Isis presents next-gen asthma drug data
antisense drugs that show potential as new treatments for asthma
could represent the future in treating this disorder that has
soared in worldwide cases, particularly amongst children.
Asthma has now become one of the world's most common long-term conditions, affecting as many as 300 million people worldwide. This number could increase by a further 150 million by 2025, according to the World Health Organisation (WHO).
In multiple preclinical studies, second-generation antisense drugs selectively inhibited activity of proteins that promote inflammation and improved a variety of symptoms in mouse models of asthma and chronic lung inflammation.
Scientists from Isis Pharmaceuticals and its partners presented data at the 100th Annual Meeting of the American Thoracic Society (ATS), demonstrating the efficacy of aerosolised second-generation antisense drugs in vivo and the potential of antisense inhibitors as inhaled therapeutics for inflammatory diseases of the lung.
"With one aerosol drug in development, and a number of aerosol drugs in late-stage preclinical research, Isis has now demonstrated the feasibility of this new route of administration for antisense drugs," said Frank Bennett, Isis' vice president of Antisense Research.
"Our presentations at the meeting demonstrate the extraordinary value of antisense technology for identifying highly specific and effective novel drug therapies for the treatment of pulmonary diseases," added Bennett.
Asthma is estimated to cost at least $13 billion (€10 billion) in the US alone each year. In the UK, there are four times as many people with asthma than with diabetes. The number of patients with asthma in the seven largest pharmaceutical markets is set to rise from 51.4 million in 2003 to 62.4 million in 2013, stimulating greater demand for cost-effective asthma therapies.
Additional data presented showcased second-generation antisense drugs targeted to p38-alpha MAPK, TNF-alpha, and VLA-4 as potential treatment for inflammatory diseases of the lungs.
Mitogen-activated protein kinases (MAPK) are important cellular mediators of inflammatory responses. Scientists showed that aerosolised selective inhibition of p38-alpha (one member of the MAPK family) improved airflow in several animal models of asthma while inhibiting p38-alpha protein levels in several inflammatory cell types in the lung.
Data also showed in the acute model of asthma in mice, local antisense inhibition of p38-alpha improved airway hyper-responsiveness to methacholine in antigen-challenged mice at doses as low as 3.3 microgram oligonucleotide/kg.
Treatment also reduced antigen-induced airway eosinophilia and mucus production, two hallmark causative factors in asthma. Local treatment with the p38-alpha antisense inhibitor was also effective in reducing airway hyper-responsiveness.
TNF-alpha has been implicated as a causative factor in persistent asthma, chronic obstructive pulmonary disease (COPD), and emphysema. Local administration of a second-generation inhibitor of TNF-alpha improved airflow, lung inflammation, and mucus production in chronically challenged mice.
However, in contrast to the results with inhibitors of IL4R-alpha, p38-alpha, or VLA-4, the TNF-alpha inhibitor had limited effects in acutely challenged mice. This data is consistent with the view that TNF-alpha is more likely to be involved in severe, persistent asthma and other chronic pulmonary inflammatory diseases.
Isis' research represents a new approach to asthma, focusing on novel targets that previously a weak link could only be established. The only new class of drug developed in the last 30 years are anti-leukotrienes, which are far less effective than inhaled corticosteroids. New bronchodilators have been difficult to develop as new drugs are less effective than b2-agonists and have more side effects. Mediator antagonists have proved disappointing, as so many mediators are involved in asthma.
