What Role will Ensifentrine Play in the Future Treatment of Chronic Obstructive Pulmonary Disease Patients? Implications from Recent Clinical Trials

Abstract

Data from the phase III ENHANCE clinical trials provide compelling evidence that ensifentrine, an inhaled ‘bifunctional’ dual phosphodiesterase 3/4 inhibitor, can provide additional benefit to existing treatments in patients with chronic obstructive pulmonary disease and represents a ‘first-in-class’ drug having bifunctional bronchodilator and anti-inflammatory activity in a single molecule. Ensifentrine, generally well tolerated, can provide additional bronchodilation when added to muscarinic receptor antagonists or β₂-agonists and reduce the exacerbation risk. This information allows us to consider better the possible inclusion of ensifentrine in the future treatment of chronic obstructive pulmonary disease. However, there is less information on whether it provides additional benefit when added to inhaled corticosteroid or ‘triple therapy’ and, therefore, when this drug is best utilized in clinical practice.

Plain language summary

Chronic obstructive pulmonary disease (COPD) is the name for a group of lung conditions that cause breathing difficulties/airflow limitations. The airflow limitation is not completely reversible and is associated with a state of chronic inflammation of lung tissue. Treatment of the disease is still heavily dependent on the use of medications called bronchodilators and corticosteroids. However, corticosteroids have little-to-no impact on the underlying inflammation in most COPD patients. Therefore, innovative anti-inflammatory approaches are required. In this context, single molecules that are capable of simultaneously inducing bronchodilation, relaxing the muscles in the lungs and widening the airways (bronchi), and anti-inflammatory activity are a highly intriguing possibility for treating COPD. One approach is to develop drugs that can simultaneously inhibit enzymes called phosphodiesterase (PDE)3 and PDE4. Enzymes are proteins that help speed up metabolism, or the chemical reactions in our bodies. PDE4 inhibitors are intracellular enzymes (work inside the cell) expressed in most inflammatory cells, even in neutrophils (a type of white blood cells), which are involved in the pathogenesis of COPD, where an infection turns into a disease. However, its inhibition does not produce severe bronchodilator effects, which is instead obtained by inhibiting PDE3, the PDE isoenzyme (a different form of the same enzyme) that is predominantly expressed in airway smooth muscle cells. A treatment called ensifentrine is a dual PDE3/4 inhibitor (inhibits both PDE3 and PDE4). Two recent phase III studies (ENHANCE-1 and ENHANCE-2) have shown that it induces significant bronchodilation and reduces the risk of COPD worsening, exerting an anti-inflammatory effect. Data from the ENHANCE studies also showed the benefit of adding ensifentrine to treatment with bronchodilators. Certainly, the drug represents a useful therapeutic option, but further clinical studies are needed to be able to correctly position ensifentrine in the context of regular COPD treatment.

Tweetable abstract

Ensifentrine, an inhaled ‘bifunctional’ dual PDE3/4 inhibitor, can provide additional benefit to existing treatments in patients with COPD and represents a ‘first in class’ drug having bifunctional bronchodilator and anti-inflammatory activity in a single molecule.

Keywords::

• anti-inflammatory activity
• bronchodilation
• combination therapy
• COPD
• ensifentrine
• pivotal RCTs

Financial disclosure

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. C Page reports receiving grants and personal fees from, and holds equity in, Verona Pharma. D Singh reports personal fees from 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.

Competing interests disclosure

The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, stock ownership or options and expert testimony.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

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. C Page reports receiving grants and personal fees from, and holds equity in, Verona Pharma. D Singh reports personal fees from 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.