Etanercept Biosimilar Switch Shows Stable Outcomes and Disease Control in RA

Patients with rheumatoid arthritis who switched from the etanercept reference product to an etanercept biosimilar maintained low disease activity or remission, with no significant worsening of disease scores, even after reducing their dosage, according to a recent study.1

The prospective, open-label, interventional, single-arm clinical trial, published in Drug Discoveries & Therapeutics, aimed to assess the efficacy of switching from the etanercept reference product to an etanercept biosimilar under real-world clinical conditions, using musculoskeletal ultrasound (MSUS) and clinical disease activity indicators to evaluate the impact of the switch and subsequent dose reduction on disease activity in rheumatoid arthritis patients.

Results showing the safety of switching between etanercept products in a Japanese cohort may inform US authorities on how similar measures may pan out in the US, where legal battles are heating up over whether the manufacturer of reference etanercept (Amgen) is illegally preventing FDA-approved etanercept biosimilars from coming to market.2

The present study was conducted at 7 centers in Japan: Nagasaki University Hospital, Sasebo Chuo Hospital, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki Medical Hospital of Rheumatology, Saga University Hospital, Miyazaki-Zenjinkai Hospital, and Kumamoto Shinto General Hospital. Eligible participants were adults (aged ≥ 20 years) with rheumatoid arthritis (RA) who met the classification criteria and had been treated with the etanercept reference product (Enbrel) at a stable dose for at least 24 weeks while in low disease activity (LDA) or remission.

Patients switched from Enbrel to the biosimilar at the same dose, and those on 50 mg/week had their dose reduced to 25 mg/week after 24 weeks to assess the maintenance of LDA/remission through 52 weeks. Concomitant conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and corticosteroid dosages had to remain unchanged. Use of other biologics, JAK inhibitors, certain immunosuppressants, and corticosteroids above 7.5 mg/day was prohibited during the trial.

Assessments were performed at baseline and weeks 12, 24, 36, and 52. Clinical disease activity was measured using the Disease Activity Score 28 with C-reactive protein (DAS28-CRP), DAS28-erythrocyte sedimentation rate (ESR), Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI). Patient function was assessed using the Health Assessment Questionnaire-Disability Index (HAQ-DI).

MSUS was performed at each time point by sonographers, following standardized protocols to evaluate 22 joints using grayscale (GS) and power Doppler (PD) scores, each rated 0 to 3. Total GS, PD, and combined PD scores were calculated, and PD remission was defined as a PD score of 0 in all joints. Radiographs of the hands and feet were used to assess joint damage progression with the van der Heijde–modified total Sharp score (vdH-mTSS). Biomarker assessments included serum rheumatoid factor (RF), anti–cyclic citrullinated peptide antibodies (CCP), matrix metalloproteinase-3 (MMP-3), and a panel of cytokines and chemokines.

The primary end point was the proportion of patients maintaining LDA/remission without clinical relapse at 24 weeks post switch. Clinical relapse was defined as 2 consecutive DAS28-ESR scores of 3.2 or higher or a clinically significant increase in DAS28-ESR. Secondary end points included LDA/remission maintenance at 12, 36, and 52 weeks; changes in GS, PD, and combined PD scores; changes in DAS28-ESR, DAS28-CRP, SDAI, and CDAI over time; and biomarker evaluations.

The researchers enrolled 20 patients with RA, of whom 17 were included in the full analysis set (FAS) and 16 completed the 52-week study. The median age was 64 years, 88% were female, and the median disease duration was 15 years. Most patients (88%) tested positive for RF, and 65% for anti-CCP antibodies. Methotrexate was used by 65% of patients, and 12% received low-dose prednisolone.

Among the FAS, 16 (94.1%; 95% CI, 71.3-99.9) maintained low disease activity or remission based on DAS28-ESR at 24 weeks. At that point, the dosage was reduced from 50 mg/week to 25 mg/week, and 9 of 11 patients (81.8%; 95% CI, 48.2-97.7) continued to sustain LDA/remission through week 52.

Ultrasound assessments showed persistent PD remission throughout the study, with no changes in total GS, PD, or combined PD scores. Similarly, clinical disease activity scores (DAS28-ESR, DAS28-CRP, SDAI, and CDAI) remained stable, confirming sustained disease control. The HAQ-DI and vdH-mTSS showed minimal changes from baseline through 52 weeks, indicating stable functional status and no radiographic progression. Biomarker levels, including RF, anti-CCP, MMP-3, and cytokine/chemokine profiles, also remained unchanged.

Regarding safety, 10 adverse events (AEs) were reported among the 20 total patients. One serious AE—a grade 3 left renal abscess—led to hospitalization, surgery, and discontinuation of the study drug. Other AEs, including acute bronchitis, nasal herpes, pneumonia, injection site reaction, drug eruption, and vomiting, were mild to moderate (grade 1 or 2), with 1 additional patient discontinuing due to drug eruption. In total, 7 patients experienced adverse drug reactions during the study.

This study was limited by a small sample size and short duration. Additionally, only 1 relapse case occurred, making it difficult to identify predictive factors, though elevated IL-6 and interferon γ–induced protein 10 levels were noted in that patient.

The authors concluded, “Switching from [Enbrel] to etanercept biosimilar is feasible in patients with stable disease activity, and subsequent dose reduction. These results have considerable clinical value.”

References

1. Sumiyoshi R, Kawashiri S-Y, Shimizu T, et al. Efficacy of etanercept biosimilar switching from etanercept reference product, using ultrasound and clinical data in outcomes of real-world therapy (ESCORT-NGSK Study). Drug Discov Ther. 2025;19(1):29-37. doi:10.5582/ddt.2024.01088

2. Sandoz files antitrust litigation against Amgen regarding patient access to etanercept biosimilar in the US. Press release. Sandoz; April 14, 2025. Accessed May 13, 2025. https://www.sandoz.com/sandoz-files-antitrust-litigation-against-amgen-regarding-patient-access-etanercept-biosimilar-us/