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Efficacy 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

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Summary

Background

Many patients with asthma or chronic obstructive pulmonary disease (COPD) routinely receive a combination of an inhaled bronchodilator and anti-inflammatory glucocorticosteroid, but those with severe disease often respond poorly to these classes of drug. We assessed the efficacy and safety of a novel inhaled dual phosphodiesterase 3 (PDE3) and PDE4 inhibitor, RPL554 for its ability to act as a bronchodilator and anti-inflammatory drug.

Methods

Between February, 2009, and January, 2013, we undertook four proof-of-concept clinical trials in the Netherlands, Italy, and the UK. Nebulised RPL554 was examined in study 1 for safety in 18 healthy men who were randomly assigned (1:1:1) to receive an inhaled dose of RPL554 (0·003 mg/kg or 0·009 mg/kg) or placebo by a computer-generated randomisation table. Subsequently, six non-smoking men with mild allergic asthma received single doses of RPL554 (three received 0·009 mg/kg and three received 0·018 mg/kg) in an open-label, adaptive study, and then ten men with mild allergic asthma were randomly assigned to receive placebo or RPL554 (0·018 mg/kg) by a computer-generated randomisation table for an assessment of safety, bronchodilation, and bronchoprotection. Study 2 examined the reproducibility of the bronchodilator response to a daily dose of nebulised RPL554 (0·018 mg/kg) for 6 consecutive days in a single-blind (patients masked), placebo-controlled study in 12 men with clinically stable asthma. The safety and bronchodilator effect of RPL554 (0·018 mg/kg) was assessed in study 3, an open-label, placebo-controlled crossover trial, in 12 men with mild-to-moderate COPD. In study 4, a placebo-controlled crossover trial, the effect of RPL554 (0·018 mg/kg) on lipopolysaccharide-induced inflammatory cell infiltration in induced sputum was investigated in 21 healthy men. In studies 3 and 4, randomisation was done by computer-generated permutation with a block size of two for study 3 and four for study 4. Unless otherwise stated, participants and clinicians were masked to treatment assignment. Analyses were by intention to treat. All trials were registered with EudraCT, numbers 2008-005048-17, 2011-001698-22, 2010-023573-18, and 2012-000742-34.

Findings

Safety was a primary endpoint of studies 1 and 3 and a secondary endpoint of studies 2 and 4. Overall, RPL554 was well tolerated, and adverse events were generally mild and of equal frequency between placebo and active treatment groups. Efficacy was a primary endpoint of study 2 and a secondary endpoint of studies 1 and 3. Study 1 measured change in forced expiratory volume in 1 s (FEV1) and provocative concentration of methacholine causing a 20% fall in FEV1 (PC20MCh) in participants with asthma. RPL554 produced rapid bronchodilation in patients with asthma with an FEV1 increase at 1 h of 520 mL (95% CI 320–720; p<0·0001), which was a 14% increase from placebo, and increased the PC20MCh by 1·5 doubling doses (95% CI 0·63–2·28; p=0·004) compared with placebo. The primary endpoint of study 2 was maximum FEV1 reached during 6 h after dosing with RPL554 in patients with asthma. RPL554 produced a similar maximum mean increase in FEV1 from placebo on day 1 (555 mL, 95% CI 442–668), day 3 (505 mL, 392–618), and day 6 (485 mL, 371–598; overall p<0·0001). A secondary endpoint of study 3 (patients with COPD) was the increase from baseline in FEV1. RPL554 produced bronchodilation with a mean maximum FEV1 increase of 17·2% (SE 5·2). In healthy individuals (study 4), the primary endpoint was percentage change in neutrophil counts in induced sputum 6 h after lipopolysaccharide challenge. RPL554 (0·018 mg/kg) did not significantly reduce the percentage of neutrophils in sputum (80·3% in the RPL554 group vs 84·2% in the placebo group; difference −3·9%, 95% CI −9·4 to 1·6, p=0·15), since RPL554 significantly reduced neutrophils (p=0·002) and total cells (p=0·002) to a similar degree.

Interpretation

In four exploratory studies, inhaled RPL554 is an effective and well tolerated bronchodilator, bronchoprotector, and anti-inflammatory drug and further studies will establish the full potential of this new drug for the treatment of patients with COPD or asthma.

Funding

Verona Pharma.

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.

Section snippets

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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