{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T06:08:34Z","timestamp":1791439714754,"version":"4.3.3"},"reference-count":19,"publisher":"European Respiratory Society (ERS)","issue":"5","license":[{"start":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T00:00:00Z","timestamp":1725926400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100022752","name":"MSD Sharp and Dohme","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100022752","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["publications.ersnet.org"],"crossmark-restriction":true},"short-container-title":["Eur Respir J"],"accepted":{"date-parts":[[2024,8,8]]},"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>MK-5475 is an investigational inhaled soluble guanylate cyclase stimulator hypothesised to avoid most side-effects of systemic vasodilation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The phase 2 INSIGNIA-PAH (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04732221\">NCT04732221<\/jats:ext-link>) trial randomised adults with pulmonary arterial hypertension (PAH) on stable background therapy 1:1:1:1 to once-daily dosing with placebo, MK-5475 32\u2005\u00b5g, 100\u2005\u00b5g or 380\u2005\u00b5g<jats:italic>via<\/jats:italic>dry powder inhalation for 12\u2005weeks.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives<\/jats:title><jats:p>The objectives were to evaluate pulmonary vascular resistance (PVR; primary), 6-min walk distance (6MWD; secondary), additional selected haemodynamic parameters, and safety and tolerability in participants with PAH.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>168 participants were randomised to placebo (n=41), MK-5475 32\u2005\u00b5g (n=42), 100\u2005\u00b5g (n=44), and 380\u2005\u00b5g (n=41). Median age was 51\u2005years. Most participants were female (73.8%), diagnosed with idiopathic PAH (63.7%), receiving concomitant phosphodiesterase type 5 inhibitors (PDE5i; 93.5%), and treated with double or triple combination therapy (85.1%). At week 12, the placebo-corrected changes in PVR by least-squares means were \u22129.2% (95% CI \u221221.3%, 2.9%; p=0.068) with 32\u2005\u00b5g, \u221222.0% (95% CI \u221233.7%, \u221210.3%; p&lt;0.001) with 100\u2005\u00b5g, and \u221219.9% (95% CI \u221233.4%, \u22126.4%; p=0.002) with 380\u2005\u00b5g MK-5475. No treatment differences<jats:italic>versus<\/jats:italic>placebo were observed in 6MWD. Treatment-related adverse events and serious adverse events were similar across treatment groups. Three participants died: two on placebo and one on MK-5475 100\u2005\u00b5g. One participant had symptomatic hypotension and one had haemoptysis (both on MK-5475 100\u2005\u00b5g).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In participants with PAH on stable background therapy, including PDE5i, inhaled MK-5475 reduced PVR and was well tolerated, without evidence of systemic side-effects such as hypotension, suggesting a pulmonary selective pharmacodynamic effect.<\/jats:p><\/jats:sec>","DOI":"10.1183\/13993003.01110-2024","type":"journal-article","created":{"date-parts":[[2024,9,10]],"date-time":"2024-09-10T11:25:23Z","timestamp":1725967523000},"page":"2401110","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["MK-5475, an inhaled soluble guanylate cyclase stimulator, for treatment of pulmonary arterial hypertension: the INSIGNIA-PAH study"],"prefix":"10.1183","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0703-2892","authenticated-orcid":false,"given":"Marc","family":"Humbert","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0601-4975","authenticated-orcid":false,"given":"Paul M.","family":"Hassoun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1214-6723","authenticated-orcid":false,"given":"Kelly M.","family":"Chin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4437-6854","authenticated-orcid":false,"given":"Guillermo","family":"Bortman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahesh J.","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"La Rosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5430-5585","authenticated-orcid":false,"given":"Maria Jos\u00e9","family":"Loureiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9086-2293","authenticated-orcid":false,"given":"Marius M.","family":"Hoeper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"81","published-online":{"date-parts":[[2024,9,10]]},"reference":[{"key":"2024120209251984000_64.5.2401110.1","doi-asserted-by":"crossref","first-page":"e000137","DOI":"10.1136\/bmjmed-2022-000137","article-title":"Pathophysiology and new advances in pulmonary hypertension","volume":"2","author":"Bousseau","year":"2023","journal-title":"BMJ Med"},{"key":"2024120209251984000_64.5.2401110.2","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01887-2018"},{"key":"2024120209251984000_64.5.2401110.3","doi-asserted-by":"publisher","DOI":"10.3390\/ijms17050761"},{"key":"2024120209251984000_64.5.2401110.4","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2011.87"},{"key":"2024120209251984000_64.5.2401110.5","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00879-2022"},{"key":"2024120209251984000_64.5.2401110.6","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-050410-100030"},{"key":"2024120209251984000_64.5.2401110.7","doi-asserted-by":"publisher","DOI":"10.1183\/16000617.0183-2023"},{"key":"2024120209251984000_64.5.2401110.8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1209655"},{"key":"2024120209251984000_64.5.2401110.9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1209657"},{"key":"2024120209251984000_64.5.2401110.10","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00105914"},{"key":"2024120209251984000_64.5.2401110.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmed.2022.107065"},{"key":"2024120209251984000_64.5.2401110.12","doi-asserted-by":"publisher","DOI":"10.1186\/1477-7525-11-161"},{"key":"2024120209251984000_64.5.2401110.13","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1214\/aos\/1176342503","article-title":"Robust regression: asymptotics, conjectures and Monte Carlo","volume":"1","author":"Huber","year":"1973","journal-title":"Ann Statist"},{"key":"2024120209251984000_64.5.2401110.14","doi-asserted-by":"publisher","DOI":"10.1002\/sim.4780040211"},{"key":"2024120209251984000_64.5.2401110.15","doi-asserted-by":"publisher","DOI":"10.2147\/COPD.S454905"},{"key":"2024120209251984000_64.5.2401110.16","unstructured":"ClinicalTrials.gov. 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