Phase 3 Antipsychotic Candidate Pimavanserin Fails to Achieve Primary Efficacy Endpoint

freshidea/AdobeStock

Recently released topline data from the phase 3 ADVANCE-2 trial reveals that the antipsychotic candidate pimavanserin did not achieve the primary efficacy endpoint of control of negative symptoms in patients with schizophrenia. Acadia Pharmaceuticals intends to discontinue research on pimavanserin for schizophrenia, following this failure.¹

"Treatments to improve the negative symptoms in schizophrenia, a large unmet need, remain elusive," said John J. Miller, MD, Editor in Chief of Psychiatric Times. "Pimavanserin (Nuplazid), an inverse serotonin 2A receptor agonist, failed to separate from placebo in a Phase 3 double-blind study of 454 adults with schizophrenia treated for 26 weeks. We will await ongoing clinical trials with drugs of different mechanisms of action in our continued attempt to develop a treatment to improve negative symptoms."

The ADVANCE-2 study—a 26-week, double-blind, randomized, placebo-controlled trial—evaluated a 34 mg dose of pimavanserin in 454 adult participants with negative symptoms of schizophrenia who had not achieved positive response with previous antipsychotic treatment. Investigators used the Negative Symptom Assessment-16 scale (NSA-16) to measure change in symptoms. At 26 weeks, those treated with pimavanserin saw an 11.8 drop in scores in NSA-16 scores, while those in the placebo group demonstrated an 11.1 drop in NSA-16 scores. The effect size (0.07) failed to reach statistical significance. Pimavanserin’s was well-tolerated, consistent with previous trials, and had an adverse event rate of 30.4%, as compared with 40.3% for the placebo group.

“We are disappointed the trial did not meet its primary endpoint given the significant unmet need in patients with negative symptoms of schizophrenia,” said Steve Davis, Chief Executive Officer of Acadia. “We will continue to analyze these data with our scientific advisors, but we do not intend to conduct any further clinical trials with pimavanserin. We want to thank the patients, their families, and the investigators for their contributions in this important study.”

The mechanism of pimavanserin is not yet fully understood and it has a spotty history with US Food and Drug Administration approval. In 2016, it was approved for the treatment of hallucinations associated with Parkinson disease psychosis, although it carries a black box warning for risk of death in older patients who have dementia-related psychosis. Then in April 2021, it was rejected for approval in dementia-related psychosis,² followed by another rejection in August 2022 for hallucinations associated with Alzheimer disease psychosis.³

This is the second rejection for a schizophrenia treatment in a month. On February 27, 2024, the FDA issued a Complete Response Letter in follow-up to the New Drug Application for roluperidone (MIN-101) as a treatment for negative symptoms of schizophrenia, claiming there was insufficient data to establish that the change in negative symptoms with roluperidone treatment was clinically meaningful. Investigators plan to “review FDA’s feedback and consider our potential paths forward.”⁴ 

References

1. Acadia Pharmaceuticals announces top-line results from phase 3 ADVANCE-2 trial of pimavanserin in negative symptoms of schizophrenia. Business Wire. March 11, 2024. https://www.businesswire.com/news/home/20240311430953/en/Acadia-Pharmaceuticals-Announces-Top-Line-Results-from-Phase-3-ADVANCE-2-Trial-of-Pimavanserin-in-Negative-Symptoms-of-Schizophrenia

2. U.S. FDA declines to approve expanded use of Acadia's antipsychotic drug. Reuters. August 5, 2022. Accessed March 12, 2024. https://www.reuters.com/business/future-of-health/us-fda-declines-approve-expanded-use-acadias-antipsychotic-drug-2022-08-05/

3. Kuntz L. Caution ahead: FDA asks for more info on expanded use of antipsychotic drug. Psychiatric Times. August 9, 2022. https://www.psychiatrictimes.com/view/caution-ahead-fda-asks-for-more-info-on-expanded-use-of-antipsychotic-drug

4. O’Brien E. FDA Issues CRL for roluperidone in the treatment of negative symptoms of schizophrenia. Psychiatric Times. February 27, 2024. https://www.psychiatrictimes.com/view/fda-issues-crl-for-roluperidone-in-the-treatment-of-negative-symptoms-of-schizophrenia