Will Nuplazid Offer a ‘New’ Choice for Treating Parkinson’s Disease Psychosis?

On September 3, Acadia Pharmaceuticals Inc. submitted its New Drug Application (NDA) to the Food and Drug Administration (FDA) for pimavanserin (Nuplazid) as a frontline therapy for treating psychosis in patients with Parkinson’s disease (PD).

The application comes on the heels of positive results in both randomized and open-label clinical studies. If successful, pimavanserin would be the first drug approved in the United States for PDP, and it might signal the start of a new era in treating the underappreciated psychiatric aspects of PD.

PD has traditionally been connected with problems in dopamine-related neurons, but research is uncovering that this disorder alters several neurologic pathways: adrenergic defects are associated with symptoms like dizziness and orthostatic hypotension, cholinergic defects are associated with the cognitive decline frequently seen in PD, and serotonergic problems are believed to contribute to psychosis.

Typically, symptoms like cognitive impairment or depression are the first manifestations of PD, sometimes occurring years before the first motor symptoms that enable a clinical diagnosis.

PD and Movement Disorders Center, Boca Raton

“Parkinson’s should really be viewed as a neuropsychiatric disorder and one that has a huge need for effective psychiatric medications,” said Stuart Isaacson, M.D., director of the Clinical Research Center at the Parkinson’s Disease and Movement Disorders Center of Boca Raton.

Treating psychosis in patients with PD can be particularly challenging, as in addition to being brought on by the pathology of disease, psychosis can be exacerbated by the dopaminergic medications used to treat the movement problems of PD. As such, psychosis is almost an invariable outcome of PD if someone lives long enough. Isaacson noted that studies have estimated the prevalence of PD psychosis as anywhere from 30 to 80 percent.

This symptom carries a heavy toll, too. “Psychosis is the leading cause for Parkinson’s patients to move from their homes to nursing homes or other institutions and leads to an increased risk of mortality, a diminished quality of life, and significant caregiver burden,” said Acadia CEO Steve Davis.

The underlying biology of PDP is also different from that of schizophrenia, so current antipsychotics are minimally effective and also pose serious health risks. A recent post-hoc analysis of an open-label study of pimavanserin found that PD patients who were receiving atypical antipsychotics in addition to the pimavanserin had a fourfold increased risk of mortality compared with those not taking antipsychotics, which is greater than the risks these drugs pose in people with Alzheimer’s disease.

Pimavanserin operates as a selective-serotonin inverse agonist (SSIA) that solely targets 5-HT2A receptors, and so far the clinical evidence suggests this pharmacological mechanism is an effective one.

As part of the NDA, Acadia pooled the results from a pair of randomized phase 3 studies totaling 268 patients. The results indicate that patients with psychosis related to PD who were treated with pimavanserin showed greater improvements in their psychosis as measured by SAPS (Scale for the Assessment of Positive Symptoms) compared with placebo, with no worsening of motor function. In addition, pimavanserin produced improvements in nighttime sleep, daytime wakefulness, and caregiver burden.

“What makes these results stand out is that the investigators, caregivers, and an independent rating board all measured improvements in the patients, and the three assessments correlated well,” said Isaacson, who was one of the lead investigators of the studies.

Acadia’s phase 3 trials, as well as some ongoing open-label studies, have also shown that pimavanserin is safe and well tolerated, a vital consideration for these compromised patients.

“After a lot of false starts with other drugs, it’s exciting to finally have a therapy pass muster in this arena,” Isaacson told Psychiatric News.

He thinks the FDA holds a similar positive view of this drug, noting that they granted pimavanserin a Breakthrough Therapy designation to speed up the development and approval process this year.

“Usually they reserve that designation for therapies like cancer drugs that may prolong the life of seriously ill patients,” he said. “So it acknowledges there are a lot of patients who are in desperate need of this therapy.”

Those patients are not only those with PD, as early clinical work with pimavanserin and related SSIAs has shown promise in treating Alzheimer’s-related psychosis and schizophrenia.

In addition to the Breakthrough Designation, Acadia requested a priority review for its application; if granted, priority status would accelerate the review timeline even more, though it still likely will be a few months down the road. ■