AstraZeneca Annual Report and Form 20-F Information 2008

COPD and asthma

COPD is expected to become the world’s third biggest health threat by 2020. 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 across COPD and asthma is a fixed-dose combination of an inhaled corticosteroid (ICS) with a long-acting beta-agonist (LABA) or for COPD specifically, inhaled long-acting muscarinic agonist (LAMA). Other major asthma treatments include oral leukotriene receptor antagonists and oral steroids for severe disease and (in combination with antibiotics) for exacerbations. Significant new product classes impacting the asthma market up to 2015 are unlikely. First novel anti-inflammatory compounds aimed mainly at prevention and/or treatment of COPD exacerbations, such as oral phosphodiesterase 4 inhibitors, may appear on the market before 2015.

Symbicort SMART flexible dosing introduced a step change to asthma care in Europe resulting in lower ICS and oral steroid use. Novel ICS/LABA combination products for this area are expected from 2009 and generic ICS/LABA combinations may be available from the early part of the next decade. Several companies are developing new biologics for severe asthma, including improved versions of anti-IgE and differentiated anti-cytokine antibodies. Post-2015, immune response modifiers could deliver intermittent therapy for moderate to severe asthma.

A number of novel COPD combinations in industry pipelines may change the way in which COPD is managed. Combinations of LABAs, LAMAs and triple-combinations with existing and new anti-inflammatories, may become future treatments of choice. There are also agents in early development with the potential to change the course of the disease by targeting the immune and inflammatory response that results in lung damage.

OUR FOCUS

Our key marketed products

Symbicort Turbuhaler provides rapid, effective control of asthma and effective reduction of exacerbations, improving symptoms and providing a clinically important improvement in the health of patients with severe COPD.

Symbicort Rapihaler (pMDI) approved for the long-term maintenance treatment of asthma in patients 12 years of age and older, was launched in the US in 2007. Further information about the progress of Symbicort since its launch in the US is set out in the Geographical Review. In December 2008, the Joint Advisory Committees of the FDA completed a review of the benefits and risks of asthma medications containing LABAs. This concluded that the benefits of Symbicort outweigh the risks in adult and adolescent asthma patients.

Symbicort SMART provides increased asthma control and simplifies asthma management through use of only one inhaler for both maintenance and relief of asthma symptoms. It is also a cost-effective treatment option for many healthcare payers. Symbicort SMART is included in the Global Initiative for Asthma, the international treatment guidelines.

The US sNDAs for Symbicort Rapihaler (pMDI) in COPD and paediatric asthma in the US were submitted as planned during the second quarter of 2008. Our existing regulatory filings for Symbicort Rapihaler (pMDI) in the EU for asthma and COPD were supplemented with data supporting two additional strengths in the second half of 2008.

Pulmicort remains one of the world’s leading asthma medicines and is available in several forms. Pulmicort pMDI is now approved in 98 countries.

Information about our settlement of the patent infringement action against IVAX in the US, which began in October 2005, in relation to IVAX’s ANDA for a budesonide inhalation suspension is set out in Note 25 to the Financial Statements.

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

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

Clinical trial developments

In the latter part of 2008, data from one of the pivotal US COPD studies were published (SHINE), confirming the efficacy and tolerability of Symbicort Rapihaler (pMDI) in COPD.

In the pipeline

Our monoclonal antibody (MAb) programmes for asthma treatments focus on targeting interleukins which appear to play a role in the regulation of inflammatory and immune responses and, therefore, may improve the treatment and/or prevention of asthma. Most of these MAbs are in Phase II to assess their potential to affect the significant remaining unmet medical need in the disease including uncontrolled asthma and moderate to severe persistent asthma. Concurrent Phase I activity is supporting our understanding of the impact of these large molecules on asthma biology.

MEDI-563 is an investigational approach that may treat or help prevent asthma by targeting the interleukin-5 (IL-5) receptor to neutralise the binding of IL-5 and deplete the cells expressing the IL-5 receptor, typically eosinophils, as both IL-5 and eosinophils are thought to play key roles in the pathology of asthma. In 2008, the results of a Phase I study presented at the European Respiratory Society meeting showed that MEDI-563 exhibited an acceptable safety profile and showed pharmacological activity in mild asthmatics. In addition, a Phase I study to measure the depletion of eosinophils in the airways of asthmatics and a Phase II study with this anti-IL-5 receptor MAb to assess whether it can reduce the incidence of asthmatic relapse in subjects following an asthmatic episode that required hospitalisation have been initiated.

Also in 2008, we completed two out of three ongoing Phase IIa studies evaluating the potential for MEDI-528 (anti-IL-9 MAb) to treat or prevent symptomatic, moderate to severe persistent asthma, and a fourth Phase IIa clinical trial, designed to assess its effectiveness in patients with stable asthma and exercise-induced bronchoconstriction, was initiated.

CAT-354 targets interleukin-13 (IL-13). In 2008, we initiated two new studies with CAT-354: a Phase II trial in Europe and Australia designed to assess the potential of this MAb in patients with uncontrolled asthma despite optimal treatment, and a US Phase I study to assess pharmacokinetics in healthy adult patients.

The early 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 antigen. These include CXCR3, as well as inhibition of molecules involved in both viral and bacterial mediated exacerbations. A number of small molecule approaches for the treatment of COPD are in development. AZD1236 is a potent MMP inhibitor currently in Phase II, the expression of these proteins are associated with key pathological features of the disease including bronchiolitis, vasculitis and emphysema. Human Neutrophil Elastase (HNE) is a key factor in cigarette smoke induced inflammation, lung injury and emphysema and AZD9668, a potent and selective oral, reversible inhibitor of HNE, also in Phase II, is expected to reduce the progression and severity of COPD.

Alongside these novel approaches and building on our capabilities in combinations and device development demonstrated through our experience with Symbicort, we are aiming to improve further the symptom relief delivered by on-market bronchodilators, the mainstay of treatment for all COPD patients. By combining two enhanced bronchodilators in one inhaler, patients should benefit from improved symptom control, as well as reducing the complications of multiple dosing or inhaler devices.

Strategic collaboration activity makes a key contribution to our respiratory pipeline. AstraZeneca and MAP Pharmaceuticals announced in December 2008 an exclusive worldwide agreement to develop and commercialise Unit Dose Budesonide (UDB), MAP Pharmaceuticals’ proprietary nebulised formulation of budesonide. This agreement is subject to review in the US under the Hart-Scott-Rodino Act and becomes effective after the waiting period has ended. UDB is being developed by MAP Pharmaceuticals as a potential treatment for paediatric asthma and is currently in Phase III clinical development. UDB has the potential to be nebulised more quickly and at a lower nominal dose than the commercially available product. AstraZeneca and Dainippon Sumitomo have a well-established alliance to discover and develop small molecules directed towards toll-like receptor 7 and the first compound from this alliance has entered early stage development.

The partnership with Dynavax Technologies Corporation, which began in 2006, continues to pursue opportunities in the field of toll-like receptors. Dynavax has unique competence in generating immunostimulatory DNA sequences that activate toll-like receptors. The alliance should enable us to expand our portfolio of small molecule and biological drugs to treat asthma and COPD.

Our 2007 discovery alliance with Argenta Discovery Limited aimed at identifying improved bronchodilators to treat COPD continues.

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

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