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

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.

Trial registration: ClinicalTrials.gov identifier: NCT03937479.

KEYWORDS:

• Asthma
• chronic obstructive pulmonary disease
• cystic fibrosis
• dual PDE3/4 inhibitor
• ensifentrine
• phosphodiesterase

Article Highlights

• A compound that simultaneously inhibits PDE3 and PDE4 should increase airway calibre by relaxing the smooth muscle and, at the same time, suppress airway inflammatory responses.

• Ensifentrine is reported as a PDE3/4 inhibitor, although its affinity for PDE3 is 3,440 times higher than that for PDE4.

• It has the potential to substantially improve lung function and quality of life of patients not satisfactorily treated with existing drugs.

• Still there is no solid evidence of the ability of ensifentrine to elicit an anti-inflammatory activity in patients with COPD or asthma.

• 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.

Declaration of interest

M Cazzola reports receiving grants and personal fees from Verona Pharma. M Cazzola and L Calzetta have patents 9717732, 9700558, 20160008363, 20160000790 and 20170266190 licensed to Verona Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.