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Randomized Controlled Trial
. 2021 Apr 22:16:1137-1148.
doi: 10.2147/COPD.S307160. eCollection 2021.

A Dose-Ranging Study of the Novel Inhaled Dual PDE 3 and 4 Inhibitor Ensifentrine in Patients with COPD Receiving Maintenance Tiotropium Therapy

Gary T Ferguson  1 , Edward M Kerwin  2 , Tara Rheault  3 , Thomas Bengtsson  4 , Kathleen Rickard  3
Affiliations
Randomized Controlled Trial

A Dose-Ranging Study of the Novel Inhaled Dual PDE 3 and 4 Inhibitor Ensifentrine in Patients with COPD Receiving Maintenance Tiotropium Therapy

Gary T Ferguson et al. Int J Chron Obstruct Pulmon Dis. .

Abstract

Purpose: Ensifentrine is an inhaled dual inhibitor of phosphodiesterase (PDE) 3 and 4 that has shown bronchodilatory effects and symptom improvement in clinical studies in patients with chronic obstructive pulmonary disease (COPD), and anti-inflammatory effects in healthy volunteers in a model of COPD-like inflammation. This manuscript reports on the results of the clinical study examining if ensifentrine provides meaningful improvements in lung function when added on to tiotropium over 4 weeks in patients with COPD who have impaired lung function and symptoms despite treatment with tiotropium.

Patients and methods: This randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study recruited patients with moderate-to-severe COPD. Patients were randomized to open-label tiotropium once daily (QD) plus (+) blinded escalating doses of ensifentrine or placebo twice daily (BID). Effects on lung function, symptoms and quality of life (QoL) were assessed over 4 weeks.

Results: A total of 416 COPD patients were randomized and 413 received at least one dose of blinded study medication + tiotropium. All ensifentrine doses produced a significant and dose-dependent increase in peak forced expiratory volume in 1 second (FEV1) from baseline to Week 4, with placebo-corrected differences of 77.5 mL when added to tiotropium (0.375 mg; 95% CI: 4.8, 150.1 mL; p=0.037) to 124.2 mL (3 mg; 95% CI: 51.0, 196.8 mL; p<0.001). A significant increase in average FEV1 (0-12h) was shown at Week 4 with the 3 mg dose (87.3 mL; 95% CI: 20.0, 154.5 mL; p=0.011). Clinically meaningful and statistically significant improvements in the St. George's Respiratory Questionnaire - COPD (SGRQ-C) additive to tiotropium were observed at Week 4, exceeding the minimally clinically important difference of 4 units with the 1.5 and 3 mg doses. Adverse events were similar in frequency between the ensifentrine and placebo arms.

Conclusion: This clinical study demonstrated that nebulized ensifentrine added on to tiotropium produced clinically important improvements in lung function and QoL over 4 weeks in COPD patients receiving tiotropium who demonstrated symptoms and lung function impairment, with a safety profile similar to placebo.

Keywords: COPD; bronchodilation; dual PDE3 and 4 inhibitor; phosphodiesterase; tiotropium.

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Conflict of interest statement

Drs Ferguson and Kerwin served as an investigator for the study, received study grant from Verona Pharma, has received consulting fees from Verona Pharma. Dr Ferguson reports grants, personal fees, and/or non-financial support from Boehringer Ingelheim, GlaxoSmithKline, Novartis, Sunovion, Theravance/Mylan, AstraZeneca, Innoviva, Circassia, Sanofi, Altvant, Knopp, Teva, Orpheris, DevPro, and Galderma, outside the submitted work. Dr Kerwin reports personal fees and non-financial support for consulting, advisory board membership, and travel reimbursement from Amphastar, AstraZeneca, Boehringer Ingelheim, Chiesi, Connect Biopharma, GlaxoSmithKline, Mylan, Novartis, Sunovion, and Theravance, outside the submitted work. Drs Rheault and Rickard are employees and shareholders for Verona Pharma. Mr Bengtsson serves as the biostatistical contractor for Verona Pharma. The authors report no other conflicts of interest in this work.

Figures

Figure 1
Figure 1
Patient flow through the study.
Figure 2
Figure 2
Peak FEV1 between 0 and 3 h post-dose in the full analysis set.
See this image and copyright information in PMC

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