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AstraZeneca Submits sNDA for Seroquel (quetiapine fumarate) for Bipolar Depression Treatment

Filing Seeks Approval of Seroquel as a Monotherapy Treatment for Bipolar Depression

WILMINGTON, DL -- December 30, 2005 -- AstraZeneca today announced that it has submitted a supplemental New Drug Application (sNDA) with the US Food and Drug Administration (FDA) to seek approval for a new indication for Seroquel(R) (quetiapine fumarate) for the treatment of patients with depressive episodes associated with bipolar disorder.

Seroquel is currently approved for the treatment of acute manic episodes associated with bipolar I disorder and the treatment of schizophrenia.

"AstraZeneca is dedicated to improving patients' lives and developing new treatments for mental illness," said Wayne Macfadden, MD, US Medical Director for Seroquel. "This sNDA submission is an important milestone in the history of Seroquel.

If Seroquel receives approval from the FDA to treat bipolar depression, it would be the only single agent indicated to treat both the depressive and manic episodes associated with bipolar disorder."

The sNDA submission is based on results from the clinical trial program known as BOLDER (BipOLar DEpRession), which comprises two studies: BOLDER I and BOLDER II. Both studies were double-blind, placebo-controlled trials of outpatients (N=1,045) with bipolar I or II disorder.

Patients were randomized to receive 8 weeks of treatment with fixed doses of Seroquel (300 mg or 600 mg) or placebo administered once daily. In both studies, patients receiving Seroquel, as compared to those receiving placebo, showed a statistically significant decrease in depression scores* at week 1, and scores continued to decrease throughout the eight-week study. More than half of the Seroquel treated patients in each trial met the criteria for remission.(1)

Additionally, Seroquel was shown to have similar safety profiles in both BOLDER I and II. The most common adverse effects reported in these trials included dry mouth, sedation, somnolence, dizziness, and constipation.(1)

Bipolar disorder, which affects more than 7 million American adults(2), consists of recurring episodes of mania and depression. Patients with bipolar disorder are symptomatic almost half of their lives, and approximately two- thirds of that time is spent in the depressed phase of the illness(3).

Prolonged periods of sadness, unexplained loss of energy, persistent lethargy, and recurring thoughts of death or suicide characterize depressive episodes(4). Up to 50% of patients with bipolar depression attempt suicide, and approximately 10 to 15% commit suicide(5). Furthermore, bipolar disorder is often misdiagnosed, and patients may suffer up to ten years before a correct diagnosis is made(6).

Seroquel (quetiapine fumarate) is the #1 prescribed atypical antipsychotic in the United States(10) and has a well-established safety and efficacy profile. In 2004, sales for Seroquel reached $2 billion. Seroquel has had more than 13 million patient exposures worldwide since its launch in 1997.

About Bipolar Disorder
Bipolar I disorder consists of recurring episodes of mania with or without depression. Bipolar II disorder consists of recurring episodes of depression and hypomania, a milder form of mania(8). In the long term, patients with bipolar I disorder spend three times longer in the depressed state than in mania. Patients with bipolar II disorder have traditionally been difficult to treat as they spend almost forty times longer in the depressed state than in mania(9). Without appropriate treatment, patients usually suffer for a lifetime with periods of wellness and functioning punctuated by severe episodes of illness. Both men and women are equally at risk for this illness, which most often emerges in adolescence or young adulthood and recurs throughout life(8).

Important Safety Information
Seroquel is indicated for the treatment of acute manic episodes associated with bipolar I disorder, as either monotherapy or adjunct therapy with lithium or divalproex, and the treatment of schizophrenia. Patients should be periodically reassessed to determine the need for continued treatment. It is recommended that Seroquel be taken in divided doses twice daily. Seroquel is not currently approved for the treatment of the depressive phase of bipolar disorder.

Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs are at an increased risk (1.6 to 1.7 times) of death compared to placebo (4.5% vs. 2.6%, respectively). Seroquel is not approved for the treatment of patients with dementia-related psychosis.

Prescribing should be consistent with the need to minimize the risk of tardive dyskinesia. A rare condition referred to as neuroleptic malignant syndrome has been reported with this class of medications, including Seroquel.

Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics, including Seroquel(R) (quetiapine fumarate). Patients starting treatment with atypical antipsychotics who have or are at risk for diabetes should undergo fasting blood glucose testing at the beginning of and during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing.

Precautions include the risk of seizures, orthostatic hypotension, and cataract development.

The most commonly observed adverse events associated with the use of Seroquel in clinical trials for schizophrenia and bipolar mania were somnolence, dry mouth, dizziness, constipation, asthenia, abdominal pain, postural hypotension, pharyngitis, SGPT increase, dyspepsia, and weight gain.

REFERENCES:
* Depression scores were measured by the Montgomery-Asberg Depression Rating Scale (MADRS).1a The MADRS scale measures the severity of a number of depressive symptoms including mood and sadness, tension, sleep, appetite, energy, concentration, and suicidal ideation.(7) The MADRS score decreases as depressive symptoms improve. Remission was defined as a MADRS score of http://www.dbsalliance.org/PDF/IntroBrochureC2.pdf. Accessed December 7, 2005.

(5) Hawton, et al. Suicide and Attempted Suicide in Bipolar Disorder: A Symptomatic Review of Risk Factors. J Clin Psychiatry. 2005;66:693-704.

(6) Depression and Bipolar Support Alliance (DBSA). Facts About Bipolar Disorder. Accessed at http://www.dbsalliance.org/media/bipolarfacts.html. Accessed December 7, 2005.

(7) Lundbeck Institute. Psychiatric Rating Scales. PDF available at: http://www.brainexplorer.org/factsheets/Psychiatry%20Rating%20Scales.pdf. Accessed December 7, 2005.

(8) Kramlinger K. Mayo Clinic on Depression. Rochester, Minn.: Mayo Clinic Health Information, 2001.

(9) Calabrese JR, Keck PE, Macfadden W, et al, for the BOLDER Study Group. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry. 2005;162;1351-1360.

(10) All atypical prescriptions: Total prescriptions Jan 05 to Oct 05. New prescriptions Sept 04 to Oct 05 IMS Health. National Prescription Audit.


SOURCE: AstraZeneca

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