Patients with dementia-related psychosis with sustained response to pimavanserin have a lower risk of relapse, according to results from a phase 3 study published in the New England Journal of Medicine.
In April 2021, the US Food and Drug Administration (FDA) rejected the use of pimavanserin in other forms of dementia due to its lack of efficacy with statistical significance in dementia subtypes.
The current phase 3 study was terminated prematurely due to its effectiveness in dementia patients.
The investigators of the HARMONY study (ClinicalTrials.gov Identifier: NCT03325556) enrolled patients with dementia-related psychosis (n = 392) from 101 centers in America and Europe between 2017 and 2019.
Patients received a daily dose of 34 mg of pimavanserin, an oral 5-HT2A inverse agonist and antagonist, over a 12-week open-label period. Responders were then randomly assigned 1: 1 to continue receiving pimavanserin or to be switched to placebo for a period of 38 weeks. At each clinical visit, patients were assessed using the Positive Symptoms Assessment Scale – Hallucinations and Delusions (SAPS-H + D), the Global Impression Improvement (CGI) Clinical Scale, and the Mini-Mental State Examination (MMSE) judged.
The mean patient age was 74.5 ± 8.3 years. The patients included had cognitive impairment for a mean of 4.3 ± 2.8 years. Alzheimer’s dementia, 15.1% Parkinson’s dementia, 9.7% vascular dementia, 7.1% dementia with Lewy bodies and 1.8% a frontotemporal dementia were diagnosed in 66.3%.
At baseline, 81.6% of patients had both delusions and hallucinations; the mean SAPS-H + D score was 24.4 ± 9.2; the mean MMSE score was 16.7 ± 4.7; and the mean CGI severity score was 4.7 ± 0.7, indicating moderate psychosis.
During the open-label phase, 217 (61.8%) of the 351 remaining eligible patients had sustained responses and were randomly assigned to further treatment with pimavanserin or placebo. The remaining patients did not meet the criteria for response (19.9%) or discontinued treatment due to an adverse event (7.7%) or for other reasons.
Adverse and serious side effects occurred in 36.2% and 5.1% of the patients, respectively. The most commonly reported events included urinary tract infections (5.1%), constipation (2.6%), high blood pressure (2.3%), nausea (2.0%), and state of confusion (2.0%).
During the double-blind phase of the study, a relapse of the psychosis occurred in 13% of the verum group (pimavanserin; n = 105) and 28% of the control cohort (placebo; n = 112; hazard ratio) [HR], 0.35; 95% CI, 0.17-0.73; P = 0.005).
The reduced risk of relapse was below the specified withdrawal limit and the study was terminated early in week 26 due to efficacy.
Each adverse event was reported by 41.0% of the active cohort and 36.6% of the placebo cohort. Serious side effects occurred in 4.8% and 3.6% of the cohorts, respectively. The most commonly reported adverse reaction for both cohorts was headache (9.5% and 4.5%, respectively).
Due to the premature discontinuation, this study was limited by the fact that the informative value for demonstrating predictors of a complete response to pimavanserin was limited.
The researchers concluded: “Longer and larger studies are needed to determine the effects of pimavanserin on dementia-related psychosis.”
Disclosure: This study was funded by Acadia Pharmaceuticals. Several authors stated links to industry. For a full list of the details, see the original article.
Tariot PN, Cummings JL, Soto-Martin ME, et al. Trial with pimavanserin in dementia-associated psychosis. N Engl J Med. 2021; 385 (4): 309-319. doi: 10.1056 / NEJMoa2034634