Product Spotlight - Saphris

Saphris
(asenapine)

Saphris (asenapine) is an atypical antipsychotic indicated for acute treatment of schizophrenia in adults and acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. Asenapine is administered via 5-mg or 10-mg sublingual tablets that are placed under the tongue and allowed to dissolve completely. For schizophrenia, the recommended starting dose of asenapine is 5 mg twice daily. For bipolar disorder the recommended starting dose is 10 mg twice daily, and the dose can be decreased to 5 mg twice daily if patients experience adverse effects.

A novel psychopharmacologic agent, asenapine is a dopamine D2 receptor modulator that controls positive symptoms of schizophrenia. According to the Food and Drug Administration (FDA) asenapine is well tolerated and has a favorable safety profile. The receptor binding profile of asenapine demonstrates the highest affinity for blocking serotonin receptors, followed by dopamine, alpha-adrenergic, and histamine receptors, with minimal affinity for muscarinic receptors. The exact mechanism of action of asenapine, as with other drugs having efficacy in schizophrenia and bipolar disorder, is unknown.

The efficacy of asenapine in treating schizophrenia was studied in 3 short-term placebo-controlled and active-drug controlled clinical trials. In 2 of the trials Saphris demonstrated superior efficacy compared to an inactive pill (placebo) in reducing the symptoms of schizophrenia.

The efficacy of asenapine in the treatment of bipolar disorder was studied in 2 short-term placebo-controlled and active-drug controlled clinical trials in which asenapine was shown to be superior to placebo in treating symptoms of bipolar disorder.

This First Report – Managed Care Product Spotlight provides a summary of results from a clinical trial of asenapine in acute schizophrenia that was reviewed as part of the FDA approval of Saphris. In addition, we have summarized results from a clinical trial of asenapine in patients experiencing manic or mixed episodes in bipolar mania.

SCHIZOPHRENIA TRIAL
Below is summary of results from a phase 3 trial that evaluated the efficacy, tolerability, and safety of asenapine—Efficacy and Tolerability of Asenapine in Acute Schizophrenia: A Placebo- and Risperidone-Controlled Trial.

Reference: Potkin SG, Cohen M, Panagides J. J Clin Psychiatry. 2007;68:1492-1500.

Study Objectives:
The trial was designed to assess the efficacy, tolerability, and safety of asenapine, compared with placebo and risperidone, for the treatment of acute schizophrenia.

Method
The study was conducted from August 2001 to May 2002. In the double-blind, double-dummy, 3-arm, fixed-dose, 6-week, placebo-controlled, and risperidone-controlled trial patients were randomly assigned to receive either 5 mg of sublingual asenapine twice daily, placebo twice daily, or 3 mg of risperidone twice daily. Patients first completed a 3- to 7-day single-blind placebo washout phase that established their adherence to study treatment; if they were >75% adherent they were randomly assigned to treatment with asenapine, placebo, or risperidone.

Treatment was administered morning and evening in an inpatient setting for weeks 1 to 3 of the trial. After the first 3 weeks, patients whose improvement allowed it were treated on an outpatient basis for weeks 4 to 6. If patients took concomitant medication for sleep they could receive no more than 10 mg/day of zolpidem tartrate, 20 mg/day of zaleplon, or 3000mg/day of chloral hydrate. Patients receiving concomitant benzodiazepine for agitation could receive daily doses equivalent to 10 mg/day of lorazepam. Patients were not allowed to receive other psychotropic medications. For trial entry, other medication regimens had to be stable, but patients could receive anticholinergics for newly emergent extrapyramidal symptoms (EPS).

To evaluate safety, patients underwent weekly laboratory and EEG screening after initial screening and baseline assessments. They also had full physical examinations at screening and study end point. After baseline, adverse events were tallied weekly. Hospital staff and tablet counts were used to determine adherence to study medication regimens, with adherent patients receiving ≥75% of their medications.

Population
Investigators recruited patients ≥18 years of age for treatment at 21 US sites. Eligible patients had a diagnosis of schizophrenia with symptoms of several disease subtypes (disorganized, paranoid, catatonic, undifferentiated) according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. There were 174 patients in the intent-to-treat population (≥1 dose of study drug and ≥1 postbaseline assessment).

For purposes of the trial, investigators defined acute exacerbation as a baseline Clinical Global Impressions-Severity of Illness (CGI-S) score ≥ and a Positive and Negative Syndrome Scale (PANSS) total score ≥60. Additional criteria included baseline scores ≥4 on ≥2 items on the PANSS positive subscale and a baseline PANSS score ≥80% of the score on prior visits. Baseline mean PANSS total scores were 96.5 in the asenapine group, 92.4 in the placebo group, and 92.2 in the risperidone group.

Patients also had to have a clinically meaningful response to previous treatment with antipsychotics if they had received them (excluding treatment with clozapine). Patients discontinued mood stabilizers ≥5 days before baseline and those receiving depot neuroleptics allowed at least 1 month to elapse after their last injection before receiving their first dose of study medications.

Patients who had a primary psychiatric diagnosis other than schizophrenia, were actively suicidal, or who were diagnosed with residual-type schizophrenia, schizophreniform disorder, or schizoaffective disorder were excluded from the trial. Other criteria excluded pregnant or breastfeeding women as well as patients who recently received experimental medication, had untreated illnesses, were previously treated with asenapine, or who had a history of neurologic illness.

Primary end points:
•    Improvement from baseline in PANSS total score

Secondary end points:
•    Change in CGI-S score
•    Scores on PANSS positive, negative, and general psychopathology subscales

Results
In the intent-to-treat population there were 58 patients in the asenapine group, 60 patients in the placebo group, and 56 patients in the risperidone group. Treatment groups were well matched for demographic and baseline characteristics. More patients completed the trial in the asenapine (46%) and risperidone (42%) groups than in the placebo group (34%). The percentage of treated patients who withdrew due to lack of efficacy was lower in the asenapine group than in the placebo and risperidone groups. The investigators also reported comparable rates of withdrawal due to adverse events and adherence rates in the treatment groups.

The mean change in PANSS total score at study end point was -15.9 for the asenapine group compared with -5.3 for the placebo group (P<.005). The mean change in PANSS total score for the risperidone group (-10.9) was nonsignificant compared with placebo. Investigators reported that from week 2 onward there were significantly greater decreases in PANSS total scores in the asenapine group than in the placebo group.

Treatment with asenapine and risperidone led to significantly greater decreases in CGI-S scores than treatment with placebo starting at week 4. At the study end point, the mean change in CGI-S scores from baseline was -0.74 in the asenapine group compared with -0.28 in the placebo group (P<.01). Mean change in CGI-S score was -0.75 with risperidone (P<.005 vs placebo).

Mean changes in PANSS positive subscale scores at the study end point were -5.5 for asenapine compared with -2.5 for placebo (P=.01). The mean change was -5.1 in the risperidone group (P<.05 vs placebo).

Mean changes in PANSS negative subscale scores at the study end point were -3.2 for asenapine compared with -0.6 for placebo (P=.01). The mean change in PANSS negative subscale score for the risperidone group (-1.05) was nonsignificant compared with placebo.

Mean changes in PANSS general psychopathology subscale score at the study end point were -7.2 in the asenapine group compared with -2.2 for placebo (P<.005). The mean change in the risperidone group (-4.8) was nonsignificant compared with placebo.

In the asenapine group 83% of patients experienced ≥1 adverse event during the study compared with 79% of patients who received placebo and 90% of patients who received risperidone. The most frequently occurring adverse events (≥10% of patients in any treatment group) included insomnia, somnolence, nausea, anxiety, agitation, headache, vomiting, and constipation.

BIPOLAR MANIA TRIAL
Below is summary of results from a phase 3 trial that evaluated the efficacy, tolerability, and safety of asenapine—A 3-week, randomized, placebo controlled trial of asenapine in the treatment of acute mania in bipolar mania and mixed states.

Reference: McIntyre RS, Cohen M, Zhao J, Alphs L, Macek TA, Panagides J. Bipolar Disorders. 2009;11:673-686.

Study Objectives: The trial was designed to assess the efficacy, tolerability, and safety of asenapine, compared with placebo and olanzapine, for the treatment of acute mania in bipolar mania and mixed states.

Method
During the 3-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group study, eligible patients were randomized in a 2:1:2 ratio to receive 10 mg of sublingual asenapine twice daily on day 1 and 5 mg or 10 mg of asenapine twice daily thereafter, placebo, or 15 mg of olanzapine twice daily on day 1 followed by 5 mg to 20 mg of olanzapine once daily. Patients first completed a single-blind placebo washout phase of ≤7 days before randomization. They also spent up to 7 days in inpatient treatment centers for screening and at least 7 days in inpatient centers for the beginning of the treatment phase until investigators determined that they could continue on an outpatient basis.

Patients received double-blind, flexible-dose treatment for 3 weeks. Primary results were assessed using analysis of covariance with last observation carried forward (LOCF), and secondary efficacy was assessed using a mixed model for repeated measures. All patients who received ≥1 dose of study medication were included in the safety and tolerability assessment. Patients who received ≥1 dose of study medication and completed ≥1 postbaseline Young Mania Rating Scale (YMRS) assessment were included in the assessment of efficacy.

Population
The trial enrolled patients at 55 centers in the United States, India, Russian Federation, Ukraine, Korea, Bulgaria, Philippines, Romania, Turkey, and Malaysia. There were 480 patients in the intent-to-treat population (189 in the asenapine group, 103 in the placebo group, and 188 in the olanzapine group). More than half were men and more than half were Caucasian.

Eligible patients were adults ≥18 with a primary diagnosis of bipolar I disorder according to DSM-IV criteria who were experiencing manic or mixed episodes. A YMRS total score of ≥20 at screening and baseline was required, as was a current manic or mixed bipolar I episode that began ≤3 months before the screening visit. Patients also needed a documented history of more than one previous moderate to severe mood episode with or without psychotic features.

The study excluded patients pregnant or at risk of pregnancy and those who had a psychotic disorder or primary diagnosis other than bipolar I. The study also excluded substance abusers and patients with rapid-cycling bipolar disorder in the past year. Other exclusion criteria included previous participation in clinical trials involving asenapine, recent exposure to other investigational drugs, laboratory abnormalities, or hypersensitivity to any of the study medications.

Patients receiving depot neuroleptics had to discontinue these treatments at least one dosing cycle before study baseline, and other antidepressants, antipsychotics, and mood stabilizers were prohibited. Study protocols also limited the use of other medications.

Primary end point:
•    Change in YMRS total score from baseline to day 21

Secondary end points:
•    Change from baseline in mania or mixed state severity measured using the CBI Bipolar Disorder    scale.
•    Change from baseline in depressive symptoms using the Montgomery-Asberg Depression Rating Scale (MADRS)
•    Percentage of responders with a ≥50% decrease in YMRS total score
•    Percentage of remitters, defined as a YMRS total score ≥12 at end point

Results
Most patients in the asenapine group remained on their initial 10-mg twice-daily dose throughout the study, and almost half of patients who received olanzapine increased their dose to 20 mg at least one time. On day 2 of treatment, significantly greater least squares (LS) mean changes in YMRS scores were observed in the asenapine group (-3.0) and olanzapine (-3.4) group than in the placebo group (-1.5 ± 0.5, both P< .01).

At day 21 the LS mean change from baseline in YMRS total score was -10.8 in the asenapine group and -12.6 in the olanzapine group compared with -5.5 in the placebo group (P<.0001). The investigators reported that superiority of the active treatments over placebo was evident on day 2 of treatment and maintained for the duration of treatment.

At day 21, using LOCF analysis, LS mean changes were -1.2 for the asenapine group (P< 0.002 vs placebo), -1.4 for the olanzapine group (P<.0001 vs placebo), and -0.7 for the placebo group.

Changes in MADRS scores at day 21 were -3.2 in the asenapine group (nonsignificant difference vs placebo), -4.2 in the olanzapine group (P< .005 vs placebo), and -1.8 in the placebo group.

There were a significantly greater (P<.01) percentage of responders in the asenapine group (42.3%) than in the placebo group (25.2%). There were also a significantly greater (P<.01) percentage of remitters in the asenapine group (40.2%) than in the placebo group (22.3%).

Significantly more patients treated with olanzapine (79.6%; P≤.001) completed the trial compared with asenapine (62.9%) and placebo (61.5%). The most common reason patients discontinued their participation in the study were lack of efficacy, treatment-emergent adverse events, withdrawal of consent, and loss to follow-up.

Safety Notes
An increased incidence of cerebrovascular adverse events such as stroke, transient ischemic attack, has been seen in elderly patients with dementia-related psychoses treated with atypical antipsychotic drugs. With respect to safety topics of interest, asenapine showed limited effects on body weight, metabolic laboratory parameters, orthostasis, and prolactin levels. Additionally, asenapine has a low propensity to induce EPS, has no increased risk of suicidality, and has no clinically relevant effects on the QT interval or liver parameters. As such, the FDA says that asenapine balances demonstrated efficacy with a limited impact on weight gain, lipids, and prolactin and is a promising alternative to existing approved therapies.

Stelara Facts
•    Saphris was approved by the FDA on August 14, 2009
•    Asenapine tablets dissolve in saliva within seconds
•    Asenapine is rapidly absorbed
•    Peak plasma concentration is reached about 1 hour after administration