Paper Questions Utility of DANBIO Results for Switching to Biosimilar Etanercept

In a newly published correspondence, Italian rheumatology providers called into question whether recently published results from the DANBIO registry can be used to guide non-medical switching from reference etanercept (Enbrel) to biosimilar SB4 (Benpali) in patients with inflammatory diseases.

The DANBIO trial, results of which have previously been reported at scientific meetings, including the European League Against Rheumatism’s European Congress of Rheumatology 2017, reported on the real-world evidence of the effectiveness of switching from the reference to the biosimilar.¹ In 2016, Denmark mandated a switch to the biosimilar from the reference among patients with rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis, providing an opportunity to compare treatment outcomes of those who switched and those who did not. The trial also compared retention against a historical cohort of reference etanercept users at 1 year.

In total, 1621 patients were switched, while 440 were not. The researchers reported that disease activity was unchanged at 3 months. One-year retention rates were 83% among the switch group (95% CI, 79%-87%) and 77% among the non-switch group (95% CI, 72%-82%). In the historic cohort, the retention rate was 90% (95% CI, 88%-92%).

During followup, 120 patients, or 7% of the switch group, transitioned back to the reference for reasons the DANBIO investigators termed “mainly subjective.”

In the correspondence on the DANBIO results², the Italian authors wrote that “at first glance, the results show a good evidence of efficacy and safety of the procedure,” but that a careful reading of the study raises concerns.

According to the authors, the fact that the switched patients had longer previous treatment with etanercept and exposure to fewer previous biologic agents than the non-switched patients suggests that this group had less severe disease. Furthermore, some of the non-switched patients were receiving lower doses of etanercept than the switched patients, and potentially significant differences existed between the groups in terms of concomitant methotrexate use.

They also highlighted the fact that data on disease activity were limited to 3 months of followup, whereas discontinuation was evaluated at 1 year.

Finally, wrote the authors, “The strength of the results was greatly influenced by the nature of the study itself, that is to say mandatory switching without a well-structured study design, and, per se, these data do not constitute a solid base to ensure the rheumatologist for non-medical switching.”

In a reply³ to the correspondence, the authors of the original study stated that their paper is an example the ways in which observational studies can be a valuable supplement to randomized trials, and noted that they described the strengths and limitations of their study in detail, though the correspondents “largely ignore” that discussion.*

“For example,” wrote the authors, “the observed differences in the demographic and clinical characteristics of switchers compared with non-switchers illustrate that, despite a national guideline, the clinical decision to switch a patient or not was associated with certain patient characteristics.” This fact may reflect uncertainty among patients and providers on how to implement biosimilars into routine care, and it explains why patients who continued to receive the reference had lower retention than did those who switched.

They also noted that the nocebo effect may have had a role in the switched patients’ outcomes, and defended the 3-month followup period, saying that it allowed the use of patients as their own controls.

Finally, concluded the authors, their paper is a “well-balanced contribution to the ongoing discussion on real-world effectiveness of biosimilar etanercept in patients with inflammatory arthritis.”

*This article has been updated to include a discussion of the reply from Glintborg et al.

References

1. Glintborg B, Loft AG, Omerovic E, et al. To switch or not to switch: results of a nationwide guideline of mandatory switching from originator to biosimilar etanercept. One-year treatment outcomes in 2061 patients with inflammatory arthritis from the DANBIO registry. Ann Rheum Dis. 2019;78:192-200. doi: 10.1136/annrheumdis-2018-213474.

2. Cantini F, Benucci M. Mandatory, cost-driven switching from originator etanercept to its biosimilar SB4: a possible fallout on non-medical switching [published online November 28, 2018]. Ann Rheum Dis. doi: 10.1136/annrheumdis-2018-214757.

3. Glintborg B, Loft AG, Omerovic E, et al. Response to: ‘Mandatory, cost-driven switching from originator etanercept to its biosimilar SB4: possible fallout on non-medical switching’ by Cantini and Benucci. 2018; 0:1-2. doi: 10.1136/annrheumdis-2018-214788.