Therapeutics

Pimavanserin

Overview

Name: Pimavanserin
Synonyms: Nuplazid, ACP-103, Pimavanserin tartrate
Therapy Type: Small Molecule (timeline)
Target Type: Other Neurotransmitters (timeline)
Condition(s): Alzheimer's Disease, Schizophrenia, Dementia
U.S. FDA Status: Alzheimer's Disease (Phase 2), Schizophrenia (Phase 3), Dementia (Phase 3)
Company: Acadia Pharmaceuticals
Approved for: Parkinson's psychosis

Background

Pimavanserin is a serotonergic agent, specifically a selective serotonin (5-HT) 2A receptor inverse agonist. In April 2016, the FDA approved this once-daily drug to treat the delusions and hallucinations that are a feature of psychosis in Parkinson's disease, and it came on the market in the United States in June (April 2016 newsprescribing information). Pimavanserin is thought to have fewer adverse effects than older antipsychotic agents used to treat Parkinson's psychosis, but evidence remains limited (e.g., Sarva and Henchcliffe, 2016Tampi et al., 2019).

Pimavanserin is in development for psychosis, agitation, and aggression in Alzheimer's disease. It is also in development for schizophrenia, and for psychosis related to all-cause dementia. A different serotonin 2A receptor inverse agonist, nelotanserin, is in Phase 2 development for dementia with Lewy bodies (DLB).

Findings

Between November 2013 and November 2016, Acadia conducted a Phase 2 study of pimavanserin in 181 nursing home residents in London, who had psychosis along with their clinical diagnosis of AD. Participants received a 12-week course of 40 mg pimavanserin or placebo, and were evaluated on the nursing home version of the neuropsychiatric inventory (NPI), the short form of the Cohen-Mansfield Agitation Inventory (CMAI-SF), and the Alzheimer’s Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC). The primary outcome was change from baseline to six weeks in the NPI-NH, where lower scores mean fewer symptoms. By two weeks, both the placebo and pimavanserin groups had improved on the test. At six weeks, those taking the drug had a 39.5 percent reduction in NPI-NH scores, compared to 19.3 percent reduction in the placebo group. However, by 12 weeks, scores were down 40 percent from baseline in both groups. These results were presented at CTAD, and later formally published (Dec 2017 conference newsBallard et al., 2018). A subsequent subgroup analysis claimed a larger treatment benefit in participants with more severe psychosis (Ballard et al., 2019). 

In November 2016, Acadia started SERENE, a phase 2 study comparing the effect of 34 mg and 20 mg Pimavanserin to placebo in people with agitation and aggression as part of their Alzheimer's disease, on the Cohen-Mansfield Agitation Inventory as primary outcome. This trial anticipated enrolling 432 patients at 56 sites, but stopped randomizing patients in November 2017 and was marked as complete in March 2018, with 111 patients enrolled and 83 of them having completed treatment. In March 2019, the trial's status was further updated to 'terminated.' Results, as well as sponsor rules restricting principal investigators from discussing and publishing results, are published in the clinicaltrials.gov History of Changes section of this trial. At 111 actual participants, the trial was underpowered to detect a treatment effect. The SERENE trial had a one-year open-label extension study, which recruited 79 patients and ended in February 2019.

In September 2017, Acadia started a Phase 3 study at 117 study locations in the U.S., Europe, and Chile, to evaluate pimavanserin’s efficacy in preventing psychosis relapse in people who had previously responded to the drug. It aimed to enroll 356 participants with all-cause dementia who had had symptoms of psychosis for at least two months. After an 12-week open-label period, during which time participants took 34 mg pimavanserin with the option to drop to 20 mg, those who responded continued with a 26-week double-blind period, in which they were randomized to pimavanserin or placebo. The primary endpoint was delay in psychosis relapse with a p value below 0.0033. Relapse was defined as hospitalization due to dementia-related psychosis, significant deterioration of dementia-related symptoms on clinical scales, withdrawal from the study due to lack of efficacy, or use of an off-label antipsychotic medication. Patients were followed until relapse occurred (Cummings et al., 2018). According to a company press release, an interim analysis indicated that this trial met its primary endpoint early (Sept 2019 news).

In May 2018, Acadia started enrolling 300 people who have clinical agitation and aggression along with a neurodegenerative disease into a Phase 3 safety study, to be conducted at 65 sites in European, Asian, South American countries and the U.S. It enrolls patients living at home or in assisted living. The study compares the effect of an eight-week course of 34 mg pimavanserin to placebo on treatement-emergent adverse events, extrapyramidal symptoms, and the MMSE; it offers a one-year open-label extension.

For all trials of pimavanserin, see clinicaltrials.gov.

Last Updated: 21 Sep 2019

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References

News Citations

  1. Pimavanserin Trial Raises Hope for Treating Dementia-Related Psychosis
  2. Phase 3 Trial Suggests Pimavanserin Assuages Psychosis in Dementia
  3. Pimavanserin Nears Approval to Treat Psychosis in Parkinson’s

Therapeutics Citations

  1. Nelotanserin

Paper Citations

  1. . Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer's disease psychosis: a phase 2, randomised, placebo-controlled, double-blind study. Lancet Neurol. 2018 Mar;17(3):213-222. PubMed.
  2. . Pimavanserin in Alzheimer's Disease Psychosis: Efficacy in Patients with More Pronounced Psychotic Symptoms. J Prev Alzheimers Dis. 2019;6(1):27-33. PubMed.
  3. . Pimavanserin: Potential Treatment For Dementia-Related Psychosis. J Prev Alzheimers Dis. 2018;5(4):253-258. PubMed.
  4. . Evidence for the use of pimavanserin in the treatment of Parkinson's disease psychosis. Ther Adv Neurol Disord. 2016 Nov;9(6):462-473. Epub 2016 Oct 3 PubMed.

External Citations

  1. clinicaltrials.gov
  2. prescribing information
  3. Tampi et al., 2019

Further Reading

Papers

  1. . Angiotensin Mediated Oxidative Stress and Neuroprotective Potential of Antioxidants and AT1 Receptor Blockers. Mini Rev Med Chem. 2016 Oct 24; PubMed.
  2. . Differential effects of angiotensin II receptor blockers on Aβ generation. Neurosci Lett. 2014 May 1;567:51-6. Epub 2014 Mar 27 PubMed.
  3. . Telmisartan Modulates Glial Activation: In Vitro and In Vivo Studies. PLoS One. 2016;11(5):e0155823. Epub 2016 May 17 PubMed.
  4. . Systolic blood pressure variation and mean heart rate is associated with cognitive dysfunction in patients with high cardiovascular risk. Hypertension. 2015 Mar;65(3):651-61. Epub 2015 Jan 12 PubMed.
  5. . [Effects of telmisartan on the level of Aβ1-42, interleukin-1β, tumor necrosis factor α and cognition in hypertensive patients with Alzheimer's disease]. Zhonghua Yi Xue Za Zhi. 2012 Oct 23;92(39):2743-6. PubMed.
  6. . Ameliorative effects of telmisartan on the inflammatory response and impaired spatial memory in a rat model of Alzheimer's disease incorporating additional cerebrovascular disease factors. Biol Pharm Bull. 2012;35(12):2141-7. PubMed.
  7. . Advances in Management of Neuropsychiatric Syndromes in Neurodegenerative Diseases. Curr Psychiatry Rep. 2019 Aug 8;21(8):79. PubMed.
  8. . Advances in Management of Psychosis in Neurodegenerative Diseases. Curr Treat Options Neurol. 2019 Jan 23;21(1):3. PubMed.