Acadia Pharmaceuticals’ Nuplazid (pimavanserin) — which is being evaluated as a potential treatment for hallucinations and delusions associated with dementia-related psychosis — is not associated with common motor side effects of conventional antipsychotics, according to an analysis of data from three clinical trials.
These findings add to previous Phase 3 trial results showing that the therapy significantly lowered the risk of psychosis relapse — a worsening of hallucinations and delusions — in a wide range of people with dementia-related psychosis, including Alzheimer’s patients.
Still, these positive clinical effects were recently deemed insufficient to approve Nuplazid for that indication by the U.S. Food and Drug Administration (FDA). Acadia’s next steps will be determined after a meeting with the agency to address its concerns.
The results of the analysis were presented by Daniel Weintraub, MD, professor of psychiatry at the Perelman School of Medicine, University of Pennsylvania, in an oral presentation at the 2021 virtual American Academy of Neurology Annual Meeting, held April 17–22.
The presentation was titled “Motor function in patients with neuropsychiatric manifestations of neurodegenerative disease treated with pimavanserin.”
Psychosis — commonly consisting of delusions and hallucinations, depression, and other neuropsychiatric disorders — is a symptom observed in people with dementia, whether due to Alzheimer’s disease, Parkinson’s disease, Lewy body dementia, or vascular dementia.
Currently, there is no approved treatment for dementia-related psychosis, and patients are often treated with off-label antipsychotics. However, these medications have substantial safety concerns, such as cognitive decline, daytime sedation, and worsening motor function and extrapyramidal symptoms.
Extrapyramidal symptoms include rigidity, slowness of movement, tremors, involuntary movements, and continuous spams or muscle contractions.
Nuplazid works by specifically blocking the activity of serotonin 5-HT2A receptors, which are involved in psychosis. Notably, due to its distinct mechanism of action, the oral therapy is thought to have fewer adverse events than conventional antipsychotics.
Nuplazid was approved by the FDA to treat Parkinson’s disease-related psychosis in 2016. The decision was supported by Phase 3 trial data showing that the therapy lessened psychosis symptoms in this patient population, while minimizing the occurrence of debilitating side effects that many antipsychotics cause, including motor function worsening.
Now, Weintraub, along with researchers at Acadia, evaluated motor function changes in more than 800 people with neuropsychiatric symptoms related to neurodegenerative or neurovascular disease who were treated with Nuplazid or a placebo in three clinical trials.
These included the Phase 2 019 trial (NCT02035553) in people with Alzheimer’s-related psychosis, the Phase 3 HARMONY trial (NCT03325556) in patients with dementia-related psychosis (76% with Alzheimer’s), and the ongoing Phase 3 046 study (NCT03575052) in people with neuropsychiatric symptoms related to neurodegenerative or neurovascular disease.
HARMONY involved an initial 12-week period in which all participants were treated daily with Nuplazid until dementia symptoms stabilized, after which they were randomly assigned to continue treatment or switch to a placebo for up to six months or until psychosis relapse.
During the trials, participants’ motor function was evaluated using the Unified Parkinson’s Disease Rating Scale Part III or the Extrapyramidal Symptom Rating Scale-Abbreviated. Motor-related adverse events, such as extrapyramidal symptoms, were also examined.
Results showed that in the 019 study, similar changes in motor function were observed at week 12 (about three months) between 74 Nuplazid-treated patients and the 65 patients who were given a placebo.
In HARMONY’s first part, in which all 392 patients were treated with Nuplazid for three months, mean change in motor function “was minimal,” with a trend towards improvement, Weintraub said.
In the trial’s randomized part, 104 Nuplazid-treated patients showed small motor changes over six months, which were similar to those observed in the placebo group (112 patients) at all time points up to six months.
An interim analysis of the 046 study showed that motor function changes at week 8 were also similar between the Nuplazid group (144 patients) and the placebo group (144 patients).
In addition, rates of motor-related adverse events “were generally similar for the [Nuplazid] and placebo groups,” Weintraub said, adding that such events were “infrequently reported” during HARMONY’s first part (2.3% of patients).
These findings highlighted that “mean changes in motor function were minimal in [Nuplazid]-treated patients and similar to placebo across three randomized placebo-controlled studies,” Weintraub said, noting, however, that motor function was examined as a safety point and that neither of these studies were powered to test differences between treatment groups.
Motor-related adverse events in Nuplazid-treated patients were also infrequently reported and at similar rates to placebo groups, he added.
“Taken together, these results indicate that [Nuplazid] did not have a negative impact in motor function of frail patients with neurodegenerative disease, consistent with what would be expected based on its selective serotonin receptor binding profile,” Weintraub said.