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Hello! Jim Phelps here with another Quick Take for the Psychopharmacology Institute.
For our next study, let’s look at pimavanserin. It’s a new medication one might lump with the atypical antipsychotics, but its mechanism is quite different. And its indication is, at this point, only for hallucinations in Parkinson’s disease. But already, people are looking at extending its use to other conditions, and Alzheimer’s disease is one of the obvious ones. Here’s a study that looks at the efficacy of pimavanserin in the treatment of delusions and hallucinations in Alzheimer’s disease.
First, let’s take a moment and remind ourselves what pimavanserin is; then we’ll look at the study results, and I’ll offer you an admittedly highly skeptical conclusion or interpretation. Pimavanserin is technically an antipsychotic that does not act on the dopamine system that’s of interest in that regard. It acts on the serotonergic system, a 5-HT2A–receptor agonist. But it’s an inverse agonist, which means that even though it binds to the agonist site, it exerts an action that is opposite to the typical agonist action. So, the result is an antipsychotic effect, and that’s really intriguing and has been shown to be quite effective in the treatment of Parkinson’s, where obviously antidopaminergic agents would be problematic. However, let’s take a look at these new results from its study in the treatment of Alzheimer’s.
I’ll give you the data first and then an interpretation. Results were that, at 6 weeks in patients with Alzheimer’s, a neuropsychiatric disability score that was kind of a composite decreased by 40% in the pimavanserin group and only 18% in the placebo group. Overall, the effect size was small, about 0.3 (small to low-medium). What was this neuropsychiatric inventory they were using? It’s called the Neuropsychiatric Inventory–Nursing Home Version. The psychotic symptoms were defined as visual or auditory hallucinations or delusions or both. So, there was a positive effect at 6 weeks. But at 2 and 4 weeks and at 9 and 12 weeks, there was no statistically significant difference between active drug and placebo. Side effects were relatively minimal. Just from the data I presented thus far, we could say it works. It doesn’t work fast, and it doesn’t maintain persistent benefit, and the effect is not strong but not weak. It’s right about in the middle.
First, a commentary and then some take-home point summaries. The commentary would be that this was an industry-sponsored study. The pharmaceutical company that makes pimavanserin was strongly involved in the assembly of the data in terms of making this whole thing possible. I want to point out to you an interesting paper by one of the Perlis brothers published in the American Journal of Psychiatry in 2005 about industry sponsorship and financial conflicts of interest. They found that in 162 randomized trials, those that reported a potential conflict of interest were 4.9 times, basically 5 times, more likely to report positive results than studies with no admitted potential conflict of interest. So, an industry sponsorship is a very strong predictor of a positive result, and that applies to interpreting the current results of this pimavanserin study as well.
Here is the take-home message: This is another relatively weak indication of efficacy for pimavanserin—now not just in Parkinson’s but in Alzheimer’s. And that’s about all we have at this point, just another signal for pimavanserin working outside the dopamine system. In my opinion, this is far too early to even consider using pimavanserin in lieu of other agents, including even other atypical antipsychotics in the treatment of Alzheimer’s. It’s too slow, it’s too expensive, and it’s too unknown. And the data are really quite weak, especially if you factor in the industry sponsorship.
Abstract
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
Prof Clive Ballard, MBChB, Carol Banister, MBChB, Zunera Khan, MSc, Prof Jeffrey Cummings, MD, George Demos, MD, Bruce Coate, MPH, James M Youakim, MD, Randall Owen, MD, Srdjan Stankovic, MD
Background: Pimavanserin is a selective 5-HT 2A receptor inverse agonist and antagonist approved in the USA for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. No safe or effective pharmacological treatment is approved for psychosis in patients with Alzheimer’s disease. Therefore, we aimed to evaluate the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer’s disease psychosis.
Methods: We did a phase 2, randomised, double-blind, placebo-controlled, single-centre (with multiple affiliated nursing home sites across the UK) study. We included participants of either sex who were aged 50 years or older with possible or probable Alzheimer’s disease and psychotic symptoms including visual or auditory hallucinations, delusions, or both. Participants were randomly assigned (1:1) to 12 weeks of oral treatment with either pimavanserin (two 17 mg tablets daily) or placebo, with use of permuted block sizes of four and stratified by baseline Mini-Mental State Examination (MMSE) total score (<6 or ≥6) and Neuropsychiatric Inventory–Nursing Home version (NPI–NH) psychosis score (<12 or ≥12). Participants, caregivers, the study sponsor, and study personnel at the clinic site were masked to treatment assignment. The primary endpoint was mean change from baseline to week 6 in the NPI–NH psychosis score for pimavanserin versus placebo in the modified intention-to-treat population. Sustained benefit and safety of pimavanserin were assessed through week 12. This study is registered at ClinicalTrials.gov, number NCT02035553.
Findings: Between Jan 16, 2014, and Oct 27, 2016, 345 participants across 133 nursing homes were screened, of whom 181 were randomly assigned treatment (n=90 pimavanserin and n=91 placebo). 178 participants were included in the modified intention-to-treat population. Mean total baseline NPI–NH psychosis scores were 9·5 (SD 4·8) for the pimavanserin group and 10·0 (5·6) for the placebo group. Mean change in the NPI–NH psychosis score at week 6 was −3·76 points (SE 0·65) for pimavanserin and −1·93 points (0·63) for placebo (mean difference −1·84 [95% CI −3·64 to −0·04], Cohen’s d=−0·32; p=0·045). By week 12, no significant advantage for pimavanserin versus placebo was observed for the overall study population (treatment difference −0·51 [95% CI −2·23 to 1·21]; p=0·561). Common adverse events were falls (21 [23%] of 90 participants in the pimavanserin group vs 21 [23%] of 91 in the placebo group), urinary tract infections (20 [22%] vs 25 [28%]), and agitation (19 [21%] vs 13 [14%]). Eight (9%) participants on pimavanserin and 11 (12%) on placebo discontinued treatment because of adverse events. No detrimental effect was observed on cognition or motor function in either group.
Interpretation: Pimavanserin showed efficacy in patients with Alzheimer’s disease psychosis at the primary endpoint (week 6) with an acceptable tolerability profile and without negative effect on cognition. Further follow-up to week 12 did not show significant advantage for pimavanserin versus placebo.
Funding: ACADIA Pharmaceuticals.
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Reference
Ballard, C., Banister, C., Khan, Z., Cummings, J., Demos, G., Coate, B., Youakim, J. M., Owen, R., Stankovic, S., Tomkinson, E. B., McDermid, J., Ocal, D., Testad, I., Qayyum, M. A., Kemos’, P., Borejko, O., Megalogeni, M., Brookes, E. V., Petrava, A., … Nunez, K. (2018). 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. The Lancet Neurology, 17(3), 213-222.
