Therapy Analysis - Asthma
Difficult-to-manage asthma
No matter how successful corticosteroids may be in general usage, a few patients still respond poorly to treatment, and others need such high doses to control the disease that side effects become a limiting factor. The UK NHS spends in excess of £680 million each year to combat difficult-to-control asthma, including in the 5% of the asthmatic population who suffer from steroid-insensitive asthma. Despite intense effortsby the pharmaceutical industry, it has proved extremely difficult to find any new treatment that comes close to the therapeutic benefit of corticosteroids in the treatment of such asthma. In an attempt to combat this, several approaches have been attempted, from add-on therapies to developing entirely novel classes of drugs. Furthermore, with the advent of molecular biology, scientists have been able to uncover some important clues as to why steroids do not work in this subpopulation.
Within the last decade, an important class of drugs known as cysteinyl leucotriene receptor antagonists have been developed in the hope they may provide treatment for those who respond poorly to corticosteroid treatment. Cysteinyl leucotriene receptors, the targets of leucotriene antagonists, are located on endothelial, eosinophil and mast cells. Upon activation, they mediate airway constriction, endothelial cell adherence, chemokine production and vascular permeability. So it is perhaps unsurprising that leucotriene receptor antagonists exhibit anti-inflammatory and bronchodilatory activity. However, as leucotriene antagonists only disrupt a specific part of the inflammatory cascade, unlike corticosteroids, which affect a variety of inflammatory and structural cells, there seems to be little justification for the use of leucotriene antagonists as first-line therapy. Additionally, the lack of long-term clinical trials demonstrating sustained effects of leucotriene antagonists vs corticosteroids needs addressing. Currently, leucotriene antagonists are recommended as treatment by the British Thoracic Society only in patients who have already failed inhaled steroids.
Zafirlukast, the first leucotriene receptor antagonist approved for the treatment of asthma, was developed by AstraZeneca. It was shortly followed by Merck and Co’s montelukast. The favourable efficacy and safety of zafirlukast, in addition to its twice-daily dosing, offers the potential for greater patient compliance and thus control of asthma. In a 52 week doubleblind Phase III trial in 1490 patients with inadequately controlled asthma, montelukast in combination with fluticasone was as effective as salmeterol in combination with fluticasone, in regard to the likelihood of unscheduled/ specialist medical visits, emergency room visits, hospitalizations and corticosteroid use during the 48 week follow-up period. Additionally, in 226 adult asthmatics, montelukast for 12 weeks, in addition to their normal corticosteroids, reduced steroid dose by an average of 45% compared with placebo, and 40% were able to stop using steroids without loss of symptom control. Additionally, in a 12- week randomized, placebo-controlled clinical trial in 642 patients with mild-to-moderate asthma, montelukast alone was less effective than BDP; however, the combination of montelukast and BDP was superior to BDP alone. This synergistic effect may be contributed to by the fact that steroids do not affect cysteinyl leucotriene levels.
Since the launch of zafirlukast in 1996, 3 other leucotriene antagonists have followed it to market (Table 1). Currently Rottapharm is completing preclinical trials of CR-3465, a potent, selective novel leucotriene antagonist with broad antiinflammatory activity, including phosphodiesterase III and IV inhibition. These additional pharmacological activities make CR-3465 the potential successor to the blockbuster montelukast, due to its broad-spectrum activity and similar pharmacokinetic profile permitting once-daily oral dosing.
