Safety, pharmacokinetic, and functional effects of the nogo-a monoclonal antibody in amyotrophic lateral sclerosis: a randomized, first-in-human clinical trial
| العنوان: | Safety, pharmacokinetic, and functional effects of the nogo-a monoclonal antibody in amyotrophic lateral sclerosis: a randomized, first-in-human clinical trial |
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| المؤلفون: | Nicola Williams, Stefano Milleri, Safa Al-Sarraj, Richard W. Orrell, Jeffrey D. Rothstein, Vincent Meininger, P. Nigel Leigh, Andrea M. Corse, Guy Meno-Tetang, Jeffrey Price, Merit Cudkowicz, Jeremy M. Shefner, Stephen J. Kolb, Gary Peters, Alienor Berges, James B. Caress, Dale J. Lange, Phil Overend, Benjamin Rix Brooks, David Krull, Jens Würthner, Pierre Pradat, Thomas Meyer, Bams Abila, Karen E. Morrison, Stewart Bates, Jonathan Bullman, Arseniy Lavrov |
| المصدر: | PLoS ONE PLoS ONE, Vol 9, Iss 5, p e97803 (2014) |
| بيانات النشر: | Public Library of Science, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Male, lcsh:Medicine, Pharmacology, law.invention, Motor Neuron Diseases, Randomized controlled trial, law, Medicine and Health Sciences, Medicine, lcsh:Science, Musculoskeletal System, Multidisciplinary, Antibodies, Monoclonal, Neurodegenerative Diseases, Middle Aged, Immunohistochemistry, Tolerability, Neurology, Research Design, RC0346, Monoclonal, Administration, Intravenous, Female, Immunotherapy, Anatomy, Dexpramipexole, Myelin Proteins, medicine.drug, Research Article, Clinical Research Design, Nogo Proteins, Immunology, Placebo, Research and Analysis Methods, Antibodies, Monoclonal, Humanized, Pharmacokinetics, Adverse Reactions, Humans, Clinical Trials, Dose-Response Relationship, Drug, business.industry, lcsh:R, Ozanezumab, Amyotrophic Lateral Sclerosis, Immunity, Biology and Life Sciences, RC0349.8, Clinical trial, lcsh:Q, Clinical Immunology, Clinical Medicine, business, Biomarkers |
| الوصف: | UNLABELLED\ud \ud The neurite outgrowth inhibitor, Nogo-A, has been shown to be overexpressed in skeletal muscle in amyotrophic lateral sclerosis (ALS); it is both a potential biomarker and therapeutic target. We performed a double-blind, two-part, dose-escalation study, in subjects with ALS, assessing safety, pharmacokinetics (PK) and functional effects of ozanezumab, a humanized monoclonal antibody against Nogo-A. In Part 1, 40 subjects were randomized (3∶1) to receive single dose intravenous ozanezumab (0.01, 0.1, 1, 5, or 15 mg/kg) or placebo. In Part 2, 36 subjects were randomized (3∶1) to receive two repeat doses of intravenous ozanezumab (0.5, 2.5, or 15 mg/kg) or placebo, approximately 4 weeks apart. The primary endpoints were safety and tolerability (adverse events [AEs], vital signs, electrocardiogram (ECG), and clinical laboratory tests). Secondary endpoints included PK, immunogenicity, functional endpoints (clinical and electrophysiological), and biomarker parameters. Overall, ozanezumab treatment (0.01-15 mg/kg) was well tolerated. The overall incidence of AEs in the repeat dose 2.5 mg/kg and 15 mg/kg ozanezumab groups was higher than in the repeat dose placebo group and repeat dose 0.5 mg/kg ozanezumab group. The majority were considered not related to study drug by the investigators. Six serious AEs were reported in three subjects receiving ozanezumab; none were considered related to study drug. No study drug-related patterns were identified for ECG, laboratory, or vital signs parameters. One subject (repeat dose 15 mg/kg ozanezumab) showed a weak, positive anti-ozanezumab-antibody result. PK results were generally consistent with monoclonal antibody treatments. No apparent treatment effects were observed for functional endpoints or muscle biomarkers. Immunohistochemical staining showed dose-dependent co-localization of ozanezumab with Nogo-A in skeletal muscle. In conclusion, single and repeat dose ozanezumab treatment was well tolerated and demonstrated co-localization at the site of action. These findings support future studies with ozanezumab in ALS.\ud \ud TRIAL REGISTRATION\ud \ud ClinicalTrials.gov NCT00875446 GSK-ClinicalStudyRegister.com GSK ID 111330. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1932-6203 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::14127f941cc6bd2c6df14dbdd2d4f7a2Test http://sro.sussex.ac.uk/id/eprint/54191/1/journal.pone.0097803.pdfTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....14127f941cc6bd2c6df14dbdd2d4f7a2 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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