The long-term extension trial, contRAst X, published in BMJ Open, showed promising results regarding the safety and efficacy of otilimab, an anti-GM-CSF monoclonal antibody, in patients with rheumatoid arthritis (RA). This phase 3 multicenter study followed patients who had completed the contRAst 1-3 trials, assessing the effects of prolonged otilimab therapy.
Among the 2,916 patients enrolled, 2,915 received otilimab for a period ranging from 7 to 896 days. The incidence of adverse events (AEs) was comparable between the 90 mg and 150 mg doses, occurring in 62% and 64% of patients, respectively. AEs of special interest were reported in 8% and 7% of patients, while serious AEs were observed in 8% of both groups. Notably, no cases of pulmonary alveolar proteinosis (PAP), active tuberculosis (TB), TB reactivation, or serious hypersensitivity reactions were identified. Disease activity remained stable throughout the trial, even among those who switched from tofacitinib or sarilumab to otilimab.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a key role in the pathogenesis of RA by driving the differentiation of inflammatory monocytes, macrophages, and dendritic cells. It also enhances the production of pro-inflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6, central to RA progression. Preclinical studies have demonstrated that targeting GM-CSF can effectively hinder disease development or reduce disease activity in collagen-induced murine models of inflammatory arthritis.
Otilimab is a high-affinity monoclonal antibody targeting GM-CSF. In a phase Ib/IIa dose-escalation trial (n=96), it demonstrated improved ACR and EULAR responses without pulmonary function abnormalities. Subsequent phase IIa and IIb trials confirmed clinical efficacy and tolerability, with reduced CCL17 levels, supporting GM-CSF’s role in inflammation. In the phase 3 contRAst 1 and 2 trials, otilimab showed superiority over placebo in achieving American College of Rheumatology 20% improvement (ACR20), Clinical Disease Activity Index (CDAI) low disease activity (LDA), and Health Assessment Questionnaire Disability Index (HAQ-DI). However, its efficacy was lower than that of tofacitinib. In contRAst 3, while otilimab retained a favorable safety profile, it failed to meet the primary endpoint (ACR20), improve secondary outcomes versus placebo, or demonstrate non-inferiority to sarilumab.
Despite available therapies, many patients with RA fail to achieve adequate disease control, highlighting a persistent unmet need for more effective treatment options. This study confirmed that long-term treatment with otilimab, up to 2.5 years, did not reveal any new safety concerns or unexpected adverse effects, reinforcing its potential as a viable long-term therapy for RA management. However, larger randomized trials are needed to validate these findings before the drug can be adopted into clinical practice.
References
- Weinblatt ME, Taylor PC, McInnes IB, Atsumi T, Strand V, Takeuchi T,et al. Long-term safety and efficacy of anti-GM-CSF otilimab in patients with rheumatoid arthritis: long-term extension of three phase 3 randomised trials (contRAst X). BMJ Open. 2025 Mar 5;15(3):e088869.
- Fleischmann RM, van der Heijde D, Strand V, Atsumi T, McInnes IB, Takeuchi T, et al. Anti-GM-CSF otilimab versus tofacitinib or placebo in patients with active rheumatoid arthritis and an inadequate response to conventional or biologic DMARDs: two phase 3 randomised trials (contRAst 1 and contRAst 2). Ann Rheum Dis. 2023 Dec;82(12):1516-1526.
- Taylor PC, Weinblatt ME, McInnes IB, Atsumi T, Strand V, Takeuchi T, et al. Anti-GM-CSF otilimab versus sarilumab or placebo in patients with rheumatoid arthritis and inadequate response to targeted therapies: a phase III randomised trial (contRAst 3). Ann Rheum Dis. 2023 Dec;82(12):1527-1537.