A new antipsychotic drug, asenapine, has been approved by the Food and Drug
Administration (FDA) for the acute treatment of schizophrenia and manic or
mixed episode in bipolar I disorder in adults.
The approval, announced on August 14, came just two weeks after an FDA
advisory committee gave a favorable review to the drug at a public meeting.
The advisors reviewed three phase 3, placebo-controlled trials of asenapine in
patients with schizophrenia and two placebo-controlled trials in patients with
a manic or mixed episode of bipolar I disorder.
The drug is expected to be available in U.S. pharmacies beginning in the
fourth quarter of this year, according to an announcement by
Similar to other second-generation antipsychotics, asenapine is an
antagonist of the serotonin 5HT2 and dopamine D2
receptors. Schering-Plough acquired the molecule and took over its development
upon the company's merger with Organon BioScience in 2007.
In two of the three phase 3 trials in schizophrenia, asenapine 5 mg twice
daily showed significantly greater efficacy, measured by total score on the
Positive and Negative Syndrome Scale (PANSS) than did placebo after six weeks
of randomized, double-blind, acute treatment. A higher dose of 10 mg twice
daily was significantly better than placebo in only one trial. Thus, the
company decided to seek approval for the indication of schizophrenia treatment
for the dose of 5 mg twice daily only. In a third trial, asenapine at both
doses did not beat placebo in the primary endpoint.
In the two bipolar disorder trials, asenapine was given in flexible doses
of between 5 mg and 10 mg twice daily for three weeks during an acute manic or
mixed episode in a double-blind manner. The primary efficacy measure,
improvement from baseline in the Young Mania Rating Scale (YMRS) total score,
showed significant advantage for asenapine over placebo.
In these short-term trials, common adverse reactions to asenapine included
somnolence, extrapyramidal symptoms, akathisia, oral hypoesthesia, and
In a long-term schizophrenia trial, in which asenapine was compared with
olanzapine, the mean body weight gain from baseline was 1.6 kg after one year;
patients who took olanzapine for one year had a gain of 5.6 kg. Clinically
meaningful weight gain (at least 7 percent increase from baseline) occurred in
14.7 percent of patients on asenapine and 36.1 percent on olanzapine.
In the short-term trials, these metabolic indicators, including glucose and
cholesterol levels, appeared to be less affected by asenapine than by
In the long-term schizophrenia trial, three of the 908 patients (0.3
percent) treated with asenapine had a QTc interval increase from baseline of
greater than 60 msec. None had a QTc interval increase of 500 msec or
Ten of the 12 advisory committee members voted to indicate that asenapine
has been shown to be effective and acceptably safe as an acute treatment for
schizophrenia. Nine agreed that the balance of its effectiveness and safety is
acceptable for approval. Three advisors were troubled by the one trial in
which asenapine did not beat placebo and were reluctant to support its
approval for this indication.
The two positive studies in bipolar I disorder convinced the committee to
vote unanimously in favor of the efficacy and safety of asenapine to treat
Asenapine is formulated as sublingual tablets to optimize its
bioavailability upon absorption, since the drug is extensively metabolized in
the liver. The tablet should not be swallowed. The approved dosage for acute
schizophrenia treatment is 5 mg twice daily. The dosage for bipolar I disorder
is to start with 10 mg twice daily with the option of decreasing to 5 mg twice
daily if the patient experiences adverse effects.
At the advisory meeting, the company said it plans to study the drug in
pediatric and adolescent populations as well as for long-term maintenance
treatment for the two disorders in adults.
Prescribing information for asenapine is posted at<www.spfiles.com/pisaphrisv1.pdf>.▪