title: 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.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Verona Pharma.
authors.affiliation: Verona Pharma, London, UK; Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Lui G
authors.initials: LG
authors.lastname: Franciosi
authors.affiliation: Centre for Human Drug Research, Leiden, Netherlands; Skane University, Department of Respiratory Diseases and Allergology, Lund, Sweden; University Medical Centre Groningen, Department of General Practice, Groningen, Netherlands.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Diamant
authors.affiliation: Verona Pharma, London, UK.
authors.forename: Katharine H
authors.initials: KH
authors.lastname: Banner
authors.affiliation: Centre for Human Drug Research, Leiden, Netherlands.
authors.forename: Rob
authors.initials: R
authors.lastname: Zuiker
authors.affiliation: Centre for Human Drug Research, Leiden, Netherlands.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Morelli
authors.affiliation: Centre for Human Drug Research, Leiden, Netherlands.
authors.forename: Ingrid M C
authors.initials: IM
authors.lastname: Kamerling
authors.affiliation: Centre for Human Drug Research, Leiden, Netherlands.
authors.forename: Marieke L
authors.initials: ML
authors.lastname: de Kam
authors.affiliation: Centre for Human Drug Research, Leiden, Netherlands.
authors.forename: Jacobus
authors.initials: J
authors.lastname: Burggraaf
authors.affiliation: Centre for Human Drug Research, Leiden, Netherlands.
authors.forename: Adam F
authors.initials: AF
authors.lastname: Cohen
authors.affiliation: Unit of Respiratory Clinical Pharmacology, Department of System Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.affiliation: Department of Respiratory Rehabilitation, San Raffaele Pisana Hospital, IRCCS, Rome, Italy.
authors.forename: Luigino
authors.initials: L
authors.lastname: Calzetta
authors.affiliation: University of Manchester, Medicines Evaluation Unit, University Hospital of South Manchester Foundations Trust, Manchester, UK.
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
authors.affiliation: Verona Pharma, London, UK; Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, UK.
authors.forename: Domenico
authors.initials: D
authors.lastname: Spina
authors.affiliation: Verona Pharma, London, UK; Department of Anesthesiology, Pharmacology, and Therapeutics, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Michael J A
authors.initials: MJ
authors.lastname: Walker
authors.affiliation: Verona Pharma, London, UK; Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, London, UK. Electronic address: clive.page@kcl.ac.uk.
authors.forename: Clive P
authors.initials: CP
authors.lastname: Page
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D005500:Follow-Up Studies; D005541:Forced Expiratory Volume / Q000187:drug effects / Q000502:physiology; D064368:Healthy Volunteers; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009330:Nebulizers and Vaporizers; D058987:Phosphodiesterase 3 Inhibitors / Q000008:administration & dosage*; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage*; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D011744:Pyrimidinones / Q000008:administration & dosage*; D016037:Single-Blind Method; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007546:Isoquinolines; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D011744:Pyrimidinones; C512996:ensifentrine