup analysis claimed a larger treatment benefit in participants with more severe psychosis (Ballard et al., 2019). Another post hoc analysis reported that people who responded to pimavanserin with a 50 percent or greater reduction in psychotic symptoms also improved on measures of agitation and aggression (Ballard et al., 2020).

In November 2016, Acadia started SERENE, a Phase 2 study comparing the effect of 34 mg and 20 mg pimavanserin to placebo in people with agitation and aggression as part of their Alzheimer's disease, on the CMAI-SF as primary outcome. This trial anticipated enrolling 432 patients at 56 sites, but stopped randomizing patients in November 2017 and was marked as complete in March 2018, with 111 patients enrolled and 83 of them having completed treatment. In March 2019, the trial's status was further updated to "terminated." Results, as well as sponsor rules restricting principal investigators from discussing and publishing results, are published in the clinicaltrials.gov History of Changes section of this trial. At 111 actual participants, the trial was underpowered to detect a treatment effect. The SERENE trial had a one-year open-label extension study, which recruited 79 patients and ended in February 2019.

From 2017 to 2019, Acadia conducted a Phase 3 study at 101 study locations in the United States, Europe, and Chile, to evaluate pimavanserin’s efficacy in preventing psychosis relapse in people who had previously responded to the drug. The HARMONY trial enrolled 392 participants with all-cause dementia who had had symptoms of psychosis for at least two months. In an initial, 12-week open-label phase, all participants took 34 mg pimavanserin with the option to drop to 20 mg. The 217 who responded with a decrease in psychotic symptoms continued into a 26-week double-blind period, in which they were randomized to pimavanserin or placebo. The primary endpoint was delay in psychosis relapse with a p value below 0.0033. 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 use of an off-label antipsychotic medication. Patients were followed until relapse occurred (Cummings et al., 2018). According to a company press release, an interim analysis indicated that this trial met its primary endpoint early, and the trial was stopped (Sep 2019 news). Trial results published after peer review reported that 13 percent of the pimavanserin group relapsed, compared to 28 percent in the placebo group (Tariot et al., 2021). Of the participants, 66 percent had Alzheimer’s, 15 percent had Parkinson’s, and the remainder had vascular dementia, dementia with Lewy bodies, or frontotemporal dementia. Common treatment-related adverse events were urinary tract infection, headache, and constipation. QT interval prolongation occurred in 1.3 percent of pimavanserin-treated people. The types of side effect commonly associated with antipsychotics were infrequent (see also Tariot et al., 2022).

In May 2018, Acadia started enrolling 300 people who had neuropsychiatric symptoms along with a neurodegenerative disease into a Phase 3 safety study, to be conducted at 116 sites in Europe, Asia, and North and South America. It is enrolling patients living at home or in assisted living. The study compares the effect of an eight-week course of 34 mg pimavanserin to placebo on treatment-emergent adverse events, extrapyramidal symptoms, and the MMSE. In October 2019, the enrollment was increased to 750. The study was completed in May 2022 with 784 participants, and has a long-term extension going through August 2023.

In June 2020, based on data from the HARMONY dementia trial, Acadia submitted a supplemental new drug application to the FDA for pimavanserin to treat hallucinations and delusions in people with dementia-related psychosis (press release). On April 5, 2021, the company announced that the agency had declined to approve, citing a lack of substantial evidence of effectiveness. The FDA reportedly noted the absence of statistically significant changes in some of the dementia subgroups, and low numbers of patients with less common dementia subtypes (press release). According to Acadia, the decision was unexpected, given that the FDA had previously approved the study design, which analyzed people with different types of dementia as a single group, and met its primary endpoints. The FDA also rejected results from the SERENE Alzheimer’s trial as supporting evidence, saying the single-center study was not adequate and well-controlled. In February 2022, Acadia resubmitted the application to seek approval for a narrower indication of Alzheimer’s disease psychosis (company release). On June 17, an FDA advisory committee voted 9-3 that the drug appeared to be ineffective for this indication (press release). On August 5, Acadia announced that the FDA had declined to approve pimavanserin (press release). The agency stated that the positive results in the Harmony study appeared to be driven by the robust response among the Parkinson’s dementia subgroup. The FDA recommended that Acadia perform another trial for Alzheimer’s dementia psychosis.

A meta-analysis of safety outcomes in four placebo-controlled trials, presented at CTAD 2020, indicated that the drug caused no cognitive decline. In people treated with pimavanserin for up to nine months, changes in MMSE scores were small and similar to placebo. Of 14 cognition-related adverse events, confusion and memory impairment were reported in all four studies and occurred in fewer than 2 percent of patients. Pimavanserin did not affect motor function.

In October 2020, a 130-person randomized controlled trial started evaluating pimavanserin for a treatment benefit on impulse control disorder in Parkinson's disease. It is projected to run until summer 2023, at 16 sites in France.

In June 2022, a PET study was planned to begin assessing 5HT2A receptor density and occupancy at baseline and after six weeks pimavanserin treatment in people with PD, using the ^18FMH.MZ tracer (Kramer et al., 2020). The study planned to enroll 75 patients at Vanderbilt University Medical Center, and run until June 2024.

For all trials of pimavanserin, see clinicaltrials.gov.