Questions Remain About Etanercept to Biosimilar Switch

Janis C. Kelly

November 21, 2018

The largest observational cohort study to assess the outcomes of nonmedical (mandated) switching of inflammatory arthritis patients from etanercept (ETA) to the biosimilar SB4 in routine clinical care supports SB4 efficacy and safety, but does not fully resolve concerns about switching between originator biologics and biosimilars.

An analysis of 2061 patients with inflammatory arthritis included in the nationwide registry of biological therapies in Denmark, called DANBIO, showed that the patients who switched from ETA to SB4 in response to a new treatment guideline had similar disease activity and flare rates before and after the change. Bente Glintborg, MD, PhD, and colleagues reported the findings in an article published online November 5 in Annals of the Rheumatic Diseases.

However, the authors caution that because of baseline differences between patients who switched and those who continued ETA, the results do not represent an unbiased comparison and do not account for other patient-related factors that might have influenced outcomes.

Fabrizio Cantini, MD, who was not involved in the study, told Medscape Medical News, "We should remember that [the] DANBIO study on switching from originator etanercept to SB4 is based on data after mandatory switching, and thus did not evaluate well-balanced groups of treatment. Indeed, relevant differences between the two groups of treatment are present, including the higher disease activity, lower ETA dosage, and lower percentage of combination therapy with methotrexate in ETA continuers. Hence, the results are rather questionable and do not add evidence to proceed to nonmedical switching." Cantini is chief of rheumatology, Prato Hospital, Italy, and recently reviewed bioequivalence and interchangeability of ETA biosimilars (Biologics. 2018;30:12:87-95).

Glintborg and colleagues studied clinical characteristics and treatment outcomes among ETA-treated patients from the DANBIO registry who were treated with biologic disease-modifying antirheumatic drugs (DMARDs). The study population included 1219 patients with rheumatoid arthritis (RA), 407 with psoriatic arthritis (PsA), and 435 with axial spondyloarthritis (AxSpA).

Of these, 1621 (79%) switched from to ETA to SB4 after a 2016 nationwide guideline required mandatory switch from 50 mg of the originator to 50 mg of the biosimilar, which costs 49% less. The investigators analyzed 3-month disease activity before and after switching in those who took SB4, as well as safety and reasons for withdrawal, and 1-year treatment-continuation rates in switchers compared with a historic cohort of ETA patients. They also examined the characteristics of nonswitchers.

They found that among those who switched to SB4, there were no significant changes in flare rate or disease activity, as measured by disease activity score (DAS28) for RA and PsA or the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for AxSpA, at 3 months after the switch compared with 3 months before the switch.

At 1 year the withdrawal rate for switchers was 18%, compared with 33% in nonswitchers. In both groups, patients in remission were more likely to have continued treatment.

"Our study indicates that patient-related factors, for example, being in remission or not, rather than drug (originator or biosimilar), were important for the decision to withdraw treatment," the authors write.

The researchers found no new safety events with SB4.

There were significant baseline differences between switchers and nonswitchers. "The 21% nonswitchers less frequently had PsA and tended to have higher disease activity than the switchers and received concomitant methotrexate less frequently (in patients with PsA and RA). Some nonswitchers received the 25-mg ETA dose, which was still available," the authors write.

Among patients with RA and AxSpA, those who switched were more likely to be in remission at baseline than those who did not (RA, 65% vs 55%; AxSpA, 28% vs 21%) but that was not the case for patients with PsA (70% vs 73%).

Mandated switching to an etanercept biosimilar in Denmark is different from the situation in the United States, but Daniel E. Furst, MD, who was not involved in the study, told Medscape Medical News that third-party payers are expected to pressure clinicians to prescribe biosimilars as they become available. Furst, who is professor of medicine at UCLA David Geffen School of Medicine, said that the DANBIO study generally shows that switching from originator ETA to SB4 is safe and does not jeopardize efficacy.

Cantini noted that in clinical practice, the question of which patient is a candidate for switching to the biosimilar is unresolved. "To date, neither biomarkers, nor clinical variables have been identified to select the right patient to be switched from originator etanercept to SB4," he said.

In addition, Furst warned that how the switch is handled is important. "The issue remains that the pharmacy needs to be sure the prescriber knows that a switch is about to take place and any potential medical issue needs to be left to the prescribing physician, as they know the patient. Notification of the physician should not be done ex post facto."

Another key unanswered question concerns the safety and efficacy of repeated switches between originator biological DMARDs (boDMARDs) and biosimilar DMARDs (bsDMARDs).

"We do not know the efficacy and safety of repeated switches between the boDMARD and the bsDMARD and other bsDMARDs of the same molecule," Roy Fleischmann, MD, who was not involved in the study, told Medscape Medical News. "This is not a problem as yet, as we don't have many bsDMARDs available, but it will be a problem. What do we do with patients who are forced to switch and then lose efficacy or have a safety issue? This does occur. Can they switch back to the boDMARD?" Fleischmann is co-medical director, Metroplex Clinical Research Center, and clinical professor of medicine, University of Texas Southwestern Medical Center, Dallas.

Fleischmann added, "It is probably reasonable to conclude that a majority of patients do well with one switch, but we can't conclude that all do well or that they will do well with multiple switches. A real prospective, double-blind switching and re-switching study with assessment of multiple clinical and safety outcomes as advised by the FDA is necessary to understand this more completely. Registry data are too limited in what they capture."

The study was partly funded by a grant from Biogen. Glintborg had disclosed competing interests from AbbVie, Biogen, Pfizer, and MSD. Other authors reported competing interests from Orion, BMS, AbbVie, Biogen, Pfizer, MSD, Celltrion, Roche, Novartis, Roche, and Medac. Cantini, Furst, and Fleischmann have disclosed no relevant financial relationships.

Ann Rheum Dis. Published online November 5, 2018. Abstract

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