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Biopharmaceuticals

 News Release - December 7, 2006

ABILIFY(R) (aripiprazole) Demonstrated Efficacy as Long-Term Maintenance Therapy in Adults With Bipolar I Disorder Following Treatment for a Recent Manic Or Mixed Episode

Longest Study to Date in Bipolar I Disorder With ABILIFY

PRINCETON, N.J., and TOKYO, Dec. 7 (HSMN NewsFeed) -- Maintenance therapy with the Bristol-Myers Squibb Company (NYSE: BMY ) and Otsuka Pharmaceutical Co., Ltd. atypical antipsychotic ABILIFYŽ (aripiprazole) for nearly two years significantly delayed time to relapse in adults with Bipolar I Disorder who had a recent manic or mixed episode and were then stabilized with the medication for at least six weeks, according to findings published in a supplement to Neuropsychopharmacology. The results - from the longest double-blind, randomized, placebo-controlled study reported to date investigating the treatment of Bipolar I Disorder with ABILIFY - were based on rigorous criteria used to define stability for Bipolar I Disorder.

"Bipolar I Disorder is a lifelong episodic illness. These findings are important because they support existing ABILIFY data for delaying the recurrence of mood symptoms," said Roger S. McIntyre, MD, Head, Mood Disorders Psychopharmacology Unit, University Health Network, Associate Professor of Psychiatry and Pharmacology, University of Toronto. "In fact, a recent study showed that nearly 50 percent of individuals who responded to initial treatment had relapses within two years, underscoring the importance of long- term maintenance treatment."

Bipolar I Disorder can be treated with antipsychotic medications. ABILIFY is indicated for the treatment of acute manic and mixed episodes associated with Bipolar I Disorder, and for maintaining efficacy in adults with Bipolar I Disorder with a recent manic or mixed episode who had been stabilized and then maintained for at least six weeks. ABILIFY is one of only two atypical antipsychotics indicated for maintenance therapy in Bipolar I Disorder. Physicians who elect to use ABILIFYŽ (aripiprazole) for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Study Design and Findings

In this double-blind, randomized, placebo-controlled long-term study, adults with Bipolar I Disorder who had recently been hospitalized and treated for a manic or mixed episode were initially stabilized with ABILIFY monotherapy (15 or 30 mg/day for 6-18 weeks). In the open-label stabilization phase, the adults in the study were required to maintain a total score of 10 or less on the Young Mania Rating Scale (Y-MRS) and 13 or less on the Montgomery-Asberg Depression Rating Scale (MADRS) for six consecutive weeks prior to randomization into the double-blind phase. One hundred and sixty one adults were randomly assigned to ABILIFY (n=78) or placebo (n=83) in a double- blind fashion and monitored for relapse. The primary endpoint was time to relapse for a manic, mixed, or depressive episode up to and including Week 26. Relapse was defined by a discontinuation from the study attributed to a lack of efficacy (indicated by hospital admission for a mood episode, or addition to or increase in psychotropic medication other than ABILIFY to treat affective symptoms). Adults who completed the 26-week phase of the trial were allowed to continue in a double-blind fashion with aripiprazole or placebo for an additional 74 weeks (for a maximum of 100 weeks). This study was terminated when a pre-determined number of subjects had relapsed for the primary endpoint.

Of the 161 adults who entered the trial, 67 completed the 26-week phase (ABILIFY n=39, placebo n=28). Sixty-six adults entered the 74-week phase (ABILIFY n=39, placebo n=27). Of these adults, 30 discontinued due to various reasons (ABILIFY n=18, placebo n=12), 24 discontinued prematurely due to study termination (ABILIFY n=14, placebo n=10), and 12 completed the additional 74 weeks of treatment (ABILIFY n=7, placebo n=5). Such drop-out rates are common in long-term studies of people with Bipolar I Disorder.

The study showed in adults with up to 100 weeks of treatment, ABILIFY continued to delay the time to relapse (manic, depressive, or mixed) compared to placebo (hazard ratio=0.53, p-value equals 0.011). The majority of the relapses were due to manic rather than depressive symptoms. There is insufficient data to know whether ABILIFY is effective in delaying the time to occurrence of depression in adults with Bipolar I Disorder.

These results were consistent with those previously reported in the 26- week findings, which showed that ABILIFY delayed the time to relapse (manic, depressive, or mixed) compared to placebo (hazard ratio=0.52, p-value equals 0.02). In addition, compared to adults treated with placebo, those treated with ABILIFYŽ (aripiprazole) experienced significantly fewer relapses (25% vs 43%, p-value equals 0.013) and fewer manic relapses (8% vs 23%, p-value equals 0.009).

In this study (up to and including 100 weeks of treatment), adverse events reported at an incidence of 5% or more with ABILIFY and at least twice the rate of placebo were the following: flu syndrome (5.2% vs 0%), pharyngitis (5.2% vs 2.4%), abnormal thinking (5.2% vs 2.4%), vaginitis (6.4% vs 0%), weight gain (6.5% vs 0%), hypertension (7.8% vs 3.6%), dry mouth (7.8% vs 1.2%), akathisia (7.8% vs 1.2%), and tremor (9.1% vs 1.2%). The safety profile was generally consistent with data reported in other long-term placebo controlled trials of ABILIFY including changes in weight, prolactin, QTc, and extrapyramidal symptoms.

About Bipolar Disorder

Bipolar disorder, formerly called manic-depressive illness, is a condition that affects more than two million Americans. People who have this illness tend to experience extreme mood swings, along with other specific symptoms and behaviors. These mood swings or "episodes" can take three forms: manic episodes, depressive episodes, or "mixed" episodes. The symptoms of bipolar disorder are thought to be caused by an imbalance of key chemicals in the brain. Although there is no cure for bipolar disorder, medicine can play a key role in helping to manage symptoms and extreme mood swings.

About ABILIFY

The first and only available dopamine partial agonist, ABILIFY is indicated for the treatment of schizophrenia including maintaining stability in adults who had been symptomatically stable on other antipsychotic medications for periods of three months or longer and observed for relapse during a period of up to 26 weeks. ABILIFY is also indicated for the treatment of acute manic and mixed episodes associated with Bipolar I Disorder, and for maintaining efficacy in adults with Bipolar I Disorder with a recent manic or mixed episode who had been stabilized and then maintained for at least six (6) weeks. Physicians who elect to use ABILIFY for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual. Initially approved in November 2002, ABILIFY is the fastest-growing atypical antipsychotic in the United States with over nine million prescriptions written through May 2006.

ABILIFYŽ (aripiprazole) is available by prescription only. The effective dose range for adults living with schizophrenia is 10-30 mg/day and 15 or 30 mg/day for adults living with Bipolar I Disorder. ABILIFY tablets are available in 2-, 5-, 10-, 15-, 20- and 30-mg strengths. ABILIFY DISCMELT(TM) orally disintegrating tablets are available in 10 mg and 15 mg strengths. ABILIFY is also available in a 1 mg/mL nonrefrigerated oral solution. The FDA recently approved ABILIFY Injection, an injectable form of ABILIFY, for intramuscular use. The safety of doses of ABILIFY above 30 mg/day has not been evaluated in clinical trials.

ABILIFY is taken once daily with or without food. It is important to talk to a healthcare professional for more information about ABILIFY.

IMPORTANT SAFETY INFORMATION for ABILIFY:

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). ABILIFY is not approved for the treatment of patients with dementia-related psychosis (see Boxed Warning).

* Neuroleptic malignant syndrome (NMS)-As with all antipsychotic medications, a rare and potentially fatal condition known as NMS has been reported with ABILIFY. NMS can cause hyperpyrexia, muscle rigidity, diaphoresis, tachycardia, irregular pulse or blood pressure, cardiac dysrhythmia, and altered mental status. If signs and symptoms appear, immediate discontinuation is recommended

* Tardive dyskinesia (TD)-The risk of developing TD and the potential for it to become irreversible may increase as the duration of treatment and the total cumulative dose increase. Prescribing should be consistent with the need to minimize TD. If signs and symptoms appear, discontinuation should be considered since TD may remit, partially or completely

* Cerebrovascular adverse events (eg, stroke, transient ischemic attack), including fatalities, have been reported at an increased incidence in clinical trials of elderly patients with dementia-related psychosis treated with ABILIFY

* Hyperglycemia and diabetes mellitus-Hyperglycemia, in some cases associated with ketoacidosis, coma, or death, has been reported in patients treated with atypical antipsychotics including ABILIFY. Patients with diabetes should be monitored for worsening of glucose control; those with risk factors for diabetes should undergo baseline and periodic fasting blood glucose testing.

Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. There have been few reports of hyperglycemia with ABILIFYŽ (aripiprazole)

ABILIFY may be associated with orthostatic hypotension and should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or conditions which would predispose them to hypotension.

As with other antipsychotic drugs, ABILIFY should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold.

Like other antipsychotics, ABILIFY may have the potential to impair judgment, thinking, or motor skills. Patients should not drive or operate hazardous machinery until they are certain ABILIFY does not affect them adversely.

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotics. Appropriate care is advised for patients who may exercise strenuously, be exposed to extreme heat, receive concomitant medication with anticholinergic activity, or be subject to dehydration.

As antipsychotics have been associated with esophageal dysmotility and aspiration, ABILIFY should be used cautiously in patients at risk for aspiration pneumonia.

As the possibility of a suicide attempt is inherent in psychotic illness and bipolar disorder, close supervision of high-risk patients should accompany drug therapy. Prescriptions for ABILIFY should be written for the smallest quantity consistent with good patient management to reduce the risk of overdose.

Physicians should determine if a patient is pregnant or intends to become pregnant while taking ABILIFY. Patients should be advised not to breast-feed while taking ABILIFY.

Physicians should advise patients to avoid alcohol while taking ABILIFY.

Both CYP3A4 and CYP2D6 are responsible for ABILIFY metabolism. Agents that induce CYP3A4 (eg, carbamazepine) could cause an increase in ABILIFY clearance and lower blood levels. Inhibitors of CYP3A4 (eg, ketoconazole) or CYP2D6 (eg, quinidine, fluoxetine, or paroxetine) can inhibit ABILIFY elimination and cause increased blood levels.

Commonly observed adverse events (greater than or equal to 5% incidence and at a rate at least twice the rate of placebo for ABILIFY vs placebo, respectively):

ABILIFY Oral In 3-week bipolar mania trials the following were reported: akathisia (15% vs 3%), constipation (13% vs 6%), sedation (8% vs 3%), tremor (7% vs 3%), restlessness (6% vs 3%), and extrapyramidal disorder (5% vs 2%).

In 4-6-week schizophrenia trials the following was reported: akathisia (8% vs 4%).

A similar adverse event profile was observed in a 26-week trial in schizophrenia except for a higher incidence of tremor (ABILIFY 8% vs. placebo 2%)

ABILIFY Injection In short-term (24-hour) trials in patients with agitation associated with schizophrenia or bipolar mania the following was reported: nausea (9% vs 3%)

Treatment-emergent adverse events reported with:

ABILIFY Oral In short-term trials of patients with schizophrenia (up to 6-weeks) or bipolar disorder (up to 3-weeks) the following were reported at an incidence greater than or equal to 10% and greater than placebo, respectively, include headache (30% vs 25%), anxiety (20% vs 17%), insomnia (19% vs 14%), nausea (16% vs 12%), vomiting (12% vs 6%), dizziness (11% vs 8%), constipation (11% vs 7%), dyspepsia (10% vs 8%), and akathisia (10% vs 4%).

ABILIFY Injection Treatment-emergent adverse events reported with ABILIFY Injection in short-term (24-hour) trials at an incidence greater than or equal to 5% and greater than placebo, respectively, include headache (12% vs 7%), nausea (9% vs 3%), dizziness (8% vs 5%), and somnolence (7% vs 4%).

About Bristol-Myers Squibb and Otsuka Pharmaceutical Co., Ltd. Bristol-Myers Squibb and Otsuka Pharmaceutical Co., Ltd. are collaborative partners in the development and commercialization of ABILIFY in the United States and major European countries.

ABILIFY was discovered by Otsuka Pharmaceutical Co., Ltd. The brand name ABILIFY is registered to Otsuka Pharmaceutical Co., Ltd. Founded in 1964, Otsuka Pharmaceutical Co., Ltd. is a healthcare company with the mission statement: "Otsuka - people creating new products for better health worldwide." Otsuka researches, develops, manufactures and markets innovative, original products, focusing its core businesses on pharmaceutical products for the treatment of disease and consumer products for the maintenance of everyday health. The Otsuka Pharmaceutical Group comprises 87 companies and employs approximately 27,000 people in 17 countries and regions worldwide. Otsuka and its consolidated subsidiaries earned US $6.8 billion in consolidated annual revenues in fiscal 2005.

Bristol-Myers Squibb is a global pharmaceutical and related health care products company whose mission is to extend and enhance human life.

For more information and FULL PRESCRIBING INFORMATION, including Boxed WARNING, visit: www.abilify.com Visit Bristol-Myers Squibb at: www.bms.com Visit Otsuka Pharmaceutical Co., Ltd. at: www.otsuka-global.com


Source: Bristol-Myers Squibb

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