Asthma has reached epidemic proportions placing a considerable burden in terms of direct medical costs and driving a massive global therapeutic market. Although currently available asthma treatments are generally effective, patient compliance is currently poor and 5% of patients are unresponsive to these treatments. While the late-stage pipeline for next-generation asthma therapeutics, a considerable number of novel therapeutics are in earlier stages of development and this crop of exciting candidates is likely to improve clinical options available to asthmatics and also to reinvigorate the growth in the sale of respiratory medicines. p38 MAPK plays a pivotal role in the etiology of various inflammatory diseases including asthma however toxicity has provided a hurdle to the development of small molecule p38 MAPK inhibitors. ISIS Pharmaceuticals have developed a p38 MAPK antisense oligonucleotide ISIS 101757. Oligonucleotides are considered more selective that traditional therapeutics and this particular candidate is active as an aerosol still further reducing the risk of adverse effects. The therapeutic efficacy of ISIS 101757 has now been demonstrated in a model of asthma and its further development is awaited.

From 1980 to 1996, the number of Americans afflicted with asthma more than doubled to almost 15 million. The steady rise in the prevalence of asthma constitutes an epidemic, which by all indications is continuing. Even if rates were to stabilize, asthma would continue to be a profound public health problem, each year responsible for 9 million visits to health care providers, over 1.8 million emergency room visits, and over 460,000 hospitalizations. As well as placing a considerable burden in terms of direct medical costs, asthma is one of the leading causes of work or school absenteeism. In 1990, the annual cost of asthma to the US economy was estimated to be $6.2 billion, with the majority of the expense attributed to medical care. This figure has since increased dramatically. The epidemic in the US is representative of many developed countries.

Paralleling the dramatic growth in its incidence, asthma drives a massive global therapeutic market. The impact that increased incidence is having on therapeutic market values is further increased by a considerable degree of under-treatment of asthma. Global revenue for 2001 from asthma therapies has been reported by some to be as high as $11.7 billion and up until recently annual growth rates of 10-15% have been reported. Most sources however predict that this level of growth is not sustainable. This may be due in part to the low numbers of drugs in late stage development.

Although currently available asthma treatments are generally effective, patient compliance is currently poor. Furthermore, 5% of patients are unresponsive to these treatments and it is this cohort that accounts for a large segment of asthma related healthcare cost. Companies are seeking the next blockbuster drug in this high potential market. While the late-stage pipeline is relatively sparse, a considerable number of novel therapeutics are in earlier stages of development and this crop of exciting candidates is likely to improve clinical options available to asthmatics and also to reinvigorate the growth in the sale of respiratory medicines. Seventy drugs in development for asthma, COPD, and allergic rhinitis have been evaluated in our recent feature "Asthma, COPD and Allergic Rhinitis - Weak Late Stage Pipeline Leaves Innovation to Phase I/II Candidates".

Drug development in the field of asthma, and indeed in inflammatory diseases in general, has greatly benefited from advances in biologics (see our feature "Biotech in Autoimmune/Inflammatory Disease 2004: Revolutionizing the Market"). Molecules that target cytokines and in particular tumor necrosis factor and interleukin-1 have been at the cutting edge of new generation anti-inflammatory therapeutics. Most successful of these to date are the monoclonal antibodies (eg. remicade and humira) and the recombinant receptor fusion protein (enbrel) which neutralizes TNF. One feature of anti-inflammatory biologics is that they span a number of indications thus extending their market value. For example remicade is approved for IBD & rheumatoid arthritis while enbrel is approved for rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis & psoriasis. The second wave of therapeutics is now advancing and once molecular target that is attracting much interest is p38 MAP kinase. Like it's predecessors this target is being investigated across a range of indications (we have evaluated the proof of concept and development activity surrounding p38 MAP kinase as a target for rheumatoid arthritis & asthma). This kinase plays a pivotal role, not only in the production of TNF and IL-1 but it is also required for the cellular response to these cytokines.

GSK have advanced compound 681323, a p38 MAPK inhibitor, to phase I evaluation for the treatment of COPD, rheumatoid arthritis & atherosclerosis. Two biotech companies, Vertex and Scios, have also been in the forefront of discovery of novel p38 inhibitors. In collaboration with Kissei Pharmaceuticals, Vertex have investigated a number of compounds. VX-745 has been in Phase II trials for rheumatoid arthritis but withdrawn due to side effects. The follow-up compound VX-702 has now reached Phase II for various chronic inflammatory conditions. Scios compounds are now being studied in clinical trials as potential treatments for rheumatoid arthritis, multiple myeloma and other potential diseases. Whilst considerable interest is focussed on the performance of the Vertex and Scios p38 MAPK inhibitors currently in the clinic, it can be assumed that most if not all the companies with an interest in the anti-inflammatory market will have similar programmes. Here we focus on ISIS Pharmaceuticals' novel approach to p38 MAPK inhibition as a treatment of asthma.

p38 MAPK inhibitors appear to have a preferential inhibitory effect on synthesis of Th2 compared to Th1 cytokines, indicating their potential application in the treatment of atopic diseases. Furthermore, p38 MAPK inhibitors have also been shown to decrease eosinophil survival by activating apoptotic pathways and appears to be involved in corticosteroid-resistance a particular problem in asthma treatment. Although there is considerable data to support the development of p38 MAP kinase inhibitors, toxicity has been an issue. This is less of a problem for asthma treatments where inhalation may be a feasible therapeutic approach. ISIS Pharmaceuticals' have used their field leading position in RNA based R&D to develop a respirable p38alpha MAPK antisense oligonucleotide.

Until recently antisense oligonucleotide have been predominantly employed as experimental tools in proof of concept studies. Companies such as ISIS have however driven this technology forwards developing antisense oligonucleotide as therapeutics agents. In their study due to be published in the journal Am J Respir Crit Care Med University of Singapore researchers in collaboration with ISIS characterize an antisense oligonucleotide targeted towards p38alpha, ISIS 101757, in a mouse asthma model.

Inhalation of aerosolized ISIS 101757 reduced eosinophil numbers and IL-4, IL-5, and IL-13 levels in bronchoalveolar lavage fluid of ovalbumin sensitized mice rechallenged with ovalbumin, a commonly employed model of asthma. In contrast to the reduction of these Th2 cytokines, Th1 cytokine levels were unaffected. Aerosolized ISIS 101757 also produced a dose-dependent inhibition of mucos hypersecretion and airway hyperresponsiveness in these mice. This important study demonstrates that the inhibitory effect of ISIS 101757 is polarized towards the block of Th2 inflammation, a characteristic of asthma. In addition this antisense oligonucleotide also limited cardinal symptomologies of asthma, airway hyperresponsiveness and mucos secretion, in this animal model.

Entry date Sunday, January 23, 2005