www.thelancet.com/respiratory Published online October 25, 2013 http://dx.doi.org/10.1016/S2213-2600(13)70187-5 1 Articles 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 Lui G Franciosi, Zuzana Diamant, Katharine H Banner, Rob Zuiker, Nicoletta Morelli, Ingrid M C Kamerling, Marieke L de Kam, Jacobus Burggraaf, Adam F Cohen, Mario Cazzola, Luigino Calzetta, Dave Singh, Domenico Spina, Michael J A Walker, Clive P Page 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 (FEV 1 ) and provocative concentration of methacholine causing a 20% fall in FEV 1 (PC 20 MCh) in participants with asthma. RPL554 produced rapid bronchodilation in patients with asthma with an FEV 1 increase at 1 h of 520 mL (95% CI 320–720; p<0·0001), which was a 14% increase from placebo, and increased the PC 20 MCh 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 FEV 1 reached during 6 h after dosing with RPL554 in patients with asthma. RPL554 produced a similar maximum mean increase in FEV 1 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 FEV 1 . RPL554 produced bronchodilation with a mean maximum FEV 1 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. Published Online October 25, 2013 http://dx.doi.org/10.1016/ S2213-2600(13)70187-5 See Online/Comment http://dx.doi.org/10.1016/ S2213-2600(13)70211-X See Online for an audio interview with Clive Page Verona Pharma, London, UK (L G Franciosi PhD, K H Banner PhD, D Spina PhD, Prof M J A Walker PhD, Prof C P Page PhD); Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, BC, Canada (L G Franciosi, Prof M J A Walker); Centre for Human Drug Research, Leiden, Netherlands (Prof Z Diamant MD, R Zuiker MD, N Morelli MD, I M C Kamerling PhD, M L de Kam MSc, Prof J Burggraaf MD, Prof A F Cohen MD); Skane University, Department of Respiratory Diseases and Allergology, Lund, Sweden (Prof Z Diamant); University Medical Centre Groningen, Department of General Practice, Groningen, Netherlands (Prof Z Diamant); Unit of Respiratory Clinical Pharmacology, Department of System Medicine, University of Rome “Tor Vergata”, Rome, Italy (Prof M Cazzola MD); Department of Respiratory Rehabilitation, San Raffaele Pisana Hospital, IRCCS, Rome, Italy (L Calzetta PhD); University of Manchester, Medicines Evaluation Unit, University Hospital of South Manchester Foundations Trust, Manchester, UK (Prof D Singh MD); and Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King’s College London, London, UK (D Spina, Prof C P Page) Introduction Asthma and chronic obstructive pulmonary disease (COPD) are common diseases of the respiratory tract that are often treated with a combination of a broncho- dilator (usually a long-acting β 2 agonist or an anti- cholinergic, or both) and an anti-inflammatory drug