Otsuka Pharmaceutical and Lundbeck: Study Shows Effects of Treatment with ABILIFY MAINTENA™ (Aripiprazole) on Psychiatric Hospitalization Rates for Patients with Schizophrenia1

Otsuka Pharmaceutical Co., Ltd. (Otsuka) and H. Lundbeck A/S (Lundbeck) today announced results from a preliminary analysis that showed statistically significant reductions (p<0.0001) in total psychiatric hospitalization rates in patients diagnosed with schizophrenia who were converted to once-monthly ABILIFY MAINTENA™ (aripiprazole) – an extended-release injectable suspension formulation of aripiprazole – compared to previous treatment with daily standard-of-care (SOC) oral antipsychotics.¹ Relapse, or an acute exacerbation of the disease, can result in hospitalization.² It also has been reported that hospitalization may contribute to higher health care costs.³ These data were presented in a poster at the 166^th American Psychiatric Association (APA) Annual Meeting in San Francisco on May 21.¹

"While further data are needed to confirm these findings, these results are exciting," said study investigator John M. Kane, M.D., Chairman of Psychiatry, The Zucker Hillside Hospital, and Vice President, Behavioral Health Services, North Shore-LIJ Health System. "Due to the nature of schizophrenia, patients are at high risk for hospitalization, which can often result from a disease relapse.² So the more we can improve the management of symptoms, the better for patients and society as a whole." ^{2, 4}

This multicenter, open-label, North American study used a mirror-image design to assess total psychiatric hospitalization rates – defined as proportion of patients with =1 inpatient psychiatric hospitalizations. The study was divided into two treatment periods: the first was a retrospective, six-month period assessing total psychiatric hospitalization rates in stable adult patients with schizophrenia treated with oral SOC antipsychotics; the second treatment period included these same patients who were then converted to treatment with ABILIFY MAINTENA (aripiprazole) once-monthly 400 mg for six months in the following prospective phases:¹

• Phase A (1-4 weeks): a conversion phase where patients cross-titrated from their current oral antipsychotic to oral aripiprazole;
• Phase B (24 weeks): an open-label treatment phase where patients received ABILIFY MAINTENA (400 mg with an option to decrease to 300 mg for tolerability). As part of the study design, patients also received concomitant oral aripiprazole for the first 14 days of Phase B and:
• Phase C: an ongoing extension phase.

A total of 183 patients entered the prospective Phase B of the study, with 121 completing = three months treatment with ABILIFY MAINTENA in Phase B. Total psychiatric hospitalization rates for the retrospective three-month analysis period in which patients received oral antipsychotics were 28.1 percent (n=34/121) compared to hospitalization rates of 6.6 percent (n=8/121) during the last three months of the prospective analysis period with ABILIFY MAINTENA (p<0.0001). Total psychiatric hospitalization rates for the retrospective six-month analysis period in which patients received oral antipsychotics were 41.5 percent (n=76/183) compared to hospitalization rates of 14.2 percent (n=26/183) for all patients who entered Phase B of the six-month prospective analysis period with ABILIFY MAINTENA (p<0.0001). The most common treatment-emergent adverse events with >5 percent incidence observed during the prospective Phase B were psychotic disorder (7.7 percent), insomnia (7.2 percent), akathisia (7.2 percent) and schizophrenia, paranoid type (5.5 percent). The incidence of weight change was 2.2 percent gained weight and 2.2 percent lost weight.¹

About Schizophrenia

Schizophrenia is a disease characterized by a distortion in the process of thinking and of emotional responsiveness. It most commonly manifests as hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and is accompanied by significant social or occupational dysfunction. Onset of symptoms typically occurs in young adulthood and the condition is chronic, often requiring life-long treatment to mitigate symptoms. It has been estimated that schizophrenia affects approximately 1% of the adult population in the U.S., and approximately 24 million people worldwide.^5,6,7 In the U.S., there are approximately 2.4 million adults with schizophrenia, prevalent equally in both genders.^7,8

It has been reported that the financial burden of schizophrenia in the United States is estimated to be greater than that of all cancers.⁹ Based on the latest data (2002), excess direct health care costs of schizophrenia in the U.S. were approximately $22.7 billion, and included expenditures for hospitalization, as well as for physician and other professional services and medications.³ Additional U.S. 2002 data sets suggest approximately two schizophrenia-related hospitalizations can be estimated per every 1,000 adults per year,^{10, 11} with a mean cost of $18,300 per hospitalization.^{10, 12} Other studies assessing health care utilization have suggested that the use of long-acting injectable medications to treat schizophrenia may help reduce psychiatric hospitalizations^{13, 14} and associated costs.¹³

About ABILIFY MAINTENA™ (aripiprazole)

ABILIFY MAINTENA for extended-release injectable suspension, an IM depot formulation of aripiprazole, is a sterile lyophilized powder that, when reconstituted with sterile water for injection, forms an injectable suspension that can be administered monthly. ABILIFY MAINTENA is indicated for the treatment of schizophrenia.

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. ABILIFY MAINTENA is not approved for the treatment of patients with dementia-related psychosis.

After an initial injection of ABILIFY MAINTENA along with an overlapping 14-day dosing of oral antipsychotic treatment, subsequent injections of ABILIFY MAINTENA provide uninterrupted medication coverage for 30 days at a time. Depot formulations of antipsychotic agents provide patients with concentrations of active drug that remain at a therapeutic range for an extended period of time.^{15, 16}

The U.S. Food and Drug Administration (FDA) approved ABILIFY MAINTENA for the treatment of adults with schizophrenia on February 28, 2013. The product became available for prescribing in the U.S. on March 18, 2013.

IMPORTANT SAFETY INFORMATION for ABILIFY MAINTENA™ (aripiprazole) for extended-release injectable suspension

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk (1.6 to 1.7 times) of death compared to placebo (4.5% vs. 2.6%, respectively). Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. ABILIFY MAINTENA (aripiprazole) is not approved for the treatment of patients with dementia-related psychosis.

Contraindication: Known hypersensitivity reaction to aripiprazole. Reactions have ranged from pruritus/urticaria to anaphylaxis.

Cerebrovascular Adverse Events, Including Stroke: Increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, have been reported in clinical trials of elderly patients with dementia-related psychosis treated with oral aripiprazole.

Neuroleptic Malignant Syndrome (NMS): A potentially fatal symptom complex sometimes referred to as NMS may occur with administration of antipsychotic drugs, including ABILIFY MAINTENA. Rare cases of NMS occurred during aripiprazole treatment. Signs and symptoms of NMS include hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (e.g., 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: 1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; 2) intensive symptomatic treatment and medical monitoring; and 3) treatment of any concomitant serious medical problems for which specific treatments are available.

Tardive Dyskinesia (TD): The risk of developing TD (a syndrome of abnormal, involuntary movements) and the potential for it to become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic increase. The syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. Prescribing should be consistent with the need to minimize TD. There is no known treatment for established TD, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn.

Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that include:

• Hyperglycemia/Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis, coma, or death, has been reported in patients treated with atypical antipsychotics including aripiprazole. Patients with diabetes should be regularly monitored for worsening of glucose control; those with risk factors for diabetes should undergo baseline and periodic fasting blood glucose testing. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia should also undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
• Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. There were no significant differences between aripiprazole- and placebo-treated patients in the proportion with changes from normal to clinically significant levels for fasting/nonfasting total cholesterol, fasting triglycerides, fasting low-density lipoproteins (LDLs), and fasting/nonfasting high-density lipoproteins (HDLs).
• Weight Gain: Weight gain has been observed. Clinical monitoring of weight is recommended.

Orthostatic Hypotension: Aripiprazole may cause orthostatic hypotension. ABILIFY MAINTENA (aripiprazole) should be used with caution in patients with known cardiovascular disease, cerebrovascular disease, or conditions which would predispose them to hypotension.

Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia, neutropenia, and agranulocytosis have been reported. Patients with a history of clinically significant low white blood cell (WBC) count or drug-induced leukopenia/neutropenia should have their complete blood count monitored frequently during the first few months of therapy while receiving ABILIFY MAINTENA. In such patients, consider discontinuation of ABILIFY MAINTENA at the first sign of a clinically significant decline in WBC count in the absence of other causative factors.

Seizures/Convulsions: ABILIFY MAINTENA should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold.

Potential for Cognitive and Motor Impairment: ABILIFY MAINTENA (aripiprazole) may impair judgment, thinking, or motor skills. Instruct patients to avoid operating hazardous machinery including automobiles until they are certain ABILIFY MAINTENA does not affect them adversely.

Body Temperature Regulation: Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Advise patients regarding appropriate care in avoiding overheating and dehydration. Appropriate care is advised for patients who may exercise strenuously, may be exposed to extreme heat, receive concomitant medication with anticholinergic activity, or are subject to dehydration.

Dysphagia: Esophageal dysmotility and aspiration have been associated with ABILIFY MAINTENA; use caution in patients at risk for aspiration pneumonia.

Alcohol: Advise patients to avoid alcohol while taking ABILIFY MAINTENA.

Concomitant Medication: Dosage adjustments are recommended in patients who are CYP2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors or CYP2D6 inhibitors for greater than 14 days. If the CYP3A4 inhibitor or CYP2D6 inhibitor is withdrawn, the ABILIFY MAINTENA dosage may need to be increased. Avoid the concomitant use of CYP3A4 inducers with ABILIFY MAINTENA for greater than 14 days because the blood levels of aripiprazole are decreased and may be below the effective levels. Dosage adjustments are not recommended for patients with concomitant use of CYP3A4 inhibitors, CYP2D6 inhibitors or CYP3A4 inducers for less than 14 days.

Most commonly observed adverse reaction: The safety profile of ABILIFY MAINTENA is expected to be similar to that of oral aripiprazole. In patients who tolerated and responded to oral aripiprazole and single-blind ABILIFY MAINTENA and were then randomized to receive ABILIFY MAINTENA or placebo injections, the incidence of adverse reactions was similar between the two treatment groups. The adverse reaction = 5% incidence and at least twice the rate of placebo for oral aripiprazole vs. placebo, respectively, was:

• Akathisia (8% vs. 4%) in adult patients with schizophrenia.

Injection Site Reactions: In the open-label, stabilization phase of a study with ABILIFY MAINTENA in patients with schizophrenia, the percent of patients reporting any injection site- related adverse reaction was 6.3% for ABILIFY MAINTENA-treated patients.

Dystonia is a class effect of antipsychotic drugs. Symptoms of dystonia may occur in susceptible individuals during the first days of treatment and at low doses.

Pregnancy/Nursing: Based on animal data, may cause fetal harm. ABILIFY MAINTENA (aripiprazole) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Aripiprazole is excreted in human breast milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Please see accompanying FULL PRESCRIBING INFORMATION, including Boxed WARNING, for ABILIFY MAINTENA.

About Otsuka Pharmaceutical Co., Ltd.

Otsuka Pharmaceutical Co., Ltd. is a global healthcare company with the corporate philosophy: 'Otsuka-people creating new products for better health worldwide.' Otsuka researches, develops, manufactures and markets innovative and original products, with a focus on pharmaceutical products for the treatment of diseases and nutraceutical products for the maintenance of everyday health.

In pharmaceuticals, Otsuka is a leading firm in the challenging area of mental health and for several decades has been active in research on tuberculosis, a significant global public health issue. These commitments illustrate more powerfully than words how Otsuka is a "big venture" company at heart, applying a youthful spirit of creativity in everything it does.

Otsuka is a wholly owned subsidiary of Otsuka Holdings Co., Ltd., the holding company for the Otsuka Group. The chairman Akihiko Otsuka is the third generation of Otsuka family members to lead the business, whose origins date from 1921. The Otsuka Group has business operations in 25 countries and regions around the world, with consolidated sales of approximately USD 13 billion (approximately € 10 billion) for fiscal year 2012 (4/1/2012-3/31/2013.) Otsuka welcomes you to visit its global website at https://www.otsuka.co.jp/en/

About H. Lundbeck A/S

Lundbeck is a global pharmaceutical company highly committed to improving the quality of life of people living with brain diseases. For this purpose, Lundbeck is engaged in the entire value chain throughout research, development, production, marketing and sales of pharmaceuticals across the world. The company's products are targeted at disorders such as depression and anxiety, psychotic disorders, epilepsy, Huntington's, Alzheimer's and Parkinson's diseases. Lundbeck's pipeline consists of several mid- to late-stage development programs. Lundbeck's U.S. business is based in Deerfield, Illinois. To learn more about Lundbeck in the U.S., visit www.lundbeckus.com.

Lundbeck employs more than 5,800 people worldwide, 2,000 of whom are based in Denmark. We have research in 57 countries and our products are registered in more than 100 countries. We have research centers in Denmark, China and the United States and production facilities in Italy, France, Mexico, China and Denmark. Lundbeck generated revenue of approximately DKK 15 billion in 2012. For additional information, we encourage you to visit our corporate site www.lundbeck.com.

References:

Photos/Multimedia Gallery Available: http://www.businesswire.com/multimedia/home/20130521005859/en/