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.

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.