Ensifentrine (RPL554): an investigational PDE3/4 inhibitor for the treatment of COPD

Expert Opin Investig Drugs. 2019 Oct;28(10):827-833. doi: 10.1080/13543784.2019.1661990. Epub 2019 Sep 1.

Abstract

Introduction: A compound that simultaneously inhibits PDE3 and PDE4 should increase airway caliber by relaxing the smooth muscle and, simultaneously, suppress airway inflammatory responses. Ensifentrine (RPL554) is considered a PDE3/4 inhibitor, although its affinity for PDE3 is 3,440 times higher than that for PDE4, that is under clinical development for the treatment of asthma and COPD and, potentially, cystic fibrosis. Areas covered: We analyze the development of this molecule from its basic pharmacology to the present clinical Phase II studies. Expert opinion: Ensifentrine is an interesting drug but there is a lack of solid studies that still does not allow us to correctly allocate this molecule in the current COPD and even asthma therapeutic armamentarium. Furthermore, apparently ensifentrine has not yet entered Phase III clinical development and, in any case, there is no reliable evidence of its ability to elicit an anti-inflammatory activity in patients with COPD or asthma. Therefore, the real anti-inflammatory profile of ensifentrine must be clarified with new studies of basic pharmacology and adequate clinical studies specifically designed. However, at present the most intriguing perspective is linked to its possible use in the treatment of cystic fibrosis, also considering the lack of valid therapeutic options for this disease.

Keywords: Asthma; chronic obstructive pulmonary disease; cystic fibrosis; dual PDE3/4 inhibitor; ensifentrine; phosphodiesterase.

Publication types

  • Review

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • Asthma / drug therapy*
  • Asthma / physiopathology
  • Cystic Fibrosis / drug therapy
  • Cystic Fibrosis / physiopathology
  • Drug Development / methods
  • Humans
  • Isoquinolines / pharmacology
  • Isoquinolines / therapeutic use*
  • Phosphodiesterase 3 Inhibitors / pharmacology
  • Phosphodiesterase 3 Inhibitors / therapeutic use
  • Phosphodiesterase 4 Inhibitors / pharmacology
  • Phosphodiesterase 4 Inhibitors / therapeutic use
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Pyrimidinones / pharmacology
  • Pyrimidinones / therapeutic use*

Substances

  • Anti-Inflammatory Agents
  • Isoquinolines
  • Phosphodiesterase 3 Inhibitors
  • Phosphodiesterase 4 Inhibitors
  • Pyrimidinones
  • ensifentrine