PMID- 24841795 OWN - NLM STAT- MEDLINE DCOM- 20150109 LR - 20240322 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 9 IP - 5 DP - 2014 TI - Safety, pharmacokinetic, and functional effects of the nogo-a monoclonal antibody in amyotrophic lateral sclerosis: a randomized, first-in-human clinical trial. PG - e97803 LID - 10.1371/journal.pone.0097803 [doi] LID - e97803 AB - 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 (3ratio1) 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 (3ratio1) 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. TRIAL REGISTRATION: ClinicalTrials.gov NCT00875446 GSK-ClinicalStudyRegister.com GSK ID 111330. FAU - Meininger, Vincent AU - Meininger V AD - Departement des Maladies du Systeme Nerveux, Assistance Publique - Hopitaux de Paris, Centre de Reference Maladies Rares SLA, Groupe Hospitalier Pitie-Salpetriere, Universite Pierre-et-Marie-Curie, Paris, France. FAU - Pradat, Pierre-Francois AU - Pradat PF AD - Departement des Maladies du Systeme Nerveux, Assistance Publique - Hopitaux de Paris, Centre de Reference Maladies Rares SLA, Groupe Hospitalier Pitie-Salpetriere, Universite Pierre-et-Marie-Curie, Paris, France; Unite Mixte de Recherche-678, Institut National de la Sante et de la Recherche Medicale - Universite Pierre-et-Marie-Curie, Groupe Hospitalier Pitie-Salpetriere, Paris, France. FAU - Corse, Andrea AU - Corse A AD - Neuromuscular Pathology Lab, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America. FAU - Al-Sarraj, Safa AU - Al-Sarraj S AD - Department of Clinical Neuropathology, Kings College Hospital/Kings College London, London, United Kingdom. FAU - Rix Brooks, Benjamin AU - Rix Brooks B AD - Carolinas Neuromuscular/Amyotrophic Lateral Sclerosis-Muscular Dystrophy Association Center, Department of Neurology, Carolinas Medical Center and University of North Carolina School of Medicine-Charlotte Campus, Charlotte, North Carolina, United States of America. FAU - Caress, James B AU - Caress JB AD - Wake Forest School of Medicine, M Reynolds Tower, Medical Center Boulevard, Winston-Salem, North Carolina, United States of America. FAU - Cudkowicz, Merit AU - Cudkowicz M AD - Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America. FAU - Kolb, Stephen J AU - Kolb SJ AD - Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America. FAU - Lange, Dale AU - Lange D AD - Department of Neurology, Weill Cornell School of Medicine, New York, New York, United States of America. FAU - Leigh, P Nigel AU - Leigh PN AD - Trafford Centre for Biomedical Research, Brighton and Sussex Medical School, Falmer, Sussex, United Kingdom. FAU - Meyer, Thomas AU - Meyer T AD - Department of Neurology, Charite - Universitatsmedizin Berlin, Berlin, Germany. FAU - Milleri, Stefano AU - Milleri S AD - Centro Ricerche Cliniche, University Hospital G.B. Rossi, Verona, Italy. FAU - Morrison, Karen E AU - Morrison KE AD - School of Clinical and Experimental Medicine, University of Birmingham and Neurosciences Department, Queen Elizabeth Hospital, Birmingham, United Kingdom. FAU - Orrell, Richard W AU - Orrell RW AD - Department of Clinical Neuroscience, Institute of Neurology, University College London, London, United Kingdom; Department of Neurology, Royal Free London NHS Foundation Trust, London, United Kingdom. FAU - Peters, Gary AU - Peters G AD - GlaxoSmithKline Clinical Unit Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom. FAU - Rothstein, Jeffrey D AU - Rothstein JD AD - Brain Science Institute, Johns Hopkins University, Department of Neurology, Baltimore, Maryland, United States of America. FAU - Shefner, Jeremy AU - Shefner J AD - Department of Neurology, SUNY Upstate Medical University, Syracuse, New York, United States of America. FAU - Lavrov, Arseniy AU - Lavrov A AD - Neurosciences Therapy Area Unit, Medicines Discovery and Development, GlaxoSmithKline, Stockley Park, Uxbridge, Middlesex, United Kingdom. FAU - Williams, Nicola AU - Williams N AD - Clinical Statistics, GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom. FAU - Overend, Phil AU - Overend P AD - Clinical Statistics, GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom. FAU - Price, Jeffrey AU - Price J AD - Clinical Pharmacology, Science and Study Operations, BioPharm and Infectious Diseases, GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom. FAU - Bates, Stewart AU - Bates S AD - BioPharm Translational Medicine, GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom. FAU - Bullman, Jonathan AU - Bullman J AD - Clinical Pharmacology Modelling & Simulation (Neurosciences), GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom. FAU - Krull, David AU - Krull D AD - Safety Assessment, GlaxoSmithKline, Research Triangle Park, North Carolina, United States of America. FAU - Berges, Alienor AU - Berges A AD - Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park, Uxbridge, Middlesex, United Kingdom. FAU - Abila, Bams AU - Abila B AD - BioPharm Translational Medicine, GlaxoSmithKline, Stevenage, Hertfordshire, United Kingdom. FAU - Meno-Tetang, Guy AU - Meno-Tetang G AD - Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline, Stockley Park, Uxbridge, Middlesex, United Kingdom. FAU - Wurthner, Jens AU - Wurthner J AD - Oncology Translational Medicine, Novartis Basel, Switzerland. LA - eng SI - ClinicalTrials.gov/NCT00875446 PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20140519 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Biomarkers) RN - 0 (Myelin Proteins) RN - 0 (Nogo Proteins) RN - 0 (RTN4 protein, human) RN - 123I05210W (ozanezumab) SB - IM MH - Administration, Intravenous MH - Amyotrophic Lateral Sclerosis/*drug therapy/*metabolism MH - Antibodies, Monoclonal/administration & dosage/adverse effects/*pharmacokinetics/*pharmacology MH - Antibodies, Monoclonal, Humanized/administration & dosage/adverse effects/*pharmacokinetics/*pharmacology MH - Biomarkers/metabolism MH - Dose-Response Relationship, Drug MH - Female MH - Humans MH - Immunohistochemistry MH - Male MH - Middle Aged MH - Myelin Proteins/*metabolism MH - Nogo Proteins PMC - PMC4026380 COIS- Competing Interests: AL, NW, PO, JP, SB, JB, DK, AB, BA and GM-T are employees of and hold stock in GlaxoSmithKline. JW was a full-time employee of GlaxoSmithKline at the time of study and holds shares in the company. He is now an employee of Novartis. GP was a full-time employee of GlaxoSmithKline at the time of study and holds shares in the company. He is now an employee of Hammersmith Medicines Research. VM has previously received a consultancy fee from GlaxoSmithKline. AC has previously acted as a consultant to GlaxoSmithKline at a single-day advisory board meeting. PNL received travel expenses and consultancy fees for his work on the advisory board of this development. JDR has previously received funding from NIH, MDA, Robert Packard Center for ALS research and has acted as a consultant for Psyadon Pharmaceutical, Biogen Pharma and Cytokinetics. MC is on the GlaxoSmithKline scientific advisory board. P-FP, BRB, JBC, SJK, DL, TM, SM, SA-S and KEM have no conflicts of interest to declare. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. EDAT- 2014/05/21 06:00 MHDA- 2015/01/13 06:00 PMCR- 2014/05/19 CRDT- 2014/05/21 06:00 PHST- 2013/12/06 00:00 [received] PHST- 2014/04/22 00:00 [accepted] PHST- 2014/05/21 06:00 [entrez] PHST- 2014/05/21 06:00 [pubmed] PHST- 2015/01/13 06:00 [medline] PHST- 2014/05/19 00:00 [pmc-release] AID - PONE-D-13-47783 [pii] AID - 10.1371/journal.pone.0097803 [doi] PST - epublish SO - PLoS One. 2014 May 19;9(5):e97803. doi: 10.1371/journal.pone.0097803. eCollection 2014.