{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T23:29:42Z","timestamp":1793230182099,"version":"4.5.0"},"reference-count":22,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,2,4]],"date-time":"2024-02-04T00:00:00Z","timestamp":1707004800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009945","name":"Merck KGaA","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009945","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ACR Open Rheumatology"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>To assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple injections of M6495, a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS\u20105)\u00a0 nanobody, in healthy volunteers and patients with osteoarthritis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Two randomized, placebo\u2010controlled, double\u2010blind studies were performed. Study 1 enrolled 54 healthy male volunteers who received one subcutaneous (s.c.) injection of M6495 (1\u2010300 mg) or placebo (ratio 2:1), evaluating safety, PK, and PD as changes in the serum aggrecan fragment alanine\u2010arginine\u2010glycine\u2010serine (ARGS). Study 2 enrolled 32 patients with osteoarthritis with Kellgren\u2013Lawrence grades 2 to 4 and pain greater than or equal to 40 on the Western Ontario and McMaster Universities Arthritis Index pain subscale at screening and evaluated the safety, PK, and PD of three doses every two weeks (75\u2010300 mg per dose) or six once\u2010weekly M6495 s.c. doses (300 mg) or placebo (ratio 3:1) over 106\u2009days\u2019 follow\u2010up.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>M6495 in single and multiple doses of less than or equal to 300 mg s.c. weekly was well tolerated with no clinically significant changes in any safety parameter. Adverse events more frequently reported in the M6495 groups were mostly mild cases of injection site reactions, myalgia, and nausea, which resolved after treatment cessation. The elimination half\u2010life of single s.c. doses of M6495 ranged from 79 to 267 hours. M6495 administration substantially reduced serum ARGS levels, indicative of target engagement and indicating disease\u2010modifying potential of M6495.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Treatment with M6495 in single and multiple doses up to and including 300 mg s.c. was found to be well tolerated and adequately safe for further clinical evaluation of potential disease\u2010modifying effects.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acr2.11610","type":"journal-article","created":{"date-parts":[[2024,2,4]],"date-time":"2024-02-04T20:34:30Z","timestamp":1707078870000},"page":"205-213","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Safety, Tolerability, and Pharmacodynamics of the <scp>ADAMTS<\/scp>\u20105 Nanobody <scp>M6495<\/scp>: Two Phase 1, <scp>Single\u2010Center<\/scp>, <scp>Double\u2010Blind<\/scp>, Randomized, <scp>Placebo\u2010Controlled<\/scp> Studies in Healthy Subjects and Patients With Osteoarthritis"],"prefix":"10.1002","volume":"6","author":[{"given":"Asger Reinstrup","family":"Bihlet","sequence":"first","affiliation":[{"name":"Nordic Bioscience Clinical Development  Herlev Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torben","family":"Balchen","sequence":"additional","affiliation":[{"name":"DanTrials ApS  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosalaram","family":"Goteti","sequence":"additional","affiliation":[{"name":"EMD Serono  Billerica Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesper","family":"Sonne","sequence":"additional","affiliation":[{"name":"Bispebjerg Hospital and Copenhagen University  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christoph","family":"Ladel","sequence":"additional","affiliation":[{"name":"Merck KGaA  Darmstadt 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