Pimavanserin a Better Option for Parkinson’s Psychosis?

PHILADELPHIA — Pimavanserin (Nuplazid) is noninferior to quetiapine in patients with Parkinson’s disease (PD) psychosis at 56 days, results from a phase 3 trial showed.

In the first prospective comparison of the two antipsychotics in this patient population, pimavanserin yielded significant improvement across all parameters of efficacy without worsening motor symptoms and was very well tolerated, said study investigator Amey Mane, MD, Sun Pharma Laboratories, Mumbai, India.

Psychosis occurs in about 50% patients with PD and is a major risk factor for hospitalization, nursing home placement, and mortality.

Antipsychotics are used to treat PD psychosis, but evidence for the efficacy of quetiapine is inconsistent and clozapine requires regular monitoring for agranulocytosis, said Mane. Cholinergic blockade by these drugs can also increase non-motor symptoms such as constipation, drooling, and cognitive impairment.

Pimavanserin is an oral 5-HT2A inverse agonist and antagonist and the only US Food and Drug Administration–approved medication for PD psychosis, he said. The drug was approved in 2016, and its label was updated in 2023 to clarify that it can be used to treat patients with PD psychosis, who also have dementia.

“To the best of our understanding, this is the first completed prospective study of pimavanserin with an active comparator, quetiapine,” in PD psychosis, he said.

The findings were presented in a late breaking abstract session at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) 2024.

Primary Outcome at 56 Days

The assessor-blinded study enrolled 247 patients with PD for at least 1 year, who were Hoehn and Yahr stage 3 or higher, with hallucinations and/or delusions on a stable dose of PD medication for at least 4 weeks. The average duration of psychosis was 1.2 years.

Patients were randomly assigned to receive daily pimavanserin 34 mg or quetiapine 25-200 mg for 56 days and evaluated at baseline and days 14, 28, 42, and 56.

The mean change in Scale for the Assessment of Positive Symptoms (SAPS)-PD nine-item total scores improved from baseline in both groups at all visits (P P = .029).

The primary outcome of mean change in SAPS-PD total score at day 56 was −9.64 in the pimavanserin group and −8.37 in the quetiapine group (P = .008). The between-group difference was −1.27, and the upper bound of the 95% CI (−2.77 to 0.24) was lower than the prespecified margin of 0.9, demonstrating noninferiority, Mane said.

Secondary Endpoints and Safety

Pimavanserin was associated with significantly greater improvement than quetiapine for the following secondary outcomes:

• SAPS-Hallucinations and Delusions at day 42 (mean, −12.70 vs −11.40; P = .009) and day 56 (mean, −17.00 vs −15.60; P = .007)
• SAPS-Hallucinations at day 42 (mean, −5.61 vs −4.75; P = .01) and day 56 (mean, −7.33 vs −6.52; P = .02)
• Clinical Global Impression-Improvement score at day 56 (−1.90 vs −1.59; P = .01)
• Scales for Outcomes in Parkinson’s disease (SCOPA) scores for nighttime sleep at day 14 (−1.12 vs −0.85; P = .03) and SCOPA daytime wakefulness at day 28 (−2.42 vs −1.70; P = .01)

Treatment-emergent adverse events (TEAEs) were reported in 7.5% and 13.5% of the pimavanserin and quetiapine groups, respectively.

Five TEAEs, all of mild intensity, were reported as related to study drugs: Pyrexia (1), headache (1), and nasopharyngitis (2) with pimavanserin and headache (1) with quetiapine, Mane said. There was one unrelated fatal stroke in the quetiapine group. No drug discontinuations occurred because of TEAEs.

Delayed Onset of Action?

During a discussion of the results, Hubert Fernandez, MD, director, Center for Neurological Restoration, Cleveland Clinic, Cleveland, asked whether the investigators observed a difference in onset between the two drugs.

“Our general impression in the United States is that pimavanserin has a slower uptake in efficacy as compared with quetiapine. If it [quetiapine] works, it works the next day or the day after, whereas with pimavanserin you have to wait for a week or two. I was just wondering if that’s validated or just anecdotal experience,” he said.

Mane said the study showed no difference in efficacy at 14 days and greater improvement in efficacy between days 14 and 56.

Another attendee pointed out that quetiapine is particularly good at inducing sleep and asked whether some of the observed differences, especially early on, were due to the need to rapidly titrate quetiapine to induce sleep and get the sleep-wake cycle back on track.

“We did discuss this with most of our investigators, and they gave the same reason. It’s the titration with the quetiapine, and that’s why it’s seen in the early parts,” said Mane.

Reached for comment, Regina Katzenschlager, MD, Karl Landsteiner Institute for Neuroimmunological and Neurodegenerative Disorders, Klinik Donaustadt, Vienna, Austria, said the majority of drugs commonly used for other types of psychosis cannot be used in PD because of motor worsening.

“Quetiapine is one of the very, very few options we have to treat people with Parkinson’s psychosis because it leads to little, if any, worsening and is the best tolerated,” she said. “Everything else is almost absolutely contraindicated. So that’s why an additional drug — this one has a slightly different mechanism — is incredibly helpful in the clinic because not everyone responds to quetiapine.”

Katzenschlager pointed out that pimavanserin is not approved in Europe and that the present study was conducted for regulatory purposes in India.

Mane is an employee of Sun Pharma Laboratories. Katzenschlager reported having no relevant financial relationships.