First-in-Class Dual PDE Inhibitor Plus Tiotropium May Improve Lung Function in COPD

This article is part of Pulmonology Advisor’s coverage of the American Thoracic Society Virtual 2020 meeting.

Nebulized ensifentrine, when added to tiotropium, produced clinically meaningful and significant improvements in lung function and quality of life in patients with chronic obstructive pulmonary disease (COPD), according to study results presented virtually at the American Thoracic Society (ATS) 2020 Virtual meeting, held August 5 to 10, 2020.

Ensifentrine (RPL554) is a first-in-class, dual phosphodiesterase (PDE) 3 and 4 inhibitor with combined bronchodilator and anti-inflammatory actions in a single compound. Ensifentrine provides direct delivery to the lungs by inhalation with minimal systemic distribution.

Patients aged 40 to 80 years with moderate to severe COPD, who remained symptomatic despite steady state tiotropium, were enrolled (N=416) in a second phase 2b, double-blind, placebo-controlled, parallel-group dose-ranging study (ClinicalTrials.gov Identifier: NCT03937479). Patients were randomly assigned to receive once-daily tiotropium plus nebulized ensifentrine (0.375 mg, 0.75 mg, 1.5 mg, or 3 mg) or placebo twice daily. Spirometry was performed prior to dosing and over 3 hours or 12 hours. The primary end point of the study was change from baseline in peak forced expiratory volume in 1 second (FEV₁) at week 4. Secondary end points included average FEV₁ over 3 and 12 hours, COPD-related quality of life (St. George’s Respiratory Questionnaire for COPD; SGRQ-C) and safety.

Researchers found that all doses of ensifentrine twice daily produced statistically significant bronchodilation when added to tiotropium once daily, with a dose-dependent increase of 78 mL to 124 mL from baseline to peak FEV₁ at week 4 (placebo-corrected; all P <.05).

Additionally, significant improvements in the secondary end points were observed after 4 weeks of therapy. A dose-dependent increase in the average FEV₁ over 12 hours was seen, with the 3 mg dose producing a significant increase of 87 mL from baseline (placebo-corrected; P =.0111). This outcome is supportive of the twice-daily dosing.

Clinically meaningful and statistically significant improvements from baseline in SGRQ-C were also observed, with both 1.5 mg and 3 mg doses exceeding the minimally important clinical difference (MCID) of 4 units at week 4 (placebo-corrected; both P <.05). Ensifentrine, in addition to tiotropium, was well-tolerated, with a similar adverse event profile to placebo.

The researchers concluded that “ensifentrine on top of tiotropium produced clinically important improvements in lung function and quality of life over 4 weeks in COPD patients who remained symptomatic and with impaired lung function despite steady state tiotropium.” They suggested that their data “support progression of ensifentrine to phase 3 as a maintenance treatment of COPD.”

Disclosure: This clinical trial was supported by Verona Pharma. Please see the original reference for a full list of authors’ disclosures.

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Reference

Ferguson GT, Kerwin EM, Rickard K, Rheault K, Bengtsson T. Ensifentrine provides significant and clinically meaningful bronchodilation and quality of life improvement on top of tiotropium in symptomatic COPD patients in a 4-week dose-ranging study. Presented at: American Thoracic Society 2020 Virtual; August 5-10, 2020. Session B983.