Pimavanserin Nears Approval to Treat Psychosis in Parkinson’s

Pimavanserin has cleared another hurdle on the road to becoming the first antipsychotic approved for use in any neurologic disease. A Food and Drug Administration committee voted 12 to two that the drug’s benefits outweigh its risks for Parkinson’s patients with psychosis. The drug’s maker, ACADIA Pharmaceuticals, announced the vote on March 29. The decision was covered by The Wall Street Journal and Business Wire. The FDA is expected to complete its review of pimavanserin, now trade named Nuplazid, by May 1.

The endorsement drew praise in the field. “Pimavanserin is a breakthrough agent,” Jeffrey Cummings at the Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, wrote to Alzforum. Cummings co-led a Phase 3 trial for the drug. “The trial and the approval process open the door to more neuropsychiatric drug development, and the availability of pimavanserin to our patients is a great stride forward,” Cummings added.

“This is definitely good news for patients with PD and psychosis,” wrote Dag Aarsland, Karolinska Institute, Stockholm. Daniel Weintraub, University of Pennsylvania, Philadelphia, agreed. “Given our recent research on increased mortality with [typical] antipsychotic use in PD patients, I am glad that a new option is likely to be available soon,” he wrote to Alzforum (see Weintraub et al., 2016). “There was good evidence for efficacy and short-term tolerability overall, and none of the current antipsychotics (except clozapine) have been shown to be efficacious,” he added.

Up to 40 percent of Parkinson’s patients develop frequent psychoses, according to the National Parkinson Foundation. No good drugs for this symptom currently exist, with older antipsychotics carrying a “black box” warning of increased mortality for dementia patients (see Oct 2005 news; Jan 2009 news; Feb 2011 news). Many of those drugs target dopaminergic systems, which are already perturbed in people with Parkinson’s. Pimavanserin, a serotonin inverse agonist, is a new class of drug, noted Jim Leverenz of the Cleveland Clinic. “The important clinical implication is that this is a fairly clean and effective drug that avoids the dopaminergic system and the motor side effects that can accompany treatment with typical antipsychotics.”

Pimavanserin diminished psychosis in a six-week Phase 3 trial of 199 Parkinson’s patients. In addition, participants reported better sleep and daytime alertness. The drug did not worsen motor function and was well-tolerated, with the most serious side effects being edema and confusion. Some participants have now taken the compound on an open-label basis for several years (see Apr 2013 news; Nov 2013 news). 

The drug is under investigation for other neurodegenerative disorders as well, with a Phase 2 trial ongoing in Alzheimer’s. In a separate Phase 2 trial, clinicians are testing another serotonin inverse agonist, nelotanserin, for dementia with Lewy bodies. “Mechanisms for psychosis in patients with DLB would be similar to those in Parkinson’s patients, and one would hope they would respond similarly to treatment,” noted Leverenz. Even in AD, psychosis is often linked to the presence of Lewy bodies as well. Testing this new class of agent in different conditions would be a reasonable next step, Leverenz said. In the meantime, scientists agreed that should pimavanserin be approved for PD, then clinicians will likely begin prescribing it off-label for other conditions.—Madolyn Bowman Rogers and Tom Fagan

Comments

  1. This development will be welcomed by people with PD and psychosis and their families, and by clinicians who struggle to manage such symptoms and who find themselves resorting to treatments of limited effectiveness but significant toxicity.

    The question about using pimavanserin to treat DLB is interesting and important. If this drug is approved for use in PD psychosis, there will immediately be pressure to use it in people with DLB, who often have severe hallucinations and delusions but who are extremely hard to treat because of their severe neuroleptic sensitivity and because of possible increased susceptibility to confusion when treated with clozapine. However, PD psychosis to DLB isn’t a straightforward extrapolation. Although PD psychosis and DLB share some similarities clinically and pathologically, there are substantial differences, likely reflecting that they are underpinned by variable patterns of change in multiple neurotransmitter systems and circuits.

    Patients with MMSE as low as 21 were included in the Acadia pimavanserin trial, and a third were on cholinesterase inhibitors (CHEIs) throughout, but since “patients with delirium” were excluded from entry few probably had the fluctuating pattern of symptoms that is typical of DLB. Elaine Perry published data on Newcastle brain bank cases as far back as the early 1990s showing that preservation of 5-HT2 receptors in the temporal cortex differentiated hallucinating from non-hallucinating DLB cases and suggested a hyper-serotinergic/hypo-cholinergic imbalance as a basis for visual hallucinations in particular. My feeling is that it is the fluctuating, cognitively impaired group who might benefit more than others. The combination of a compound like pimavanserin together with a cholinergic enhancer in DLB might have very significant positive effects upon attention and visual hallucinations, with secondary benefits in delusions and other neuropsychiatric symptoms such as anxiety. But the neurochemical volatility that might make these DLB patients more responsive to treatment could also lead to increased side effects, as we see with neuroleptics and to a lesser extent with CHEIs. So I would urge some careful early dose-finding work to establish safety in DLB, before hopefully moving quickly on to finding which patients and which symptoms benefit most.

    View all comments by Ian McKeith

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References

News Citations

  1. More Trouble for Atypical Antipsychotics—Dementia Patients at Risk
  2. Antipsychotics on Trial Again—DART-AD Confirms Increased Mortality
  3. Warning on Antipsychotics Heeded, But What’s the Alternative?
  4. Drug Data Dash at AAN Annual Conference
  5. Parkinson’s Antipsychotic Looks Good in Phase 3 Trial

Paper Citations

  1. Weintraub D, Chiang C, Kim HM, Wilkinson J, Marras C, Stanislawski B, Mamikonyan E, Kales HC. Association of Antipsychotic Use With Mortality Risk in Patients With Parkinson Disease. JAMA Neurol. 2016 May 1;73(5):535-41. PubMed.

External Citations

  1. The Wall Street Journal
  2. Business Wire
  3. Phase 3 trial
  4. Phase 2 trial
  5. Phase 2 trial

Further Reading

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