FDA New Drug Approval Watch
Aripiprazole (Abilify), a new drug for schizophrenia, received FDA approval November 15, 2002. Aripiprazole is a joint product of both Bristol-Myers Squibb and Otsuka Pharmaceutical Co. Aripiprazole is the first of a new generation of atypical antipsychotics with a complex mechanism of action that involves partial agonism at dopamine D2, and serotonin 5-HT1A and antagonism at serotonin 5-HT2A receptors. In animal models of dopamine hypoactivity, aripiprazole has the properties of a functional agonist and in models of dopamine hyperactivity, it functions as an antagonist. Therefore, it has been referred to as a "dopamine-serotonin system stabilizer"—more of a dopamine "dimming switch" as opposed to an "on-off switch" that we have seen with the current typicals and atypicals. It was approved as an oral, once-daily drug and will be marketed in the 15-mg and 30-mg dosages. The pivotal data included 4 short term (4- and 6-week) placebo-controlled trials of acutely relapsed inpatients with DSMIV criteria for schizophrenia. In all the studies, aripiprazole was superior to placebo and equal to comparators (risperidone or haldol) on the Positive and Negative Syndrome Scale (PANSS). In a longer-term 52 week, 1294-subject study, aripiprazole 30 mg was found superior to haldol 10 mg in responders demonstrating a 30% improvement in PANSS.
While clearly effective, aripiprazole’s side effect profile is what differentiates it from the typicals and atypicals. In the pivotal data set there was no difference from placebo with respect to prolactin levels, extra-pyramidal symptoms, weight gain, or QTc prolongation. Mild headache, insomnia, agitation, and nervousness were the only significant side effects vs placebo. Only 2 cases of NMS were reported in the entire premarketing worldwide database comprising about 6000 patients. The efficacy and safety data are provided by the package insert.
There are 2.2 million Americans with schizophrenia. It is estimated that 33% switch or discontinue antipsychotic medication and most cite side effects issues as the reason. Given the problem of EPS side effects from the older, typical antipsychotics and with the growing concern for diabetes, weight gain, and QTc prolongation caused by the newer atypicals, aripiprazole is a welcome addition to the neuropsychopharmocologist armamentarium. We also look for additional postmarketing studies to assess aripiprazole’s efficacy in bipolar, Alzheimer’s disease, and even migraine.
More Progress on New Sleep Drug
In a previous Neurology Alert we reported on a development of a new sleep drug now named indiplon, which is currently under investigation, and we continue to follow its clinical progress. On November 14, 2002, Neurocrine Biosciences Inc. announced positive results from its first phase III clinical trial with indiplon-IR achieving primary and secondary end points of sleep initiation. Indiplon-IR is an immediate-release formulation of a nonbenzodiazepine GABA-A agonist. In the current randomized, double-blind, placebo-controlled, parallel group trial, both doses of indiplon-IR (10 mg and 20 mg) proved effective on primary end points of latency to persistant sleep (LPS) as measured by polysomnography. Mean improvements over placebo were 36% and 50% for both dosages, respectively (P < 0.0001). Safety profile was undifferentiated from placebo. The full data set are expected to be presented at the yet undisclosed scientific meeting of spring 2003. A new drug application for FDA submission is likely by the end of 2003 for both the immediate-release and modified formulations.
December CDC Highlights
The Center for Disease Control and Prevention reports that the death rate from brain injuries in the United States has fallen 11% from 1998. Over the past decade, the death rate stemming from brain injury lowered from 21.9 deaths per 100,000 people to 19.4 per 100,000. The CDC attributes this positive trend to stricter seat belt laws.
— Jeffrey Reich, MD, Assistant Professor of Neurology, New York Presbyterian Hospital-Cornell Campus, Assistant Editor, Neurology Alert.
Aripiprazole (Abilify), a new drug for schizophrenia, received FDA approval November 15; on November 14, Neurocrine Biosciences Inc. announced positive results from its first phase III clinical trial with indiplon-IR achieving primary and secondary end points of sleep initiation.
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