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Attacking asthma

In the future, treatments for asthma sufferers are likely to focus on targeted therapies

Asthma is a chronic inflammatory disease of the airways, which results in restricted airflow into and out of the lungs. It is characterised by wheezing, shortness of breath, excessive mucus production and coughing. It is common in people who have a familial history of allergies or eczema, although it also often occurs spontaneously.

The symptoms of asthma are usually triggered by inhaled allergens, but may also be induced by exercise, infection or drug allergies. An asthmatic episode or attack may range in severity from a mild shortness of breath to a life-threatening medical emergency during which patients suffer the complete inability to breathe. 

There are, according to the World Health Organisation, up to 180 million asthma sufferers worldwide, with mortality in 2004 exceeding 180,000 individuals. The total annual cost of asthma care exceeded $13bn in the US alone.

The majority of current drug treatments for asthma have been available for some time. However, intense focus now lies on developing new amalgamations of these therapies; combinations of existing drugs are constantly being shown to be superior to recommended monotherapies.

One major area of current interest is the reduction of corticosteroid use through adjunctive use of other drugs and drug classes with more favourable tolerability profiles. If a novel treatment regimen can display the same efficacy as its predecessors, but with a reduced toxicity profile, market demand will bring down high initial costs, and new and improved therapeutic guidelines may then be formulated.

Existing treatment for asthma falls into two main classes: preventive medicine, and rescue medicine. The estimated total sales for all asthma treatments in 2005 exceeded $35bn.

Preventive treatment
Inhaled corticosteroids, considered to be the Gold Standard preventive treatment, act locally to decrease inflammation within the bronchial tree. Beclomethasone (Beclovent; GlaxoSmithKline), budesonide (Pulmicort; AstraZeneca) and fluticasone (Flovent; GlaxoSmithKline) are the market leaders in this area.

Oral or intravenous steroids, such as methylprednisolone (Medrol; Pfizer), may be administered if inhaled treatments fail. Due to problems associated with chronic corticosteroid administration, drugs such as leukotriene inhibitors are increasingly being added to asthma regimens with the aim of decreasing steroid dosing.

These medicines, such as montelukast (Singulair; Merck) and zafirlukast (Accolate; AstraZeneca) work on a similar principle to corticosteroids, in that they target the inflammatory processes involved in the disease. Long-acting ?-agonists, such as formoterol (Foradil; Novartis) and salmeterol (Serevent; GlaxoSmithKline) relax the smooth muscle within the bronchial wall, and can be used in addition to other preventive medications.

These drugs can be useful in the control of exercise-induced asthma.

Rescue medicine
Rescue medicine for asthma is designed to treat acute attacks of the disease, rather than prevent onset. This class consists primarily of short-acting ?-agonists, such as salbutamol (Ventolin; GlaxoSmithKline and Proventil; Schering-Plough), which act rapidly to dilate airways and provide relief from acute attacks.

Although not as effective as salbutamol, the drug ipratropium bromide (Atrovent; Boehringer Ingelheim) is now being used increasingly to enhance the effects of standard rescue medication.

This anti-cholinergic drug acts to reduce bronchospasm and mucus production in affected individuals, and may reduce the dose required of ?-agonist. Other drugs, such as the mast cell inhibitor nedocromil [Tilade; Aventis] and the methylxanthine theophylline [Theo-Dur; AstraZeneca], are also used together with ?-agonists to relieve symptoms and treat acute attacks.

In June 2003, the US Food and Drug Administration approved a monoclonal antibody, omalizumab (Xolair; Novartis), for the treatment of asthma. Omalizumab is a recombinant humanised monoclonal antibody that binds to immunoglobulin E on the surface of mast cells and basophils.

This inhibits the release of inflammatory mediators from these cells which, in turn, reduces the swelling in the bronchi. As with other non-steroidal anti-asthmatics, omalizumab is effective in reducing the required dosage of corticosteroids.

Omalizumab trial data
In a recent pooled analysis of randomised trials involving more than 4,000 patients, the addition of omalizumab to standard anti-asthmatics resulted in a 38 per cent reduction in the rate of exacerbations, when compared with conventional anti-asthmatic treatment alone.

A sub-study of the same analysis showed also that the addition of omalizumab to conventional anti-asthmatics reduced emergency department visits by some 47 per cent. Futhermore, a recent meta-analysis of 12 clinical trials of over 2,000 patients with severe disease has shown that adjunctive omalizumab therapy improves significantly patient quality of life during the steroid stablisation and reduction phases of asthma treatment.

Omalizumab provides significant clinical benefit and a low toxicity profile, but has been shown in post-marketing trials to be non cost-effective for the treatment of asthma. The cost of omalizumab therapy is estimated at $12,000 to $15,000 per year: significantly higher than any other current treatments.

The future of asthma treatment, as for all allergic disease, is expected to focus on targeted immunomodulation. While new therapies, including down-regulation of the entire immune system, are being investigated, current opinion suggests that targeted therapies towards specific cytokines, signalling pathways and their associated receptors, will provide a more likely route to effective asthma control.

Another approach using a vaccine (ISS; Dynavax) is being trialled in patients with persistent disease. DNA from a common micro-organism, Mycobacterium vaccae, has been shown to mediate the release of inflammatory substances from immune cells and, in preclinical testing, has also reversed asthma-induced lung damage.

The author
Pipeline is written by William Stow of Adis International, using information derived from Adis Clinical Trials Insight and R&D Insight.

2nd September 2008

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