Background/Purpose: GM-CSF mediates a range of immunological processes, such as stimulating the production of inflammatory mediators and differentiation of proinflammatory T-helper 17 cells, and may play an important role in the pathogenesis of inflammatory diseases including RA. Namilumab (AMG203) is an investigational monoclonal antibody with high affinity for the GM-CSF ligand. The aim of this Phase Ib study (PRIORA; NCT01317797) was to evaluate the safety and tolerability, pharmacokinetics/pharmacodynamics and preliminary efficacy of namilumab in patients with active RA.

Methods: This was a double-blind, placebo-controlled, randomised, dose-escalating study in patients with mild-to-moderate RA (according to ACR 1987 revised criteria) receiving stable MTX doses for ≥12 weeks prior to randomisation. Patients received 3 single subcutaneous injections of namilumab 150 or 300 mg or matching placebo on Days 0, 15 and 29, with 12 weeks’ follow-up. Clinical efficacy was an exploratory endpoint and originally measured by DAS44; a pre-defined post hoc efficacy analysis was performed to evaluate the effect of namilumab on signs and symptoms of RA using DAS28, swelling joint counts, tender joint counts, and patient outcome measures.

Results: 24 patients were enrolled (71% female, mean age 55.9 years): Cohort 1 (n=13; namilumab 150 mg, n=8; placebo, n=5); and Cohort 2 (n=11; namilumab 300 mg, n=7, placebo, n=4). Disease activity at baseline was moderate (mean DAS28-ESR: placebo = 4.7; namilumab 150 mg = 4.9; namilumab 300 mg = 4.4). Namilumab was generally well tolerated. A total of 49 treatment-emergent adverse events (TEAEs) were observed in 14 patients (58%). The most common TEAEs were nasopharyngitis (n=4; 17%), exacerbation/worsening of RA (n=3; 13%) and musculoskeletal pain (n=2; 8%). The percentage of patients with any TEAE was similar (namilumab 150 mg: 63%; namilumab 300 mg: 57%; placebo: 56%). There was no evidence of immunogenicity. Median time to maximum observed plasma concentration (t_max) after the third dose of namilumab was 5–6 days. Dose-normalised exposure (C_max/D and AUC_tau/D) was similar at both namilumab dose levels. Accumulation was ongoing after the third injection (Day 43), as expected given the observed mean t_1/2 of ~3 weeks. The post hoc efficacy analysis included 21 patients (1 patient on namilumab 150 mg and 2 patients on placebo were excluded due to major protocol violations). In general, improvements in DAS28 scores (ESR and CRP) and joint counts were greater with namilumab than placebo as early as Day 29. Both namilumab groups were associated with greater improvements in DAS28-CRP than placebo from Day 27 until the end of the study. Furthermore, the difference in mean DAS28-CRP changes from baseline between namilumab and placebo favoured namilumab at all time points.

Conclusion: Results of PRIORA show that namilumab was generally well tolerated in active RA and preliminary efficacy was demonstrated; further evaluation is needed due to the small sample size. Two Phase II studies have been initiated in patients with moderate-to-severe RA (NEXUS, NCT02379091; TELLUS, NCT02393378).

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/namilumab-an-anti-granulocyte-macrophage-colony-stimulating-factor-gm-csf-monoclonal-antibody-results-of-the-first-study-in-patients-with-mild-to-moderate-rheumatoid-arthritis-ra/