The director emeritus of the Cleveland Clinic Lou Ruvo Center for Brain Health discussed the significance of the HARMONY study findings and what they mean for the future treatment of dementia-related psychosis.
Jeffrey Cummings, MD, ScD
Dementia-related psychosis (DRP) remains a serious complication with an enormous unmet treatment need that is associated with increased morbidity and mortality, repeated hospital admission, and nursing home placement. Top-line results from the phase 3 HARMONY study of pimavanserin demonstrate a significant reduction in the risk of relapse of psychosis. The results were presented at the 12th Clinical Trials on Alzheimer’s Disease (CTAD) meeting, December 4-7, 2019 in San Diego, California.1
The double-blind, placebo-controlled trial (N = 392) was halted in September after an interim efficacy analysis identified a statistically significant effect on DRP. The top-line data presented at CTAD showed that treatment with pimavanserin, which has been previously FDA-approved for the treatment of Parkinson disease-related psychosis, reduced risk of psychosis relapse by 2.8-fold compared with placebo (HR 0.353; one-sided P = .0023), and also reduced risk of discontinuation for any reason by 2.2-fold (HR 0.452; one-sided P = .0024). .
Results also showed that patients tolerated the drug well, as patients who received the study drug reported no worsening in cognition or motor symptoms from baseline. Overall, adverse events occurred in 41% and 36.6% of patients who received pimavanserin compared with placebo. Notably, treatment with pimavanserin did not result in changes to vital signs, weight, or daytime sedation compared with placebo.
In an interview with NeurologyLive, HARMONY study investigator Jeffrey Cummings, MD, ScD, director emeritus of the Cleveland Clinic Lou Ruvo Center for Brain Health and vice chair of the department of brain health at the University of Nevada Las Vegas, discussed the need for an effective treatment for DRP and what makes pimavanserin a unique treatment option.
Jeffrey Cummings, MD, ScD: There is no approved treatment for psychosis in any form of dementia, so it's a completely unmet need. It's estimated that there are about 2.4 million patients who have dementia plus psychosis. For example, in Alzheimer disease where you have about 5.5 million people, roughly 30% of them have psychosis at some point in the course of their illness. If you look across Alzheimer disease, dementia with Lewy bodies, Parkinson's dementia, and vascular dementia, all that adds up to about 2.4 million people who have dementia and psychosis. It’s a lot of people who could benefit from an approved antipsychotic agent.
The study was terminated early because there was a very robust difference between drug and placebo, in terms of relapse of the psychosis when people were taken off of pimavanserin in a randomized way. For enrollment in this study, people presented with psychosis to their doctors. Upon entering the study, everyone was put on pimavanserin, which is really great because that's what families want; you want treatment. After 3 months, if the person had responded to treatment with pimavanserin, then they were randomly assigned to continue on pimavanserin or to placebo. The placebo group relapsed much more quickly, usually within several weeks, whereas relatively few of the pimavanserin patients relapsed, and therefore that aided the drug-placebo differential, demonstrating that pimavanserin was effective in maintaining the antipsychotic properties that had been created in the initial study work.
The drug has such an interesting history. The traditional treatment for psychosis is of course, antipsychotics like risperidone and haloperidol. The company originally looked at what receptor is shared by all of these different types of antipsychotics; there must be a dozen or more on the market. What is their common factor? And what they discovered was that the 5-HT2A receptors. receptor was antagonized by all of these drugs; that was the one receptor that they all had in common. They decided to make a drug that focuses on that receptor, and they created pimavanserin. It was a hypothesis that all psychosis in different dementias might share enough of a basic biology that this receptor would be involved across these different disease states. That hypothesis was confirmed by the study because there was a reduction in the psychosis in all of the disease states. Although it should be noted that, frontotemporal dementia for example, is much rarer than Alzheimer disease and there are many fewer frontotemporal patients in the study than there are Alzheimer patients in this study. It's a little hard to be equally confident, but you can see from the results that all of them had a reduction in psychosis.
We have no drugs specifically approved for depression in Alzheimer disease or dementia or anxiety in any of these disorders. This is the first drug that, if it goes from the HARMONY study to the FDA, will be, if it's approved, the first drug to be approved for any neuropsychiatric syndrome in any dementia disorder. I think that signals a real point of progress. Now of course, we don't know yet that the FDA is going to approve this treatment, but we do know that this study met its goals, robustly so, and we think it has a good chance of having a positive review by the FDA.
1. ACADIA Pharmaceuticals presents positive top-line results from pivotal phase 3 HARMONY trial of pimavanserin in patients with dementia-related psychosis at 12th Clinical Trials on Alzheimer’s Disease (CTAD) Meeting [news release]. San Diego, CA: Acadia Pharmaceuticals. December 4, 2019.