Cardiovascular

Therapy area world market (MAT/Q3/09)

CV is the single largest therapy area in the global healthcare market with a worldwide market value of $160 billion

CV disease remains the greatest risk to life for adults, accounting for 17 million deaths worldwide each year. In the US, 23 million people suffer from diabetes and two in five people with diabetes still have poor lipid profiles, one in three have poor blood pressure control and one in five have poor glucose control.

160bn CV is the single largest therapy area in the global healthcare market. Worldwide market value of $160 billion

Crestor¹ (rosuvastatin calcium) is a statin for the treatment of dyslipidaemia and hypercholesterolemia, and to slow the progression of atherosclerosis.

Atacand² (candesartan cilexetil) is an angiotensin II antagonist for the 1st line treatment of hypertension and symptomatic heart failure.

Seloken/Toprol-XL (metoprolol succinate) is a beta-blocker once-daily tablet for 24-hour control of hypertension and for use in heart failure and angina.

Tenormin (atenolol) is a cardioselective beta-blocker for hypertension, angina pectoris and other CV disorders.

Zestril³ (lisinopril dihydrate) is an ACE inhibitor used for the treatment of a wide range of CV diseases, including hypertension.

Plendil (felodipine) is a calcium antagonist for the treatment of hypertension and angina.

Onglyza™⁴ (saxagliptin) is a dipeptidyl peptidase IV inhibitor for the treatment of Type 2 diabetes.

¹

Licensed from Shionogi & Co. Ltd.

²

Licensed from Takeda Chemicals Industries Ltd.

³

Licensed from Merck & Co., Inc.

⁴

Co-developed and co-commercialised with Bristol-Myers Squibb Company.

¹

Includes sales of the authorised generic of Toprol-XL to Par Pharmaceutical Companies, Inc.

An estimated 17.5 million people died from cardiovascular (CV) disease in 2005, 7.6 million due to heart attacks, despite improvements in the quality of diagnosis and treatment. Direct and indirect costs of treating coronary heart disease were estimated to be €192 billion in Europe in 2008¹ and $313 billion in the US in 2009².

Backed by over 40 years' experience, AstraZeneca is a world leader in CV medicines. We aim to build on our strong position, focusing on the growth areas of atherosclerosis (hardening of the arteries), thrombosis (blood clotting), diabetes and atrial fibrillation.

¹

European cardiovascular disease statistics, 2008 edition, Steven Allender et al, British Foundation Health Promotion Research Group.

²

National Heart, Lung, and Blood Institute. Fact Book, Fiscal Year 2008, hlbi.nih.gov/about/factbook/FactBookFinal.pdf.

High blood pressure (hypertension) and abnormal levels of blood cholesterol (dyslipidaemia) damage the arterial wall and thereby lead to atherosclerosis. CV events driven by atherosclerotic disease remain the leading cause of death in the western world. Lipid-modifying therapy, primarily statins, is a cornerstone for the treatment of atherosclerosis. Within the lipid-modifying market, generics are taking a significant share of the market and it is anticipated that generic atorvastatin (Lipitor™) will be available late in 2011.

Our focus

Our key marketed products

Since its launch in 2003, our statin, Crestor, has continued to gain market share, based on its differentiated profile in managing cholesterol levels and its unique recent label indication for treating atherosclerosis. Crestor approval has broadened to every EU country with launches in Germany and Spain in 2009.

Fewer than half of the people thought to have high levels of low-density lipoprotein cholesterol (LDL-C) 'bad cholesterol' get diagnosed and treated and, of those people, only about half reach their physician's recommended cholesterol target using existing treatments. Crestor is the most effective statin in lowering LDL-C and the majority of patients reach their LDL-C goals using the usual 10mg starting dose. Crestor also produces an increase in high-density lipoprotein cholesterol (HDL-C) 'good cholesterol', across a range of doses. At its usual 10mg starting dose, Crestor has been shown, versus placebo, to reduce LDL-C by up to 52% and raise HDL-C by up to 14%, with eight out of 10 patients reaching their lipid goals.

In December, the FDA approved Crestor for use as an adjunct to diet for slowing the progression of atherosclerosis in patients with elevated cholesterol. Crestor is the only statin with an atherosclerosis indication in the US which is not limited by disease severity or restricted to patients with coronary heart disease.

Atacand, first launched in 1997, is approved for the treatment of hypertension in over 100 countries and for symptomatic heart failure in 70 countries. Atacand is an angiotensin II antagonist, and this class of medicine is the fastest-growing segment of the global hypertension market. Atacand Plus (candesartan cilexetil/hydrochlorothiazide) is a fixed-dose combination of Atacand and the diuretic hydrochlorothiazide, indicated for the treatment of hypertension in patients who require more than one hypertensive therapy. Atacand Plus is approved in 88 countries. In 2008, AstraZeneca sought approval in Europe and other markets for two additional dose strengths of Atacand Plus. In 2009, the new strengths of Atacand Plus (32mg/12.5mg and 32mg/25mg) were approved in Canada, Australia, Sweden and nine other markets. Further approvals and launches are anticipated in 2010.

Following an sNDA submission in April 2009, the FDA has approved Atacand for the treatment of hypertension in children one to 17 years of age. This sNDA submission has also resulted in the granting of an additional six-month period of exclusivity to market Atacand in the US.

Clinical studies of our key marketed products

GALAXY, our long-term global clinical research programme for Crestor, which investigates links between optimal lipid control, atherosclerosis and CV morbidity and mortality, has completed a number of studies involving over 65,000 patients in over 55 countries. Some of the studies undertaken as part of the GALAXY programme are referred to below, namely the JUPITER, PLUTO, AURORA, SATURN and PLANETS I and II studies.

Regulatory submissions for Crestor based on the JUPITER study results, details of which were included in our 2008 Annual Report and Form 20-F Information, are under review in the US and the EU as well as in other markets with approvals in Malaysia and Colombia. The JUPITER study was the subject of an FDA Advisory Committee in December with the Committee voting positively on the benefit/risk profile demonstrated in the study. A decision by the FDA on the submission is expected in the first quarter of 2010.

The PLUTO study evaluated the efficacy and safety of Crestor in patients 10 to 17 years of age with heterozygous familial hypercholesterolemia. Completion of the PLUTO study fulfilled our paediatric exclusivity requirements in the US and resulted in an additional six-month period of exclusivity to market Crestor in the US being granted in July. In October, a successful paediatric registration for Crestor was achieved.

The AURORA study, published in April 2009, evaluated the effects of Crestor 10mg and placebo on survival and major CV events in patients with end-stage renal disease on chronic hemodialysis and demonstrated that Crestor had no positive impact on such patients. The findings of the AURORA study are consistent with other previously published results with other statins and suggest that the CV disease present in chronic hemodialysis patients is different from other clinical settings and is not positively impacted by statin treatment.

Ongoing studies of Crestor include the SATURN study and the PLANETS I and II studies. The SATURN study, which is designed to measure the impact of Crestor 40mg and atorvastatin (Lipitor™) 80mg on the progression of atherosclerosis in high-risk patients, is expected to report in 2011. The PLANETS I and II studies, which are designed to compare the efficacy and safety of Crestor 10mg and 40mg to atorvastatin (Lipitor™) 80mg in patients with proteinuric renal disease in diabetics and nondiabetics, respectively, are expected to report in the first half of 2010.

In the pipeline

We continue the search for the next major therapy to reduce atherosclerotic risk. In collaboration with Abbott, we are developing an investigational compound, Certriad, a fixed-dose combination of the active ingredients in Crestor (rosuvastatin calcium) and Abbott's Trilipix™ (fenofibric acid). An NDA submission in respect of Certriad for the treatment of mixed dyslipidaemia was announced jointly by both companies in June.

Certriad is a potential new approach to help patients with mixed dyslipidaemia achieve their treatment goals using a single capsule, which targets all three major blood lipids: LDL-C, HDL-C and triglycerides. Study results presented in 2008 showed that this combination provides greater benefit across multiple lipid parameters than the individual monotherapies, with significantly improved HDL-C and triglycerides compared to Crestor therapy alone, and significantly improved LDL-C compared to Trilipix™ alone.

In 2009, AstraZeneca and the University of Virginia entered into a strategic research collaboration to enhance development of new treatments primarily for coronary artery disease with a secondary focus on peripheral vascular disease. The collaborative pre-clinical research projects will focus on identifying disease mechanisms and biological targets that have the potential to be starting points for successful and commercially viable treatments for these diseases, both major causes of CV morbidity and mortality worldwide.

The number of people affected by Type 2 diabetes continues to grow, predominantly driven by obesity. Type 2 diabetes is a chronic progressive disease and patients often require multiple medications to control their condition. There are a number of established oral generic and branded classes, such as sulfonylureas and thiazolidinediones; however, newer classes such as oral dipeptidyl peptidase IV inhibitors are entering the market successfully by offering effective blood sugar control and improved tolerability. Several new classes of drugs are in development in this area. CV safety has been given particular emphasis in recent regulatory reviews and guidance documents provided by the FDA. Additional patient safety requirements for new medicines can also be anticipated from other regulatory authorities.

Our focus

Our key marketed products

The collaboration on a worldwide basis¹ between AstraZeneca and BMS to develop and commercialise two compounds discovered by BMS (Onglyza™ (saxagliptin) and dapagliflozin) for the treatment of Type 2 diabetes continues to make good progress.

During 2009, Onglyza™ was launched in the US, Canada, Mexico, Germany, the UK and Denmark and was approved in Argentina, Brazil, India and the EU. A large worldwide study assessing CV events will be conducted as a US post-marketing requirement.

¹

The collaboration for saxagliptin excludes Japan.

In the pipeline

In December, AstraZeneca and BMS submitted an NDA for the once-daily fixed-dose combination of Onglyza™ (saxagliptin) and metformin.

Dapagliflozin is a potential oral anti-diabetic, which belongs to the novel class of sodium-glucose co-transporter 2 inhibitors. It is designed to be used both as monotherapy and in combination with other therapies for Type 2 diabetes. Early Phase III data demonstrate that, when compared to a placebo, 24 weeks' treatment with dapagliflozin improved blood glucose parameters, resulted in weight loss and was well tolerated in patients with Type 2 diabetes. The extensive Phase III programme is ongoing.

Our activities in the glucokinase activator (GKA) area continued during 2009, and Phase II studies for AZD1656 are ongoing. The GKA mechanism of action induces insulin release from the pancreas and reduces glucose output from the liver, with marked blood glucose reducing effects in situations of hyperglycaemia.

During 2009, we also progressed our AZD4017, AZD8329 and AZD7867 projects into early clinical testing. These potential medicines aim to increase insulin sensitivity and thereby induce better glycaemic control with beneficial effects on body weight and blood lipids.

In December, AstraZeneca concluded an agreement with Biovitrum AB (publ) (Biovitrum) for the acquisition of all Biovitrum's rights to its leptin modulator programme aimed at treating obesity. The leptin modulator programme is currently in pre-clinical development.

Acute coronary syndromes (ACS) is an umbrella term for sudden chest pain and other symptoms due to insufficient blood supply (ischaemia) to the heart muscles. ACS is the acute culmination of ischemic heart disease, the leading cause of death worldwide (WHO 2008). There remains a significant need to improve outcomes and reduce the costs of treating ACS.

Our focus

In the pipeline

Brilinta/Brilique (ticagrelor) is the first reversibly binding, oral, adenosine diphosphate receptor antagonist being developed to reduce the risk of blood clots and thrombotic events in patients diagnosed with ACS. In August, AstraZeneca announced results from the Phase III study, PLATO, a head-to-head 18,624 patient outcomes study of ticagrelor plus aspirin versus the active comparator, clopidogrel (Plavix™/Iscover™), plus aspirin. The PLATO study was designed to establish whether ticagrelor could achieve meaningful CV and safety endpoints in ACS patients. The PLATO study included all the major ACS patient types (unstable angina, ST segment elevation myocardial infarction and non-ST segment elevation myocardial infarction) and followed patients who underwent invasive procedures (eg stent placement or surgery) or were managed with prescription medication.

The data from the PLATO study suggests that ticagrelor has achieved greater efficacy in the primary endpoint, reduction of CV events (CV death, heart attack, stroke), over clopidogrel without an increase in major bleeding. This efficacy endpoint was driven by a statistically significant reduction in both CV deaths and heart attacks with no difference in strokes. Ticagrelor is the first investigational antiplatelet that has demonstrated a reduction in CV death versus clopidogrel in patients with ACS. The reduction in the risk of CV events with ticagrelor occurred early and this benefit increased over time compared to clopidogrel.

The PLATO trial design prospectively identified 66 subgroups. The findings from 62 of the 66 subgroups were consistent with the results of the overall study population. Given the large number of subgroups evaluated, the four inconsistent findings may have been due to chance. One of the four subgroups showed a difference in efficacy results between patients in North America and those enrolled elsewhere. Alongside explanation by the play of chance, this raised questions of whether geographic differences between populations of patients or practice patterns influenced the effects of the randomised treatments. While no definitive explanation has been found to date, further analyses suggest a possible association between aspirin dose and the primary efficacy results, such that reduced efficacy was observed with ticagrelor and increasing aspirin doses. AstraZeneca and the PLATO investigators are continuing to explore these and other hypotheses, as well as other follow-on analyses of the PLATO trial data set, and plan to publish in due course.

AstraZeneca filed an MAA for ticagrelor in October and an NDA in November.

Axanum is a single capsule of aspirin (acetylsalicylic acid (ASA)) (75-325mg) and Nexium. Low-dose ASA (75-325mg) is the mainstay therapy for patients who are at high risk of having a CV event such as a heart attack or stroke. Patients report that low-dose ASA treatment can cause gastrointestinal (GI) problems and up to 30% of patients with upper GI problems (ie complications and symptoms) caused by the use of low-dose ASA discontinue or take deliberate breaks from their low-dose ASA treatment due to GI problems, which leaves them without adequate CV protection and puts them at greater risk of having a CV event. The risk of a CV event increases as early as 10 days from the discontinuation of the treatment.

An NDA in respect of Axanum was submitted to the FDA in April 2009 for risk reduction of peptic ulcers associated with low-dose ASA (75-325mg) therapy in patients at risk. The proposed labelling also includes the approved low-dose ASA indications. The submission was based on the results of the OBERON and ASTERIX studies evaluating the safety and efficacy of Nexium in reducing the risk of gastric and/or duodenal ulcers in patients taking low-dose ASA (75-325mg) continuously during the studies, which is defined as at least five days per week.

The data from the recent OBERON study, a double-blind, randomised, prospective analysis of 2,426 patients taking low-dose ASA (75-325mg), revealed that each of Nexium 20mg and 40mg reduced the cumulative proportion of patients with peptic ulcers after 26 weeks of treatment by 80-85% compared to placebo. Upper GI symptoms were assessed showing that the proportion of patients treated with Nexium with upper GI symptoms was significantly lower than in the placebo arm.

The ASTERIX study was a randomised, double-blind, placebo-controlled, study in 991 patients. Patients were randomised to treatment with either once-daily Nexium 20mg or placebo for six months while continuing to take their low-dose ASA therapy. After six months, Nexium was shown to reduce the risk of developing an ulcer by 70%.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Rhythm-control therapy to control the symptoms of AF is dominated by generic amiodarone, which is effective at maintaining patients in normal heart rhythm but very poorly tolerated. AF is associated with an increased risk of cerebral embolism resulting in stroke and disability. To reduce the risk of such AF-related complications, anti-coagulation with vitamin K antagonists can be used. New anti-coagulation therapies with improved convenience are emerging.

Our focus

In the pipeline

For the control of heart rhythm in AF, our focus is on atrial-specific agents as a way to reduce the risk of pro-arrhythmic effects. Our first compound in this area is in pre-clinical development. During 2009, the development of AZD1305, a combined ion-channel blocker which was in Phase II concept testing, was discontinued due to an emerging unfavourable benefit/risk profile.

Our oral, direct thrombin inhibitor (AZD0837) is ready to be taken into Phase III testing for the prevention of strokes and other embolic events in AF patients, using a once-daily extended release formulation that provides a sustained anti-coagulation effect throughout the dosing interval. AstraZeneca is considering the potential for AZD0837 in a number of indications as well as evaluating potential collaborations with third parties for its future development.

Detailed information about material legal proceedings relating to our CV products can be found in Note 25 to the Financial Statements.

Performance 2009

Reported performance

CV sales were up 20% as reported to $8,376 million (2008: $6,963 million). Strong growth from Crestor, driven by the promotion of the atherosclerosis indication, and substantially increased sales of Toprol-XL and the authorised generic version of the drug in the US were the major contributors to growth in CV sales.

Performance - CER growth rates

CV sales were up 25% from 2008 at CER.

Crestor sales increased by 29% to $4,502 million. US sales for Crestor for the full year increased by 25% to $2,100 million. The total prescription share of Crestor in the US statin market increased to 11.3% in December 2009 from 9.9% in December 2008, and it was the only branded statin to gain market share. Crestor sales outside the US were up 33% for the full year to $2,402 million, over half of global sales for the product. Sales of Crestor were up 24% in our Western Europe markets to $968 million and 58% in Japan, driving sales growth in Other Established Markets and Canada up 33% in total. Sales of Crestor in Emerging Markets increased by 32%.

Sales of Seloken/Toprol-XL and its authorised generic increased by 84% to $1,443 million in 2009, as a result of increased sales of Toprol-XL and its authorised generic in the US. Sales in the US increased by 227% to $964 million following the withdrawal from the market of two other generic metoprolol succinate products in early 2009. However, we expect further generic competition in 2010.

Sales of Atacand in the US for the full year were unchanged from 2008 at $263 million, and account for 18% of global Atacand sales. Atacand sales outside the US were up 5% to $1,173 million, with a 3% increase in Other Established Markets and Canada and a 13% increase in Emerging Markets.

Alliance revenue from the Onglyza™ collaboration with BMS totalled $11 million in 2009.

Performance 2008

Reported performance

CV sales were up 4% as reported to $6,963 million (2007: $6,686 million). Strong growth from Crestor, fuelled by the promotion of the atherosclerosis indication, and increased sales of Atacand offset the continuing significant declines in Seloken/Toprol-XL.

Performance - CER growth rates

CV sales were unchanged from 2007 at CER. Crestor sales increased by 26% to $3,597 million. US sales for Crestor for the full year increased by 18% to $1,678 million. Crestor total prescription share in the US statin market increased to 9.9% in December 2008 from 8.6% in December 2007, and was the only branded statin to gain market share. Crestor sales outside the US were up 34% for the full year to $1,919 million, over half of global sales for the product. Sales of Crestor were up 16% in our Western Europe markets to $836 million and 93% in Japan. Sales of Crestor in Emerging Markets increased by 41%.

Sales of Toprol-XL and authorised generic sales of the drug in the US were down 70% for the full year to $295 million. For the full year, Seloken sales outside the US were up 1% to $512 million.

US sales for Atacand for the full year increased 1% to $262 million. Atacand sales outside the US were up 12% to $1,209 million, a 10% increase in Other Established Markets and Canada, and an 18% increase in Emerging Markets.