Granulocyte-macrophage colony-stimulating factor neutralisation in patients with axial spondyloarthritis in the UK (NAMASTE): a randomised, double-blind, placebo-controlled, phase 2 trial.

Autor:	Worth C; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. Electronic address: claudia.worth@ndorms.ox.ac.uk., Al-Mossawi MH; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK., Macdonald J; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK., Fisher BA; Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; National Institute for Health Research (NIHR), Birmingham Biomedical Research Centre, Department of Rheumatology, University Hospitals Birmingham, NHS Foundation Trust, Birmingham, UK., Chan A; Royal Berkshire, NHS Foundation Trust, Reading, UK., Sengupta R; Royal United Hospitals, Bath, UK., Packham J; University of Nottingham, Nottingham, UK., Gaffney K; Norfolk and Norwich University Hospitals, NHS Foundation Trust, Norwich, UK., Gullick N; University Hospitals Coventry and Warwickshire, Warwick Medical School, University of Warwick, Warwick, UK., Cook JA; Centre for Statistics in Medicine, University of Oxford, Oxford, UK., Corn TH; Asclepius Consulting (Izana Bioscience), London, UK., Teh J; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK., Machado PM; Centre for Rheumatology and Department of Neuromuscular Diseases, University College London, London, UK; NIHR, University College London Hospitals, Biomedical Research Centre, NHS Foundation Trust, London, UK; Department of Rheumatology, Northwick Park Hospital, London North West University Healthcare, NHS Trust, London, UK., Taylor PC; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK., Bowness P; Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
Jazyk:	angličtina
Zdroj:	The Lancet. Rheumatology [Lancet Rheumatol] 2024 Aug; Vol. 6 (8), pp. e537-e545. Date of Electronic Publication: 2024 Jun 25.
DOI:	10.1016/S2665-9913(24)00099-7
Abstrakt:	Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a proinflammatory cytokine overproduced in several inflammatory and autoimmune diseases, including axial spondyloarthritis. Namilumab is a human IgG1 monoclonal anti-GM-CSF antibody that potently neutralises human GM-CSF. We aimed to assess the efficacy of namilumab in participants with moderate-to-severe active axial spondyloarthritis. Methods: This proof-of-concept, randomised, double-blind, placebo-controlled, phase 2, Bayesian (NAMASTE) trial was done at nine hospitals in the UK. Participants aged 18-75 years with axial spondyloarthritis, meeting the Assessment in SpondyloArthritis international Society (ASAS) criteria and the ASAS-defined MRI criteria, with active disease as defined by a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), were eligible. Those who had inadequately responded or had intolerance to previous treatment with an anti-TNF agent were included. Participants were randomly assigned (6:1) to receive subcutaneous namilumab 150 mg or placebo at weeks 0, 2, 6, and 10. Participants, site staff (except pharmacy staff), and central study staff were masked to treatment assignment. The primary endpoint was the proportion of participants who had an ASAS ≥20% improvement (ASAS20) clinical response at week 12 in the full analysis set (all randomly assigned participants). This trial is registered with ClinicalTrials.gov (NCT03622658). Findings: From Sept 6, 2018, to July 25, 2019, 60 patients with moderate-to-severe active axial spondyloarthritis were assessed for eligibility and 42 were randomly assigned to receive namilumab (n=36) or placebo (n=six). The mean age of participants was 39·5 years (SD 13·3), 17 were women, 25 were men, 39 were White, and seven had previously received anti-TNF therapy. The primary endpoint was not met. At week 12, the proportion of patients who had an ASAS20 clinical response was lower in the namilumab group (14 of 36) than in the placebo group (three of six; estimated between-group difference 6·8%). The Bayesian posterior probability η was 0·72 (>0·927 suggests high clinical significance). The rates of any treatment-emergent adverse events in the namilumab group were similar to those in the placebo group (31 vs five). Interpretation: Namilumab did not show efficacy compared with placebo in patients with active axial spondyloarthritis, but the treatment was generally well tolerated. Funding: Izana Bioscience, NIHR Oxford Biomedical Research Centre (BRC), NIHR Birmingham BRC, and Clinical Research Facility. Competing Interests: Declaration of interests CW received funding from the Arthritis Therapy Acceleration Program (grant KENN161704) and Izana Bioscience. MHA-M holds stocks in GSK, UCB, and AstraZeneca; is an employee of AstraZeneca; and was an employee of UCB. BAF has received research funding from Janssen, Galapagos, and Celgene; and consultation fees from Novartis, Galapagos, Servier, Janssen, Roche, Sanofi, Bristol Myers Squibb, and UCB. AC has received payment or honoraria from Novartis, UCB, Amgen, AbbVie, and Janssen; and support for attending meetings or travel (or both) from Eli Lilly, UCB, and Novartis. RS has received research funding from Celgene and Novartis; payment or honoraria from AbbVie, Biogen, Eli Lilly, MSD, Novartis, Roche, and UCB; support for attending meetings or travel (or both) from AbbVie, Novartis, Eli Lilly, and UCB; participated on a data safety monitoring board or advisory board for AbbVie, Novartis, Eli Lilly, and UCB; is part of a chairmanship of trustees for the British Society for Spondyloarthritis and a trustee of the Bath Institute for Rheumatic Diseases. JP is a member of the executive committee of the British Society for Spondyloarthritis. KG has received research funding from Biogen, AbbVie, Pfizer, Novartis, Eli Lilly, Celltrion, Janssen, and Gilead; consulting fees from AbbVie, Novartis, UCB, and Eli Lilly; honoraria from AbbVie, Novartis, UCB, and Eli Lilly; and support for attending meetings or travel (or both) from Novartis, UCB, and Eli Lilly. NG has received research funding from Izana Bioscience, AbbVie, AstraZeneca, Eli Lilly, and Novartis; consulting fees from AbbVie, Novartis, and UCB; and payment or honoraria from AbbVie, Eli Lilly, Janssen, Novartis, and UCB; support for attending meetings or travel (or both) from AbbVie, Eli Lilly, UCB, and Novartis; receipt of equipment, materials, drugs, medical writing gifts, or other services from Eli Lilly and Novartis. THC was a chief medical officer at Izana Bioscience, received salary and stock options from Izana Bioscience, and participated in data safety monitoring board meetings. PMM has received consulting or speakers fees from AbbVie, BMS, Celgene, Eli Lilly, Galapagos, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche, and UCB; and is supported by the National Institute for Health Research (NIHR), University College London Hospitals, and Biomedical Research Centre (BRC). PCT has received research funding from Galapagos and Izana Bioscience; consulting fees from AbbVie, Biogen, Galapagos, Gilead, GSK, Janssen, Eli Lilly, Pfizer, Sanofi, Nordic Pharma, Fresenius, UCB, and Izana Bioscience; payment or honoraria from AbbVie; support for attending meetings or travel (or both) from Eli Lilly; and participated on data safety monitoring boards for Kymab and Immunovant. PB has received research funding from Regeneron, BenevolentAI, GSK, and Novartis. JM, JAC, and JT declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)
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