title: V0162 a new long-acting bronchodilator for treatment of chronic obstructive lung diseases: preclinical and clinical results.
abstract: BACKGROUND
  Long acting bronchodilators are the standard of care in the management of chronic obstructive pulmonary disease (COPD). The aim of this study was to investigate the efficacy and safety of V0162, a novel anticholinergic agent with bronchodilator properties, in preclinical models and in patients with COPD.
  
  
  METHODS
  Guinea pigs were used to evaluate the impact of V0162 on the acetylcholine or histamine-induced bronchoconstriction. V0162 was also investigated in an allergic asthma model on ovalbumin-sensitized guinea pig. For clinical investigations, healthy volunteers were included in a dose-escalation, randomized, placebo-controlled phase I study to determine the maximal tolerated dose, followed by a randomized, placebo-controlled, cross-over phase II study in patients with COPD. V0162 was given via inhalation route. The objectives of the phase I/II study were to assess the safety and efficacy of V0162, in terms of bronchodilation and reduction in hyperinflation.
  
  
  RESULTS
  Preclinical results showed that V0162 was able to prevent bronchoconstriction induced either by acetylcholine or histamine. V0162 reversed the bronchoconstriction and airway inflammation caused by ovalbumin challenge in sensitized guinea pigs. In the healthy volunteers study, 88 subjects were enrolled: 66 received V0162 and 22 received placebo. No particular safety concerns were raised. The maximal tolerated dose was not reached and the dose escalation was stopped at 2400 μg. A total of 20 patients with COPD were then enrolled. All patients received a single-dose of V0162 1600 μg and of placebo in two alternating periods. In COPD patients, V0162 demonstrated a significant increase in FEV1 compared with placebo (148 ± 137 ml vs. 36 ± 151 ml, p = 0.003). This bronchodilatory effect was corroborated by a reduction in hyperinflation. There was a trend toward dyspnea relief (change in visual analog scale at 22 h, -15.1 ± 26.0 mm vs.- 5.3 ± 28.8 mm with placebo, p = 0.054). No serious adverse events (AEs) were reported. Most common AEs were productive and non-productive cough, dyspnea and pruritus.
  
  
  CONCLUSIONS
  V0162 improved pulmonary function and tended to improve dyspnea in patients with COPD over more than 24 h. The slight plasmatic exposure observed might support the good safety profile.
  
  
  BACKGROUND
  ClinicalTrials.gov identifier: NCT01348555.
authors.affiliation: UPRES EA 220, Hôpital Foch, Université de Versailles Saint Quentin, 11 rue Guillaume Lenoir, Suresnes, 92150, France. p.devillier@hopital-foch.org.
authors.forename: Philippe
authors.initials: P
authors.lastname: Devillier
authors.affiliation: Centre de Recherche et de Développement Pierre Fabre Toulouse, 3 Avenue Hubert Curien BP 13562, 31035, Toulouse, France. eric.garrigue@pierre-fabre.com.
authors.forename: Eric
authors.initials: E
authors.lastname: Garrigue
authors.affiliation: Centre de Recherche et de Développement Pierre Fabre Toulouse, 3 Avenue Hubert Curien BP 13562, 31035, Toulouse, France. guillaume.d.auzers@pierre-fabre.com.
authors.forename: Guillaume
authors.initials: G
authors.lastname: D'Auzers
authors.affiliation: Institut de Recherche Pierre Fabre, Service de Pharmacologie, CEPC Bel Air de Campans, Castres Cedex, 81106, France. nicolas.monjotin@pierre-fabre.com.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Monjotin
authors.affiliation: AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles Foix, Service de Pneumologie et Réanimation Médicale (Département "R3S"), 47-83 Bd de l'Hôpital, F-75013, Paris, France. thomas.similowski@psl.aphp.fr.|Sorbonne Universités, UPMC Paris 06, UMR_S 1158 "Neurophysiologie Respiratoire Expérimentale et Clinique", F-75005, Paris, France. thomas.similowski@psl.aphp.fr.|INSERM, UMR_S 1158 "Neurophysiologie Respiratoire Expérimentale et Clinique", F-75005, Paris, France. thomas.similowski@psl.aphp.fr.
authors.forename: Thomas
authors.initials: T
authors.lastname: Similowski
authors.affiliation: Centre de Recherche et de Développement Pierre Fabre Toulouse, 3 Avenue Hubert Curien BP 13562, 31035, Toulouse, France. thierry.clerc@pierre-fabre.com.
authors.forename: Thierry
authors.initials: T
authors.lastname: Clerc
mesh_terms: D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000818:Animals; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage*; D029424:Pulmonary Disease, Chronic Obstructive / Q000175:diagnosis* / Q000188:drug therapy*; D016037:Single-Blind Method; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001993:Bronchodilator Agents; D003692:Delayed-Action Preparations; D018727:Muscarinic Antagonists