Lurasidone shows efficacy in bipolar depression

HOLLYWOOD, FLA. – Lurasidone has hit all of its primary and secondary efficacy endpoints in a phase III clinical trial for the treatment of bipolar I depression.

As a result, the drug, already marketed as Latuda for the treatment of schizophrenia, has been approved by the Food and Drug Administration for a requested expanded indication in treating bipolar I depression. The approval, which came July 1, was made for lurasidone as monotherapy and adjunctive therapy with lithium or valproate.

The phase III PREVAIL 2 (Program to Evaluate the Antidepressant Impact of Lurasidone) study was a 6-week, double-blind, placebo-controlled, multicenter clinical trial involving 505 patients with bipolar I depression. They were randomized to once-daily, flexibly dosed lurasidone at either 20-60 mg/day or 80-120 mg/day, or to placebo.

The primary efficacy endpoint was change from baseline through week 6 in scores on MADRS (the Montgomery-Åsberg Depression Rating Scale). From a mean baseline score of 30, both the lower- and higher-dose lurasidone groups averaged identical 15.4-point reductions, a significantly greater improvement than the 10.7-point decrease in placebo-treated controls, Dr. Antony D. Loebel reported at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

This pattern of closely similar efficacy in the lower- and higher-dose lurasidone groups, whose mean modal doses were 34.9 and 92.3 mg/day, respectively, was repeated for the other study endpoints, observed Dr. Loebel, executive vice president and chief medical officer at Sunovion Pharmaceuticals, Fort Lee, N.J.

For example, the Clinical Global Impression, Bipolar Severity depression score decreased from a baseline of 4.5 by a mean of 1.8 points in the lower-dose lurasidone group and 1.7 points in the higher-dose arm, significantly greater than the 1.1-point decline with placebo.

Similarly, 53% and 51% of the lower- and higher-dose lurasidone groups, respectively, were deemed treatment responders based upon at least a 50% reduction in MADRS scores, compared with 30% of controls.

The remission rate, defined as a final MADRS score of 12 or less, was 42% in the lower-dose lurasidone arm, 40% in patients on higher-dose therapy, and 25% with placebo.

All three patient groups showed similarly modest decreases over time in the Young Mania Rating Scale: a mean 1-point drop in the lower-dose lurasidone arm, a 0.7-point reduction with higher-dose therapy, and a 0.9-point reduction with placebo. That’s an important and reassuring finding, because attempts to treat bipolar mania using conventional antidepressants can result in a switch to mania. In this study, treatment-emergent mania occurred in just 1% of subjects on lower-dose lurasidone, 0% on higher-dose therapy, and 1% on placebo, Dr. Loebel continued.

Numerous other studies have established that roughly 90% of patients with bipolar depression experience severe functional impairment. Of note, PREVAIL 2 patients in the lower-dose lurasidone arm displayed a highly significant mean 9.5-point reduction from a baseline score of 20 on the Sheehan Disability Scale, and the higher-dose lurasidone group showed a 9.8-point decrease. In contrast, scores did not change over time in the control group.

In a similar vein, scores on the Quick Inventory of Depressive Symptomatology-Self-Report improved from a baseline of 33.5 by 19.3 and 19.8 points, respectively, in the lower- and higher-dose lurasidone arms, significantly better than the 12.8-point improvement with placebo, reported Dr. Loebel also of the department of psychiatry at New York University.

A total of 6%-7% of subjects in each study arm discontinued the trial because of adverse events. Nausea and akathisia were the two adverse events that were seen more frequently with lurasidone than placebo. No significant changes in lipids, body weight, or glycemic control were observed.

Lurasidone’s efficacy in bipolar depression is attributed to the drug’s unique pharmacodynamic profile. It is a more potent blocker of the serotonin 5HT7 receptor than are other atypical antipsychotics. It also is a strong antagonist of the dopamine D2 and 5-HT2A receptors, a moderate partial agonist at the 5HT1a receptor, and has a moderate antagonist effect at the alpha-2c receptor.

Before the approval, quetiapine (Seroquel) was the only drug approved as monotherapy for bipolar depression. 

Sunovion Pharmaceuticals sponsored the phase III trial. Dr. Loebel is a company employee.

bjancin@frontlinemedcom.com

*This story was updated 7/3/2013.

HOLLYWOOD, FLA. – Lurasidone has hit all of its primary and secondary efficacy endpoints in a phase III clinical trial for the treatment of bipolar I depression.

As a result, the drug, already marketed as Latuda for the treatment of schizophrenia, has been approved by the Food and Drug Administration for a requested expanded indication in treating bipolar I depression. The approval, which came July 1, was made for lurasidone as monotherapy and adjunctive therapy with lithium or valproate.

The phase III PREVAIL 2 (Program to Evaluate the Antidepressant Impact of Lurasidone) study was a 6-week, double-blind, placebo-controlled, multicenter clinical trial involving 505 patients with bipolar I depression. They were randomized to once-daily, flexibly dosed lurasidone at either 20-60 mg/day or 80-120 mg/day, or to placebo.

The primary efficacy endpoint was change from baseline through week 6 in scores on MADRS (the Montgomery-Åsberg Depression Rating Scale). From a mean baseline score of 30, both the lower- and higher-dose lurasidone groups averaged identical 15.4-point reductions, a significantly greater improvement than the 10.7-point decrease in placebo-treated controls, Dr. Antony D. Loebel reported at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

This pattern of closely similar efficacy in the lower- and higher-dose lurasidone groups, whose mean modal doses were 34.9 and 92.3 mg/day, respectively, was repeated for the other study endpoints, observed Dr. Loebel, executive vice president and chief medical officer at Sunovion Pharmaceuticals, Fort Lee, N.J.

For example, the Clinical Global Impression, Bipolar Severity depression score decreased from a baseline of 4.5 by a mean of 1.8 points in the lower-dose lurasidone group and 1.7 points in the higher-dose arm, significantly greater than the 1.1-point decline with placebo.

Similarly, 53% and 51% of the lower- and higher-dose lurasidone groups, respectively, were deemed treatment responders based upon at least a 50% reduction in MADRS scores, compared with 30% of controls.

The remission rate, defined as a final MADRS score of 12 or less, was 42% in the lower-dose lurasidone arm, 40% in patients on higher-dose therapy, and 25% with placebo.

All three patient groups showed similarly modest decreases over time in the Young Mania Rating Scale: a mean 1-point drop in the lower-dose lurasidone arm, a 0.7-point reduction with higher-dose therapy, and a 0.9-point reduction with placebo. That’s an important and reassuring finding, because attempts to treat bipolar mania using conventional antidepressants can result in a switch to mania. In this study, treatment-emergent mania occurred in just 1% of subjects on lower-dose lurasidone, 0% on higher-dose therapy, and 1% on placebo, Dr. Loebel continued.

Numerous other studies have established that roughly 90% of patients with bipolar depression experience severe functional impairment. Of note, PREVAIL 2 patients in the lower-dose lurasidone arm displayed a highly significant mean 9.5-point reduction from a baseline score of 20 on the Sheehan Disability Scale, and the higher-dose lurasidone group showed a 9.8-point decrease. In contrast, scores did not change over time in the control group.

In a similar vein, scores on the Quick Inventory of Depressive Symptomatology-Self-Report improved from a baseline of 33.5 by 19.3 and 19.8 points, respectively, in the lower- and higher-dose lurasidone arms, significantly better than the 12.8-point improvement with placebo, reported Dr. Loebel also of the department of psychiatry at New York University.

A total of 6%-7% of subjects in each study arm discontinued the trial because of adverse events. Nausea and akathisia were the two adverse events that were seen more frequently with lurasidone than placebo. No significant changes in lipids, body weight, or glycemic control were observed.

Lurasidone’s efficacy in bipolar depression is attributed to the drug’s unique pharmacodynamic profile. It is a more potent blocker of the serotonin 5HT7 receptor than are other atypical antipsychotics. It also is a strong antagonist of the dopamine D2 and 5-HT2A receptors, a moderate partial agonist at the 5HT1a receptor, and has a moderate antagonist effect at the alpha-2c receptor.

Before the approval, quetiapine (Seroquel) was the only drug approved as monotherapy for bipolar depression. 

Sunovion Pharmaceuticals sponsored the phase III trial. Dr. Loebel is a company employee.

bjancin@frontlinemedcom.com

*This story was updated 7/3/2013.

HOLLYWOOD, FLA. – Lurasidone has hit all of its primary and secondary efficacy endpoints in a phase III clinical trial for the treatment of bipolar I depression.

As a result, the drug, already marketed as Latuda for the treatment of schizophrenia, has been approved by the Food and Drug Administration for a requested expanded indication in treating bipolar I depression. The approval, which came July 1, was made for lurasidone as monotherapy and adjunctive therapy with lithium or valproate.

The phase III PREVAIL 2 (Program to Evaluate the Antidepressant Impact of Lurasidone) study was a 6-week, double-blind, placebo-controlled, multicenter clinical trial involving 505 patients with bipolar I depression. They were randomized to once-daily, flexibly dosed lurasidone at either 20-60 mg/day or 80-120 mg/day, or to placebo.

The primary efficacy endpoint was change from baseline through week 6 in scores on MADRS (the Montgomery-Åsberg Depression Rating Scale). From a mean baseline score of 30, both the lower- and higher-dose lurasidone groups averaged identical 15.4-point reductions, a significantly greater improvement than the 10.7-point decrease in placebo-treated controls, Dr. Antony D. Loebel reported at a meeting of the New Clinical Drug Evaluation Unit sponsored by the National Institute of Mental Health.

This pattern of closely similar efficacy in the lower- and higher-dose lurasidone groups, whose mean modal doses were 34.9 and 92.3 mg/day, respectively, was repeated for the other study endpoints, observed Dr. Loebel, executive vice president and chief medical officer at Sunovion Pharmaceuticals, Fort Lee, N.J.

For example, the Clinical Global Impression, Bipolar Severity depression score decreased from a baseline of 4.5 by a mean of 1.8 points in the lower-dose lurasidone group and 1.7 points in the higher-dose arm, significantly greater than the 1.1-point decline with placebo.

Similarly, 53% and 51% of the lower- and higher-dose lurasidone groups, respectively, were deemed treatment responders based upon at least a 50% reduction in MADRS scores, compared with 30% of controls.

The remission rate, defined as a final MADRS score of 12 or less, was 42% in the lower-dose lurasidone arm, 40% in patients on higher-dose therapy, and 25% with placebo.

All three patient groups showed similarly modest decreases over time in the Young Mania Rating Scale: a mean 1-point drop in the lower-dose lurasidone arm, a 0.7-point reduction with higher-dose therapy, and a 0.9-point reduction with placebo. That’s an important and reassuring finding, because attempts to treat bipolar mania using conventional antidepressants can result in a switch to mania. In this study, treatment-emergent mania occurred in just 1% of subjects on lower-dose lurasidone, 0% on higher-dose therapy, and 1% on placebo, Dr. Loebel continued.

Numerous other studies have established that roughly 90% of patients with bipolar depression experience severe functional impairment. Of note, PREVAIL 2 patients in the lower-dose lurasidone arm displayed a highly significant mean 9.5-point reduction from a baseline score of 20 on the Sheehan Disability Scale, and the higher-dose lurasidone group showed a 9.8-point decrease. In contrast, scores did not change over time in the control group.

In a similar vein, scores on the Quick Inventory of Depressive Symptomatology-Self-Report improved from a baseline of 33.5 by 19.3 and 19.8 points, respectively, in the lower- and higher-dose lurasidone arms, significantly better than the 12.8-point improvement with placebo, reported Dr. Loebel also of the department of psychiatry at New York University.

A total of 6%-7% of subjects in each study arm discontinued the trial because of adverse events. Nausea and akathisia were the two adverse events that were seen more frequently with lurasidone than placebo. No significant changes in lipids, body weight, or glycemic control were observed.

Lurasidone’s efficacy in bipolar depression is attributed to the drug’s unique pharmacodynamic profile. It is a more potent blocker of the serotonin 5HT7 receptor than are other atypical antipsychotics. It also is a strong antagonist of the dopamine D2 and 5-HT2A receptors, a moderate partial agonist at the 5HT1a receptor, and has a moderate antagonist effect at the alpha-2c receptor.

Before the approval, quetiapine (Seroquel) was the only drug approved as monotherapy for bipolar depression. 

Sunovion Pharmaceuticals sponsored the phase III trial. Dr. Loebel is a company employee.

bjancin@frontlinemedcom.com

*This story was updated 7/3/2013.