ArticlesEfficacy and safety of RPL554, a dual PDE3 and PDE4 inhibitor, in healthy volunteers and in patients with asthma or chronic obstructive pulmonary disease: findings from four clinical trials
Introduction
Asthma and chronic obstructive pulmonary disease (COPD) are common diseases of the respiratory tract that are often treated with a combination of a bronchodilator (usually a long-acting β2 agonist or an anticholinergic, or both) and an anti-inflammatory drug (usually an anti-inflammatory glucocorticosteroid), frequently in the same inhaler. In patients with severe disease, different classes of bronchodilator are often used in combination to improve efficacy and decrease the risk of side-effects compared with increasing the dose of a single bronchodilator or treating the patient with glucocorticosteroids alone.1 Although presently used respiratory drugs are generally effective, there remain concerns about their safety. For example, in 2011 the US Food and Drug Administration raised questions about the safety of drugs containing long-acting β2 agonists, including fixed-dose combination inhalers.2 Furthermore, available drugs are not equally effective in all patients,3 especially in those with severe disease and frequent exacerbations. A novel drug from a different pharmacological class that could provide additional bronchodilation alone, or in combination with available treatments, would therefore be highly desirable. Even more useful would be a drug that combines clinically relevant symptom control with substantial anti-inflammatory activity in one molecule.
Phosphodiesterases (PDEs) are an extensive family of 11 enzyme subtypes that modulate intracellular concentrations of the cyclic nucleotides involved in various cellular functions. In the context of respiratory diseases, an increase in cyclic AMP is associated with relaxation of airway smooth muscle and broad spectrum anti-inflammatory actions.4 In airway smooth muscle, PDE3 is the predominant enzyme regulating cyclic AMP concentrations,5 whereas PDE4 is the most important PDE isoenzyme within inflammatory cells (including macrophages and monocytes, lymphocytes, dendritic cells, and neutrophils) because of its ability to inhibit inflammatory cell activation.4, 6 A large body of evidence has shown that PDE3 inhibitors cause airway smooth muscle relaxation in vitro,5, 7 bronchodilation in vivo,8 and increases in forced expiratory volume in 1 s (FEV1) in patients with asthma.8, 9 PDE4 inhibitors can inhibit the function of a wide range of inflammatory cells in vitro4 and have pronounced anti-inflammatory effects, both in animal models4, 10 and in patients with inflammatory airway disease.11, 12 Furthermore, experimental data suggest that combined inhibition of PDE3 and PDE4 isoenzymes can have synergistic effects.6 Thus, a dual PDE3 and PDE4 inhibitor is potentially more effective than an inhibitor of either isoenzyme alone.5, 6 PDE3 inhibitors caused bronchodilation in a clinical experimental study in patients with asthma9 but have not progressed into later stage development. By contrast, the selective PDE4 inhibitor roflumilast is licensed as an oral treatment for distinct subsets of patients with severe COPD (as an add-on treatment for Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 3 and 4 COPD and frequent exacerbations),13, 14 but poor tolerability limits the usefulness of this drug.13, 14
A rational approach to providing a potential alternative to existing bronchodilator and anti-inflammatory treatments would be to combine the known beneficial properties of PDE3 and PDE4 inhibitors6, 15 into one bifunctional molecule and deliver this by inhalation to reduce potential systemic side-effects. RPL554, a dual PDE3 and PDE4 inhibitor derived from a series of analogues of trequinsin, is one such molecule. RPL554 exhibits both bronchodilator and anti-inflammatory activities in animals in vitro and in vivo.16 We aimed to assess the safety and efficacy of inhaled RPL554 in healthy participants and in patients with asthma or COPD in four clinical trials.
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Study designs and procedures
Between February, 2009, and January, 2013, we undertook four clinical trials to assess the safety and efficacy of inhaled RPL554 in healthy participants and in patients with asthma or COPD. Table 1 summarises the designs of the four clinical studies. Details of the inclusion and exclusion criteria are provided in the trial protocols.
We undertook these clinical studies because preclinical data generated with RPL554 led us to hypothesise that RPL554 might have bronchodilator and anti-inflammatory
Results
Overall, 39 healthy participants, 28 people with asthma, and 12 patients with COPD were studied. One participant with unstable asthma in study 2 dropped out after 1 day (owing to dyspnoea, 2 days before scheduled first study drug administration), but was replaced. Figure 1, Figure 2 show the study profiles. Table 2 lists the demographics and baseline characteristics of the participants who were enrolled.
Overall, the inhalation of single doses of RPL554 by nebulisation (0·003–0·018 mg/kg) was
Discussion
In this series of exploratory clinical studies, RPL554, a novel inhaled dual PDE3 and PDE4 inhibitor, showed substantial bronchodilator, bronchoprotector, and anti-inflammatory effects in healthy participants, patients with mild-to-moderate asthma, and in patients with mild-to-moderate COPD, with minimum side-effects (panel). RPL554 produced a rapid and significant bronchodilator response in patients with asthma or COPD, comparable with peak effects reported in such patients with inhaled β2
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