Ensifentrine, a novel dual phosphodiesterase (pde) 3 and 4 inhibitor, reduces exacerbation rate and risk regardless of exacerbation history in pooled enhance trial analyses

SESSION TITLE: Latest Advances in Management of Obstructive Lung Disease SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/09/2023 12:00 pm - 12:45 pm PURPOSE: Ensifentrine is a first-in-class, inhaled dual inhibitor of phosphodiesterase (PDE)3 and PDE4 with demonstrated bronchodilation and anti-inflammatory effects. METHODS: Two Phase 3, 24-week, multi-center, randomized, double-blind, placebo-controlled trials were performed to evaluate nebulized ensifentrine-3mg twice-daily (BID) compared to placebo in subjects aged 40-80 years with symptomatic moderate to severe COPD (post-bronchodilator FEV1 30–70% predicted, FEV1/FVC ratio <0.7, ≥2 mMRC, and smoking history ≥10 pack-years. Stable background maintenance bronchodilator medication was permitted (LABA or LAMA, ±ICS). Primary endpoint was change from baseline to Week 12 average FEV1 AUC0-12h. Other endpoints included annualized rate and time to first moderate/severe COPD exacerbation. A post-hoc sub-group analysis was completed for subjects with (W-EXAC) or without (WO-EXAC) a COPD exacerbation within 15 months of screening. RESULTS: 1549 subjects were randomized and treated in the ENHANCE trials, (ensifentrine n=975; placebo n=574). 23% of subjects (ensifentrine n=220; placebo n=136) were included in the W-EXAC subgroup. Within the W-EXAC subgroup, 87% of ensifentrine-treated and 83% of placebo-treated subjects were reported to have chronic bronchitis (WO-EXAC subgroup had 68% and 67%, respectively). The W-EXAC subgroup included 54% of ensifentrine-treated and 51% of placebo-treated subjects with severe COPD (WO-EXAC subgroup had 39% and 45%, respectively). Over 24 weeks in the W-EXAC subgroup there were 32 exacerbations (annualized event rate 0.36) in ensifentrine-treated and 29 (annualized event rate 0.51) in the placebo-treated subjects. In the WO-EXAC subgroup, the annualized event rates were lower in both ensifentrine-treated and placebo-treated subjects. The magnitude of reduction in exacerbation rate and risk (measured by time to first event) was similar in both subgroups and consistent with the primary analysis (W-EXAC rate ratio [RR]: 0.70 [95% CI: 0.43, 1.17]; WO-EXAC RR: 0.57 [95% CI: 0.39, 0.84]; W-EXAC hazard ratio [HR]: 0.69 [95% CI: 0.41, 1.18]; WO-EXAC HR: 0.57 [95% CI: 0.39, 0.83]). CONCLUSIONS: The ENHANCE studies were designed to enroll a broad population of moderate to severe COPD patients, and exacerbation rates observed during the trials are consistent with population analyses describing exacerbation events in approximately 29-47% of COPD patients per year.1, 2 In the ENHANCE program, treatment with ensifentrine substantially reduced exacerbation rate and risk in a broad COPD population, regardless of recent exacerbation history. CLINICAL IMPLICATIONS: Treatment with ensifentrine substantially reduced exacerbation rate and risk in a broad COPD population, regardless of recent exacerbation history. 1. Sethi S, et al. Int J Chron Obstruct Pulmon Dis. 2022 Mar 20;17:593. 2. Hurst JR, et al. N Engl J Med. 2010;363(12):1128. DISCLOSURES: Consultant relationship with Verona Pharma Please note: $5001 - $20000 by Thomas Bengtsson, value=Consulting fee Employee relationship with Verona pharma Please note: >$100000 by Tara Rheault, value=Stock Employee relationship with Verona Pharma Plc Please note: >$100000 by Kathleen Rickard, value=Salary Grant Support relationship with Gala Therapeutics, Inc Please note: 9/2018-Present by Frank Sciurba, value=Grant/Research Support Grant Support relationship with Pulmonx Please note: 9/2014-Present by Frank Sciurba, value=Grant/Research Support Grant Support relationship with Nuvaira, Inc Please note: 5/2018-Present by Frank Sciurba, value=Grant/Research Support Grant Support relationship with PCORI Please note: 6/2019-Present by Frank Sciurba, value=Grant/Research Support Grant Support relationship with PneumRx Please note: 10/2012 by Frank Sciurba, value=Grant/Research Support Grant Support relationship with American Lung Assosciation Please note: 7/2021-Present by Frank Sciurba, value=Grant/Research Support Grant Support relationship with Gala Therapeutics, Inc Please note: 9/2019-Present by Frank Sciurba, value=Grant/Research Support Grant Support relationship with PneumRx Please note: 10/2013-Present by Frank Sciurba, value=Grant/Research Support Grant Support relationship with ResMed Corp Please note: 8/2018-Present by Frank Sciurba, value=Grant/Research Support Grant Support relationship with Regeneron/Sanofi US Services, Inc Please note: 5/2018-Present Added 04/10/2023 by Frank Sciurba, value=Grant/Research Support Advisory Committee Member relationship with Glaxosmithkline (GSK) Please note: 2/2023 Added 04/10/2023 by Frank Sciurba, source=Web Response, value=Honoraria Grant Support relationship with Verona Pharma Please note: 4/2019-Present Added 04/10/2023 by Frank Sciurba, source=Web Response, value=Grant/Research Support Grant Support relationship with AstraZeneca Please note: 2/2020-Present Added 04/10/2023 by Frank Sciurba, source=Web Response, value=Grant/Research Support