ASTHMA

What is asthma?

Asthma is a group of disorders involving inflammation and constriction of the airways in the lungs, leading to the production of thick mucus which impairs breathing. Asthma attacks may be triggered by many substances to which people are allergic (allergens), or by anxiety, cold air, exercise and chemicals such as sulphur dioxide. Asthma provoked by allergens is known as 'extrinsic' asthma, and involves a blood protein called immunoglobulin E (IgE). Extrinsic asthma is estimated to account for 80 per cent of cases of asthma in children and more than half of those in adults. People with asthma but no apparent allergy are said to have 'intrinsic' asthma. Acute asthma with severe constriction of the airways is a dangerous condition, often needing hospitalisation and emergency treatment.

Who does asthma affect and what does it cost?

Asthma incidence in the United Kingdom has increased markedly in recent years and an Asthma UK audit has found that 1 in 10 children and 1 in 12 adults are currently being treated for asthma, a total of 5.2 million people, of whom half have severe symptoms. In severe cases, the symptoms of asthma are intense and frequent enough to cause significant restrictions on many aspects of daily life. Asthma causes over 78,000 hospital admissions and about 1,400 deaths each year. It is the most frequent cause of being off sick from school and among the most common reasons for GP visits. The total cost to the NHS of treating asthma averages £889 million per year. In addition, over 20 million working days are lost due to asthma each year, costing the economy some £2.5 billion.

Present treatments and shortcomings

Present medications can be divided into two main categories - bronchodilators and anti-inflammatory compounds, mostly given by inhalation. The bronchodilators may be grouped broadly into:

• short-acting beta₂ stimulants (agonists): salbutamol (Ventolin, Allen & Hanburys) and terbutaline (Bricanyl, AstraZeneca), mainly used for symptom relief as required
• long-acting beta₂ agonists (LABA): salmeterol (Serevent, Allen & Hanburys), formoterol (Foradil, Novartis and Oxis, AstraZeneca) and bambuterol (Bambec, AstraZeneca)
• anticholinergics: short-acting ipratropium (Atrovent, Boehringer Ingelheim) and long-acting tiotropium (Spiriva, Boehringer Ingelheim)

while the anti-inflammatory compounds are comprised of:

• corticosteroids: beclometasone (e.g. Becotide, Allen & Hanburys), budesonide (e.g. Pulmicort, AstraZeneca), fluticasone (Flixotide, Allen & Hanburys), ciclesonide (Alvesco, Altana) and mometasone (Asmanex, Schering- Plough)

and some other agents, including montelukast (Singulair, Merck Sharp & Dohme) and zafirlukast (Accolate, AstraZeneca). There are also a number of inhaled products containing both a bronchodilator and an anti-inflammatory agent. Also, a monoclonal anti-IgE antibody (Xolair, Novartis) is available for use with steroids in severe and persistent allergic asthma.

Guidelines for the use of these medicines in chronic asthma advocate a cascade approach, starting with the minimal dose of a beta₂-agonist (bronchodilator) needed to control symptoms, progressing to low-dose steroids (anti-inflammatory), higher dose/frequency steroids, then the addition of other bronchodilators to reduce the steroid requirement and, finally, adding oral steroids. The shortcomings of these agents are dependent on their type. Recent clinical studies have suggested that existing long-acting beta agonists, for example, may increase the risk of developing severe asthma and caution is therefore required in their use. Another significant problem in treatment is limited response, or the development of tolerance, requiring gradually stronger medication.

What's in the development pipeline?

An allergic reaction in extrinsic asthma (Figure 2) involves two stages: sensitisation and activation. Sensitisation occurs when allergens (e.g. pollen grains, animal hairs, scales or faeces of the house dust mite, types of food, etc.) are processed in the body by specialised cells which then overproduce IgE antibodies specific for each allergen. IgE circulates in the blood and eventually attaches to mast cells and eosinophils in the lungs. This stage does not cause any symptoms, but will have primed the individual concerned for the future.

An asthma attack follows activation (Figure 2), which occurs when the patient is exposed to the allergen again, when it binds to the specific IgE on the mast cells and eosinophils. These then respond by releasing molecules (leukotrienes, platelet activating factor, complement components, cytokines and neuropeptides) that cause the airway constriction and inflammation that signal an asthma attack. With successive attacks, the accumulation of these and other potentially inflammatory cells gets worse and a deteriorating spiral starts. Ultimately, this may lead to chronic asthma that is less responsive to treatment.

Allergic rhinitis (hay fever) has similar causes to asthma, but the allergic process occurs in the upper respiratory tract instead of the lung and does not lead to similarly severe consequences.

With such a complex process, there are many possibilities for new therapies (Figure 2, arrows 1 to 6). A significant amount of research is aimed at developing improved ways of delivering existing medicines into the lung, since inadequate dosing of prescribed medicines is a problem for the patient and a major cause of unsatisfactory treatment. GlaxoSmithKline's dry power inhaler combining fluticasone and salmeterol (Seretide Diskus) and AstraZeneca's combination of budesonide and formoterol (Symbicort pMDI), are examples of such developments.

Other research aims to develop new chemical substances for asthma therapy. Some of the possible approaches are outlined below.

1. Prevention of cell accumulation in the lung (Fig 2, arrow 1):
Cells are attracted to inflammatory sites through chemical signals. Blocking the formation of the signal substances or slowing cell responsiveness to them can reduce cell accumulation. This is one of the ways in which phosphodiesterase (PDE) inhibitors act. Several companies have them in development. Nycomed is conducting Phase 3 trials of the oral PDE-4 inhibitor roflumilast, while Glenmark has another agent of this type (oglemilast) in Phase 2 studies. Ono Pharmaceuticals also has an oral PDE-4 inhibitor (ONO-6126) in Phase 2 study and GlaxoSmithKline is investigating an inhaled compound (GSK 256066) at Phase 2 for both asthma and allergic rhinitis. Tolerability problems have hampered development of earlier oral PDE-4 inhibitors, and administration by the inhaled route may therefore have some advantages.

Cell recruitment is a multi-step process, and several other compounds in development are designed to interrupt these pathways. Selectins are receptors on cells that are involved in the adhesion of inflammatory cells in the early steps of their migration into the lung. Revotar's pan-selectin inhibitor bimosiamose is being studied for its ability to prevent this process, and has now reached Phase 2 trials. Inflazyme Pharma's oral IPL512,602 is also in Phase 2 study.

2. Agents blocking the production or release of inflammatory molecules (Fig. 2, arrow 2):
Many small inflammatory molecules are released in chronic asthma. These include leukotrienes (LT), prostaglandins and numerous cytokines. Mast cells carry adenosine A2b receptors and adenosine can trigger an asthmatic response in sensitive individuals. CV Therapeutics is investigating an oral adenosine antagonist (CVT-6883) in Phase 1 trials which may be able to modulate such a response, blocking release of further inflammatory molecules.

Another approach involves inhibiting an enzyme inside mast cells called Syk kinase, preventing signal molecules from triggering a subsequent release of inflammatory factors. Rigel Pharmaceuticals has developed an inhaled small molecule Syk kinase inhibitor (R343) and Pfizer will now take the compound into clinical trials.

Probably acting even earlier in the process, Avanir Pharma's AVP 13358 targets IgE, preventing it from initiating the cascade of inflammatory mediators. This compound, now in Phase 1, also appears to inhibit the release of various cytokines, such as IL-4 and IL-5.

3. Antihistamines (Fig.2, arrow 3):
One cause of constriction of the airways in acute allergic asthma is the release of histamine from sensitised mast cells. Therapy with antihistamines is successful in such cases and already well established. UCB has a new antihistamine, efletirizine, in development for allergic rhinitis and this compound has completed Phase 1 studies.

4. The blockade of other inflammatory molecules (Fig. 2, arrow 4):
In this category are human antibodies or other compounds designed to block some of the receptors to which cytokines or other inflammatory molecules bind, or which neutralise them directly. GSK has a monoclonal antibody (mepolizumab) in Phase 2 trial and Wyeth's etanercept is at the same stage. AstraZeneca's CAT-354 is directed against the cytokine IL-13 and is in Phase 1 trial, as is Amgen's AMG 317, which acts against IL-13 and IL-4. Aerovance has AER-001 that can be inhaled and which binds to IL-4 and IL-13 receptors, blocking inflammation. It is in Phase 2 development. MediciNova, meanwhile, has an orally administered inflammatory inhibitor (MN-001) in Phase 2 trial.

5. Agents blocking the action of neuropeptides (Fig.2, arrow 5):
Neuropeptides are small molecules that act as neurotransmitters. They are produced in the brain but can be released at nerve endings, where they cause inflammation and contraction of smooth muscle, including that in the airways. The possibility that compounds that block neurokinin (NK) receptors might be beneficial in asthma is being explored by Daiichi-Sankyo, whose compound CS-003 is in Phase 2 trial.

6. Agents which open the airways in the lungs (bronchodilators) (Fig. 2, arrow 6):
Although they have long been the established therapies, there are a large number of new bronchodilators and steroid anti-inflammatory compounds (and combinations of both) in clinical development. GlaxoSmithKline has five new long-acting bronchodilators in Phase 2 trials (GSK 159797, 159802, 597901, 642444 and 678007), either singly or in combination with a glucocorticoid agonist, and three new glucocorticoid agonists - (GSK 685698, 870086 and 799943) at Phase 2. In addition, Trinity-Chiesi has a new long-acting beta₂-agonist (carmoterol) in Phase 2 development. New steroids under study include the inhaled corticosteroid QAE 397 (Novartis) and the non-glucocorticoid EPI-12323 from Epigenesis, both at Phase 2. Among combination products under development, Novartis has a combination of formoterol and mometasone (MMF 258) in Phase 3 and sanofi-aventis is developing a combination of formoterol and ciclesonide, which has reached Phase 2.

Asthma research is an area of intense activity, building on a growing understanding of the complex processes involved in both acute attacks and the development of chronic asthma. Many new compounds can also be expected to have value in the management of chronic obstructive pulmonary disease (COPD), which shares many inflammatory features with allergic asthma. More needs to be done to understand and counteract the various environmental triggers thought to promote asthma if the current trend towards an increasing burden of disease is to be reversed.

FOR FURTHER INFORMATION CONTACT:

Asthma UK
Summit House, 70 Wilson Street
London, EC2A 2DB
Phone: 0845 701 0203 (Helpline)
Website: www.asthma.org.uk

British Lung Foundation
Lung Foundation House, 73-75 Goswell Road
London, EC1V 7ER
Phone: 0845 850 5020 (Helpline)
Website: www.lunguk.org