Neuroscience

Therapy area world market (MAT/Q3/09)

The neuroscience world market totals $132 billion. The medical need in neuroscience is significant

Depression and anxiety disorders remain under-diagnosed and under-treated, with 15% of the population suffering from major depression at least once in their lives. Schizophrenia affects around 1% of the adult population, and 17 million people suffer from bipolar disorder across the major markets. Chronic pain is the most common reason for seeking medical care. Alzheimer's disease affects approximately 24 million people worldwide (predicted to reach 40 million by 2020) and current therapy does not significantly change the course of this progressive neuro-degenerative disorder.

132bn The neuroscience world market totals $132 billion

Seroquel (quetiapine fumarate) is an atypical anti-psychotic drug approved for the treatment of schizophrenia and bipolar disorder (mania, depression and maintenance). Seroquel XR (an extended release formulation of quetiapine fumarate) is generally approved for the treatment of schizophrenia, bipolar disorder and in some territories for MDD and GAD. Approved use for Seroquel and Seroquel XR varies based on territory.

Zomig (zolmitriptan) is used for the treatment of migraines with or without aura.

Diprivan (propofol) is an intravenous general anaesthetic used in the induction and maintenance of anaesthesia, light sedation for diagnostic procedures and for intensive care sedation.

Naropin (ropivacaine) is a long-acting local anaesthetic, replacing the previous standard treatment of bupivacaine.

Xylocaine (lidocaine) is a widely used short-acting local anaesthetic.

EMLA (lidocaine + prilocaine) is a local anaesthetic for topical application.

Disorders of the central nervous system (CNS) represent the number one disease burden today in high-income countries¹. In many other world regions, including Asia, the prevalence of CNS disorders is expected to grow substantially² as the standard of living increases. We aim to strengthen our position in neuroscience through further growth of Seroquel and Seroquel XR and by the successful introduction of a range of new medicines aimed at significant medical need in psychiatry, analgesia (pain control) and cognition, including Alzheimer's disease and attention deficit hyperactivity disorder.

¹

WHO ranking 2008, disease burden measured by disability adjusted life years.

²

Brookmeyer R et al, Alzheimer’s & Dementia 2007; Arthritis Foundation, American Chronic Pain Foundation, Reforming Chinese Healthcare through Public-Private Partnership, Swiss Re May 2007.

Most branded schizophrenia products will face generic competition in the period 2012 to 2015, with major current atypical anti-psychotic patents expiring by 2018. Future demand will be for products with significantly improved efficacy and tolerability. The depression and anxiety markets are currently dominated by generic selective serotonin re-uptake inhibitors and serotonin norepinephrine re-uptake inhibitors. As growth in the US slows, the Japanese and other Asian markets continue to expand due to increased diagnosis and use of pharmacological treatments in response to both targeted government programmes and wider acceptance of pharmacological treatments. Generic growth is anticipated over the next five years as patents expire, which will make market entry for new innovative products more difficult in the medium and longer term.

It will be increasingly important to develop new medicines addressing the needs of specific patient segments, and to work closely with the specialists in the medical community and the public health sector to address the growing burden of psychiatric disease on society.

Our focus

Our key marketed products

Seroquel is a leading atypical anti-psychotic treatment for schizophrenia and bipolar disorder. Seroquel remains the most commonly prescribed atypical anti-psychotic treatment in the US, where it is the only atypical anti-psychotic approved as monotherapy treatment for both bipolar depression and bipolar mania as well as the leading atypical brand globally by sales value.

First launched in 1997, Seroquel is now approved in 94 countries. Seroquel XR, an extended release formulation that offers patients and doctors a once-daily treatment, was launched in the US for the treatment of schizophrenia in 2007 and is now approved in 63 countries for schizophrenia, 38 countries for bipolar mania, 37 countries for bipolar depression and eight countries, including the US, for bipolar maintenance, in three markets for major depressive disorder (MDD), and in one market for generalised anxiety disorder (GAD).

In January 2009, the FDA granted a six-month Paediatric Exclusivity to Seroquel for its licensed indications, based on studies that we conducted in adolescents with schizophrenia, and in children and adolescents with bipolar mania. The six-month Paediatric Exclusivity will extend the exclusivity to market Seroquel in the US to March 2012.

In September, Seroquel and Seroquel XR were approved in the EU for the prevention of recurrence of bipolar disorder in patients whose manic, mixed or depressive episode has responded to treatment with Seroquel or Seroquel XR. Following this new indication, Seroquel and Seroquel XR are the only agents approved in the EU to treat all phases of bipolar disorder, acute depressive episodes, acute manic episodes and maintenance treatment to prevent recurrence of any mood event in bipolar disorder.

In 2008, regulatory submissions were made for the use of Seroquel XR in MDD and GAD. In December 2008, the FDA approved Seroquel XR as an adjunctive treatment to anti-depressants in adults with MDD. The FDA also issued Complete Response Letters in December 2009 for the monotherapy submissions as acute and maintenance therapy in adults and acute therapy in the elderly. The MDD application in the EU was rejected in May and AstraZeneca has now referred the application to the CHMP, with the outcome anticipated in early 2010.

Complete Response Letters for the Seroquel XR GAD submission were received from the FDA in February 2009 (adult population) and September (elderly population). The application was considered unfavourably by an FDA Advisory Committee in April 2009; dialogue with the FDA remains ongoing.

In December, the FDA approved Seroquel for the treatment of schizophrenia in adolescents 13 to 17 years of age as monotherapy, and for the acute treatment of manic episodes associated with bipolar disorder in children and adolescents 10 to 17 years of age, both as monotherapy and as an adjunct to lithium or divalproex.

In the pipeline

AstraZeneca and Targacept have entered into a strategic collaboration and licence agreement for the global development and commercialisation of Targacept's late-stage compound, TC-5214. TC-5214 is being developed as an adjunct to anti-depressant therapy in adults with MDD who do not respond adequately to 1st line anti-depressant treatment. TC-5214, which recently completed a Phase IIb study, is a nicotinic ion channel blocker that is thought to treat depression by modulating the activity of various neuronal nicotinic receptor subtypes. AstraZeneca and Targacept will jointly design a global Phase III clinical programme, anticipated to begin in mid‑2010, with the goal of filing an NDA in 2012.

We have progressed AZD8418 into Phase I and AZD8529 into Phase II for the treatment of schizophrenia. AZD7268 entered into Phase II for the treatment of depression and anxiety. Development of AZD7325 was discontinued.

In 2009, AstraZeneca entered into a number of research collaborations, including those mentioned below. AstraZeneca has entered into a research collaboration with Jubilant in the area of new chemical lead generation and optimisation effectiveness to support our efforts in analgesia and neurology. AstraZeneca has also entered into a collaboration with PsychoGenics, Inc. to support behaviour profiling of new medicines across several disease areas. Furthermore, AstraZeneca has entered into a research agreement with Duke University to identify novel strategies and targets for better treatment of bipolar disorder using optogenetics.

Major unmet need remains for improvements in both efficacy and tolerability in the neuropathic pain market, including addressing the needs of specific patient segments such as those with debilitating conditions, for example mechanical hypersensitivity. It is believed that advances in the understanding of the mechanisms which lead to neuropathic pain will allow for improved patient segmentation and, potentially, this could increase the success rate of research in this condition.

The osteoarthritis (OA) market is steadily growing, due to ageing populations and novel agents entering the market. However, the established use of branded generic treatment makes market entry more difficult. Biologics are an emerging treatment option for OA, and this is an area in which we have an active interest through our biologics activities.

Our focus

Our key marketed products

In 2009, Zomig nasal spray was approved for the acute treatment of migraine attacks in adolescents (12 to 17 years of age) in 14 member states in the EU.

Diprivan is the world's best-selling intravenous general anaesthetic. A complete changeover to Diprivan EDTA, a microbial-resistant formulation, will be effective from 2010.

EMLA submissions/approvals of patch presentation have continued, particularly in Europe. In Japan, EMLA is out-licensed to Sato Pharmaceuticals Co., Ltd. which expects to file a Japanese new drug application for EMLA cream in 2010.

In the pipeline

Vimovo (PN400) is a fixed-dose combination tablet of enteric-coated naproxen and immediate release esomeprazole which uses proprietary technology licensed from Pozen Inc. through a collaboration established in August 2006. It is being developed for the relief of signs and symptoms of OA, rheumatoid arthritis and ankylosing spondylitis in patients at risk of developing NSAID-associated gastric ulcers. Risk factors for the NSAID-associated gastric ulcers include age, a documented history of gastric ulcers, or concomitant use of low-dose aspirin. OA is the most common form of arthritis and the most common cause of chronic pain, affecting nearly 151 million individuals worldwide. The PN400 Phase III studies demonstrated that patients at risk of developing NSAID-associated gastric ulcers taking PN400 experienced significantly fewer endoscopically confirmed gastric ulcers compared with patients taking enteric-coated naproxen (500mg) alone. An NDA was filed in June. The FDA has confirmed that the proposed trade name for PN400, Vimovo, is acceptable and that it will be re-reviewed 90 days prior to the approval of the NDA. A regulatory filing in the EU was submitted in October.

In September, AstraZeneca licensed two potential products, NKTR-118 and NKTR-119, from Nektar. NKTR-118, an oral peripherally-acting opioid antagonist, is in clinical development for the treatment of opioid induced constipation (OIC), which is the key gastrointestinal (GI) side effect of opioid treatment for pain, for which there are limited therapeutic treatment options. Data from a Phase II study demonstrated that oral NKTR-118 improved lower GI dysfunction by increasing the frequency of bowel movements in patients with OIC, while simultaneously preserving opioid-mediated pain relief. NKTR-119 is an earlier-stage programme that combines NKTR-118 with an opioid, with the goal of treating pain without the side effect of constipation traditionally associated with opioid therapy.

AZD2423 has progressed into Phase I studies and AZD2066 has entered into Phase II studies for the treatment of neuropathic (caused by nerve damage) pain. AZD3043, a short-acting anaesthetic, has entered Phase I studies. Additionally, we have extended our research collaboration with the University of Heidelberg to further understanding of the pathophysiology of chronic pain conditions.

Alzheimer's disease (AD) remains one of the largest areas of unmet medical need and also one of high risk for neuroscience product development, due in part to the challenges of establishing efficacy in clinical studies. Current treatments, which physicians consider inadequate, target the symptoms, not the underlying cause, of the disease. Growth in this area is strong (20% to 40% across the world) but all existing marketed treatments will face patent expiry by 2015. Disease modification, delivered through biologics and/or small molecule treatments, is clearly the hope for AD patients. Along with better diagnostics, it is expected to allow for earlier intervention and better clinical outcomes, but the first wave of disease modifiers is still several years away.

Attention deficit hyperactivity disorder (ADHD) affects 22 million children worldwide³ (plus another several million adults). While there are a number of treatments available today, which work well for many of these young patients, they also carry certain risks because a great majority of them are psycho-stimulants (mostly amphetamines and methylphenidate). We continue to work on treatment options that would offer strong efficacy without the challenges that current treatments bring. We also hope to offer new options to adult ADHD patients, many of whom remain undiagnosed or untreated today.

³

Decision Resources 2008.

Our focus

In the pipeline

The current portfolio of potential medicines in this area includes six development programmes, of which three are in clinical evaluation in AD, ADHD and cognitive disorders in schizophrenia (CDS). In addition to developing molecules for cognitive disorders, we continue to progress one development phase molecule for the treatment of other neurodegenerative diseases.

Through our collaboration with the Karolinska Institute in Sweden, the Banner Alzheimer's Institute in Phoenix, Arizona and others, our R&D capabilities in positron emission tomography (PET) imaging of the human brain continue to progress. AstraZeneca's amyloid PET ligands may enable us to detect AD early and to assess drug effects in AD. We have discovered and taken into patient studies two C-11 amyloid PET ligands, which are being developed as research biomarkers. Additionally, a collaboration with the Mental Health Research Institute in Australia has been initiated to develop new ways of identifying AD patients at early stages of the disease.

Compounds in clinical evaluation include products deriving from our relationship with Targacept (AZD3480, TC-5619 and AZD1446). AZD3480, a neuronal nicotinic receptor agent, is currently in Phase II clinical testing in ADHD. In 2009, Targacept announced top-line results from a Phase IIa ADHD study in which the primary outcome measure was met. TC-5619 has entered a Phase IIa study in CDS. AZD1446 has entered Phase IIa studies in ADHD and AD.

Detailed information about material legal proceedings in respect of our Neuroscience products can be found in Note 25 to the Financial Statements.

Performance 2009

Reported performance

Neuroscience sales on a reported basis grew by 7% to $6,237 million in 2009 from $5,837 million in 2008.

Performance - CER growth rates

Neuroscience sales grew by 10% to $6,237 million from $5,837 million last year.

US sales for Seroquel (all formulations) for the full year were $3,416 million, 13% ahead of last year. Seroquel (all formulations) remains the market leader in the US anti-psychotic market, with a total prescription share of 31.3% in December 2009.

For the full year, Seroquel (all formulations) sales outside the US increased by 8% to $1,450 million. In the Rest of World (ie excluding the US and Canada) value and volume growth for Seroquel were well ahead of the atypical anti-psychotic market.

Sales of Zomig for the full year were down 3% in the US to $182 million. Sales outside the US were up 3% to $252 million.

Performance 2008

Reported performance

Neuroscience sales grew by 9% in 2008, up to $5,837 million from $5,340 million in 2007. All geographic areas experienced growth and Seroquel (all formulations) grew strongly by 11%.

Performance - CER growth rates

Neuroscience sales grew by 6% to $5,837 million from $5,340 million in 2007.

US sales for Seroquel (all formulations) for the full year were $3,015 million. For the full year, Seroquel (all formulations) sales outside the US increased by 8% to $1,437 million. In the Rest of World (ie excluding the US and Canada) value and volume growth for Seroquel were well ahead of the atypical anti-psychotic market in all regions.

Sales of Zomig for the full year were up 6% in the US to $187 million. Sales outside the US were down 5% to $261 million.