Evaluation of cytokine modulators for asthma

Th2 cytokines play an important role in producing and maintaining airway inflammation in asthma. As a consequence, there is considerable interest in developing agents that modulate their effects. Therapeutic strategies include decreasing cytokine synthesis or release, blocking their effects by antibodies or soluble receptors, as well as administration of anti-inflammatory cytokines. Initial studies of three of these approaches have shown interesting results. The first is suplatast tosilate, a selective Th2-inhibitor that suppresses the synthesis of IL-4 and IL-5 in vitro. In a randomised double-blind placebo-controlled parallel study, suplatast, given orally TID, improved lung function and symptom control when added to inhaled beclomethasone for 4 weeks and prevented deterioration when the beclomethasone dose was decreased by 50% during a second 4 weeks. The second is CDP840, a second generation phosphodiesterase type 4 inhibitor, that may decrease the release of cytokines from eosinophils and Th2 lymphocytes. In a double-blind placebo-controlled crossover study, CDP840, given orally BID for 9 days, attenuated the late response to allergen by 30% when compared to placebo. The third is a recombinant human soluble IL-4 receptor (altrakincept) that neutralises endogenously produced IL-4. In inhaled steroid-dependent subjects, weekly nebulisation of altrakincept prevented lung function decline and asthma exacerbations after abrupt withdrawal of inhaled corticosteroids. In contrast, studies of anti-IL-5 monoclonal antibodies (mepolizumab and SCH55700) indicate that this strategy only partially depletes eosinophils from the bronchial mucosa and shows no benefit on clinical markers of asthma activity. Of these novel therapeutic approaches, inhibiting Th2 synthesis of IL-4 and IL-5 (suplatast) appears to offer the greatest potential and long-term studies of this approach should be undertaken.