{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T09:00:29Z","timestamp":1791536429268,"version":"4.3.4"},"reference-count":20,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2021,5,14]],"date-time":"2021-05-14T00:00:00Z","timestamp":1620950400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Evaluate safety, tolerability, pharmacokinetics (PK) and target engagement (TE) of losmapimod in blood and muscle in facioscapulohumeral dystrophy (FSHD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This study included Part A: 10 healthy volunteers randomized to single oral doses of losmapimod (7.5\u00a0mg then 15\u2009mg; <jats:italic>n\u2009=<\/jats:italic>\u00a08) or placebo (both periods; <jats:italic>n\u2009=<\/jats:italic>\u00a02); Part B: 15 FSHD subjects randomized to placebo (<jats:italic>n\u2009=<\/jats:italic>\u00a03), or losmapimod 7.5\u00a0mg (<jats:italic>n\u2009=<\/jats:italic>\u00a06) or 15\u2009mg (<jats:italic>n\u2009=<\/jats:italic>\u00a06); and Part C: FSHD subjects received open\u2010label losmapimod 15\u2009mg (<jats:italic>n\u2009=<\/jats:italic>\u00a05) twice daily for 14\u2009days. Biopsies were performed in FSHD subjects at baseline and Day 14 in magnetic resonance imaging\u2010normal appearing (Part B) and affected muscle identified by abnormal short\u2010tau inversion recovery sequence\u2009+\u2009(Part C). PK and TE, based on pHSP27:total HSP27, were assessed in muscle and sorbitol\u2010stimulated blood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>PK profiles were similar between healthy volunteers and FSHD subjects, with mean C<jats:sub>max<\/jats:sub> and AUC<jats:sub>0\u201312<\/jats:sub> for 15\u2009mg in FSHD subjects (Part B) of 85.0\u00a0\u00b1\u200916.7\u00a0ng*h\/mL and 410\u2009\u00b1\u200950.3\u00a0ng*h\/mL, respectively. Part B and Part C PK results were similar, and 7.5\u00a0mg results were approximately dose proportional to 15\u2009mg results. Dose\u2010dependent concentrations in muscle (42.1\u00a0\u00b1\u00a010.5\u00a0ng\/g [7.5\u00a0mg] to 97.2\u00a0\u00b1\u200922.4\u00a0ng\/g [15\u2009mg]) were observed, with plasma\u2010to\u2010muscle ratio from ~0.67 to ~1 at estimated t<jats:sub>max<\/jats:sub> of 3.5\u00a0hours postdose. TE was observed in blood and muscle. Adverse events (AEs) were mild and self\u2010limited.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Losmapimod was well tolerated, with no serious AEs. Dose\u2010dependent PK and TE were observed. This study supports advancing losmapimod into Phase 2 trials in FSHD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Clinical Trial Registration<\/jats:title><jats:p>Clinical trial identifier ToetsingOnline: NL68539.056.18 Nederlands Trials Register NL8000.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.14884","type":"journal-article","created":{"date-parts":[[2021,5,1]],"date-time":"2021-05-01T06:38:36Z","timestamp":1619851116000},"page":"4658-4669","source":"Crossref","is-referenced-by-count":41,"title":["Phase 1 clinical trial of losmapimod in facioscapulohumeral dystrophy: Safety, tolerability, pharmacokinetics, and target engagement"],"prefix":"10.1111","volume":"87","author":[{"given":"Michelle L.","family":"Mellion","sequence":"first","affiliation":[{"name":"Fulcrum Therapeutics  Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucienne","family":"Ronco","sequence":"additional","affiliation":[{"name":"Fulcrum Therapeutics  Cambridge MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8721-4682","authenticated-orcid":false,"given":"Cecile L.","family":"Berends","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research (CHDR)  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Pagan","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research (CHDR)  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sander","family":"Brooks","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research (CHDR)  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8159-0273","authenticated-orcid":false,"given":"Michiel J.","family":"van Esdonk","sequence":"additional","affiliation":[{"name":"Centre for Human Drug Research (CHDR)  Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie M. 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