Respiratory & Inflammation

Therapy area world market (MAT/Q3/09)

The prescription respiratory world market value is $54 billion
WHO estimates that 300 million people worldwide suffer from asthma and more than 200 million have COPD, which is currently the fourth leading cause of death worldwide with further increases anticipated in future decades.

54bn The prescription respiratory world market value is $54 billion

Symbicort pMDI (budesonide/formoterol in a pressurised metered-dose inhaler) is used for the maintenance treatment of asthma and COPD in the US.

Symbicort SMART (our Symbicort Maintenance and Reliever Therapy) is approved for maintenance and reliever therapy in persistent asthma.

Symbicort Turbuhaler (budesonide/formoterol in a dry powder inhaler) is a combination of an inhaled corticosteroid and a fast onset, long-acting bronchodilator used for the treatment of asthma and COPD.

Pulmicort (budesonide) is a corticosteroid anti-inflammatory inhalation drug that helps prevent symptoms and improves the control of asthma.

Pulmicort Respules (budesonide inhalation suspension) is the first nebulised corticosteroid in the US for the treatment of asthma in children as young as 12 months.

Rhinocort (budesonide) is a nasal steroid treatment for allergic rhinitis (hay fever), perennial rhinitis and nasal polyps.

Oxis (formoterol) is a fast onset, long-acting beta-agonist used for the treatment of asthma and COPD.

Accolate (zafirlukast) is an oral leukotriene receptor antagonist used for the treatment of asthma.

We aim to build on our strong position in the respiratory field through the growth of key products, particularly Symbicort, with new indications and market launches, including chronic obstructive pulmonary disease (COPD), as well as through developing a strong pipeline of novel small molecule and biologics approaches to COPD and asthma. We aspire to enter the rheumatology market predominantly through our biologics pipeline.

According to WHO, COPD is currently the fourth leading cause of death worldwide, with future increases anticipated. Current treatment has recently demonstrated some survival benefit but the prognosis of the COPD patient remains poor. In asthma, morbidity and mortality remain important issues and disease normalisation is not achieved by any treatment.

The typical treatment for both COPD and asthma is a fixed-dose combination of an inhaled corticosteroid (ICS) with a long-acting beta-agonist (LABA) (for example Symbicort) or for COPD specifically, an inhaled long-acting muscarinic antagonist (LAMA). Other major asthma treatments include monotherapy ICSs, oral leukotriene receptor antagonists and/or oral steroids for severe disease and (in combination with antibiotics) for exacerbations.

While there are not many significant new treatment modalities on the horizon for asthma and COPD, some pharmaceutical companies have once- and twice-daily ICS/LABAs in late-stage development and the first regulatory approvals for a new LABA and a novel anti-inflammatory mechanism, an oral phosphodiesterase 4 inhibitor, have been seen this year. Significant new product classes impacting the asthma market are unlikely before 2015. However, specifically for the treatment of COPD, the new product class of fixed combination LABA/LAMA is estimated to impact the market in early 2013. Longer term, novel anti-inflammatory compounds and/or anti-proteases, alone or in combinations of LABAs or LAMAs aimed mainly at the prevention and/or treatment of COPD exacerbations, are likely to appear on the market. Generic ICS/LABA combinations may be available from the early part of this decade.

Our focus

Our key marketed products

Symbicort Turbuhaler improves symptoms and provides a clinically important improvement in the health of many patients with either asthma or COPD by providing rapid, effective control and effective reduction of exacerbations.

In October, Symbicort Turbuhaler was approved in Japan for the treatment of adult asthma and it was launched in Japan in January 2010. AstraZeneca and Astellas have entered into an agreement for the co-promotion of Symbicort Turbuhaler in Japan.

Symbicort pMDI (pressurised metered dose inhaler) is approved, in the US, for the long-term maintenance treatment of asthma in patients 12 years of age and older and was launched in the US in 2007. The COPD indication was approved and launched in the US in early 2009. In December 2008, the Joint Advisory Committees of the FDA completed a review of the benefits and risks of asthma medications containing LABAs. The Advisory Committees concluded that the benefits of Symbicort pMDI outweigh the risks in adult and adolescent asthma patients. However, a final decision has not yet been communicated by the FDA.

An sNDA for Symbicort pMDI in paediatric asthma was submitted in 2008. AstraZeneca received a Complete Response Letter in April 2009 for this application and has since submitted a response outlining an additional programme to address the FDA's questions.

Symbicort SMART provides increased asthma control and simplifies asthma management through the use of only one inhaler for both maintenance and relief of asthma symptoms. As well as being a cost-effective treatment for many healthcare payers, the Symbicort SMART approach can also result in lower ICS and oral steroid use compared to other treatment options.

Pulmicort remains the world's leading inhaled corticosteroid for the treatment of asthma and is available in several forms. Teva now has an exclusive licence to sell generic Pulmicort Respules in the US.

Rhinocort combines powerful efficacy with rapid onset of action and minimal side effects and is available as a once-daily treatment for allergic rhinitis (hay fever), perennial rhinitis and nasal polyps in the Rhinocort Aqua (nasal spray) and the Turbuhaler (dry powder inhaler) forms.

Oxis is added to the treatment regimen for asthma and COPD when corticosteroid treatment alone is not adequate. Oxis is also indicated for symptom relief in COPD.

Clinical studies of our key marketed products

During 2009, the data from the SUN study, the second pivotal Symbicort pMDI study, was published. This study is part of the COPD NDA submission. The study confirmed the clinical benefits of Symbicort pMDI in moderate and severe COPD patients and showed that Symbicort pMDI 160/4.5 two inhalations twice-daily had a greater improvement in pre-dose forced expiratory volume I tests averaged over the treatment period compared with formoterol and placebo. In addition, several other important clinical studies in COPD were published showing the benefit of early onset effect relieving morning symptoms as well as improved outcomes when added to LAMAs.

Clinical data from the CLIMB study demonstrated that Symbicort added to Spiriva™ (tiotropium) provided greater clinical improvements than tiotropium alone over a 12-week treatment period. Results from the CLIMB study also showed that the occurrence of severe COPD exacerbations was reduced by as much as 62% in patients where Symbicort was added to tiotropium compared to patients on tiotropium alone. Furthermore, the CLIMB study showed that patients treated with the Symbicort/tiotropium inhaled combination experienced benefits.

In the pipeline

AZD9668, currently in Phase IIb studies, is an oral inhibitor of neutrophil elastase, an enzyme strongly implicated in the inflammatory process, mucus hypersecretion and matrix degradation that drives the signs and symptoms of and disease progression in COPD.

Alongside this novel approach and building on our capabilities in combinations and device development demonstrated through our experience with Symbicort, we are aiming to improve further the mainstay of treatment for all COPD patients by combining two long-acting bronchodilators, AZD3199 and AZD9164, in one inhaler. The individual compounds are currently in Phase II studies (AZD3199 is in Phase IIb studies). Patients should benefit from improved symptom control, as well as from the reduction in the complications arising from multiple dosing or inhaler devices and the combination supports the recommendations of the international guidelines for the treatment of COPD for maximal bronchodilation as 1st line therapy.

AZD1981, a prostanoid receptor CRTh2 antagonist currently in Phase IIa studies, is a potential new oral small molecule approach to treating uncontrolled asthma. AZD1981 is expected to prevent the recruitment and activation of Th2 cells and eosinophils, which are both increased in asthma.

AZD8848 is a novel small molecule toll-like receptor-7 agonist in Phase II studies for the treatment of asthma being developed in collaboration with Dainippon Sumitomo Pharmaceuticals Co. Ltd (Dainippon Sumitomo).

MEDI-563 is an investigational approach that may help treat inadequately controlled asthma by targeting the interleukin-5 (IL-5) receptor, blocking the binding of IL-5 to the receptor and depleting the cells expressing the IL-5 receptor, typically eosinophils, which are thought to play a key role in the pathology of asthma. In addition, two Phase II studies are ongoing to assess the ability of MEDI-563 to reduce the asthmatic relapse rate following an acute care episode, as well as its ability to reduce the rate of asthma exacerbations overall.

In 2009, we initiated a Phase IIb study to determine the chronic dosing of MEDI-528 (an anti-IL-9 MAb) on asthma exacerbations in moderate to severe asthma.

CAT-354 targets interleukine-13, one of the key cytokines implicated in asthma pathogenesis. In 2009, we initiated a Phase IIa study to investigate the potential of a subcutaneous injection form of CAT-354 to treat patients with moderate to severe persistent asthma who are inadequately controlled despite current standard of care.

In addition, the early pipeline for respiratory biologics was bolstered by the entry of three new development programmes targeting COPD, which will likely progress to human studies in late 2010.

The early biologic pipeline has been reshaped to focus more on COPD, looking for novel strategies to inhibit exacerbations in COPD, which include regulation of inflammatory cell migration and activation with MAbs directed to antigens.

Strategic collaboration activity continues to be important to our respiratory pipeline. Our collaboration with Dynavax Technologies Corporation (Dynavax), which began in 2006, continues to pursue opportunities in the field of toll-like receptor-9 with immunostimulatory DNA sequences. Our collaborations with Dainippon Sumitomo (referred to above) and Dynavax both aim to find treatments for the normalisation of disease in asthma and the prevention of exacerbations in COPD.

Our 2007 discovery alliance with Argenta Discovery Limited aimed at identifying improved bronchodilators to treat COPD continues and is now entirely focused on the combined anti-muscarinic and beta-2 adrenergic agonists. AstraZeneca continues to develop the LAMA compounds identified in the collaboration.

Our three-year research collaboration with Silence Therapeutics A.G. (Silence), established in 2007, is continuing. In 2008, we entered into a new collaboration with Silence focused on the development of a range of novel approaches for the delivery of siRNA molecules, which allows both Silence and AstraZeneca to commercialise the novel delivery systems which we develop together.

AstraZeneca announced in July that it had terminated the licence agreement with MAP Pharmaceuticals, Inc. (MAP), regarding unit dose budesonide (UDB). UDB, an investigational treatment for paediatric asthma, was the subject of an initial Phase III clinical study conducted by MAP. In February 2009, MAP announced that the study failed to meet its primary endpoints. In light of the clinical study results, AstraZeneca exercised its right to terminate the licence agreement.

Rheumatoid arthritis (RA) is currently treated with generic disease-modifying anti-rheumatic agents and, where the relevant criteria are met, biologic disease-modifiers. There remains a need for novel effective treatments since only about a third of patients treated with biologics achieve their treatment goals. The RA therapy market will experience modest annual growth over the 2008-2018 forecast period, as sales increase from $8.2 billion to $13.1 billion. In 2008, sales of the biologic tumour necrosis factor (TNF) alpha blockers accounted for 80% of major-market RA sales. Launches of additional TNF blockers are ongoing, and use of other biologic approaches, currently reserved for TNF failures, is expected to increase. Targeted novel oral drugs aimed at patients that currently choose not to take, are ineligible for or do not respond to biologics, are in development to provide anti-TNF-like efficacy with safety benefits and more convenient dosing. (Source: Decision Resources 2009).

Current treatment of systemic lupus erythematosus (SLE) focuses on controlling disease flares, preventing renal failure and suppressing symptoms to an acceptable level while minimising toxicity. Despite considerable recent development activity, no targeted disease-modifying agents have yet been successfully launched for SLE. Most emerging biologic agents will likely be used initially in combination with corticosteroids or immunosuppressants to provide incremental benefit and/or allow reduced doses or numbers of these agents.

Our focus

In the pipeline

In 2009, we invested in several novel multi-functional MAbs in inflammatory and autoimmune conditions.

MEDI-545 is a MAb which targets interferon-alpha, which regulates processes involved in autoimmune diseases. In 2009, we completed enrolment for a Phase IIa study in patients with SLE and a Phase I study in patients with active dermatomyositis or polymyositis.

CAM-3001 (licensed from CSL Limited) is a MAb in Phase I development with potential to help patients with RA through targeting the alpha sub-unit of the granulocyte-macrophage colony stimulating factor receptor.

In 2009, we initiated a Phase I study in scleroderma for a MAb, which targets the anti-interferon alpha receptor. We also filed an initial new drug application for a MAb which targets the CD-19 receptor.

AZD9056 and AZD5672, which were in Phase II development, have been terminated. AstraZeneca continues to explore approaches and mechanisms which have the potential to improve therapy and to deliver better outcomes for patients with rheumatological conditions.

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

Performance 2009

Reported performance

Respiratory & Inflammation (R&I) sales were $4,132 million, almost level with the $4,128 million in 2008.

Performance - CER growth rates

R&I sales grew by 6% at CER.

Total sales of Symbicort grew by 23% to $2,294 million. In the US, sales of Symbicort pMDI were $488 million, up 91%. This strong growth is lead by physicians' increasing use of Symbicort pMDI, particularly in those patients newly starting fixed combination therapy. For these patients, more than one in three prescriptions written by specialists and more than one in four prescriptions written by primary care physicians, is for Symbicort pMDI. Symbicort (Turbuhaler and SMART) sales outside the US in the year were $1,806 million, up 13%.

Total sales for Pulmicort were down 10% to $1,310 million. Total US sales for Pulmicort for the full year were down 18% to $804 million due to generic competition for Pulmicort Respules. Pulmicort Respules accounted for around 86% of total Pulmicort sales in the US. Total sales of Pulmicort outside the US were up 4% for the full year to $506 million.

Performance 2008

Reported performance

Sales in R&I increased by 11% to $4,128 million from $3,711 million in 2007.

Performance - CER growth rates

R&I sales grew by 7% at CER.

Total sales of Symbicort grew by 22% to $2,004 million. In the US, sales of Symbicort pMDI were $255 million. Symbicort (Turbuhaler and SMART) sales outside the US in the year were $1,749 million, up 9%.

Total Pulmicort sales were flat at $1,495 million, with US sales up 2% as the generic competition from the Teva product affected quarter four sales. US sales for Pulmicort were down 15% to $260 million in the fourth quarter of 2008 and Pulmicort Respules sales were down 18% as a result of the 'at risk' launch of generic budesonide inhalation suspension (BIS) on 18 November 2008. The patent litigation between Teva and AstraZeneca was subsequently settled on 25 November 2008. The agreement allows Teva to commence sales of BIS under an exclusive licence from AstraZeneca beginning on 15 December 2009. The agreement also provided that any product already shipped by Teva would remain in the market to be further distributed and dispensed. As a result, Teva products accounted for nearly 15% of total prescriptions for BIS products dispensed during the fourth quarter of 2008, including a 40% share in December 2008. US sales for Pulmicort for the full year were $982 million. Pulmicort Respules accounted for around 90% of total Pulmicort sales in the US. Total sales of Pulmicort outside the US were down 2% for the full year to $513 million.