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Phase 4 Study Finds Comparable Safety, Efficacy Between Etanercept Biosimilar, Enbrel for Autoimmune Diseases


The first phase 4 postmarketing surveillance study for SB4 in South Korea as the first approved biosimilar of etanercept demonstrated comparable effectiveness and safety to previous SB4 evidence.

The first phase 4 postmarketing surveillance study for SB4 in South Korea, the first approved biosimilar of etanercept, a biologic tumor necrosis factor (TNF) inhibitor that treats various autoimmune diseases, showed comparable effectiveness and safety to previous SB4 real-world evidence.

The reference biologic TNF inhibitor etanercept treats such autoimmune diseases as axial spondylarthritis (axSpA), rheumatoid arthritis (RA), psoriatic arthritis (PsA), and plaque psoriasis (PsO). Previously, SB4, from Samsung Bioepis, had proved safe and effective in patients with stable RA and axSpA.

In the current study, the researchers were trying to evaluate end points of safety (primary end point) and effectiveness (secondary end point) of SB4 in routine clinical practice, as is customary in the Korean drug approval process.

In the United States, there are 2 approved etanercept biosimilars, and 3 etanercept biosimilars have been approved in the European Union.

Patients in the prospective, multicenter, open-level, observational study included both those who were etanercept-naïve or those who were switched from reference etanercept; patients had axSpA, RA, PsA, and PsO. The study ran from September 2015 to September 2019. In the safety analysis, 176 patients had axSpA and 138 had RA.

Patients were administered SB4 weekly via subcutaneous injections with a prefilled syringe. Safety was evaluated by the incidence of adverse events (AEs), adverse drug reactions (ADRs), and serious adverse events (SAEs). Effectiveness was evaluated by the change from baseline of investigator-rated Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in patients with ankylosing spondylitis (AS) and disease activity score-28 (DAS28) in patients with RA.

Following injection, AEs were seen in 17.8% of patients, ADRs in 9.9%, and serious AEs in 1.3%. Most AEs were mild or moderate (66.7% and 31.1%, respectively) and unrelated to SB4 (58.9%).

The most frequent AEs were injection-site pruritus (1.9%) and injection-site rash (1.3%). At week 24, mean disease activity scores were significantly lower compared with baseline in etanercept-naïve patients with AS and RA (BASDAI, 2.7 vs 6.2; P < .0001; DAS28, 3.8 vs 5.7; P < .0001) and in switched patients with AS and RA (BASDAI, 1.0 vs 1.3; P = .0018; DAS28, 2.4 vs 2.9; P = .0893).

The general incidence rates of AEs and SAEs in this study were lower than those seen in 299 RA patients in the phase 3 study of SB4 (55.2 and 4.3%, respectively). The researchers of the present study think this may be because of different baseline patient characteristics since this study included naïve and switched patients, while the phase 3 study only included naïve patients. Only patients with RA had arthralgia, synovitis, and tenosynovitis SAEs because of their underlying disease. Nausea, pneumonia, and dizziness SAE’s were determined as drug-related.

The study had a high retention rate, similar to a previous study. The researchers noted that routine monitoring of patients on biosimilars can help address disease flares and provide an opportunity to educate patients to resolve possible negative perceptions of biosimilars, thereby increasing acceptance of these products and reducing discontinuation.

A limitation of the study is the small number of subjects (naïve or switched patients per indication) and that only patients with axSpA and RA were enrolled. In addition, how long patients received reference etanercept and a record of when they switched to SB4 was not recorded, so the impact of this is unknown. Additionally, efficacy-related outcomes were not recorded in complete detail. Biases may have been introduced by the noncomparative open label design, the shortness of the study (24 weeks), and quantity of patients.


Yoo WH, Kang YM, Kim DW, et al. Safety and effectiveness of etanercept biosimilar SB4 for rheumatic diseases in South Korea: real-world post-marketing surveillance data. Rheumatol Ther. Published online December 8, 2022. doi:10.1007/s40744-022-00515-z

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