Safety, Tolerability, and Pharmacodynamics of the ADAMTS‐5 Nanobody M6495: Two Phase 1, Single‐Center, Double‐Blind, Randomized, Placebo‐Controlled Studies in Healthy Subjects and Patients With Osteoarthritis.
Objective: 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‐5) nanobody, in healthy volunteers and patients with osteoarthritis. Methods: Two randomized, placebo...
| Publicado en: | ACR Open Rheumatology Vol. 6; no. 4; pp. 205 - 214 |
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| Autores principales: | , , , , , , , , , , |
| Formato: | research tables/charts randomized controlled trial Journal Article |
| Publicado: |
Wiley-Blackwell
Apr2024
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=176608721&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 176608721 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 25785745 LXGC jtl: ACR Open Rheumatology issn: 25785745 maglogo: N pubinfo: dt: Apr2024 vid: 6 iid: 4 pid: 480 pub: Wiley-Blackwell place: Malden, Massachusetts artinfo: ui: 176608721 175188384 176608721 176608721 10.1002/acr2.11610 176608721 ppf: 205 ppct: 9 formats: tig: atl: Safety, Tolerability, and Pharmacodynamics of the ADAMTS‐5 Nanobody M6495: Two Phase 1, Single‐Center, Double‐Blind, Randomized, Placebo‐Controlled Studies in Healthy Subjects and Patients With Osteoarthritis. aug: au: Bihlet, Asger Reinstrup Balchen, Torben Goteti, Kosalaram Sonne, Jesper Ladel, Christoph Karsdal, Morten Asser Ona, Victor Moreau, Flavie Waterhouse, Roseann Bay‐Jensen, Anne‐Christine Guehring, Hans affil: Nordic Bioscience Clinical Development, Herlev, Denmark sug: subj: Osteoarthritis Drug Therapy Immunoglobulins Administration and Dosage Immunoglobulins Pharmacodynamics Immunoglobulins Pharmacokinetics Patient Safety Evaluation Drug Tolerance Evaluation Antirheumatic Agents Therapeutic Use Injections Human Male Female Middle Age Aged Randomized Controlled Trials Double-Blind Studies Placebos Metalloproteins Clinical Assessment Tools Pain Measurement Adverse Drug Event Random Assignment Drug Monitoring Biological Markers Blood Biological Assay Descriptive Statistics Immune System Funding Source Middle Aged: 45-64 years Aged: 65+ years Male Female ab: Objective: 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‐5) nanobody, in healthy volunteers and patients with osteoarthritis. Methods: Two randomized, placebo‐controlled, double‐blind studies were performed. Study 1 enrolled 54 healthy male volunteers who received one subcutaneous (s.c.) injection of M6495 (1‐300 mg) or placebo (ratio 2:1), evaluating safety, PK, and PD as changes in the serum aggrecan fragment alanine‐arginine‐glycine‐serine (ARGS). Study 2 enrolled 32 patients with osteoarthritis with Kellgren–Lawrence 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 (75‐300 mg per dose) or six once‐weekly M6495 s.c. doses (300 mg) or placebo (ratio 3:1) over 106 days' follow‐up. Results: 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‐life 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‐modifying potential of M6495. Conclusion: 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‐modifying effects. pubtype: Academic Journal doctype: research tables/charts randomized controlled trial Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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