In the JournalsPerspective

No impact on safety, efficacy in etanercept-to-biosimilar switch in RA

Patients with moderate-to-severe rheumatoid arthritis who switch from etanercept to the biosimilar etanercept-szzs experienced no impacts on drug efficacy, safety or immunogenicity, according to data published in Arthritis Research & Therapy.

“Pharmacokinetic equivalence and comparable safety for [etanercept-szzs] and reference etanercept was demonstrated in a phase 1 study in healthy subjects,” Janusz Jaworski, MD, PhD, of Reumatika-Center for Rheumatology, and colleagues wrote. “The phase 3 EGALITY study demonstrated equivalent efficacy and comparable safety and immunogenicity of [etanercept-szzs] and etanercept in patients with moderate-to-severe chronic plaque-type psoriasis.”

“The randomized, double-blind, EQUIRA study demonstrated similar efficacy and comparable safety and immunogenicity profile of [etanercept-szzs] to etanercept at week 24 in patients with moderate-to-severe RA who had an inadequate response to either conventional synthetic and/or biologic disease-modifying anti-rheumatic drugs (DMARDs),” they added.

To analyze the effects of a single switch from etanercept (Embrel, Amgen) to the biosimilar etanercept-szzs (Erelzi, Sandoz) in patients with moderate-to-severe RA, Jaworski and colleagues expanded the EQUIRA study to 48 weeks. In the original, 24-week run of the phase 3 study, 376 eligible adults with RA, recruited from 83 centers in 16 countries, were randomly assigned to receive 50-mg weekly doses of either the biosimilar or the reference product. Of those participants, 181 patients in the biosimilar group and 172 in the reference product group completed the 24-week run.

At 24 weeks, patients in the biosimilar group who achieved at least a moderate treatment response continued with their regimen with 169 patients completing the 48-week study period. Meanwhile, 166 patients from the reference product group entered the 48-week period and switched to the biosimilar, 155 of whom completed the 48-weeks of treatment.

The primary endpoint was change in disease activity score including 28 joint count C-reactive protein (DAS28-CRP) from baseline to week 24. Secondary endpoints included change in DAS28-CRP from baseline to week 48, proportion of patients demonstrating good and moderate EULAR response, patients achieving ACR20/50/70 improvements, physical function and fatigue. Additionally, the researchers identified 148 patients in the continued-biosimilar group, and 131 in the switched group — all participants who had completed the study without major protocol deviations — for inclusion in the “per-protocol” set.

According to the researchers, least squares mean change in DAS28-CRP from baseline up to week 48 was comparable between per-protocol patients who continued their biosimilar regimen (standard error = –2.9) and those who switched (–2.78). Further, the proportion of patients who demonstrated good-to-moderate EULAR and ACR20/50/70 responses were also comparable between the two groups.

Regarding safety, the rate of patients with at least one treatment-emergent adverse effect was 42.9% in the continued-biosimilar group, and 38% among those who switched. Four patients in each group experienced serious adverse events. None of the patients who switched treatments developed anti-drug antibodies after week 24. Meanwhile, four patients in the continued-biosimilar had single-event, very low titer, non-neutralizing anti-drug antibodies detected.

The advent of biosimilars has increased the possibility for switching between the reference medicine and its biosimilars, and this process is being evaluated in several countries,” Jaworski and colleagues wrote. “The 48-week results from the EQUIRA study demonstrates that switching patients from etanercept to [etanercept-szzs] did not impact the efficacy, safety, or immunogenicity of etanercept in patients with moderate-to-severe RA.” – by Jason Laday

Disclosure: The researchers report funding from Hexal AG, a Sandoz Company. Jaworski reports trial payment for this research and lecture fees from Sandoz. Please see the full study for additional author disclosures.

Patients with moderate-to-severe rheumatoid arthritis who switch from etanercept to the biosimilar etanercept-szzs experienced no impacts on drug efficacy, safety or immunogenicity, according to data published in Arthritis Research & Therapy.

“Pharmacokinetic equivalence and comparable safety for [etanercept-szzs] and reference etanercept was demonstrated in a phase 1 study in healthy subjects,” Janusz Jaworski, MD, PhD, of Reumatika-Center for Rheumatology, and colleagues wrote. “The phase 3 EGALITY study demonstrated equivalent efficacy and comparable safety and immunogenicity of [etanercept-szzs] and etanercept in patients with moderate-to-severe chronic plaque-type psoriasis.”

“The randomized, double-blind, EQUIRA study demonstrated similar efficacy and comparable safety and immunogenicity profile of [etanercept-szzs] to etanercept at week 24 in patients with moderate-to-severe RA who had an inadequate response to either conventional synthetic and/or biologic disease-modifying anti-rheumatic drugs (DMARDs),” they added.

To analyze the effects of a single switch from etanercept (Embrel, Amgen) to the biosimilar etanercept-szzs (Erelzi, Sandoz) in patients with moderate-to-severe RA, Jaworski and colleagues expanded the EQUIRA study to 48 weeks. In the original, 24-week run of the phase 3 study, 376 eligible adults with RA, recruited from 83 centers in 16 countries, were randomly assigned to receive 50-mg weekly doses of either the biosimilar or the reference product. Of those participants, 181 patients in the biosimilar group and 172 in the reference product group completed the 24-week run.

At 24 weeks, patients in the biosimilar group who achieved at least a moderate treatment response continued with their regimen with 169 patients completing the 48-week study period. Meanwhile, 166 patients from the reference product group entered the 48-week period and switched to the biosimilar, 155 of whom completed the 48-weeks of treatment.

The primary endpoint was change in disease activity score including 28 joint count C-reactive protein (DAS28-CRP) from baseline to week 24. Secondary endpoints included change in DAS28-CRP from baseline to week 48, proportion of patients demonstrating good and moderate EULAR response, patients achieving ACR20/50/70 improvements, physical function and fatigue. Additionally, the researchers identified 148 patients in the continued-biosimilar group, and 131 in the switched group — all participants who had completed the study without major protocol deviations — for inclusion in the “per-protocol” set.

According to the researchers, least squares mean change in DAS28-CRP from baseline up to week 48 was comparable between per-protocol patients who continued their biosimilar regimen (standard error = –2.9) and those who switched (–2.78). Further, the proportion of patients who demonstrated good-to-moderate EULAR and ACR20/50/70 responses were also comparable between the two groups.

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Regarding safety, the rate of patients with at least one treatment-emergent adverse effect was 42.9% in the continued-biosimilar group, and 38% among those who switched. Four patients in each group experienced serious adverse events. None of the patients who switched treatments developed anti-drug antibodies after week 24. Meanwhile, four patients in the continued-biosimilar had single-event, very low titer, non-neutralizing anti-drug antibodies detected.

The advent of biosimilars has increased the possibility for switching between the reference medicine and its biosimilars, and this process is being evaluated in several countries,” Jaworski and colleagues wrote. “The 48-week results from the EQUIRA study demonstrates that switching patients from etanercept to [etanercept-szzs] did not impact the efficacy, safety, or immunogenicity of etanercept in patients with moderate-to-severe RA.” – by Jason Laday

Disclosure: The researchers report funding from Hexal AG, a Sandoz Company. Jaworski reports trial payment for this research and lecture fees from Sandoz. Please see the full study for additional author disclosures.

    Perspective
    Allan Gibofsky

    Allan Gibofsky

    Since the introduction of biosimilars into clinical practice, significant concerns have remained for both physicians and patients. Would the biosimilar show the same results in clinical practice as in clinical trials? Would the biosimilar have the same clinical effect on patients already stable on the reference biologic if they are switched? Would the biosimilar result in a different incidence or spectrum of adverse events not seen while the patient was on the reference biologic?

    The study by Jaworski and colleagues was a randomized, double-blind study of patients with moderate-to-severe RA with an inadequate response to methotrexate or other conventional DMARDs, who were given either bio-originator etanercept or the biosimilar etanercept manufactured by Sandoz. At 24 weeks, stable patients in the etanercept arm were switched to the etanercept biosimilar for up to 48 weeks. No differences in efficacy, safety or immunogenicity were observed.

    While the results provide reassurance that biosimilarity means exactly that, significant additional questions remain. This study only looked at a period of 24 weeks after a switch — will similar efficacy, safety and (lack of) immunogenicity continue after longer dosing? Etanercept is a soluble TNF receptor fusion protein: Are the results seen with this biologic extrapolatable to other classes of biosimilars e.g. the monoclonal antibodies? Finally, and most important, what about multiple switches among multiple biosimilars to the same reference biologic? Further studies will be needed to answer them.

    • Allan Gibofsky, MD, JD
    • Professor of medicine and public health
      Weill Medical College of Cornell University
      Attending rheumatologist
      Hospital for Special Surgery
      Member, Medical Policy Committee
      United Rheumatology

    Disclosures: Gibofsky reports consulting and speaking for Abbvie, Celgene, Flexion, Merck, Novartis, Pfizer, and Sandoz; consulting for Fortress, Relburn, and Samumed; and being a stockholder for Abbvie, Amgen, J & J, Pfizer, and Regeneron.

    Perspective
    Amanda Mixon

    Amanda Mixon

    Anti-TNF therapy has changed the face of rheumatology. We no longer have patients coming into our clinics in wheelchairs or with severe disability secondary to their inflammatory arthritis. We have all heard of biosimilars and likely have patients that, at some point, will be switched to a biosimilar secondary to insurance requirements or will be a new start to a biosimilar for that same reason.

    The question that looms is: Are biosimilars as effective as the trade product, and, if we are required to change a patient, does the risk of immunogenicity increase? This particular article looked at these very questions with regards to the etanercept biosimilar made by Sandoz.

    As we would expect with etanercept, the risk of immunogenicity does not increase. More importantly, changing to this biosimilar did not impact efficacy or safety. I do want to see more trials addressing these questions; however, this does give me more confidence in prescribing biosimilars.

    • Amanda Mixon, PA-C
    • Physician Assistant Board Liaison
      Rheumatology Nurses Society
      Physician assistant
      Arthritis and Rheumatology Clinic of Northern Colorado

    Disclosures: Mixon reports reports she serves on the speakers bureau for AbbVie, Celgene, Eli Lilly and Novartis, and is a consultant for AbbVie, Eli Lilly and Regeneron.

    See more from Biosimilars in the United States: Current Status and Future Implications