LBEC0101, an etanercept biosimilar for the treatment of rheumatoid arthritis

Figures & data

Figure 1. LBEC0101 drug substance and ETN-RP binding affinities to (a) sTNFα, (b) mTNFα, (c) sLTα, and (d) TNFα neutralization

Reprinted and adapted from [37] with permission from The Japanese Pharmacological Society: Folia Pharmacologica Japonica. 2018;151(6):261–272. [Quality characteristics and nonclinical/clinical profiles of Etanercept BS SC [MA]] (Japanese). Kyono H, et al. Copyright 2018.Each symbol shows the mean value of triplicate assays. Each horizontal bar shows mean value of the three sets of assays.ETN-RP, etanercept reference product; mTNFα, transmembrane TNFα; sLTα, soluble lymphotoxin alpha; sTNFα, soluble TNFα; TNF, tumor necrosis factor.^†Relative inhibitory activity was calculated based on the following formula: Relative inhibitory activity = median inhibition concentration (IC₅₀) of tentative standard substance (ETN-RP (Korea))/IC₅₀ of each test substance × 100 (%).

Table 1. Summary of pharmacokinetic parameters of LBEC0101 and etanercept reference product after a single 25-mg subcutaneous injection in healthy males

Parameter	LBEC0101 N = 43	Etanercept reference product N = 43	Geometric mean ratio (90% CI)
Tmax (h)	72.0 (24.0–169.1)	60.0 (24.0–169.2)
Cmax (mg/L)	1.77 ± 1.04 (0.32–4.67)	1.71 ± 1.00 (0.38–4.52)	1.02 (0.92–1.13)
AUClast (mg·h/L)	345.86 ± 172.82 (40.47–760.88)	348.14 ± 154.46 (113.36–718.40)	0.96 (0.87–1.06)
AUCinf (mg·h/L)	365.45 ± 171.89 (53.19–780.08)	370.41 ± 151.95 (130.40–731.82)	0.96 (0.87–1.05)
t½ (h)	115.30 ± 26.28 (48.10–183.20)	122.03 ± 43.59 (80.74–327.11)
CL/F(L/h)	0.09 ± 0.07 (0.03–0.47)	0.08 ± 0.04 (0.03–0.19)
Vd/F (L)	14.81 ± 10.49 (4.04–66.43)	14.65 ± 9.91 (4.15–49.49)

Pharmacokinetic data are presented as mean ± standard deviation (minimum to maximum), except for T_max, which is presented as median (minimum to maximum).

AUC_inf, area under the concentration-time curve from time 0 to infinity; AUC_last, area under the concentration-time curve from time 0 to the last quantifiable concentration; CI, confidence interval; C_max, maximum concentration; CL/F, apparent clearance; t_½, terminal half-life; T_max, time to reach C_max; Vd/F, apparent volume of distribution.

Reprinted from [38] with permission from Springer Nature: BioDrugs. 2017;31(4):349–355. LBEC0101, A proposed etanercept biosimilar: pharmacokinetics, immunogenicity, and tolerability profiles compared with a reference biologic product in healthy male subjects. Lee H, et al. Copyright 2017.

Figure 2. DAS28-ESR change from baseline (LBEC0101 versus the ETN-RP)

This figure is adapted from Figure 2(a) of the Phase III double-blind study [39] in compliance with the terms of the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license.LS mean change from baseline in DAS28-ESR at week 24 and its 95% confidence interval (CI) adjusted for the country of the study center, status of previous use of a biological disease-modifying antirheumatic drugs and DAS28-ESR at baseline.DAS28-ESR, disease activity score in 28 joints based on erythrocyte sedimentation rate; ETN-RP, etanercept reference product; FAS, full analysis set; LS, least squares; PPS-24, per protocol set up to week 24.

Figure 3. DAS28-ESR over time to week 100 in the maintenance and switch groups

This figure is adapted from Figure 2 of the Phase III extension study manuscript [42] in compliance with the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) license.^†± standard error.DAS28-ESR, disease activity score in 28 joints based on erythrocyte sedimentation rate.

Table 2. Summary of AEs during the Phase III double-blind study and the extension study

	Phase III double-blind study		Phase III extension study
Parameter	LBEC0101 N = 187	Etanercept reference product N = 187	LBEC0101 Maintenance group N = 70	LBEC0101 Switch group N = 78
All AEs, n (%)	172 (92.0)	173 (92.5)	49 (70.0)	55 (70.5)
All ADRs*, n (%)	96 (51.3)	116 (62.0)	20 (28.6)	26 (33.3)
Serious AEs, n (%)	31 (16.6)	20 (10.7)	6 (8.6)	8 (10.3)
Serious ADRs*, n (%)	13 (7.0)	13 (7.0)	3 (4.3)	4 (5.1)
Deaths, n (%)	3 (1.6)	1 (0.5)	0	0
AEs leading to discontinuation, n (%)	12 (6.4)^†	13 (7.0)^†	1 (1.4)	3 (3.8)
AEs leading to temporary drug interruption, n (%)	49 (26.2)^†	39 (20.9)^†	13 (18.6)	8 (10.3)
Most common AEs, n (%)^‡
Nasopharyngitis	46 (24.6)	44 (23.5)	7 (10.0)	4 (5.1)
URTI	19 (10.2)	22 (11.8)	4 (5.7)	9 (11.5)
Arthralgia	14 (7.5)	8 (4.3)	3 (4.3)	8 (10.3)
Headache	14 (7.5)	6 (3.2)	0^†	1 (1.3)^†
Back pain	12 (6.4)	10 (5.3)	1 (1.4)^†	0^†
Abnormal hepatic function	12 (6.4)	6 (3.2)	0^†	0^†
Constipation	11 (5.9)	4 (2.1)	0^†	1 (1.3)^†
Upper abdominal pain	10 (5.3)	5 (2.7)	0^†	3 (3.8)^†
Injection site erythema	10 (5.3)	47 (25.1)	0^†	1 (1.3)^†
Injection site pruritus	7 (3.7)	38 (20.3)	0^†	1 (1.3)^†
Latent tuberculosis	5 (2.7)	10 (5.3)	6 (8.6)^†	3 (3.8)^†
Cough	5 (2.7)	14 (7.5)	3 (4.3)	4 (5.1)
Injection site swelling	4 (2.1)	13 (7.0)	0^†	1 (1.3)^†

The data in this table are sourced and adapted from the published double-blind Phase III study and the subsequent extension study [39,42] in compliance with the terms of the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license [39] and the Creative Commons Attribution 4.0 International (CC BY 4.0) license [42].

*In the source material for the published double-blind Phase III study, adverse drug reactions (ADRs) and serious ADRs are referred to as related AEs and serious related AEs, respectively [42].

^†These data are not reported in the published double-blind Phase III study or the subsequent extension study, and are taken from each of the clinical study reports.

^‡AEs experienced by >5% of patients in either group (by preferred term).

AE, adverse event; ADR, adverse drug reaction; URTI, upper respiratory tract infection.

Table

Drug name:	LBEC0101 (etanercept biosimilar)
Phase:	Approved in South Korea and Japan
Indication:	South Korea: rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, and psoriasis in adults; juvenile idiopathic arthritis in pediatric patients Japan: rheumatoid arthritis in adults, juvenile idiopathic arthritis in pediatric patients
Pharmacology description/mechanism of action:	TNF inhibitor
Pivotal trials:	Phase III, multicenter, double-blind, randomized, parallel-group study showed equivalent efficacy and comparable safety between LBEC0101 and etanercept reference product (NCT02357069) Long-term extension of Phase III study showed sustained efficacy and acceptable safety in patients after continued therapy or after switching from etanercept reference product to LBEC0101 (NCT02715908)

Kyono H, Haraguchi K, Kojima S, et al. Quality characteristics and nonclinical/clinical profiles of Etanercept BS SC [MA]. Folia Pharmacol Jpn. 2018;151(6):261–272. Japanese.

 PubMedGoogle Scholar

Lee H, Chung H, Lee S, et al. LBEC0101, A proposed etanercept biosimilar: pharmacokinetics, immunogenicity, and tolerability profiles compared with a reference biologic product in healthy male subjects. BioDrugs. 2017;31(4):349–355.

 PubMed Web of Science ®Google Scholar

Matsuno H, Tomomitsu M, Hagino A, et al. Phase III, multicentre, double-blind, randomised, parallel-group study to evaluate the similarities between LBEC0101 and etanercept reference product in terms of efficacy and safety in patients with active rheumatoid arthritis inadequately responding to methotrexate. Ann Rheum Dis. 2018;77(4):488–494.

 PubMed Web of Science ®Google Scholar

Park MC, Matsuno H, Kim J, et al. Long-term efficacy, safety and immunogenicity in patients with rheumatoid arthritis continuing on an etanercept biosimilar (LBEC0101) or switching from reference etanercept to LBEC0101: an open-label extension of a phase III multicentre, randomised, double-blind, parallel-group study. Arthritis Res Ther. 2019;21(1):122.

 PubMed Web of Science ®Google Scholar