Switching to Biosimilar Etanercept Shows No Impact on Efficacy, Safety Across 18 Trials

Patients with inflammatory rheumatic and musculoskeletal diseases who switched from reference etanercept to a biosimilar version maintained comparable treatment outcomes, according to a narrative literature review published in Advances in Therapy.1

Researchers conducted the review in response to persistent barriers limiting biosimilar adoption worldwide, particularly prescriber and patient concerns about whether switching from a reference biologic to a biosimilar could compromise safety or efficacy.2 Despite cost-saving potential, biosimilar uptake has remained suboptimal in several countries, including Canada and the United States, where the reference etanercept price in 2019 was reported to be more than 3 times higher than in Germany. The nocebo effect, in which patients experience new or worsening symptoms driven by negative expectations rather than pharmacological changes, has been identified as one of the more difficult barriers to address.3

To examine the current body of evidence, investigators searched PubMed in November 2024 using terms related to etanercept biosimilar switching. After removing duplicates and screening for relevance, the team identified 18 peer-reviewed original articles meeting inclusion criteria: 4 reporting data from controlled clinical trials and 14 from real-world studies. Articles were excluded if they involved healthy volunteers, did not specify the biosimilar used, or were congress abstracts only.

The 4 included phase 3, randomized, double-blind trials evaluated 3 biosimilars—SDZ-ETN (Erelzi), SB4 (Benepali), and LBEC0101 (Eucept)—across a combined switching population of 1091 patients. Enrolled patients carried diagnoses of either rheumatoid arthritis (RA) or plaque psoriasis (PsO).

In the EQUIRA trial, 376 patients with moderate-to-severe RA who switched from reference etanercept to SDZ-ETN at week 24 demonstrated Disease Activity Score in 28 joints with C-reactive protein and functional assessment score changes from baseline to week 48 that were comparable to those who remained on continuous SDZ-ETN.

Similarly, the EGALITY trial, the only controlled trial to evaluate multiple switches, enrolled 531 patients with PsO who underwent up to 3 switches between reference etanercept and SDZ-ETN, with Psoriasis Area and Severity Index scores remaining similar across pooled continued and switched treatment groups through week 52. Trials evaluating SB4 and LBEC0101 in patients with RA produced consistent findings through 100 weeks of follow-up. No new or unexpected safety signals were reported in any of the 4 trials, and anti-drug antibody presence was infrequent and comparable between switchers and non-switchers.

The 14 real-world studies enrolled a combined 7174 patients, of whom 4044 switched between reference etanercept and a biosimilar. More than half of all switchers carried a diagnosis of RA, with the remainder having psoriatic arthritis, axial spondyloarthritis, ankylosing spondylitis, or PsO. Nine studies examined single switches to SB4, 2 evaluated multiple switches involving SB4 and SDZ-ETN, and 1 study each addressed SDZ-ETN, YLB113, and LBEC0101.

Across studies, switching did not meaningfully affect disease activity scores or patient-reported outcome measures. One-year retention rates in the COMPACT study following a switch to SDZ-ETN reached 91.2%, while rates among SB4 switchers ranged from 83.0% to 88.6% across studies. Two SB4 studies identified a potential nocebo effect in patients with RA, in which those who discontinued treatment showed statistically significant increases in subjective disease activity measures but minimal changes in objective inflammatory markers such as C-reactive protein and swollen joint counts. Patients with RA who had a longer duration on reference etanercept prior to switching demonstrated higher biosimilar withdrawal rates in these studies, though the observational designs precluded causal conclusions.

The authors acknowledged several limitations. The included studies varied substantially in design, patient characteristics, follow-up duration, and geographic setting, limiting direct cross-study comparisons. As a narrative rather than systematic review, the manual selection process introduced potential for selection bias. Additionally, data on multiple biosimilar switches, patient-reported outcomes following switching, and the prevalence of the nocebo effect across different patient populations remained limited, with the authors calling for further research in each of these areas.

The review was funded by Sandoz, and 2 authors were employees of Sandoz Limited at the time of publication. The remaining authors disclosed consulting fees, speaker honoraria, or other relationships with various pharmaceutical manufacturers.

References

1. 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. 2026;43(1):49-75. doi:10.1007/s12325-025-03367-5

2. Jeremias S. Biosimilars account for 23% market share, with wide uptake disparities across molecules. The Center for Biosimilars®. May 22, 2024. Accessed March 16, 2026. https://www.centerforbiosimilars.com/view/biosimilars-account-for-23-market-share-with-wide-uptake-disparities-across-molecules

3. Jeremias S. Nocebo effect is difficult to diagnose in patients switched to biosimilars. The Center for Biosimilars. March 17, 2020. Accessed March 16, 2026. https://www.centerforbiosimilars.com/view/nocebo-effect-is-difficult-to-diagnose-in-patients-switched-to-biosimilars