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Abstract

Purpose: To investigate the disease activity in real-world patients with rheumatoid arthritis (RA) who switched from originator etanercept (ETN) to biosimilar YLB113. Methods: Forty one RA patients who switched from ETN to YLB113 were divided into 2 groups based on the Disease Activity Score based on the 28-joint count (DAS28) 12 months after switching (R group: DAS28 < 2.6, N group: DAS28 ≥ 2.6), and the baseline characteristics were statistically examined. A receiver operating characteristics (ROC) analysis was performed to estimate the cut-off value of DAS28 at baseline to achieve remission 12 months after switching. Results: There was no significant difference in the DAS28 at baseline and 12 months after switching (p = .83). Sixteen out of the 20 patients in remission at baseline achieved remission after switching. A univariate analysis revealed the rheumatoid factor (p = .04) and DAS28 (p < .001) at baseline were significantly lower in the R group than in the N group. Furthermore, logistic regression analysis revealed DAS28 was an independent factor (p = .004) for achieving remission 12 months after switching. An ROC curve analysis showed the optimal cut-off value for DAS28 at baseline to achieve remission at 12 months after switching was 2.5. Conclusions: RA patients who achieved remission using originator ETN, were able to maintain remission even if they switched to YLB113.

Keywords

etanercept YLB113 biosimilar rheumatoid arthritis

Introduction

Originator etanercept (ETN) is an important biological anti-rheumatic drug in the treatment of rheumatoid arthritis (RA), and its efficacy and safety have been proven not only in trials but also in clinical practice.^1–4 However, using biologics for RA is an economical problem due to their high price.^5,6

A biosimilar is a product developed subsequent to the originator biologic that has a lower drug price than the originator.^6,7 Their efficacy and safety have been confirmed in clinical trials,^8–10 so adopting biosimilars is expected to lead to lower medical costs and better access to biologics for active RA patients.

YLB113 was developed as a biosimilar to the ETN, and is available in Japan. It was approved in Japan in March 2019 by the Japan’s Medicines Regulatory Agency and the Pharmaceuticals and Medical Devices Agency.¹¹ YLB113 is a recombinant fusion protein consisting of a subunit dimer of the Fc region of human immunoglobulin G1 and the extracellular domain of the human tumor necrosis factor type II receptor, and is produced by a culture method using Chinese hamster ovary cells. In the global phase III study of patients with moderate-to-severe RA, the clinical efficacy, safety and immunogenicity were comparable between originator ETN and biosimilar YLB113.¹²

However, while other ETN biosimilars have been deemed effective and safe through trials and experience in clinical practice,^13–15 the clinical results of YLB113 are not yet clear.

The present study compared the efficacy before and after switching from originator ETN to biosimilar YLB113 in the real world.

Materials and methods

This was a retrospective study. A total of 51 RA patients were switched from ETN originator (Enbrel®, manufactured and marketed by Pfizer, Inc., Tokyo, Japan) to YLB113 biosimilar (Etanercept BS “TY”, manufactured and marketed by Yoshindo, Inc., Toyama, Japan) at a single rheumatic center from November 2019 to November 2020. YLB113 is an anti-rheumatic drug developed as a biosimilar to the anti-tumor necrosis factor-α antagonist ETN. All patients met the American College of Rheumatology 1987 criteria.¹⁶ Patients who had been treated with YLB113 for 12 months were included, while those whose dose changed when switching from the preceding originator or changing dosage for other anti-rheumatic drugs were excluded. The dosages of ETN and YLB113 were 25 mg or 50 mg once weekly, and were decided at the discretion of the each treating physician. Ultimately, 41 patients were enrolled in this study (Figure 1). Six months after switching to YLB113, one patient with RA complained of pain at the injection site and switched back to ETN. The study was conducted by the ethical principles derived from the Declaration of Helsinki and in compliance with the Good Clinical Practice guideline. The study protocol was approved by the local ethics committees, and written informed consent for participation was obtained from all patients.

Figure 1.

Flow diagram of the present study.

Patients were retrospectively assessed clinically at 6 and 3 months before switching, at switching, and 3, 6, 9, and 12 months after switching. The Disease Activity Score based on the 28-joint count (DAS28) and the levels of C-reactive protein (CRP), as well as the erythrocyte sedimentation rate (ESR) were evaluated. Rheumatoid factor (RF) and anti-CCP antibody (ACPA) at baseline were also collected.

Statistical analyses

The Mann-Whitney U test was used for the comparison of continuous data, and the chi-squared test or Fisher’s exact test was used for categorical variables. The DAS28, CRP, and ESR values at each observation point were compared with baseline data by Wilcoxon’s signed-rank test. A logistic regression analysis was performed to identify risk factors for achieving remission 12 months after switching from ETN to YLB113. A receiver operating characteristics (ROC) analysis was performed to estimate the cut-off value of DAS28 at baseline for achieving remission 12 months after switching. The SPSS Statistics software program, version 25 (IBM Corp., Armonk, NY, USA), was used for all statistical analyses.

Results

Baseline characteristics

Demographic and clinical data at baseline in this study are shown in Table1. The mean age was 62.8 years old, the mean disease duration was 17.4 years, and the mean duration of prior ETN was 108.1 months. The mean DAS28 at baseline was 2.5.

Table 1.

The comparison of baseline characteristics with or without achieving remission 12 months after switching from ETN to YLB113.

	Total (n = 41)	With achieving remission (n = 21)	Without achieving remission (n = 20)	p Value
Age (years)	62.8 ± 14.7	60.6 ± 14.2	65.2 ± 15.2	0.341
Gender (male/female)	5/36	3/18	2/18	0.524
BMI	21.6 ± 3.7	21.6 ± 4.3	21.7 ± 3.2	0.33
Disease duration (years)	17.4 ± 9.3	17.2 ± 10.5	17.7 ± 8.2	0.345
Duration of treatment with originator etanercept (months)	108.1 ± 40.8	60.6 ± 14.6	65.2 ± 15.6	0.955
Etanercept or YLB113 dose (25 mg/50 mg)	19/22	10/11	9/11	0.867
ACPA positive (%)	88.2
ACPA (U/mL)	324.3 ± 491.6	327.4 ± 419.6	321.3 ± 567.8	0.57
RF positive (%)	87.8
RF (U/mL)	116.4 ± 184.2	71.2 ± 82.5	163.9 ± 244.2	0.038
Steinbrocker stage (I/II/III/IV)	7/1/12/21
MTX use (%)	46.3	57.1	35	0.15
Dose of MTX (mg/week)	7.3 ± 2.4
PSL use (%)	19.5	14.3	25	0.45
Dose of PSL (mg/day)	3.9 ± 1.9
ESR (mm/h)	32.2 ± 20.1	19.8 ± 13.3	44.9 ± 18.1	<0.001
CRP (mg/dL)	0.2 ± 0.3	0.2 ± 0.2	0.3 ± 0.3	0.092
DAS28	2.5 ± 2.4	2.1 ± 0.7	3.0 ± 0.6	<0.001

ACPA, anti-CCP antibody; BMI, body mass index; CRP, C-reactive protein; DAS28, disease activity score assessing 28 joints; ESR, erythrocyte sedimentation rate; ETN, etanercept; MTX, methotrexate; PSL, prednisolone; RF, rheumatoid factor.

The comparison of baseline characteristics based on the presence or absence of remission 12 months after switching from ETN to YLB113

Patients were divided into two groups based on the presence or absence of remission at 12 months (Table 1). The age, sex, body mass index, RA disease duration, treatment duration of ETN, ETN or YLB113 dose, usage of methotrexate and prednisolone, DAS28, and levels of CRP, ESR, RF, and ACPA at baseline were compared between these two groups. In the group with remission, the value of RF was significantly higher and the DAS28 lower than in the group without remission (p = .04, p < .001, respectively).

Changes in DAS28 after switching from ETN to YLB113

Figure 2 showed the changes in the DAS28 before and after switching from ETN to YLB113.

Figure 2.

Changes in DAS28 for patients who switched ETN to YLB113 over time to 12 months.

The mean DAS28 values at 6 months before switching, at the time of switching (baseline), and 6 and 12 months after switching were 2.5, 2.5, 2.5, and 2.6 respectively. There was no significant difference in the DAS28 between the subjects at baseline and 12 months after switching (p = .83).

Of the 41 patients, 20 were in remission at baseline and 16 achieved remission 12 months after switching. In contrast, 16 out of the 21 patients with low or moderate disease activity at baseline failed to achieve remission after switching (Table 2).

Table 2.

Changes in disease activity categories 12 months after switching.

Disease activity categories at baseline (n = 41)	Disease activity categories 12 months after switching
Disease activity categories at baseline (n = 41)	REM	LDA	MDA	HDA
REM (n = 20)	16	3	1	0
LDA (n = 12)	4	5	3	0
MDA (n = 9)	1	3	5	0
HDA (n = 0)	0	0	0	0

HDA, high disease activity; LDA, low disease activity; MDA, moderate disease activity; REM, remission.

Factors associated with maintaining remission 12 months after switching from ETN to YLB113

A logistic regression analysis was performed to identify associated factors with remission 12 months after switching in RA patients. The presence or absence of achieving remission at 12 months after switching from ETN to YLB113 was defined as a dependent variable, while the disease duration, sex, RF value, and DAS28 at baseline were used as independent variables. The DAS28 at baseline (odds ratio [OR]: 0.081, p = .004, 95% confidence interval [CI]: 0.015 -0.449) was defined as independently associated with remission at 12 months after switching in RA patients (Table 3). An ROC curve analysis also showed that the optimal cut-off value for DAS28 at baseline for achieving remission at 12 months after switching from ETN to YLB113 was 2.5, with a sensitivity of 76.2%, specificity of 85.0%, and area under the curve of 0.84 (Figure 3).

Table 3.

Multivariate logistic regression analysis for factors associated with achieving remission 12 months after switching from ETN originator to biosimilar YLB113.

	Odds ratio	95% CI	p Value
Disease duration	1.011	0.902 - 1.132	0.855
Female	0.02	0.000 - 4.113	0.15
RF value	0.995	0.989 - 1.001	0.131
DAS28	0.081	0.015 - 0.449	0.004

CI, confidence interval; DAS28, disease activity score assessing 28 joints; ETN, etanercept; RF, rheumatoid factor.

Figure 3.

ROC curve to identify the optimal cut off value of DAS28 at baseline to achieve remission (DAS28 < 2.6) at 12 months was 2.5, with a sensitivity of 76.2%, specificity of 85.0%, and AUC of 0.84.

Safety after switching from ETN to YLB113

The adverse effects were observed in 5 patients (12.2%) after switching from ETN to YLB113. Pruritus (2 patients), cystitis (1 patient), sinusitis (1 patient), and mild transaminase elevation when switching from ETN to YLB113 after 3 months (1 patient) were reported. However, adverse effects leading to discontinuation were not observed in any of the patients. Furthermore, none of the patients reported injection-site reactions.

Discussion

In the present study, we retrospectively examined the efficacy of switching from the originator ETN to the biosimilar YLB113. As a result, switching from ETN to YLB113 did not reduce the efficacy of treatment, and the disease activity in RA patients treated with ETN was maintained even after switching to YLB113.

Previous studies have demonstrated that switching from originator ETN to a biosimilar that was not YLB113 did not result in any significant change in status after switching.^17–19 In our study, no significant changes in DAS28 were observed at the time of switching from ETN to YLB113 and 12 months after switching. Although this biosimilar is different from those evaluated in previous reports, the subjects’ backgrounds are comparable and similar results were obtained.

Regarding YLB113, there is a report of a clinical trial with a short ETN administration period.²⁰ In that study of 52 weeks of ETN followed by 96 weeks of YLB113, the mean DAS28 was 2.22 at switching and 2.06 at the end of the study, showing that efficacy had been maintained on switching from ETN to YLB113. Although the duration of ETN administration was different that in our study, the results were similar in terms of the maintenance of efficacy.

In the present study, the optimal baseline DAS28 cut-off for remission 12 months after switching from ETN to YLB113 was 2.5. In a previous retrospective study of 120 RA patients who switched from ETN to SB4, of the 102 patients who were in remission at the time of switching, 85 (83%) maintained remission after switching, while 27 (22.5%) moved from a lower disease state to a higher disease state.²¹ In a DANBIO registry-based observational study in Denmark, patients who switched from ETN to SB4, not in remission had significantly lower retention rates than patients in remission.²² Stable disease control after switching from the originator to a biosimilar requires sufficient suppression of the disease activity at the time of originator use.

In our study, no serious complications or injection site reactions were observed with the switch from ETN to YLB113. Previous studies have reported that the incidence of injection site reactions in patients treated with YLB113 was lower in comparison to patients treated with ETN.^12,20 The reason for this is that ETN uses syringe needles with latex coating and involves L-arginine in its formulation, whereas YLB113 does not use latex and involves L-arginine. Latex is known to cause allergic skin reactions, which may have contributed to the low incidence of injection site reactions with YLB113.¹² Considering these facts, the low response rate during the injection of YLB113 may be one of the reasons why switching from the originator ETN to YLB113 is recommended.

Our research has some limitations. First, this was a retrospective study and the sample size was relatively small. Second, the subjects in this study were mainly long-term ETN users. Finally, long-term assessment after switching from ETN to YLB113 was not possible. From an economic perspective, it seems that switching from originator to a biosimilar will continue, so further research on the long-term outcomes will be necessary.

Conclusions

In conclusion, RA patients who have achieved remission using the originator ETN, were able to maintain remission even after switching to the biosimilar YLB113.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Hideo Sakane

Koichi Okamura

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Efficacy of switching from originator etanercept to biosimilar YLB113 in real-world patients with rheumatoid arthritis: A retrospective 12 months follow-up study