Switching From Originator Etanercept to Biosimilar Version Proves Safe, Effective in RA

Patients with rheumatoid arthritis (RA) who switched from the etanercept originator to a biosimilar had similar disease activity and drug persistence as those who remained on the originator, indicating that nonmedical switching does not negatively impact treatment outcomes, according to a Danish study.¹

The analysis, which was published in Rheumatology, investigated clinical outcomes associated with switching between etanercept products. Patients were monitored for changes in 28-joint disease activity scores (DAS28) at 6 and 12 months.

Although FDA and European Medicines Agency approval of a biosimilar confirms the safety and efficacy of the product in comparison with its originator in a particular patient population, switching studies can provide additional context into the safety of moving a patient off of the originator and putting them on a biosimilar. | Image credit: AI generated using Dall-E3

Reference etanercept, marketed as Enbrel, has been on the European market since 2000, making it one of the first tumor necrosis (TNF) inhibitors to be approved in the European Union for the treatment of RA.² The prevalence percentages of RA in the US and Northern European countries are typically higher than the worldwide prevalence percentage (0.5%-1.0% vs 0.24%).³ The annual incidence of RA in the US and Northern Europe is estimated to be about 40 per 100,000 persons.

After the patent for the Enbrel expired in 2015, biosimilar versions were introduced, leading to many patients being switched from the originator to the biosimilar for cost-saving reasons. While small studies on other TNF inhibitors have shown mixed results regarding treatment discontinuation and the nocebo effect, there is limited research comparing patients who switch from the etanercept originator to a biosimilar with those who do not. The present analysis aimed to address this gap by investigating drug survival and disease activity in RA patients after switching from the originator to the biosimilar.

The study was conducted using data from the British Society for Rheumatology Biologics Register for RA (BSRBR-RA), an observational prospective cohort that tracks patients with RA who start biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs).

Patients were matched based on factors such as gender, age, and disease duration. Data on disease activity and drug persistence were collected at the time of switching, as well as 6 and 12 months afterward. Statistical methods were used to assess drug survival, while logistic regression and multiple imputation were employed to analyze changes in disease activity. Sensitivity analyses were also conducted to ensure the robustness of the findings.

In this study, 1024 patients who switched from etanercept originator to a biosimilar were matched 1:1 with patients who remained on the originator. At the point of switching (or the index date for the originator cohort), both groups were similar in age (median, 64 years), gender (female, 76%), and disease duration (median, 19 years). Most patients (71% in the biosimilar cohort and 69% in the originator cohort) had initiated etanercept as their first-line b/tsDMARD therapy. The median time on the originator before switching was 9.3 years for the biosimilar cohort and 9.6 years for the originator cohort. The biosimilar group had a slightly longer median follow-up after the switch (2.7 years) compared to the originator group (2.2 years).

Kaplan-Meier estimates showed that 81% of biosimilar patients and 84% of originator patients remained on treatment after 1 year, 72% and 74% remained on treatment at 2 years, and 65% and 65% remained on treatment at 3 years, respectively. The HR for discontinuation was 1.06 (95% CI, 0.89-1.26), indicating no significant difference between the groups.

In the originator cohort, 326 patients (32%) switched to a biosimilar during the follow-up period, while 205 patients (20%) stopped etanercept treatment altogether. In the biosimilar cohort, 346 patients (34%) discontinued therapy, with 127 of these patients (37%) switching back to the originator, and 95 of them (9% of the entire biosimilar group) doing so within the first year. Most biosimilar patients stopped treatment due to ineffectiveness (n = 161), with 42% switching back to the originator and 55% changing to another b/tsDMARD. Among those who stopped due to adverse events (n = 96), 48% remained off b/tsDMARD therapy at their last follow-up.

For the 505 patients in each cohort with available disease activity data, disease activity at the index date was low and similar across both groups. The median tender joint count was 1, the median C-reactive protein level was 5 mg/L, and the median DAS28 score was 2.9. After 6 months, disease activity remained stable, with no significant differences between the cohorts.

The median DAS28 was 3.1 in the biosimilar group and 2.8 in the originator group, with no median change in DAS28. The proportion of patients in DAS28 remission was 34% in the biosimilar group and 42% in the originator group. At 1 year, the median DAS28 was 2.8 for the biosimilar cohort and 3.0 for the originator cohort, with 42% and 38% in remission, respectively. Additionally, 36% of the biosimilar patients and 31% of the originator cohort experienced an improvement in DAS28 by more than 0.6 units.

Similar results were observed when the analysis was restricted to patients who started etanercept as their first b/tsDMARD therapy.

References

1. Kearsley-Fleet L, Rokad A, Tsoi M-F, et al. Outcomes following switching from etanercept originator to etanercept biosimilar in 1024 patients with RA: a matched-analysis of the BSRBR-RA. Rheumatology (Oxford). 2024;63(8):2082-2092. doi:10.1093/rheumatology/kead470

2. Hassett B, Singh E, Mahgoub E, O’Brien J, Vicik SM, Fitzpatrick B. Manufacturing history of etanercept (Enbrel): consistency of product quality through major process revisions. MAbs. 2018;10(1):159-165. doi:10.1080/19420862.2017.1388483

3. England BR, Mikuls TR. Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis. UpToDate. Updated February 19, 2024. Accessed August 20, 2024. https://www.uptodate.com/contents/epidemiology-of-risk-factors-for-and-possible-causes-of-rheumatoid-arthritis#:~:text=Estimates%20of%20RA%20prevalence%20in,persons%20%5B2%2C4%5D