AstraZeneca Annual Report and Form 20-F Information 2008

Hypertension, atherosclerosis and dislipidaemia

High blood pressure (hypertension) and abnormal levels of blood cholesterol (dyslipidaemia) are well known to 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 of treating atherosclerotic risk. Within the lipid-modifying market, generics are taking a significant share of the market and it is anticipated that generic atorvastatin will be available late 2011. Recent studies of some competitor products created uncertainty about clinical efficacy leading to reduced sales of these products, whilst AstraZeneca’s study (see below) provided positive data on the effect of rosuvastatin.

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 atherosclerotic disease. Following new approvals during 2008 in Germany, Spain, Poland, Norway and Malta, Crestor is now approved in every EU country.

Less 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 the US, Crestor is also approved 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 over 70 countries. Angiotensin II antagonists are the fastest growing sector of the global hypertension market. Available as a once a day tablet, launches of the 32mg dosage strength outside the US continued during the year, and this dosage is now available in most Established Markets. In July 2008, we sought approval in Europe for two dose strengths of Atacand Plus (candesartan cilexetil/hydrochlorothiazide) which is a fixed combination of Atacand and the diuretic hydrochlorothiazide (HCTZ), indicated for the treatment of hypertension in patients who need more than monotherapy.

Clinical trial developments

GALAXY, our long-term global clinical research programme for Crestor investigating links between optimal lipid control, atherosclerosis and CV morbidity and mortality, has completed a number of studies involving over 69,000 patients in over 55 countries.

Data from the latest study, JUPITER, published in November 2008, demonstrated that Crestor 20mg significantly reduced major CV events (defined in this study as the combined risk of myocardial infarction, stroke, arterial revascularisation, hospitalisation for unstable angina, or death from CV causes) by 44% compared to placebo among men and women with elevated high-sensitivity C-reactive protein (hsCRP) (and other risk factors) but low to normal cholesterol levels. Results also showed that for patients taking Crestor, the combined risk of heart attack, stroke or CV death was reduced by nearly half, risk of heart attack was cut by more than half, risk of stroke was cut by nearly half and total mortality was significantly reduced by 20%. Crestor 20mg was well tolerated in nearly 9,000 patients during the course of the study. There was no difference between treatment groups for major adverse events, including cancer or myopathy. There was a small increase in physician reported diabetes consistent with data from other large placebo controlled statin trials.

GISSI-HF, an investigator sponsored study published in September 2008, evaluated Crestor 10mg and placebo in a heart failure population and confirmed the results of our CORONA study in showing no difference between the treatments in the primary endpoints of death or CV hospitalisation in patients with heart failure, over and above optimised heart failure treatment. Both studies were also consistent with the safety profile of Crestor in this vulnerable population. In both studies, outcome events appeared to be driven primarily by heart muscle failure rather than ischemic events where statins would be expected to have an effect.

Ongoing studies of Crestor include SATURN, which is designed to measure the impact of Crestor 40mg and atorvastatin (Lipitor^™) 80mg on the progression of atherosclerosis in high-risk patients and is expected to report in 2011. AURORA, an outcomes study in patients with end stage renal disease is expected to present data by mid 2009.

The clinical programme (DIRECT) investigating the effect of Atacand (up to 32mg dosage) on retinopathy in hypertensive and normotensive diabetic patients completed in 2008 but failed to meet the primary endpoint. The results were published in September 2008.

In the pipeline

We continue the search for the next major therapy to reduce atherosclerotic risk. In collaboration with Abbott, we are developing a fixed dose combination of Crestor and Abbott’s Trilipix^™ and are anticipating a US submission in the third quarter of 2009.

The combination of Crestor (a statin) and Trilipix^™ (a fibrate) is a potential new approach to helping patients with mixed dyslipidaemia achieve their treatment goals using a single capsule targeting all three major blood lipids: LDL-C, HDL-C, and triglycerides. Study results presented in 2008 showed that the combination of Crestor and Trilipix^™ provides greater benefit across multiple lipid parameters than monotherapy, with significantly improved HDL-C and triglycerides compared to statin therapy alone, and significantly improved LDL-C compared to Trilipix^™ alone.

We have stopped work on cholesterol absorption inhibitors because of failure to meet target product profiles.

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