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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.
Arthritis Res Ther 2019; 21(1):101AR

Abstract

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.

Authors+Show Affiliations

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.Takeda Development Centre, London, UK. Present Address: GSK Medicines Research Centre, Stevenage, UK.Institute of Rheumatology, Prague, Czech Republic.Division of Rheumatology, Keio University School of Medicine, Tokyo, Japan.Kumamoto Shinto General Hospital, Kumamoto, Japan.Clinical Rheumatology Hospital #25, Saint-Petersburg, Russian Federation.Statistics, Takeda International, Deerfield, IL, USA.Modeling and Simulation, Takeda Pharmaceuticals International GmbH, Zurich, Switzerland. Present Address: thinkQ2 AG, Baar, Switzerland.Takeda Development Centre, London, UK. Present Address: Sangamo Therapeutics, London, UK.No affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30999929

Citation

Taylor, Peter C., et al. "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." Arthritis Research & Therapy, vol. 21, no. 1, 2019, p. 101.
Taylor PC, Saurigny D, Vencovsky J, et al. 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. Arthritis Res Ther. 2019;21(1):101.
Taylor, P. C., Saurigny, D., Vencovsky, J., Takeuchi, T., Nakamura, T., Matsievskaia, G., ... Souberbielle, B. (2019). 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. Arthritis Research & Therapy, 21(1), p. 101. doi:10.1186/s13075-019-1879-x.
Taylor PC, et al. 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. Arthritis Res Ther. 2019 Apr 18;21(1):101. PubMed PMID: 30999929.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Taylor,Peter C, AU - Saurigny,Didier, AU - Vencovsky,Jiri, AU - Takeuchi,Tsutomu, AU - Nakamura,Tadashi, AU - Matsievskaia,Galina, AU - Hunt,Barbara, AU - Wagner,Thomas, AU - Souberbielle,Bernard, AU - ,, Y1 - 2019/04/18/ PY - 2018/12/12/received PY - 2019/03/26/accepted PY - 2019/4/20/entrez PY - 2019/4/20/pubmed PY - 2019/4/20/medline KW - GM-CSF KW - Namilumab KW - Rheumatoid arthritis SP - 101 EP - 101 JF - Arthritis research & therapy JO - Arthritis Res. Ther. VL - 21 IS - 1 N2 - 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. SN - 1478-6362 UR - https://www.unboundmedicine.com/medline/citation/30999929/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 L2 - https://arthritis-research.biomedcentral.com/articles/10.1186/s13075-019-1879-x DB - PRIME DP - Unbound Medicine ER -