Three-month paliperidone palmitate, an investigational atypical antipsychotic, significantly delayed time to relapse compared to placebo in patients with schizophrenia, according to a new Phase 3 clinical study published in the Journal of the American Medical Association (JAMA) Psychiatry. Results of the study served as the basis for the recent New Drug Application (NDA) filing for three-month paliperidone palmitate injection to treat schizophrenia in adults with the U.S. Food and Drug Administration ("FDA") by Janssen Research & Development, LLC, ("Janssen"), the study sponsor. The FDA granted the filing Priority Review status in January, with a regulatory action date of May 18, 2015.
If approved, the treatment would enable patients to receive injections once every three months, compared to currently available formulations that are administered monthly, or oral medicines that must be taken daily. It would be the first and only long-acting atypical antipsychotic with a dosing schedule of four times a year. Janssen plans filings for three-month paliperidone palmitate in many markets outside of the U.S. later this year.
The final published analysis results are consistent with previously announced interim analysis results which showed a statistically significant benefit of three-month paliperidone palmitate compared to placebo. In March 2014, following an Independent Data Monitoring Committee (IDMC) recommendation based on positive efficacy, Janssen halted this study early.
The study data also are being presented this week at the 23rd annual European Congress of Psychiatry in Vienna, Austria, and at the 15th annual International Congress on Schizophrenia Research in Colorado Springs, Colorado.
"There remains significant unmet need for the approximately 2.4 million people in the United States who live with schizophrenia. The results of this study reinforce the need for this unprecedented treatment option for patients with schizophrenia who may benefit from a new, less frequently dosed treatment choice," said Husseini K. Manji, MD, Global Head, Neuroscience Therapeutic Area, Janssen. "We look forward to continuing to work with the FDA and other regulatory authorities to bring this innovative three-month formulation to patients as soon as possible."
"Physicians need a broad range of treatments to help patients with schizophrenia early in the course of their disease," said David Hough, MD, Schizophrenia Disease Area Leader, Janssen, a study author. "This clinical trial showed three-month paliperidone palmitate demonstrated a statistically significant difference from placebo in delaying time to relapse, validating its potential as a new treatment option which could positively affect the care of people with schizophrenia."
This Phase 3, international, randomized, multicenter, double-blind, placebo-controlled, relapse prevention study evaluated 305 adults in the double-blind phase. There were 160 study patients in the three-month paliperidone palmitate treatment group and 145 patients in the placebo group. All of the patients enrolled in the study met the DSM-IV diagnosis of schizophrenia and had a Positive and Negative Syndrome Scale (PANSS) total score of less than 120 at screening and baseline. Prior to randomization, individuals were first stabilized with INVEGA SUSTENNA® (paliperidone palmitate) one-month formulation during a 17-week, open-label transition period. Patients who met criteria for clinical stability then received a single three-month paliperidone palmitate injection during a 12-week, open-label maintenance phase. Stable patients were then randomized to treatment with either three-month paliperidone palmitate or placebo. Patients remained in the double-blind phase until they relapsed, withdrew from the study, or the study terminated.
Relapse was defined as worsening schizophrenia symptoms as determined by PANSS assessment criteria, hospitalization for schizophrenia symptoms, clinically significant self-injury, suicidal or homicidal ideation or violent behavior.
After the first 42 relapse events occurred in the double-blind phase, a pre-specified interim analysis overseen by an IDMC showed that three-month paliperidone palmitate significantly delayed time to relapse compared to placebo (hazard ratio [HR] 3.45; 95% CI: 1.73-6.88; p=0.0002; median time to relapse for placebo group: 274 days). While there were 11 relapses in the three-month paliperidone palmitate treatment group, these were too few to provide a reliable estimate of the duration of time until relapse for that group of patients. Final analysis results were consistent with that of the interim analysis, confirming three-month paliperidone palmitate's superiority over placebo for delaying time to relapse of schizophrenia symptoms (HR 3.81; 95% CI: 2.08-6.99; p<0.0001; median time to relapse for placebo group: 395 days, and three-month paliperidone palmitate group: not estimable).
In this study, the most common treatment-emergent adverse events (TEAEs), which occurred in at least 3% of patients in the double-blind phase of the study and that occurred more frequently in the three-month paliperidone palmitate group than placebo group, were headache (9% vs. 4%), increased weight (9% vs. 3%), nasopharyngitis (6% vs. 1%) and akathisia, a movement disorder (4% vs. 1%). During the double-blind phase, a total of 6 patients (4%) in the three-month paliperidone palmitate group reported injection site-related TEAEs; of which, injection site pain (2 patients [1%]) was most frequently reported. Prolactin-related TEAEs occurred in 1 of 42 female patients in the three-month paliperidone palmitate group (2%). Serious TEAEs occurred 4 times more often in the placebo group than in the three-month paliperidone palmitate group (10% vs. 3%), and were mostly related to an increase in psychiatric symptoms reflecting the course of the underlying disease.
INVEGA SUSTENNA® (paliperidone palmitate) was approved by the U.S. FDA in July 2009 as the first once-monthly atypical long-acting injection to treat schizophrenia and is now approved in more than 80 countries. Late last year the FDA approved INVEGA SUSTENNA® for the treatment of schizoaffective disorder, making it the first and only once-monthly medication to treat this condition. INVEGA SUSTENNA® and three-month paliperidone palmitate utilize Alkermes' proprietary NanoCrystal® technology, which enables solubility of poorly water-soluble compounds.
For additional study information, visit ClinicalTrials.gov.