PMID- 26050967 OWN - NLM STAT- MEDLINE DCOM- 20160212 LR - 20181113 IS - 1465-993X (Electronic) IS - 1465-9921 (Print) IS - 1465-9921 (Linking) VI - 16 IP - 1 DP - 2015 Jun 8 TI - V0162 a new long-acting bronchodilator for treatment of chronic obstructive lung diseases: preclinical and clinical results. PG - 68 LID - 10.1186/s12931-015-0227-1 [doi] LID - 68 AB - 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 mug. A total of 20 patients with COPD were then enrolled. All patients received a single-dose of V0162 1600 mug 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. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01348555. FAU - Devillier, Philippe AU - Devillier P AD - UPRES EA 220, Hopital Foch, Universite de Versailles Saint Quentin, 11 rue Guillaume Lenoir, Suresnes, 92150, France. p.devillier@hopital-foch.org. FAU - Garrigue, Eric AU - Garrigue E AD - Centre de Recherche et de Developpement Pierre Fabre Toulouse, 3 Avenue Hubert Curien BP 13562, 31035, Toulouse, France. eric.garrigue@pierre-fabre.com. FAU - D'Auzers, Guillaume AU - D'Auzers G AD - Centre de Recherche et de Developpement Pierre Fabre Toulouse, 3 Avenue Hubert Curien BP 13562, 31035, Toulouse, France. guillaume.d.auzers@pierre-fabre.com. FAU - Monjotin, Nicolas AU - Monjotin N AD - Institut de Recherche Pierre Fabre, Service de Pharmacologie, CEPC Bel Air de Campans, Castres Cedex, 81106, France. nicolas.monjotin@pierre-fabre.com. FAU - Similowski, Thomas AU - Similowski T AD - AP-HP, Groupe Hospitalier Pitie-Salpetriere Charles Foix, Service de Pneumologie et Reanimation Medicale (Departement "R3S"), 47-83 Bd de l'Hopital, F-75013, Paris, France. thomas.similowski@psl.aphp.fr. AD - Sorbonne Universites, UPMC Paris 06, UMR_S 1158 "Neurophysiologie Respiratoire Experimentale et Clinique", F-75005, Paris, France. thomas.similowski@psl.aphp.fr. AD - INSERM, UMR_S 1158 "Neurophysiologie Respiratoire Experimentale et Clinique", F-75005, Paris, France. thomas.similowski@psl.aphp.fr. FAU - Clerc, Thierry AU - Clerc T AD - Centre de Recherche et de Developpement Pierre Fabre Toulouse, 3 Avenue Hubert Curien BP 13562, 31035, Toulouse, France. thierry.clerc@pierre-fabre.com. LA - eng SI - ClinicalTrials.gov/NCT01348555 PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial DEP - 20150608 PL - England TA - Respir Res JT - Respiratory research JID - 101090633 RN - 0 (Bronchodilator Agents) RN - 0 (Delayed-Action Preparations) RN - 0 (Muscarinic Antagonists) SB - IM MH - Administration, Inhalation MH - Adolescent MH - Adult MH - Animals MH - Bronchoconstriction/drug effects MH - Bronchodilator Agents/*administration & dosage MH - Cross-Over Studies MH - Delayed-Action Preparations/administration & dosage MH - Dose-Response Relationship, Drug MH - Double-Blind Method MH - Drug Evaluation, Preclinical/methods MH - Guinea Pigs MH - Humans MH - Male MH - Middle Aged MH - Muscarinic Antagonists/*administration & dosage MH - Pulmonary Disease, Chronic Obstructive/*diagnosis/*drug therapy MH - Single-Blind Method MH - Treatment Outcome MH - Young Adult PMC - PMC4462001 EDAT- 2015/06/09 06:00 MHDA- 2016/02/13 06:00 PMCR- 2015/06/08 CRDT- 2015/06/09 06:00 PHST- 2014/12/05 00:00 [received] PHST- 2015/05/29 00:00 [accepted] PHST- 2015/06/09 06:00 [entrez] PHST- 2015/06/09 06:00 [pubmed] PHST- 2016/02/13 06:00 [medline] PHST- 2015/06/08 00:00 [pmc-release] AID - 10.1186/s12931-015-0227-1 [pii] AID - 227 [pii] AID - 10.1186/s12931-015-0227-1 [doi] PST - epublish SO - Respir Res. 2015 Jun 8;16(1):68. doi: 10.1186/s12931-015-0227-1.