Evidence Supports Safe, Effective Switching to Etanercept Biosimilars

Access to tumor necrosis factor inhibitors has expanded rapidly across Europe over the past decade, yet lingering questions about whether people can safely and effectively switch from reference biologics to biosimilars have continued to shape prescribing behavior.1,2 These questions have been especially prominent for etanercept, one of the earliest and most widely used biologic disease-modifying antirheumatic drugs, as health systems have sought savings without compromising outcomes for people living with chronic inflammatory diseases.1

To address these concerns, investigators conducted a narrative literature review evaluating clinical trial and real-world evidence on switching between reference etanercept and its approved biosimilars.3 The review was a response to persistent variability in biosimilar uptake across countries, which has been driven in part by clinician and patient uncertainty around switching, concerns about immunogenicity, and fears of loss of efficacy or increased adverse events. The authors aimed to synthesize available data to support informed decision-making for clinicians, payers, and people receiving treatment.

The review included evidence from 18 original studies identified through a PubMed search conducted in November 2024. Four were randomized, double-blind phase 3 clinical trials, and 14 were real-world observational studies. The studies evaluated switching from reference etanercept to biosimilars such as SB4, SDZ-ETN, LBEC0101, and YLB113 across multiple indications, including rheumatoid arthritis (RA), psoriatic arthritis, axial spondyloarthritis (AxSpA), plaque psoriasis, and juvenile idiopathic arthritis.

Across the controlled clinical trials, 1091 patients were included in switching populations. Of these, 769 had RA and 531 had plaque psoriasis, reflecting the primary indications studied in phase 3 programs. Trial designs varied, but all compared outcomes among people who continued reference etanercept or a biosimilar with those who switched treatments, typically at week 24 or week 52. One study, EGALITY, specifically evaluated multiple switches between reference etanercept and SDZ-ETN in people with moderate to severe plaque psoriasis.

Efficacy outcomes were consistent across trials. In RA populations, changes in disease activity scores such as DAS28-CRP and DAS28-ESR from baseline through follow-up were similar between continuous-treatment and switched groups. Proportions of patients achieving American College of Rheumatology 20%, 50%, or 70% response criteria and European Alliance of Associations for Rheumatology good or moderate responses were also comparable. In plaque psoriasis, mean changes in Psoriasis Area and Severity Index scores and response rates through 52 weeks did not differ meaningfully between those who underwent multiple switches and those who remained on a single product.

Safety findings from clinical trials showed no increase in treatment-emergent adverse events or serious adverse events following a switch. The proportion of patients experiencing at least 1 adverse event was similar between switched and nonswitched groups across indications. Immunogenicity rates were low overall, and antidrug antibodies were infrequently detected, with no consistent differences attributable to switching.

Real-world evidence reinforced these findings. Observational studies drawn from national registries and multicenter cohorts included thousands of patients across Europe and Canada. The studies captured broader and more heterogeneous populations compared with clinical trials, including people with long disease duration, multiple comorbidities, and prior biologic exposure. In these settings, disease activity measures generally remained stable following nonmedical switching from reference etanercept to a biosimilar. Rates of treatment discontinuation and serious adverse events were comparable to those observed before switching, although some cohorts reported higher discontinuation driven by subjective complaints rather than objective loss of efficacy.

Patient demographics varied widely across real-world studies but were representative of routine clinical practice. Most cohorts included adults with established inflammatory rheumatic disease, with mean ages typically in the fifth or sixth decade of life. Women were overrepresented in RA populations, while AxSpA cohorts included a higher proportion of men. Prior duration of etanercept use ranged from several months to multiple years before switching.

The authors noted several limitations. The review was narrative rather than a formal meta-analysis, and the included studies differed in design, outcomes measured, and length of follow-up. Evidence on multiple switches between different biosimilars was limited, and patient-reported outcomes were not consistently assessed. Most real-world data came from European health systems with established biosimilar policies, which may limit how well the findings apply to other regions.

The review found no evidence that switching between reference etanercept and its biosimilars adversely affected efficacy, safety, or immunogenicity across approved indications. The authors concluded that the accumulated clinical and real-world evidence supported broader adoption of etanercept biosimilars, while underscoring that “these gaps in the literature warrant further research efforts to better understand the long-term effects of biosimilar switching and to develop strategies to optimize patient outcomes.”

References

1. Mestre-Ferrandiz J, Czech M, Smolen JS, et al. Capturing the holistic value of biosimilars in Europe – part 1: a historical perspective. Expert Rev Pharmacoecon Outcomes Res. 2024;24(2):237-250. doi:10.1080/14737167.2023.2297926

2. Biosimilar approvals. The Center for Biosimilars®. Updated November 12, 2025. Accessed January 5, 2026. https://www.centerforbiosimilars.com/biosimilar-approvals

3. Schmalzing M, Askari A, Girolomoni G, Perez-Coleman JCV. Salvati C, Bachinskaya E. Clinical and real-world evidence on etanercept biosimilar switching: a narrative literature review of efficacy and safety. Adv Ther. Published online November 18, 2025. doi:10.1007/s12325-025-03367-5