PMID- 30999929 OWN - NLM STAT- MEDLINE DCOM- 20200513 LR - 20200513 IS - 1478-6362 (Electronic) IS - 1478-6354 (Print) IS - 1478-6354 (Linking) VI - 21 IP - 1 DP - 2019 Apr 18 TI - Efficacy and safety of namilumab, a human monoclonal antibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) ligand in patients with rheumatoid arthritis (RA) with either an inadequate response to background methotrexate therapy or an inadequate response or intolerance to an anti-TNF (tumour necrosis factor) biologic therapy: a randomized, controlled trial. PG - 101 LID - 10.1186/s13075-019-1879-x [doi] LID - 101 AB - BACKGROUND: Namilumab (AMG203), an immunoglobulin G1 monoclonal antibody that binds with high affinity to granulocyte-macrophage colony-stimulating factor (GM-CSF), was evaluated in a phase II randomized, double-blind, placebo-controlled study to investigate the efficacy and safety in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX-IR) or anti-tumour necrosis factor therapy (TNF-IR). METHODS: Subcutaneous namilumab (20, 80, or 150 mg) or placebo was administered at baseline and weeks 2, 6, and 10 in patients on stable background methotrexate therapy who were with MTX-IR or TNF-IR. Primary endpoint was mean change from baseline in the 28-joint Disease Activity Score, C-reactive protein version (DAS28-CRP) at week 12 comparing each of the three doses of namilumab to placebo. Safety and tolerability were assessed by adverse events (AEs) and pulmonary parameters. Results were analysed using the per-protocol population. RESULTS: One hundred eight patients from Europe and Japan (48.4 +/- 12.02 years old; 77.8% female; mean DAS28-CRP 5.60-5.79; rheumatoid factor/anti-citrullinated protein antibodies + 75%) were randomized to placebo or namilumab 20, 80, or 150 mg (n = 27, 28, 25, and 28, respectively). Ninety-two were MTX-IR; 16 were TNF-IR. At week 12, a statistically significant difference in DAS28-CRP (p = 0.005) was seen for namilumab 150 mg versus placebo and separation was seen as early as week 2 for namilumab 150 mg (p < 0.05), with higher ACR50 and response rates versus placebo at week 12. A dose-response effect was observed across the DAS28-CRP endpoint with separation versus placebo evident from week 2. The most common treatment-emergent AEs were nasopharyngitis (18.5%, 17.9%, 4.0%, 14.3%), dyspnoea (0.0%, 3.6%, 8.0%, 10.7%), bronchitis (7.4%, 3.6%, 4.0%, 3.6%), and headache (3.7%, 3.6%, 12.0%, 0.0%) for placebo and 20, 80, or 150 mg of namilumab, respectively. No serious infections were observed. One serious AE (myocardial infarction) was observed with 150 mg of namilumab. There was no apparent dose relationship for AEs. A biomarker-based disease activity score showed a dose-dependent decrease at week 12. CONCLUSIONS: This phase II study demonstrates the benefit of inhibiting macrophage activity targeting the GM-CSF for RA. The study met its primary endpoint with a clear dose-response effect. An acceptable tolerability profile was demonstrated over the 12-week study. TRIAL REGISTRATION: ClinicalTrials.gov, NEXUS; NCT02379091 , submitted November 28, 2014. FAU - Taylor, Peter C AU - Taylor PC AUID- ORCID: 0000-0001-7766-6167 AD - Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Windmill Road, Oxford, OX3 7LD, UK. peter.taylor@kennedy.ox.ac.uk. FAU - Saurigny, Didier AU - Saurigny D AD - Takeda Development Centre, London, UK. AD - Present Address: GSK Medicines Research Centre, Stevenage, UK. FAU - Vencovsky, Jiri AU - Vencovsky J AD - Institute of Rheumatology, Prague, Czech Republic. FAU - Takeuchi, Tsutomu AU - Takeuchi T AD - Division of Rheumatology, Keio University School of Medicine, Tokyo, Japan. FAU - Nakamura, Tadashi AU - Nakamura T AD - Kumamoto Shinto General Hospital, Kumamoto, Japan. FAU - Matsievskaia, Galina AU - Matsievskaia G AD - Clinical Rheumatology Hospital #25, Saint-Petersburg, Russian Federation. FAU - Hunt, Barbara AU - Hunt B AD - Statistics, Takeda International, Deerfield, IL, USA. FAU - Wagner, Thomas AU - Wagner T AD - Modeling and Simulation, Takeda Pharmaceuticals International GmbH, Zurich, Switzerland. AD - Present Address: thinkQ2 AG, Baar, Switzerland. FAU - Souberbielle, Bernard AU - Souberbielle B AD - Takeda Development Centre, London, UK. AD - Present Address: Sangamo Therapeutics, London, UK. CN - NEXUS Study Group LA - eng SI - ClinicalTrials.gov/NCT02379091 PT - Clinical Trial, Phase II PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20190418 PL - England TA - Arthritis Res Ther JT - Arthritis research & therapy JID - 101154438 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antirheumatic Agents) RN - 0 (Tumor Necrosis Factor-alpha) RN - 83869-56-1 (Granulocyte-Macrophage Colony-Stimulating Factor) RN - MED485W763 (namilumab) RN - YL5FZ2Y5U1 (Methotrexate) SB - IM MH - Adult MH - Aged MH - Antibodies, Monoclonal, Humanized/*administration & dosage MH - Antirheumatic Agents/*administration & dosage MH - Arthritis, Rheumatoid/diagnosis/*drug therapy/metabolism MH - Dose-Response Relationship, Drug MH - Double-Blind Method MH - Female MH - Granulocyte-Macrophage Colony-Stimulating Factor/*antagonists & inhibitors/metabolism MH - Humans MH - Injections, Subcutaneous MH - Male MH - Methotrexate/*therapeutic use MH - Middle Aged MH - Treatment Outcome MH - Tumor Necrosis Factor-alpha/*antagonists & inhibitors/metabolism PMC - PMC6471864 OTO - NOTNLM OT - GM-CSF OT - Namilumab OT - Rheumatoid arthritis COIS- ETHICS APPROVAL AND CONSENT TO PARTICIPATE: Institutional review boards or ethics committees at the participating investigational centres approved the study, which was conducted according to the principles set out in the Declaration of Helsinki, International Conference on Harmonisation Guidelines for Good Clinical Practice, and additional local regulations. CONSENT FOR PUBLICATION: Not applicable. COMPETING INTERESTS: Dr. Wagner was an employee of Takeda Pharmaceuticals International GmbH. Both Bernard Souberbielle and Didier Saurigny were employees of Takeda at the time of the study. Barbara Hunt is an employee of Takeda International, Deerfield, IL, USA. The other authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2019/04/20 06:00 MHDA- 2020/05/14 06:00 PMCR- 2019/04/18 CRDT- 2019/04/20 06:00 PHST- 2018/12/12 00:00 [received] PHST- 2019/03/26 00:00 [accepted] PHST- 2019/04/20 06:00 [entrez] PHST- 2019/04/20 06:00 [pubmed] PHST- 2020/05/14 06:00 [medline] PHST- 2019/04/18 00:00 [pmc-release] AID - 10.1186/s13075-019-1879-x [pii] AID - 1879 [pii] AID - 10.1186/s13075-019-1879-x [doi] PST - epublish SO - Arthritis Res Ther. 2019 Apr 18;21(1):101. doi: 10.1186/s13075-019-1879-x.