COLORADO SPRINGS, Colorado — The long-term formulation of the antipsychotic paliperidone (Invega, Janssen Pharmaceuticals, Inc) significantly delays relapse in schizophrenia patients with no increase in adverse events (AEs), results of an international phase 3 randomized controlled trial show.
"Three-month paliperidone palmitate reduces the risk of relapse compared with placebo and offers a unique treatment option for patients with schizophrenia," said Adam Savitz, MD, PhD, of Janssen Research and Development, LLC, in presenting the findings here at the 15th International Congress on Schizophrenia Research (ICOSR).
In addition, said Dr Savitz, the drug was "generally tolerable with a similar safety profile consistent with other marketed paliperidone formulations."
The study was presented here and was also published this week in JAMA Psychiatry.
Under FDA Review
The drug is currently under review by the US Food and Drug Administration (FDA). If approved, it may be the first atypical antipsychotic administered on a four-times-a-year dosing schedule.
Paliperidone palmitate is currently available in a once-monthly formulation that was approved by the FDA in 2009 as the first once-monthly atypical long-acting injection treatment for schizophrenia. In 2014, its approval was extended to include schizoaffective disorder.
In the new phase 3, multicenter, double-blind study, the Janssen researchers evaluated relapse prevention with the 3-month formulation.
The study involved 506 patients with schizophrenia who met DSM-IV diagnosis and whose total score on the Positive and Negative Syndrome Scale (PANSS) was less than 120 at screening and baseline.
Patients were initially enrolled in a 17-week open transition phase, in which they were treated with the 1-month formulation of paliperidone. Those who achieved stability were then transitioned to a 12-week open-label maintenance phase, which would be required in standard practice. Those who remained stable were then randomly assigned in the double-blind phase of the study to receive either a single injection of the 3-month formulation (n = 160) or a placebo injection (n = 145).
Relapse was defined as worsening schizophrenia symptoms according to PANSS criteria, hospitalization for schizophrenia symptoms, self-injury, suicidal or homicidal ideation, or violent behavior.
With the results of a prespecified interim analysis after 42 relapse events showing significantly higher rates of relapse in the placebo group (P = .0002), an independent data monitoring committee determined that the study could be terminated at that point.
A final analysis showed an additional 14 relapses, for a total of 56, including 42 (29%) patients in the placebo group and 14 (9%) in the paliperidone group.
The hazard ratio for relapse in the placebo group vs the group receiving the 3-month injection was 3.45 (95% confidence interval, 1.73; 6.88).
Although the median time to relapse in the placebo group was 274 days, it was not estimable for the 3-month injection group.
Secondary endpoints of change from baseline in PANSS total scores showed greater improvement in the paliperidone group (−0.5 [8.36]). The scores worsened significantly in the placebo group (6.7 [14.40]; P < .001). For patients in the treatment group, there was also greater improvement in the Clinical Global Impressions Scale scores (0.1 [0.60]) compared with patients receiving placebo (0.4 [0.87]; P < .001).
Dr Savitz noted that the drug's safety profile was consistent with that of the other marketed paliperidone formations, and there was only one withdrawal during the double-blind phase, which involved a patient in the placebo group.
In the double-blind phase, 19% of treatment-emergent AEs were considered possibly drug related in the placebo group vs 34% in the paliperidone group.
The most commonly reported AEs related to treatment were nasopharyngitis (5.6% in the paliperidone group vs 1.4% in placebo), increased weight (8.8% vs 3.4%), headache (8.8% vs 4.1%), and akathisia (4.4% vs 0.7%).
The median peak plasma levels of the 3-month formulation were only slightly higher than the those of the 1-month formulation, and there were no signs of cardiac side effects or long QT syndrome, Dr Savitz said.
He added that the 3-month paliperidone formulation can be used either as a gluteal or deltoid injection.
"The half-life is a little longer for gluteal than deltoid, but even with deltoid, it is still approximately 90 days."
"Due to its extended half-life, paliperidone 3-month may reduce the risk of relapse and offer a unique treatment option in patients with schizophrenia," he said.
Low Side-effect Profile a Surprise
Commenting on the study for Medscape Medical News, session moderator Christophe U. Correll, MD, echoed comments from the audience concerning what would appear to be an otherwise convenient treatment ― side effects.
"The main potential concern [with this formulation] is that if a severe side effect occurs, one cannot stop the medication promptly and that it will stay in the system for several months," said Dr Correll, who is medical director of the Recognition and Prevention Program and professor of psychiatry at Hofstra Northshore-LIJ School of Medicine, in Glen Oaks, New York.
"However, patients will need to have tolerated the once-monthly formulation of paliperidone first, so it is very unlikely that a side effect would emerge that would not be manageable even during the relatively slow washout phase."
"In addition, if a clinician would want to switch a patient to another antipsychotic, there would be a very long period of combination treatment during the slow washout of the 3-month injectable paliperidone. This is something clinicians will need to consider when dosing the new antipsychotic."
Dr Correll noted that he was surprised to see the relatively low rate side effects.
"In order to have therapeutic blood levels for as long as 3 months, one needs to load the patient with a relatively high dose to begin with," he explained.
"These higher peak levels in the beginning of the injection interval could be associated with more side effects than with once-monthly or biweekly injectable antipsychotics."
"However, since paliperidone 3-month has a relatively slow rising Cmax at 4 weeks after the injection, this seems to mitigate the risk for peak level–related side effects, such as akathisia or sedation."
The FDA granted new drug application filing priority review status in January, and a regulatory action date has been set for May 18, 2015.
Dr Savitz is an employee of Janssen Research and Development. Dr Correll has been a consultant and/or advisor to or has received honoraria from AbbVie, Actavis, Alkermes, Bristol-Myers Squibb, Eli Lilly, Genentech, Gerson Lehrman Group, IntraCellular Therapies, Janssen/J&J, Lundbeck, MedAvante, Medscape, Otsuka, Pfizer, ProPhase, Reviva, Roche, Sunovion, Supernus, and Takeda. He has received grant support from BMS, Otsuka, and Takeda.
15th International Congress on Schizophrenia Research (ICOSR) Abstract 2087240. Presented March 31, 2015.
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Cite this: Long-term Injectable Antipsychotic Cuts Schizophrenia Relapse - Medscape - Apr 06, 2015.