- Pimavanserin as an adjunct to an antipsychotic showed significant improvements in the negative symptoms of schizophrenia vs. antipsychotic treatment alone

- Pimavanserin well-tolerated among study participants

Acadia Pharmaceuticals Inc. (Nasdaq: ACAD) announced today that The Lancet Psychiatry published results from the Phase 2 ADVANCE study. ADVANCE was an international, 26-week, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of adjunctive pimavanserin treatment in outpatients with moderate-to-severe predominant negative symptoms of schizophrenia who had achieved control of positive symptoms with their ongoing antipsychotic treatment.

ADVANCE met its primary endpoint, with significant improvement observed with pimavanserin for the change from baseline to week 26 on the Negative Symptoms Assessment-16 (NSA-16) total score, compared with placebo (-10.4 vs. -8.5; p=0.043). In a post hoc analysis, greater improvement in the NSA-16 total score compared to placebo was observed in the 53.8% of patients (n=107) who received the highest pimavanserin dose of 34 mg (-11.6 vs. -8.5; unadjusted p=0.0065).

“Negative symptoms of schizophrenia are associated with higher overall morbidity and decreased functioning, and there are no approved treatments,” said Dragana Bugarski-Kirola, M.D., MBA, MSci, Vice President, Clinical Development, Acadia Pharmaceuticals, GmbH. “These findings lend confidence in our continued evaluation of pimavanserin for the treatment of negative symptoms of schizophrenia. We look forward to sharing results of the ongoing, similarly-designed, Phase 3 ADVANCE-2 study, evaluating pimavanserin 34 mg in patients with predominant negative symptoms of schizophrenia.”

In the study, pimavanserin was well-tolerated with high completion rates of approximately 86% in both the pimavanserin and placebo treatment groups through 26 weeks and similar rates of adverse events between pimavanserin (39.8%) and placebo (35.1%). Additionally, no clinically significant differences in vital signs, weight, metabolic syndrome or extrapyramidal symptoms were observed in the pimavanserin group compared to placebo. Serious adverse events were reported in 2.0% of patients on pimavanserin and 0.5% of patients on placebo and discontinuations due to adverse events were also low, 5.0% for pimavanserin and 3.0% for placebo.

“The clinically and statistically significant improvement in negative symptoms of schizophrenia with pimavanserin as an adjunctive treatment with other antipsychotics, combined with the observed favorable tolerability profile, suggest pimavanserin may offer a promising approach in treating negative symptoms of schizophrenia, a severe and difficult condition to treat and significant area of unmet need for patients,” said Henry Nasrallah, M.D., study co-author, Professor-Emeritus, Psychiatry & Behavioral Neuroscience, University of Cincinnati College of Medicine, Cincinnati, Ohio.

The ADVANCE study is available here.

About ADVANCE

The Phase 2 ADVANCE study was a 26-week, randomized, double-blind, placebo-controlled, multi-center, international study designed to examine the efficacy and safety of pimavanserin in patients with schizophrenia who have predominant negative symptoms while on a stable background antipsychotic therapy. 403 patients were randomized to receive once-daily pimavanserin (n=201) or placebo (n=202) as an adjunct treatment to their ongoing antipsychotic in a flexible dosing regimen. The starting daily dose of 20 mg of pimavanserin at baseline could have been adjusted to 34 mg or 10 mg during the first eight weeks of treatment. 53.8% of patients who were randomized to receive pimavanserin completed the trial on 34 mg, 44.7% on 20 mg, and 1.5% on 10 mg. The primary endpoint of the study was the change from baseline to week 26 on the Negative Symptom Assessment-16 (NSA-16) total score.

Baseline characteristics were similar across two treatment arms. The most prevalent background antipsychotics in the study included risperidone (38.5%), aripiprazole (32.5%), and olanzapine (28.0%). The average age of patients in the study was 37.2 years.

About Schizophrenia and Negative Symptoms

According to the National Mental Health Institute, approximately one percent of the U.S. population develops schizophrenia during their lifetime.¹ Schizophrenia is a chronic, debilitating and often progressive mental illness characterized by disturbances in thinking, emotional reaction, and behavior. These disturbances may include positive symptoms, such as hallucinations and delusions, and a range of negative symptoms, including loss of interest, emotional withdrawal, and cognitive disturbances.

Studies show that about 40 to 50 percent of schizophrenia patients suffer from predominant negative symptoms.² While currently available antipsychotic treatments for schizophrenia target positive symptoms, most patients remain functionally impaired because of negative symptoms, cognitive deficits, and limited social function. Negative symptoms have been shown to impair patient outcomes, e.g., personal relationships, household and work performance and lower quality of life.^3,4,5 Negative symptoms have also been shown to be associated with an increased likelihood of relapse and hospital admission, as well as a longer duration of hospital admissions.^3,6

About Pimavanserin

Pimavanserin is a selective serotonin inverse agonist and antagonist preferentially targeting 5-HT_2A receptors. These receptors are thought to play an important role in psychiatric and neuropsychiatric disorders. In vitro, pimavanserin demonstrated no appreciable binding affinity for dopamine (including D2), histamine, muscarinic, or adrenergic receptors. Pimavanserin was approved for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis by the U.S. Food and Drug Administration in April 2016 under the trade name NUPLAZID^®. NUPLAZID is not approved for treatment of negative symptoms of schizophrenia. In addition, Acadia is developing pimavanserin in other psychiatric and neuropsychiatric conditions.

About Acadia Pharmaceuticals

Acadia is trailblazing breakthroughs in neuroscience to elevate life. For more than 25 years we have been working at the forefront of healthcare to bring vital solutions to people who need them most. We developed and commercialized the first and only approved therapy for hallucinations and delusions associated with Parkinson’s disease psychosis. Our late-stage development efforts are focused on dementia-related psychosis, negative symptoms of schizophrenia and Rett syndrome, and in early-stage clinical research we are exploring novel approaches to pain management, and cognition and neuropsychiatric symptoms in central nervous system disorders. For more information, visit us at www.acadia-pharm.com and follow us on LinkedIn and Twitter.

Important Safety Information and Indication for NUPLAZID^® (pimavanserin)

Indication

NUPLAZID is indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.

Important Safety Information

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS

• Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
• NUPLAZID is not approved for the treatment of patients with dementia-related psychosis unrelated to the hallucinations and delusions associated with Parkinson’s disease psychosis.

• Contraindication: NUPLAZID is contraindicated in patients with a history of a hypersensitivity reaction to pimavanserin or any of its components. Rash, urticaria, and reactions consistent with angioedema (e.g., tongue swelling, circumoral edema, throat tightness, and dyspnea) have been reported.

• Warnings and Precautions: QT Interval Prolongation

• NUPLAZID prolongs the QT interval. The use of NUPLAZID should be avoided in patients with known QT prolongation or in combination with other drugs known to prolong QT interval including Class 1A antiarrhythmics or Class 3 antiarrhythmics, certain antipsychotic medications, and certain antibiotics.
• NUPLAZID should also be avoided in patients with a history of cardiac arrhythmias, as well as other circumstances that may increase the risk of the occurrence of torsade de pointes and/or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and presence of congenital prolongation of the QT interval.

• Adverse Reactions: The common adverse reactions (≥2% for NUPLAZID and greater than placebo) were peripheral edema (7% vs 2%), nausea (7% vs 4%), confusional state (6% vs 3%), hallucination (5% vs 3%), constipation (4% vs 3%), and gait disturbance (2% vs <1%).

• Drug Interactions:

• Coadministration with strong CYP3A4 inhibitors (e.g., ketoconazole) increases NUPLAZID exposure. Reduce NUPLAZID dose to 10 mg taken orally as one tablet once daily.
• Coadministration with strong or moderate CYP3A4 inducers reduces NUPLAZID exposure. Avoid concomitant use of strong or moderate CYP3A4 inducers with NUPLAZID.

Dosage and Administration

Recommended dose: 34 mg capsule taken orally once daily, without titration.

NUPLAZID is available as 34 mg capsules and 10 mg tablets.

Please read the full Prescribing Information including Boxed WARNING.

Forward-Looking Statements

Statements in this press release that are not strictly historical in nature are forward-looking statements. These statements include but are not limited to statements regarding the timing of future events. These statements are only predictions based on current information and expectations and involve a number of risks and uncertainties. Actual events or results may differ materially from those projected in any of such statements due to various factors, including the risks and uncertainties inherent in drug development, approval and commercialization. For a discussion of these and other factors, please refer to Acadia’s annual report on Form 10-K for the year ended December 31, 2020 as well as Acadia’s subsequent filings with the Securities and Exchange Commission. You are cautioned not to place undue reliance on these forward-looking statements, which speak only as of the date hereof. This caution is made under the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. All forward-looking statements are qualified in their entirety by this cautionary statement and Acadia undertakes no obligation to revise or update this press release to reflect events or circumstances after the date hereof, except as required by law.

References

¹NAMI, Mental Help, PsyCom, SAMHSA study, NIMH data consolidation.

²Patel et al. 2015; Haro et al. 2015; Bobes et al. 2010; Chue and Lalonde, 2014.

³Patel R, Jayatilleke N, Broadbent M, et al. Negative symptoms in schizophrenia: a study in a large clinical sample of patients using a novel automated method. BMJ Open 2015 Sep 7;5(9):e007619.

⁴Andrianarisoa M, Boyer L, Godin O, et al. Childhood trauma, depression and negative symptoms are independently associated with impaired quality of life in schizophrenia. Results from the national FACE-SZ cohort. Schizophr Res. 2017;185:173-81.

⁵Milev P, Ho BC, Arndt S, et al. Predictive values of neurocognition and negative symptoms on functional outcome in schizophrenia: a longitudinal first-episode study with 7-year follow-up. Am J Psychiatry. 2005;162:495-506.

⁶Bowtell M, Ratheesh A, McGorry P, et al. Clinical and demographic predictors of continuing remission or relapse following discontinuation of antipsychotic medication after a first episode of psychosis. A systematic review. Schizophr Res. 2018;197:9-18.

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