Contact: Rachel Bloom, Zeneca Pharmaceuticals, 302/886-7858 - [email protected]

FDA CLEARS ZENECAíS SEROQUEL (quetiapine fumarate) TABLETS, A NEW TREATMENT FOR THE MANAGEMENT OF THE MANIFESTATIONS OF PSYCHOTIC DISORDERS, INCLUDING SCHIZOPHRENIA

WILMINGTON, Del. -- September 29, 1997 -- Zeneca Pharmaceuticals today announced that the US Food and Drug Administration (FDA) has cleared for marketing SEROQUEL" (quetiapine fumarate) tablets, an oral medication indicated for the management of the manifestations of psychotic disorders, including schizophrenia. The compound was discovered and developed by Zeneca Pharmaceuticals in its US research laboratories.

ìClinical trials demonstrate that therapy with SEROQUEL benefits many patients with schizophrenia by controlling both positive and negative symptoms of the disease,î said Lisa A. Arvanitis, MD, senior medical director, Medical Research and Communications Group, Zeneca Pharmaceuticals. ìSEROQUEL was shown to have a low incidence of troublesome side effects such as the movement disorders known as extrapyramidal symptoms (EPS) and elevations of plasma prolactin levels which are associated with such problems as menstrual irregularities and impotence. This, coupled with a dosing regimen of two to three times daily, should provide added convenience for patients.î

SEROQUEL is manufactured in the US and will be available by prescription by mid-October in strengths of 25 mg, 100 mg, and 200 mg tablets. In clinical trials, efficacy was demonstrated in a dose range of 150 mg/day to 750 mg/day. A maximum therapeutic effect was seen at 300 mg/day in a dosing trial. In other studies, doses in the range of 400-500 mg/day were effective. A dosing regimen of two to three times daily is recommended.

The efficacy of SEROQUEL, as well as the ìatypicalî profile which distinguishes the compound from standard antipsychotic agents, is supported by three placebo- and comparator-controlled Phase II and III clinical trials in patients hospitalized for acute exacerbation of chronic or subchronic schizophrenia. SEROQUEL was

shown to be effective in treating both the positive symptoms (i.e., hallucinations, delusions) and negative symptoms (i.e., emotional withdrawal, blunted affect) associated with schizophrenia. SEROQUEL was well tolerated in more than 4,000 male and female patients ages 18 years and older. As with other agents in its class, the labeling for SEROQUEL includes a warning relative to a rare condition known as tardive dyskinesia (which is often associated with long term use of antipsychotic agents) and neuroleptic malignant syndrome (NMS). Symptoms of NMS include muscle rigidity or irregular pulse. Precautions include orthostatic hypotension (which may result in dizziness) and tachycardia (fast heartbeat). Also included is a precaution for seizures. As with other antipsychotics, SEROQUEL should be used cautiously in patients with a history of seizures or with conditions that can potentially lower the seizure threshold. The most common adverse events exhibited across placebo-controlled trials included somnolence (18%), headache (19%), and dizziness (10%), and the majority of events rated as mild or moderate. The safety and effectiveness of SEROQUEL in pediatric patients less than 18 years of age has not been established. SEROQUEL interacts with multiple neurotransmitter receptors in the brain, though the specific mechanism of action, as with other antipsychotic drugs, is unknown. However, it has been proposed that the antipsychotic activity and low EPS liability of SEROQUEL are mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) receptor antagonism. Antagonism at receptors other than dopamine and serotonin may also contribute to the pharmacologic effects of SEROQUEL.

The incidence of EPS with SEROQUEL was not different from placebo across the clinical dose range. Although an elevation of prolactin levels was not demonstrated in clinical trials with SEROQUEL, increased prolactin levels were observed with animal studies.

Studies also showed that SEROQUEL exhibits a low incidence of anticholinergic side effects (i.e., dry mouth, constipation) and no significant prolongation of QTc intervals which may cause cardiac arrhythmias. Patients enrolled in long-term (two year) studies of continuation therapy with SEROQUEL after completion of Phase III clinical trials yielded data which show that SEROQUEL was well tolerated with no additional safety or tolerability issues arising beyond those adverse events seen in short-term trials.

Schizophrenia is a severe, chronic brain disorder which generally manifests itself between the ages of 15 and 30 years and afflicts nearly three million Americans. This form of psychosis is one of the most common and most devastating mental illnesses and results in as much as $65 billion annually in direct medical costs and lost productivity. Worldwide sales of antipsychotic medications are currently estimated at more than $2.5 billion annually and are expected to grow to approximately $4.1 billion by the year 2000. The current US market could reach $1.5 billion by yearís end and is expected to grow to nearly $2 billion by the year 2000. Market growth is due principally to the introduction of new medicines which are both effective and well-tolerated in the treatment of psychosis.

ìFor more than 30 years, Zeneca Pharmaceuticals has made a significant commitment to the discovery of compounds to treat central nervous system (CNS) disorders,î said Robert C. Black, president of Zeneca Pharmaceuticals. ìSEROQUEL represents our first entry into the antipsychotic market. We anticipate that the drug will provide Zeneca with a strong foundation for continued long-term success in the CNS market.î The portfolio of CNS products developed by Zeneca worldwide includes treatments for the management of migraine, epilepsy, anesthesia, anxiety, and depression. Approximately 21 percent of the companyís R&D expenditure is dedicated to the CNS area.

On August 4, 1997, Zeneca announced that it had received approval from the UK Medicines Control Agency to market SEROQUEL. The company is also pursuing approvals to market the product in other countries.

Zeneca Pharmaceuticals is a business unit of Zeneca Inc., a $3.1 billion bioscience business with approximately 7,200 employees in the US. Zeneca Inc. is a wholly-owned subsidiary of the UK-based Zeneca Group PLC (NYSE:ZEN), a major $9 billion international bioscience business engaged in the research, development, manufacturing and marketing of ethical (prescription) pharmaceuticals, agricultural and specialty chemical products, and the supply of health care services.

###