- Studies Evaluated Improvement in Symptoms Both in the Short and Long Term
WILMINGTON, Del., May 5 /PRNewswire-FirstCall/ -- AstraZeneca (NYSE: AZN) today announced new study data on SEROQUEL XR(TM) (quetiapine fumarate) Extended-Release Tablets for the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD) in adult patients. The results from the studies were presented today at the 161st Annual Meeting of the American Psychiatric Association (APA) in Washington, DC. In February 2008, the company submitted a supplemental new drug application (sNDA) for SEROQUEL XR for the treatment of MDD as monotherapy, adjunct therapy, and maintenance therapy. AstraZeneca plans to submit a sNDA for SEROQUEL XR for the treatment of GAD, including maintenance of antianxiety effect, during the second quarter of 2008.
The SEROQUEL XR clinical development programs for MDD and GAD included seven Phase III, placebo-controlled studies in MDD as well as four Phase III, placebo-controlled studies in GAD. The three MDD studies presented today investigated SEROQUEL XR in the treatment of adult patients diagnosed with MDD-as monotherapy in both short-term and maintenance treatment and as short- term adjunct treatment versus placebo.(1-3) The two GAD studies presented today investigated treatment with SEROQUEL XR in adult patients diagnosed with GAD-as monotherapy in both short-term and maintenance treatment versus placebo.(4,5) Across all MDD and GAD studies presented today, efficacy with SEROQUEL XR was superior to placebo, as assessed by the primary endpoints. In addition, adverse events reported for SEROQUEL XR in these studies were generally similar to those reported in previous clinical trials with quetiapine (See detailed study data below).(1-5)
MDD affects approximately 15 million American adults and studies have shown that at least one-third of patients with MDD treated with antidepressants fasleep, appetite, and energy; difficulty thinking, concentrating, and remembering; physical slowing or agitation; lack of interest in or pleasure from activities that were once enjoyed; feelings of guilt, worthlessness, hopelessness, and emptiness; recurrent thoughts of death or suicide; and persistent physical symptoms for two or more weeks that do not respond to treatment, such as headaches, digestive disorders, and chronic pain.(6) Symptomatically, a major depressive episode in MDD is similar to a depressive episode of bipolar disorder with the major distinguishing feature between the disorders being the absence of manic or hypomanic symptoms in MDD.(9) It has been reported that 69 percent of patients with bipolar disorder were misdiagnosed, with the most frequent misdiagnosis being MDD.(16)
Without treatment, the frequency of depressive illness as well as the severity of symptoms tends to increase over time. Left untreated, depression can lead to suicide.(6)
About Generalized Anxiety Disorder
GAD is characterized by chronic anxiety, exaggerated worry, and tension, even when there is little or nothing to provoke it.(8,9) People with GAD anticipate disaster and are overly concerned about health issues, money, family problems, or difficulties at work.
People with GAD can't seem to get rid of their concerns, even though they usually realize that their anxiety is more intense than the situation warrants.(8,9) They can't relax, startle easily, and have difficulty concentrating. Often they have trouble falling asleep or staying asleep. Physical symptoms that often accompany the anxiety include fatigue, headaches, muscle tension, muscle aches, difficulty swallowing, trembling, twitching, irritability, sweating, nausea, lightheadedness, having to go to the bathroom frequently, feeling out of breath, and hot flashes. GAD is diagnosed when someone excessively worries about a number of everyday problems for at least 6 months.
In the U.S. GAD affects about 6.8 million adults, with women twice as likely to develop GAD as men.(8,9) The disorder comes on gradually and can begin across the life cycle. GAD rarely occurs alone and is often accompanied by other anxiety disorders, depression, or substance abuse. Genetic factors are also thought to be involved.
AstraZeneca is a major international healthcare business engaged in the research, development, manufacturing and marketing of meaningful prescription medicines and supplier for healthcare services. AstraZeneca is one of the world's leading pharmaceutical companies with healthcare sales of $29.55 billion and is a leader in gastrointestinal, cardiovascular, neuroscience, respiratory, oncology and infectious disease medicines. In the United States, AstraZeneca is a $13.35 billion dollar healthcare business with 12,200 employees committed to improving people's lives. AstraZeneca is listed in the Dow Jones Sustainability Index (Global) as well as the FTSE4Good Index.
For more information visit http://www.astrazeneca-us.com.
The statements contain herein include forward-looking statements. Although we believe our expectations are based on reasonable assumptions, any forward-looking statements, by their very nature, involve risks and uncertainties and may be influenced by factors that could cause actual outcomes and results to be materially different from those predicted. The forward-looking statements reflect knowledge and information available at the date of the preparation of this press release and the Company undertakes no obligation to update these forward-looking statements. Important factors that could cause actual results to differ materially from those contained in forward-looking statements, certain of which are beyond our control, include, among other things, those risk factors identified in the Company's Annual Report/Form 20-F for 2007. Nothing contained herein should be construed as a profit forecast.
(*) The MADRS scale measures the severity of a number of depressive symptoms including mood and sadness, tension, sleep, appetite, energy, concentration, suicidal ideation, and restlessness. The MADRS score decreases as depressive symptoms improve.(12)
(+) The CGI-S score refers to the global impression of the patient and requires clinical experience with the syndrome under assessment. The CGI improvement scale can be completed only following or during treatment. The concept of improvement refers to the clinical distance between the individual's current condition and that prior to the start of treatment.(12)
(++) The HAM-A rating scale consists of 14 items and measures the severity of symptoms such as anxiety, tension, depressed mood, palpitations, breathing difficulties, sleep disturbances, restlessness, and other physical symptoms.(12)
(S) HAM-A response is defined as greater than or equal to 50% decrease in HAM-A total score from baseline(4)
(**) HAM-A remission is defined as HAM-A total score less than or equal to 7.4
(1) Weisler R, Joyce M, McGill L, et al. Extended release Quetiapine fumarate (quetiapine XR) monotherapy for major depressive disorder (MDD): a double-blind, placebo-controlled study [poster]. Presented at: The Annual Meeting of the American Psychiatric Association; May 3-8, 2008, Washington, D.C., USA.
(2) Datto C, Lam RW, Lepola U, et al. Double-blind study of extended release quetiapine fumarate (quetiapine XR) monotherapy for maintenance treatment of major depressive disorder (MDD) [poster]. Presented at: The Annual Meeting of the American Psychiatric Association; May 3-8,2008, Washington, D.C., USA.
(3) El-Khalili N, Joyce M, Atkinson S, et al. Adjunctive extended-release quetiapine fumarate (quetiapine XR) in patients with major depressive disorder and inadequate antidepressant response [poster]. Presented at: The Annual Meeting of the American Psychiatric Association; May 3-8, 2008, Washington, D.C., USA.
(4) Joyce M, Khan A, Atkinson S, et al. Efficacy and safety of extended release Quetiapine fumarate (quetiapine XR) monotherapy in patients with generalized anxiety disorder (GAD) [poster]. Presented at: The Annual Meeting of the American Psychiatric Association; May 3-8, 2008, Washington, D.C., USA.
(5) Katzman M, Brawman-Mintzer O, Reyes E, et al. Extended release quetiapine fumarate (quetiapine XR) monotherapy in maintenance treatment of generalized anxiety disorder (GAD): efficacy and tolerability results from a randomized, placebo-controlled trial
[poster]. Presented at: The Annual Meeting of the American Psychiatric Association; May 3-8, 2008, Washington, D.C., USA.
(6) National Alliance on Mental Illness: Major Depression Fact Sheet. 2007. Available at: http://www.nami.org/Template.cfm?Section=By_Illness&Template=/TaggedPage/Ta gge dPageDisplay.cfm&TPLID=54&ContentID=26414. Accessed November 30, 2007.
(7) Nemeroff, CB. Prevalence and Management of Treatment-Resistant Depression. J Clin Psychiatry. 2007; 68:17-25.
(8) National Institute of Mental Health: Anxiety Disorders. NIH Publication No. 06-3879. Available at: http://www.nimh.nih.gov/health/publications/anxiety-disorders/generalized- anxiety-disorder-gad.shtml Accessed March 20, 2008.
(9) Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000: 472- 475.
(10) Rickels K. and Rynn M. Pharmacotherapy of Generalized Anxiety Disorder. J Clin Psychiatry. 2002;63(suppl 14): 9-16.
(11) Data on file, DA-SXR-12, AstraZeneca LP.
(12) Lundbeck Institute. Psychiatric Rating Scales. PDF available at: http://www.brainexplorer.org/factsheets/Psychiatry%20Rating%20Scales.pdf. Accessed on May 2, 2008.
(13) Data on File, DA-SXR-15, AstraZeneca LP.
(14) Chouinard G, Bandelow B, Ahokas A, et al. Once-daily extended release of quetiapine fumarate (quetiapine XR) monotherapy in generalized anxiety disorder: a Phases III, double-blind, placebo-controlled study [poster]. Presented at: The Annual Meeting of The American College of Neuropsychopharmacology; December 9-13, 2007, Boca Raton, FL.
(15) Schmitt R, Gazalle FK, Silva de Lima M, et al. The efficacy of antidepressants for generalized anxiety disorder: a systematic review and meta-analysis. The Brazilian Journal of Psychiatry. 2005; 27(1):18-24.
(16) Hirschfeld RM, Lewis L, Vornik LA. Perceptions and Impact of Bipolar Disorder: How Far Have We Really Come? Results of the National Depressive and Manic-Depressive Association 2000 Survey of Individuals with Bipolar Disorder. J Clin Psychiatry. 2003; 64:161-174.
261673 05/08il to achieve a satisfactory response.(6,7) GAD affects about 6.8 million adults in the U.S., with women twice as likely to develop it compared to men, and approximately 30% of patients do not achieve an adequate response to short-term treatment.(8-10) AstraZeneca has investigated the use of SEROQUEL XR, an atypical antipsychotic, in the treatment of MDD as well as GAD, aiming to develop another potential treatment option for patients.
SEROQUEL XR MDD Clinical Studies
In the SEROQUEL XR clinical development program in MDD, short-term monotherapy studies (Studies 1, 2, 3, and 4) and short-term adjunct therapy studies (Studies 6 and 7) used the change in Montgomery-Asberg Depression Rating Scale (MADRS)* scores as the primary assessment of depression symptoms. In the long-term study (Study 5), the primary assessment was time to a depressed event using criteria including the MADRS. Doses of 50 mg, 150 mg and 300 mg of SEROQUEL XR were studied in the MDD program.(11)
"New MDD therapy options are clearly needed. Studies have shown that at
least one-third of MDD patients who are treated with antidepressants fail
to achieve a satisfactory response," said Dr. Richard Weisler, Adjunct
Professor of Psychiatry at University of North Carolina School of Medicine,
Adjunct Assistant Professor at Duke University Medical Center and lead
investigator on the MDD short-term monotherapy study presented today.
"Additionally, for those patients who do achieve a response from treatment
with antidepressants, it may often take a few weeks of treatment before a
benefit is seen. In the short- term monotherapy study presented today at
APA, patients taking SEROQUEL XR had a significant improvement in
depressive symptom scores as early as the fourth day of treatment compared
with patients taking placebo."
The following MDD studies were presented at the APA meeting:
-- Study 1 (Poster # NR3-101) -- In a six-week, multicenter, double-blind
study, 723 patients were randomized to receive SEROQUEL XR 50 mg/day,
SEROQUEL XR 150 mg/day, SEROQUEL XR 300 mg/day, or placebo. At Week 6,
all SEROQUEL XR groups had significantly reduced mean MADRS score
versus placebo (-11.07): -13.56 (p<0.05) for 50 mg/day; -14.50
(p<0.001) for 150 mg/day; and -14.18 (p<0.01) for 300 mg/day. By Day
4, all SEROQUEL XR groups significantly reduced mean MADRS score versus
placebo (-3.27): -4.91 (p<0.01) for 50 mg/day; -5.43 (p<0.001) for 150
mg/day; and -5.35 (p<0.001) for 300 mg/day. The most common adverse
events (AEs) (greater than or equal to 5% and double the rate of
placebo in any SEROQUEL XR dose group) were dry mouth, sedation,
somnolence, dizziness, constipation, back pain, irritability, and
-- Study 6 (Poster # NR3-088) -- In a six-week, multicenter, double-blind
study, 446 patients were randomized to receive antidepressant (AD) plus
SEROQUEL XR 150 mg/day, SEROQUEL XR 300 mg/day, or placebo. SEROQUEL XR
300/mg day plus an antidepressant showed statistically significant
advantage versus placebo plus an AD for 1) change in MADRS total score
at Week 6 (-14.70 versus -11.7; p<0.01); 2) improvement in MADRS from
Week 1 onwards; 3) response (58.9% versus 46.2%; p<0.05); and 4)
remission (42.5% versus 24.5%; p<0.01). For SEROQUEL XR 150 mg/day plus
AD, improvements in these variables were not significantly different
versus placebo, except for MADRS improvement at Weeks 1 and 2. The most
common adverse events (AEs) (greater than or equal to 5% and double the
rate of placebo in any SEROQUEL XR dose group) were dry mouth,
somnolence, sedation, dizziness, constipation, fatigue, and weight
-- Study 5 (Poster # NR3-017) -- In a time-to-event, double-blind,
randomized-withdrawal, parallel-group, maintenance study, 787 patients
were randomized to SEROQUEL XR or placebo and dose-adjusted as
clinically indicated. The mean daily dose of study drug at
randomization (last open-label dose) was similar for the SEROQUEL XR
group (176.6 [95.5] mg/day) and the placebo group (177.9 [90.8]
mg/day). In total, 89.0% (n=348) of SEROQUEL XR patients were receiving
the same doses at study end as at open-label baseline, 5.1% (n=20) were
receiving a higher dose, and 5.9% (n=23) a lower dose. The risk of a
depressed event was significantly reduced for SEROQUEL XR compared with
placebo suggesting increased time to event (HR = 0.34 [0.25, 0.46];
p<0.001). In total, 55 (14.2%) SEROQUEL XR-treated patients and 132
(34.4%) placebo-treated patients experienced a depressed event. During
the randomized phase, mean changes in MADRS were 0.15 versus 2.03
(p<0.001), and mean changes in Clinical Global Impression-Severity
(CGI-S)(+) were -0.03 versus 0.23 (p<0.001) for SEROQUEL XR versus
placebo, respectively. Open label adverse events (AEs) were similar to
previous experience with SEROQUEL XR. The most common AEs (greater than
or equal to 5% in the SEROQUEL XR group) occurring during the
randomized treatment phase were weight increased, nasopharyngitis,
headache, dizziness, insomnia, and diarrhea.(2)
SEROQUEL XR GAD Clinical Studies
In the SEROQUEL XR clinical development program in GAD, short-term studies (Studies 9, 10 and 11) used the Hamilton Rating Scale for Anxiety (HAM-A)(++) as the primary assessment of anxiety symptoms.(13) In the long-term study (Study 12), the primary assessment was time from randomization to an anxiety event.(5) Doses of 50 mg, 150 mg and 300 mg of SEROQUEL XR were studied in the GAD program.(4-5,13-14) While treatment for GAD typically includes an antidepressant, approximately 30% of patients do not achieve an adequate response to short-term treatment.(10) Benzodiazepines, which are also commonly prescribed antianxiety medications, may be used for the rapid relief of anxiety symptoms but long-term use of these agents is not generally recommended.(15)
"Given that many people suffering from generalized anxiety disorder do
not achieve an adequate response from current treatments, new treatment
options are needed; specifically for those who are not suited for existing
therapies or who are simply not benefiting enough from the previously
available approaches," said Professor Martin Katzman, Assistant Professor
at the University of Toronto, and the Northern Ontario School of Medicine,
and lead investigator on the GAD long-term study presented today.
The following GAD studies were presented at the APA meeting:
-- Study 9 (Poster # NR3-138) -- In a 10-week (eight weeks active; two
weeks tapering discontinuation), multicenter, double-blind, parallel-
group study, 951 patients were randomized to receive SEROQUEL XR 50
mg/day, 150 mg/day, 300 mg/day, or placebo. The mean change from
baseline to week 8 in HAM-A total score was significantly greater for
SEROQUEL XR 50 mg/day (-13.31, p<0.001) and 150 mg/day (-13.54,
p<0.001), but not 300 mg/day (-11.87, p=0.24), versus placebo
(-11.10). HAM-A response(S) at week 8 was significantly higher for 50
mg/day (60.3%, p<0.05) and 150 mg/day (61.5%, p<0.05), but not for 300
mg/day (54.9%, p=0.37), versus placebo (50.7%). HAM-A remission(**) at
week 8 was significantly higher for 150 mg/day versus placebo (37.2%
versus 27.6%; p<0.05) and was 36.1% (p=0.08) and 28.6% (p=0.96), for 50
mg/day and 300 mg/day doses, respectively. The most common adverse
events (AEs) (greater than or equal to 5% and double the rate of
placebo in any SEROQUEL XR dose group) were dry mouth, somnolence,
sedation, and constipation. The incidence of serious AEs was <2.5% in
-- Study 12 (Poster # NR3-140) -- In a time-to-event, double-blind,
randomized-withdrawal, parallel-group, placebo-controlled study, 433
patients were randomized to SEROQUEL XR or placebo following open-label
stabilization for a minimum of 12 weeks. The SEROQUEL XR dose was
flexible-50 mg, 150 mg, or 300 mg once daily, based on the clinical
judgment of the investigator. The risk of an anxiety event was
significantly reduced for SEROQUEL XR compared with placebo, suggesting
increased time to the event (HR=0.19 [0.12, 0.31]; p<0.001). Twenty-two
(10.2%) SEROQUEL XR-treated patients and 84 (38.9%) placebo-treated
patients experienced an anxiety event. The most common adverse events
(AEs) (greater than or equal to 5% in the SEROQUEL XR group) during the
randomized phase was headache and nasopharyngitis. The incidence of
serious AEs (randomized phase) was <2% in both groups.(5)
About SEROQUEL XR
In 2007, SEROQUEL XR was approved in the U.S. for the treatment of schizophrenia in adult patients and for maintenance treatment of schizophrenia in adult patients. In January 2008, AstraZeneca announced the submission of two separate sNDAs to the FDA for SEROQUEL XR to seek approval for the treatment of manic episodes associated with bipolar disorder and the treatment of depressive episodes associated with bipolar disorder. In February 2008, AstraZeneca filed a sNDA for SEROQUEL XR to seek approval for the treatment of MDD as monotherapy, adjunct therapy, and maintenance therapy. The FDA has not completed its review of these submissions.
IMPORTANT SAFETY INFORMATION SEROQUEL XR
SEROQUEL XR is indicated for the acute and maintenance treatment of schizophrenia. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose.
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 XR is not approved for the treatment of patients with dementia-related psychosis. (See Boxed Warning.)
Antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults in short-term studies of major depressive disorder and other psychiatric disorders. Patients of all ages started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. SEROQUEL XR is not approved for use in patients under the age of 18 years. SEROQUEL XR is not approved for the treatment of depression; however, an immediate release form of quetiapine is approved for the treatment of bipolar depression. (See Boxed Warning.)
Hyperglycemia, in some cases extreme and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics, including quetiapine. The relationship of atypical use and glucose abnormalities is complicated by the possibility of increased risk of diabetes in the schizophrenic population and the increasing incidence of diabetes in the general population. However, epidemiological studies suggest an increased risk of treatment-emergent, hyperglycemia-related adverse events in patients treated with atypical antipsychotics. 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 periodically during treatment. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing.
A potentially fatal symptom complex, sometimes referred to as Neuroleptic Malignant Syndrome (NMS), has been reported in association with administration of antipsychotic drugs, including quetiapine. Rare cases of NMS have been reported with quetiapine. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The management of NMS should include immediate discontinuation of antipsychotic drugs.
Tardive dyskinesia (TD), a potentially irreversible syndrome of involuntary dyskinetic movements, may develop in patients treated with antipsychotic drugs. The risk of developing TD and the likelihood that it will become irreversible are believed to increase as the duration of treatment and total cumulative dose of antipsychotic drugs administered to the patient increase. TD may remit, partially or completely, if antipsychotic treatment is withdrawn. Quetiapine should be prescribed in a manner that is most likely to minimize the occurrence of TD.
Leukopenia, neutropenia, and agranulocytosis (including fatal cases), have been reported temporally related to atypical antipsychotics, including quetiapine. Patients with a pre-existing low white blood cell (WBC) count or a history of drug induced leukopenia/neutropenia should have their complete blood count monitored frequently during the first few months of therapy. In these patients, SEROQUEL XR should be discontinued at the first sign of a decline in WBC absent other causative factors. Patients with neutropenia should be carefully monitored, and SEROQUEL XR should be discontinued in any patient if the absolute neutrophil count is less than 1000/mm3.
Warnings and Precautions also include the risk of orthostatic hypotension, cataracts, seizures, hyperlipidemia, and possibility of suicide attempts. Examination of the lens by methods adequate to detect cataract formation, such as slit lamp exam or other appropriately sensitive methods, is recommended at initiation of treatment or shortly thereafter, and at 6-month intervals during chronic treatment. The possibility of a suicide attempt is inherent in schizophrenia, and close supervision of high risk patients should accompany drug therapy.
The most commonly observed adverse events associated with the use of SEROQUEL XR versus placebo in clinical trials for schizophrenia were dry mouth (12% vs 1%), constipation (6% vs 5%), dyspepsia (5% vs 2%), sedation (13% vs 7%), somnolence (12% vs 4%), dizziness (10% vs 4%), and orthostatic hypotension (7% vs 5%).
In long-term clinical trials of quetiapine, hyperglycemia (fasting glucose greater than or equal to 126 mg/dL) was observed in 10.7% of patients receiving quetiapine (mean exposure 213 days) vs 4.6% in patients receiving placebo (mean exposure 152 days).
Please see Prescribing Information, including Boxed Warnings, for SEROQUEL XR.
About Major Depressive Disorder
Major depressive disorder is a serious medical illness affecting approximately 15 million American adults, or approximately 5 to 8 percent of the adult population in a given year. Depression occurs twice as frequently in women as in men. Unlike normal emotional experiences of sadness, loss, or passing mood states, major depressive disorder is persistent and can significantly interfere with an individual's thoughts, behavior, mood, activity, and physical health. Among all medical illnesses, major depressive disorder is the leading cause of disability in the U.S. and many other developed countries.(6)
Symptoms of major depressive disorder characteristically represent a
significant change from how a person functioned before the illness. The
symptoms of depression include: persistently sad or irritable mood;
pronounced changes in
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