ENSIFENTRINE ADDED ON TO TIOTROPIUM SIGNIFICANTLY IMPROVES INSPIRATORY CAPACITY IN PATIENTS WITH SYMPTOMATIC COPD

Abstract

SESSION TITLE: Obstructive Lung Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Ensifentrine (RPL554) is an investigational, first-in-class, inhaled dual inhibitor of PDE3 and PDE4 that combines bronchodilator and anti-inflammatory actions in a single compound. In a previously completed dose-ranging study in patients with COPD, nebulized ensifentrine delivered clinically meaningful and significant improvements versus placebo in lung function and symptoms (Singh et al. 2020). In a second dose-ranging study, nebulized ensifentrine (0.375, 0.75, 1.5 or 3 mg) or placebo was given in addition to tiotropium for 4 weeks in symptomatic COPD patients following a 14-day run-in on tiotropium. All ensifentrine doses produced significant bronchodilation on top of tiotropium with a dose-dependent increase from baseline to peak FEV1 (primary endpoint) at week 4 of 78 to 124 mL (placebo-corrected; all p<0.05). This abstract reports on the pre-specified exploratory investigation of the effect of twice-daily nebulized ensifentrine versus placebo on inspiratory capacity (IC) in the same study. METHODS: Analysis was performed on all randomized patients with sufficient data collected after intake of study treatment to compute the pharmacodynamic parameters based on FEV1 on at least one occasion. The analysis comprised 413 patients with 83, 83, 81, 82 in the 0.375, 0.75, 1.5, 3.0 mg ensifentrine + tiotropium groups and 84 in the placebo + tiotropium treatment group. IC maneuvers were conducted according to ATS/ERS guidelines (Miller et al, 2005) prior to the forced maneuvers 30 minutes pre-dose and 2 hours post-dose following randomization (Day 1) and at the last dose at Week 4. The change from baseline was calculated. RESULTS: Mean age was 64.3 years, with 52.2% under 65 years of age. Patients were primarily female (57.5%), caucasian (90.1%) and current smokers (55.3%) with chronic bronchitis (59%). Day 1 baseline IC was similar between treatment groups. Placebo-corrected change from baseline in IC on Day 1 (2h post-dose) was 76, 62, 115 and 108 mL for the 0.375, 0.75, 1.5, 3.0 mg ensifentrine + tiotropium groups, respectively. The 1.5 and 3 mg doses showed statistically significant improvements (p<0.01). After 4 weeks of twice-daily ensifentrine added to once daily tiotropium, there was a statistically significant improvement of 110.2 mL in IC (2 h post-dose) compared with placebo (tiotropium alone, p=0.0290) with the 3 mg ensifentrine dose + tiotropium treatment group. CONCLUSIONS: This study demonstrates a clinically meaningful response in IC after treatment with 4 weeks of ensifentrine in COPD patients who remain symptomatic and with impaired lung function despite the use of tiotropium. CLINICAL IMPLICATIONS: Measurement of IC as a marker of dynamic lung hyperinflation has been shown to correlate with dyspnea and exercise performance in stable COPD. Results suggest a physiological mechanism by which ensifentrine improved symptoms and health-related quality of life. DISCLOSURES: Consultant relationship with Verona Pharma Please note: $5001 - $20000 Added 06/01/2020 by Thomas Bengtsson, source=Web Response, value=Consulting fee Employee relationship with Verona pharma Please note: >$100000 by Tara Rheault, source=Admin input, value=Stock Employee relationship with Verona Pharma Please note: >$100000 Added 05/20/2020 by Kathleen Rickard, source=Web Response, value=Salary