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Following the PRISMA guidelines, we conducted a systematic review and meta-analysis, systematically searching PubMed, Web of Science, Scopus, and Cochrane library up to 12 December 2024, for randomized controlled trials (RCTs) evaluating ensifentrine compared to placebo in COPD patients. Eligibility criteria included studies reporting outcomes such as pulmonary function tests, exacerbation rates, and adverse events. Subgroup analysis was conducted based on the timing of outcome evaluation and the doses administered. Additionally, a meta-regression model was employed to evaluate the possible correlations between the Ensifentrine doses and \u201cAverage\u00a0forced expiratory volume (FEV 1)\u201d results and identify the optimal dose. Trial sequential analysis (TSA) was implemented to ensure the conclusiveness of our results. Furthermore, the GRADE approach was used to assess the certainty of evidence and for quality assessment the RoB-2 tool was used. Four RCTs were included in our analysis with a total of 2370 COPD patients. Compared to placebo, ensifentrine 3\u00a0mg significantly improved lung functions as measured by change in average\u00a0FEV1 (MD\u2009=\u20090.09, 95% CI: [0.07 to 0.12]), change in peak FEV1 (0\u20133\u00a0h) (MD\u2009=\u20090.15, 95% CI: [0.13 to 0.18]), and change in morning trough FEV1 (MD\u2009=\u20090.04, 95% CI: [0.02 to 0.07]). Subgrouping based on the administrated dose found that ensifentrine 3\u00a0mg showed higher, yet non-significant results compared to the included doses (0.75, 1.5, and 6\u00a0mg) in all pulmonary function tests. Moreover, meta-regression revealed a significant dose\u2013response relationship for average FEV1 up to 3\u00a0mg, indicating optimal efficacy at 3-mg dose. Ensifentrine also significantly improved quality of life measures, with no significant increase in adverse events across doses. Ensifentrine has proven to be effective in improving lung functions and respiratory symptoms with an acceptable safety profile, thus suggesting a valuable addition to the management of COPD with consideration of potential adverse effects. Nevertheless, further studies with extended long-term follow-up are essential to fully assess the sustained efficacy and safety of ensifentrine and support its optimal therapeutic integration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical trial number<\/jats:title>\n                    <jats:p>Not applicable.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00210-025-04558-1","type":"journal-article","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T07:46:00Z","timestamp":1757576760000},"page":"2797-2818","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A comprehensive systematic review and meta-analysis of ensifentrine in COPD: dose-dependent effects, safety profile, and GRADE-based certainty of evidence"],"prefix":"10.1007","volume":"399","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8806-2624","authenticated-orcid":false,"given":"Amr M.","family":"Abou Elezz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kareem","family":"Khalefa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5802-2291","authenticated-orcid":false,"given":"Ahmed Farid","family":"Gadelmawla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lamees","family":"Taman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Habiba Tariq","family":"Saeed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amr Alaa Azzouz","family":"Elkelany","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Habiba Abdelhameed","family":"Elrefaey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Abo Zeid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,11]]},"reference":[{"key":"4558_CR1","doi-asserted-by":"publisher","first-page":"406","DOI":"10.1164\/rccm.202306-0944OC","volume":"208","author":"A Anzueto","year":"2023","unstructured":"Anzueto A, Barjaktarevic IZ, Siler TM et al (2023) Ensifentrine, a novel phosphodiesterase 3 and 4 inhibitor for the treatment of chronic obstructive pulmonary disease: randomized, double-blind, placebo-controlled, multicenter phase III trials (the ENHANCE Trials). 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