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SummaryBackgroundDysregulated inflammation is associated with poor outcomes in Coronavirus disease 2019 (COVID-19). We assessed the efficacy of namilumab, a granulocyte-macrophage colony-stimulating factor inhibitor and infliximab, a tumour necrosis factor inhibitor in hospitalised patients with COVID-19 in order to prioritise agents for phase 3 trials.MethodsIn this randomised, multi-arm, parallel group, open label, adaptive phase 2 proof-of-concept trial (CATALYST) we recruited hospitalised patients ≥ 16 years with COVID-19 pneumonia and C-reactive protein (CRP) ≥ 40mg/L in nine UK hospitals. Participants were randomly allocated with equal probability to usual care, or usual care plus a single 150mg intravenous dose of namilumab (150mg) or infliximab (5mg/kg). Randomisation was stratified for ward versus ICU. The primary endpoint was improvement in inflammation in intervention arms compared to control as measured by CRP over time, analysed using Bayesian multi-level models. ISRCTN registry number 40580903.FindingsBetween 15thJune 2020 and 18thFebruary 2021 we randomised 146 participants: 54 to usual care, 57 to namilumab and 35 to infliximab. The probabilities that namilumab and infliximab were superior to usual care in reducing CRP over time were 97% and 15% respectively. Consistent effects were seen in ward and ICU patients and aligned with clinical outcomes, such that the probability of discharge (WHO levels 1-3) at day 28 was 47% and 64% for ICU and ward patients on usual care, versus 66% and 77% for patients treated with namilumab. 134 adverse events occurred in 30/55 (54.5%) namilumab patients compared to 145 in 29/54 (53.7%) usual care patients. 102 events occurred in 20/29 (69.0%) infliximab patients versus 112 events in 17/34 (50.0%) usual care patients.InterpretationNamilumab, but not infliximab, demonstrated proof-of-concept evidence for reduction in inflammation in hospitalised patients with COVID-19 pneumonia which was consistent with secondary clinical outcomes. Namilumab should be prioritised for further investigation in COVID-19.FundingMedical Research Council.

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

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is more familiar to clinicians as a hemopoietic growth factor. However, it also modulates functions of myeloid cells such as macrophages. Experimental work has demonstrated its significant contribution to the pathogenesis of rheumatoid arthritis (RA). It was a long-time concern that targeted therapies against this cytokine could cause severe side effects such as neutropenia or pulmonary alveolar proteinosis. Nevertheless, different compounds successfully entered clinical development for RA targeting the cytokine itself or its receptor. Currently, a monoclonal antibody against its receptor has completed phase II trials with a profound and rapid onset of response, normalization of acute phase reactants, and an overall good safety profile. The development of compounds targeting the GM-CSF pathway represents a promising approach in RA. However, the obtained ACR20 and ACR50 responses were rather similar with marketed biologic agents when added to MTX. So, it is appropriate to ask the question, whether we do really need another group of agents with a similar performance? In this context, the tumor necrosis factor (TNF)-independent mode-of action of GM-CSF blockade supports the assumption that it could be a useful alternative especially in anti-TNF-resistant patients. Furthermore, a higher efficacy with concurrent blockade of IL-17 and GM-CSF, as reported from preclinical studies, also suggests that such strategies are of interest for future approaches. Therefore, comprehensive assessment of GM-CSF blockade in anti-TNF-resistant patients and combination strategies will be of major importance. Taken together, rapid onset of action, sustained effectiveness, and shown favorable safety data from phase 2 trials warrant further evaluations of anti-GM-CSF agents in different subgroups of RA patients.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) can be viewed as a pro-inflammatory cytokine rather than as a key regulator of steady state and systemic myelopoiesis. Key aspects of GM-CSF biology need to be clarified such as pro-survival vs activation/differentiation function, its cellular sources, its responsive cell populations, its downstream mediators/pathways, and when GM-CSF is relevant. Striking effects of GM-CSF depletion/deletion in some pre-clinical autoimmune/inflammation models have been reported. Systemic effects of administered GM-CSF are not necessarily informative about its local blockade in disease. Recent clinical RA trials, particularly Phase II trials with mavrilimumab (anti-GM-CSFRα Ab), show rapid and impressive efficacy with no significant adverse effects. Larger and longer trials targeting GM-CSF are needed and with careful monitoring of unwanted side effects. This review summarizes the most recent information on these topics.

Background Namilumab (AMG203) is an immunoglobulin G1 monoclonal antibody that binds with high affinity to the GM-CSF ligand. This was a phase 1b, randomized, double-blind study (PRIORA) to assess namilumab in active, mild-to-moderate rheumatoid arthritis (RA). The primary outcome was the safety and tolerability of repeated subcutaneous injections of namilumab in patients with mild-to-moderate RA. Methods Adults with mild-to-moderate RA on stable methotrexate doses for ≥12 weeks were eligible. Patients received three subcutaneous injections of namilumab 150 or 300 mg, or placebo on days 1, 15, and 29, with 12 weeks’ follow-up. Primary objective was safety/tolerability. Results Patients in cohort 1 were randomized to namilumab 150 mg (n = 8) or placebo (n = 5). In cohort 2, patients were randomized to namilumab 300 mg (n = 7) or placebo (n = 4). Incidence of treatment-emergent adverse events (TEAEs) was similar across the three groups (namilumab 150 mg: 63%; namilumab 300 mg: 57%; placebo: 56%). TEAEs in ≥10% of patients were nasopharyngitis (17%) and exacerbation/worsening of RA (13%). No anti-namilumab antibodies were detected. The pharmacokinetics of namilumab were linear and typical of a monoclonal antibody with subcutaneous administration. In a post hoc efficacy, per protocol analysis (n = 21), patients randomized to namilumab showed greater improvement in Disease Activity Score 28 (erythrocyte sedimentation rate and C-reactive protein [CRP]), swelling joint counts and tender joint counts compared with placebo. Difference in mean DAS28-CRP changes from baseline between namilumab and placebo favored namilumab at both doses and at all time points. In addition area under the curve for DAS28-CRP was analyzed as time-adjusted mean change from baseline. A significant improvement in DAS28-CRP was shown with namilumab (150 and 300 mg groups combined) compared with placebo at day 43 (p = 0.0117) and also 8 weeks after last dosing at day 99 (p = 0.0154). Conclusions Subcutaneous namilumab was generally well tolerated. Although namilumab demonstrated preliminary evidence of efficacy, patient numbers were small; phase 2 studies are ongoing. Trial registration ClinicalTrials.gov, NCT01317797. Registered 18 February 2011. Electronic supplementary material The online version of this article (doi:10.1186/s13075-017-1267-3) contains supplementary material, which is available to authorized users.

Background Granulocyte macrophage-colony stimulating factor (GM-CSF) plays an important role in inflammation. Namilumab (AMG 203) is a neutralising human IgG1 anti-GM-CSF monoclonal antibody currently in development for the treatment of inflammatory diseases including rheumatoid arthritis (RA). Objectives The primary objective was to investigate safety and tolerability of repeated subcutaneous injections of namilumab in patients with active RA. Signs of efficacy were investigated as an exploratory objective. Methods PRIORA (NCT01317797) was a double-blind, placebo-controlled, randomised, dose-escalating phase Ib study in patients with mild-to-moderate RA on stable MTX doses for at least 12 weeks prior to randomisation. Patients received a total of 3 single injections of namilumab 150 or 300mg or matching placebo on Days 0, 15 and 29, with 12 weeks9 follow-up. Results A total of 24 patients were enrolled (70.8% female, mean age 55.9 years, mean baseline DAS28-ESR 4.7). Patients were randomised to namilumab 150mg (n=8), namilumab 300mg (n=7), or placebo (n=9). Namilumab was generally well tolerated and safety outcomes were consistent across treatment groups. A total of 49 treatment-emergent adverse events (TEAEs) were observed in 14 patients (58.3%) across the 3 groups. The percentage of patients with any TEAE was similar (namilumab 150mg: 62.5%; namilumab 300mg: 57.1%; placebo: 55.6%). Anti-namilumab antibodies were not detected. One patient on namilumab 150mg and 2 patients on placebo were excluded from the per-protocol post-hoc efficacy analysis due to major protocol violations related to not being on stable doses of corticosteroids and/or MTX prior to randomisation or receiving additional doses of corticosteroids and/or DMARDs during the study. In general, improvements in DAS28 scores (ESR and CRP) and joint counts were greater in the namilumab groups than placebo as early as Day 29. All 3 groups had moderate disease activity at baseline (mean DAS28-ESR: placebo =4.7; namilumab 150mg =4.9; namilumab 300mg =4.4). At Day 56 (4 weeks after the last study dose), more namilumab patients (10/14, 71.4%) had a DAS28-ESR response (>1.2 decrease from baseline) than placebo patients (2/7, 28.6%). The highest proportion of responders was in the namilumab 150mg group (6/7, 85.7%) compared with the namilumab 300mg group (4/7, 57.1%). No differences were observed across groups in DAS28-ESR response at 10 weeks after the last study dose. Conclusions Namilumab was generally well tolerated in patients with active RA. The PRIORA results provide preliminary evidence of efficacy. This study supports further development of namilumab in patients with RA and potentially in those with other immune-related inflammatory diseases. Disclosure of Interest T. Huizinga Grant/research support from: EU and Dutch Arthritis Foundation, Consultant for: Merck, UCB, Bristol-Myers Squibb, Biotest AG, Pfizer, Novartis, Roche, Sanofi-Aventis, Abbott, Crescendo Bioscience, Nycomed, Boeringher, Takeda, and Eli Lilly, Employee of: Leiden University Medical Center, Speakers bureau: UCB, Bristol-Myers Squibb, Roche, A. Batalov: None declared, K. Yablanski: None declared, R. Stoilov: None declared, E. Lloyd Employee of: Takeda Pharmaceuticals International, T. Wagner Employee of: Takeda Pharmaceuticals International GmbH, D. Saurigny Shareholder of: Takeda Pharmaceuticals International, Employee of: Takeda Development Centre Europe Ltd., B. Souberbielle Shareholder of: Takeda Pharmaceuticals International, Employee of: Takeda Pharmaceuticals International, E. Esfandiari Shareholder of: Takeda Europe, Employee of: Takeda Europe