Impact of ensifentrine on trough FEV1 in COPD: a meta-analysis

<bold>Background:</bold> Ensifentrine, a PDE3/4 inhibitor, is an investigational drug under evaluation by FDA for the maintenance therapy of COPD. Trough FEV1 is a main outcome for the approval of drugs in COPD, however it has never been investigated as a primary endpoint for ensifentrine (1). <bold>Aim:</bold> To provide the quantitative synthesis of the impact of ensifentrine on trough FEV1 in COPD. <bold>Methods:</bold> A meta-analysis was performed by searching for RCTs investigating the effect of ensifentrine on trough FEV1 in COPD patients. Detailed information concerning the search strategy, study selection, risk of bias, data extraction and analysis are available in the registered protocol (PROSPERO registration number: CRD42023478153). <bold>Results:</bold> Data obtained from 2,397 COPD patients were extracted from 5 RCTs. The investigated doses of ensifentrine ranged from 0.375 mg to 6 mg. Overall, ensifentrine elicited a significant (P<0.001) increase in trough FEV1 when administered on top of concomitant maintenance therapy (LABA, LAMA, ICS/LABA, ICS/LAMA, compared to placebo (+33 mL 95%CI 15 – 50; I^2=0%, P=0.59). When considering only ensifentrine 3 mg, that is the dose undergoing evaluation by FDA, the improvement in trough FEV1 remained significant (P<0.001) and increased at 46 mL (95%CI 22 – 69; I^2=0%, P=0.84) compared to placebo. No significant risk of bias was detected according to the funnel plot and Egger’s test. <bold>Conclusions:</bold> Ensifentrine administered on top of concomitant maintenance therapy is effective in improving trough FEV1. At the dose of 3 mg, its effect overlaps the minimal clinically important difference for trough FEV1 (>60 mL) when a drug is administered on top of active treatments. 1. Calzetta et al., Am J Respir Crit Care Med. 2024;209:224-225