Emerging Therapeutic Approaches
Triple therapy with LAMA plus LABA/ICS has also been investigated, demonstrating benefits over monotherapy on lung function. Additionally, a pilot study of patients with advanced COPD reported that triple therapy combined with pulmonary rehabilitation provided a benefit in terms of lung function. Some reports also suggest that triple therapy can provide additional benefits, such as reduction in exacerbation rate and mortality, although a recent systematic review concluded that further, longer-term studies are required to determine the benefits of tiotropium plus LABA and ICS, or the additional benefit of ICS on top of LAMA/LABA combinations.
Dual Muscarinic Antagonist-β2-agonists (MABAs)
Another interesting concept is that of single molecules with muscarinic antagonist-β2-agonist (MABA) activity. While the prospect of combining muscarinic antagonism and β2-agonism into one entity is highly attractive, this is a new and challenging area of research. The optimal MABA should be designed to achieve balanced, high potencies at both muscarinic and β2 receptors, for consistency. The furthest developed MABA is GSK961081, which has demonstrated effective bronchoprotection in vivo as proof of concept (NCT00478738) and is currently in Phase IIb studies. MABAs provide a fixed ratio of muscarinic antagonist and β2-agonist activity at a cellular level, have a single pharmacokinetic profile, and deliver a fixed ratio of muscarinic antagonist and β2-agonist to the whole lung, simplifying both combination delivery device and clinical development programs. These properties suggest that MABAs have the potential to act as a useful platform for triple therapy with an anti-inflammatory agent.
A number of new bronchodilators with novel modes of action are currently in early stages of development, including K channel openers, Rho kinase inhibitors, and analogs of vasoactive intestinal peptide; these have been reviewed more extensively elsewhere. Given the substantial evidence supporting a role of Rho kinase in bronchoconstriction, Rho kinase inhibitors such as Y-27632, Y-30141, Y-30694, and fasudil may currently hold the most promise, demonstrating smooth muscle relaxant properties in vitro. Once further evidence of efficacy and safety is available, these newer classes might be used in combination with more conventional bronchodilators, leading to additional therapeutic options and increased potential for individualized medication.