BioDrugs (2020) 34:89–98
https://doi.org/10.1007/s40259-019-00393-y
ORIGINAL RESEARCH ARTICLE
Retention Rate and Safety of Biosimilar CT‑P13 in Rheumatoid
Arthritis: Data from the Korean College of Rheumatology Biologics
Registry
Hyoun‑Ah Kim1
Kichul Shin4
· Eunyoung Lee2,3 · Sun‑Kyung Lee4 · Yong‑Beom Park5 · Young Nam Lee6
· Hee Jung Kang6 ·
Published online: 16 November 2019
© The Author(s) 2019
Abstract
Objective The aim was to evaluate long-term drug retention, discontinuation, efficacy and safety of CT-P13 and reference
infliximab in patients with rheumatoid arthritis (RA) enrolled in the Korean College of Rheumatology Biologics (KOBIO)
registry.
Methods Patients included adults with RA who received CT-P13 or reference infliximab between December 2012 and
December 2017. Drug retention, efficacy (Disease Activity Score in 28 joints [DAS28]–erythrocyte sedimentation rate [ESR]
or DAS28–C-reactive protein [CRP] and American College of Rheumatology [ACR] core set measure), and adverse events
(AEs) were assessed over 4-years’ follow-up.
Results Data from 199 RA patients (CT-P13: n = 147; reference infliximab: n = 52) were analyzed. Median treatment duration was 1.22 years for CT-P13 and 1.40 years for reference infliximab (p = 0.67). Overall, 82% of patients received first-line
therapy. Drug retention of CT-P13 versus reference infliximab was comparable for the overall population (p = 0.84) and for
first-line (p = 0.66) and subsequent treatment lines (p = 0.96). Treatment changes or discontinuations occurred in 65.2% of
patients with CT-P13 and 69.6% with reference infliximab. The most common reason for treatment changes or discontinuing
treatment was lack of efficacy (CT-P13: 31.9%; reference infliximab: 34.8%). CT-P13 demonstrated comparable improvements in DAS28-ESR, DAS28-CRP and ACR responses to reference infliximab. Overall, 19 grade 3 AEs were reported for
CT-P13 and eight for reference infliximab.
Conclusion Long-term data from patients with RA treated in routine clinical practice in Korea showed that CT-P13 had a
comparable drug retention rate to reference infliximab, with similar efficacy and an acceptable safety profile.
ClinicalTrials.gov identifier NCT01965132.
1 Introduction
CT-P13, a chimeric monoclonal antibody against tumor
necrosis factor (TNF), is a biosimilar of infliximab reference product [1]. CT-P13 was the first biosimilar monoclonal antibody to be approved by the European Medicines
Agency in 2013 for the same indications as reference infliximab, including rheumatoid arthritis (RA) (in combination
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s40259-019-00393-y) contains
supplementary material, which is available to authorized users.
* Kichul Shin
kideb1@gmail.com
Extended author information available on the last page of the article
with methotrexate), ankylosing spondylitis, Crohn’s disease,
ulcerative colitis, psoriatic arthritis and psoriasis [1, 2]. As
of July 2019, CT-P13 has been approved in 91 countries
worldwide.
Supporting clinical evidence for the approval of CT-P13
came from two randomized clinical trials [3]: PLANETAS,
involving patients with ankylosing spondylitis [4], and
PLANETRA, involving RA patients with an inadequate
response to methotrexate [5]. The PLANETAS [4, 6] and
PLANETRA [5, 7] studies showed that CT-P13 and reference infliximab had equivalent pharmacokinetic profiles,
comparable efficacy, and no clinically important differences in safety profiles up to week 54. In the PLANETRA
extension study, comparable efficacy and tolerability were
observed in those patients who switched from reference
infliximab to CT-P13 for an additional year and in those
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90
Key Points
Patients with rheumatoid arthritis (RA) enrolled in the
Korean College of Rheumatology Biologics (KOBIO)
registry were managed according to routine clinical practice, providing a comprehensive and accurate real-world
assessment.
Long-term data from the KOBIO registry showed that,
in Korean patients with RA, CT-P13 had a comparable
drug retention rate to reference infliximab, with similar
efficacy and an acceptable safety profile.
The comparability of CT-P13 and reference infliximab
with regard to safety, tolerability and efficacy, combined
with the lower price of CT-P13, offers the opportunity
for substantial cost-savings without compromising on
quality of treatment or patient outcomes.
H.-A. Kim et al.
longer follow-up, retention rates of reference infliximab and
CT-P13 appeared to be identical, which confirms the safety,
efficacy and acceptability of switching in the long-term [14].
These findings highlight the need for long-term follow-up
data in real-world studies.
The Korean College of Rheumatology Biologics
(KOBIO) registry is an ongoing, multi-center, prospective, observational study designed to collect real-world data
on patients being treated with biologic disease-modifying
antirheumatic drugs (DMARDs) in Korea [19–21]. The aim
of this analysis from the KOBIO registry was to evaluate
drug retention rates, discontinuations, efficacy and safety
of CT-P13 and reference infliximab in Korean patients with
RA who were followed for up to 4 years. In addition, we also
investigated outcomes in patients receiving CT-P13 or reference infliximab as first-line or subsequent therapy.
2 Materials and Methods
who received CT-P13 for 2 years [8]. Additional support
regarding the comparable efficacy and safety of CT-P13 and
reference infliximab comes from a randomized, double-blind
trial in Japanese RA patients with an inadequate response to
methotrexate [9]. Results from the extension phase of this
study demonstrated that treatment with CT-P13, either longterm or after switching from reference infliximab, was well
tolerated with persistent efficacy [10]. Furthermore, results
from the 52-week randomized, double-blind, non-inferiority,
phase IV NOR-SWITCH trial involving patients with a range
of inflammatory diseases, including RA, demonstrated that
switching to CT-P13 was not inferior to continued treatment
with reference infliximab, with similar drug discontinuation
rates [11].
As well as demonstrating the equivalence of CT-P13 and
reference infliximab under clinical study conditions, it is
important to show that long-term patient outcomes are comparable in the real-world clinical setting. Several real-world
studies have shown that the efficacy and safety of CT-P13
are maintained during long-term treatment in patients
with inflammatory rheumatologic diseases, including RA
[12–17]. Although data from the DANBIO registry showed
that the adjusted 1-year retention rate of CT-P13 was slightly
lower than reference infliximab in a historic cohort, this difference may represent a nocebo effect [15], where patients
can have worsening symptoms induced by a negative attitude
towards an intervention (including switching to a biosimilar) [18]. In a recent real-life study of patients with rheumatic disease who had switched from reference infliximab
to CT-P13, comparison with a historic reference infliximab
cohort revealed an initial nocebo effect [14]. However, with
2.1 Study Population
Data were collected through KOBIO, a nationwide registry in Korea established in December 2012 to capture data
on the use of biologic agents (ClinicalTrials.gov identifier:
NCT01965132) [21]. The KOBIO registry was established
as an inception cohort, enrolling patients with a diagnosis
of RA, ankylosing spondylitis or psoriatic arthritis at the
time of initiating, restarting or changing a biologic [19–21].
Patients aged ≥ 18 years were eligible for inclusion in
the KOBIO registry if they had RA that required treatment
with a biologic or non-biologic DMARD, as deemed by their
rheumatologist [21]. Patients already on biologic therapy at
screening were excluded from the registry. Participation in
the registry did not require any additional visits or laboratory
tests outside routine clinical practice.
This analysis presents data from patients with RA who
had received CT-P13 or reference infliximab, concurrent
with methotrexate per the label, between December 2012
and December 2017. Patients were excluded from this analysis if they did not receive treatment with CT-P13 or reference infliximab.
All patient treatments were determined by the treating
physician, including the selection of biologic, dosing and
treatment duration. The present analysis was conducted
according to the principles of the Declaration of Helsinki.
All patients provided written consent to participate in the
registry, and the data collection form and study protocol
were approved by institutional review boards (Ajou University Hospital; AJIRB-MED-MDB-17-505) or local ethics
committees at each participating center.
CT-P13 Treatment of Rheumatoid Arthritis
91
2.2 Data Collection and Outcomes Measured
3 Results
Data were collected annually from participating hospitals
using standardized case report forms. The following baseline
data were collected for this analysis: age, gender, body mass
index, smoking history, disease duration, disease activity,
erythrocyte sedimentation rate (ESR), C-reactive protein
(CRP), rheumatoid factor positivity, anti-cyclic citrullinated
peptide positivity, previous DMARD use, corticosteroid use
and line of therapy.
The primary outcome measure for this analysis was drug
retention (i.e., time to treatment discontinuation or changing to another biologic). Data were collected on treatment
dates and lines of therapy, treatment changes and reasons for
changing, and discontinuations and reasons for discontinuation. Discontinuation was defined as permanent discontinuation of biologic therapy.
Efficacy was assessed using the Disease Activity Score
in 28 joints (DAS28)-ESR or DAS28-CRP score, and the
American College of Rheumatology (ACR) core set measure. The response rates were reported using per-protocol
analysis. The DAS28 scale ranges from 0 to 9.4, where a
score < 2.6 indicates remission, ≥ 2.6 to < 3.2 low disease
activity, ≥ 3.2 to ≤ 5.1 moderate disease activity, and > 5.1
highly active disease [22]. ACR20 indicates a 20% improvement in both tender and swollen joint counts and three out of
five other measures within the ACR core set of disease activity measures [23]. ACR50 and ACR70 correspond to 50%
and 70% improvement, respectively. The number of patients
with adverse events (AEs), defined using the Medical Dictionary for Regulatory Activities (version 17.0), during treatment with biologics was evaluated. AEs were also assessed
after changing biologic or after discontinuation of biologic
therapy. Those patients who did not have a documented time
to discontinuation were included in the analyses of baseline
demographics, efficacy and safety, but were excluded from
analysis of drug retention rate.
3.1 Patient Characteristics
2.3 Statistical Analyses
Drug retention rates were analyzed using Kaplan–Meier survival curves and were compared statistically using a log-rank
test. Confidence bands were calculated using the method of
Hall and Wellner [24]. Baseline demographics and disease
characteristics were compared between treatment groups
using a Chi squared test of homogeneity for categorical variables and t test for continuous variables. Efficacy measured
by DAS28 score was compared statistically with p values
calculated using a two-sided Wilcoxon rank-sum test. All
statistical analyses were performed using SAS statistical
software (version 9.4, SAS Institute), and p values < 0.05
were considered statistically significant.
Data from 199 patients with RA enrolled in the KOBIO
registry between December 2012 and December 2017 were
analyzed, of whom 147 patients were treated with CT-P13
and 52 patients with reference infliximab. Data are presented
for the number of enrolled patients, although missing data,
such as ESR, CRP or questionnaire answers meant that for
some parameters, data were not available for all patients. In
addition, 12 patients treated with CT-P13 and eight patients
treated with reference infliximab were lost to follow-up and
were excluded from some analyses.
Patient baseline demographics and characteristics were
similar between groups (Table 1). Patients had a mean
age of 51.8 years [standard deviation (SD) ± 12.2 years].
Mean DAS28-CRP (5.0, SD ± 1.2) and DAS28-ESR (5.7,
SD ± 1.1) scores at baseline were consistent with a patient
population with moderate-to-severely active RA [22].
The mean duration of disease at baseline was 7.4 years
(SD ± 7.6 years), indicative of a patient population with
long-established RA. At baseline, almost all patients (96.5%)
had been previously treated with DMARDs and concurrent
corticosteroid use was reported in 87.9% of patients. The
majority of patients (82.4%) received first-line infliximab
therapy (CT-P13: n = 124/147, 84.4%; reference infliximab: n = 40/52, 76.9%), with second or subsequent lines of
therapy received by 17.6% of patients (CT-P13: n = 23/147,
15.6%; reference infliximab: n = 12/52, 23.1%).
3.2 Treatment Duration and Drug Retention
Treatment duration is shown in Supplementary Table 1
(see the electronic supplementary material, Online
Resource 1). Overall, the median duration of treatment
was 1.22 years (range 0.54–2.31) with CT-P13 and
1.40 years (range 0.43–3.16) with reference infliximab
(p = 0.67). Irrespective of treatment group, duration of
first-line therapy was longer than subsequent lines of therapy (Supplementary Table 1 in Online Resource 1). The
median treatment duration in patients receiving first-line
or subsequent CT-P13 therapy was 1.32 (range 0.58–2.47)
and 0.83 years (range 0.35–1.97), respectively, and in
those receiving first-line or subsequent reference infliximab therapy, it was 1.65 (range 0.43–3.16) and 0.58 years
(range 0.42–3.42), respectively.
Overall, there was no difference in drug retention with
CT-P13 and reference infliximab (log-rank p = 0.84; Fig. 1a).
Drug retention was also similar between CT-P13 and reference infliximab groups in patients who received first-line
therapy (p = 0.66; Fig. 1b) and subsequent treatment lines
92
H.-A. Kim et al.
Table 1 Baseline patient characteristics
Characteristic
All patients (N = 199)
CT-P13 (N = 147)
Reference infliximab
(N = 52)
P value
Age, years
Disease duration, years
Male, n (%)
BMI, kg/m2
Smoking history, n (%)
Ex-smoker
Current smoker
Never
Tender joint count
Swollen joint count
ESR, mm/h
CRP, mg/dL
DAS28-ESR
DAS28-CRP
Rheumatoid factor (positivity), n (%)
Anti-CCP (positivity), n (%)
Previous DMARD use, n (%)
Methotrexate dose, mg/week, median (IQR)
Corticosteroid use, n (%)
Corticosteroid dose, dose equivalent for prednisolone in mg/day, median (IQR)
Infliximab treatment line, n (%)
1st line
≥ 2nd line
51.8 (12.2)
7.4 (7.6)
28 (14.1)
22.9 (4.0)
51.3 (12.4)
7.7 (7.6)
18 (12.2)
23.0 (4.2)
53.3 (11.5)
6.5 (7.7)
10 (19.2)
22.8 (3.3)
13 (6.5)
14 (7.0)
172 (86.4)
9.9 (8.2)
7.5 (6.2)
52.6 (27.4)
2.9 (5.3)
5.7 (1.1)
5.0 (1.2)
163 (81.9)
139 (69.8)
192 (96.5)
15 (10─15)
175 (87.9)
5 (2.5─7.5)
9 (6.1)
12 (8.2)
126 (85.7)
9.9 (7.5)
7.7 (5.9)
53.8 (28.1)
3.1 (6.0)
5.7 (1.2)
5.0 (1.2)
117 (79.6)
99 (67.3)
142 (96.6)
15 (12.5─15)
127 (86.4)
5 (2.5─7.5)
4 (7.7)
2 (3.8)
46 (88.5)
9.8 (10.1)
6.9 (7.2)
49.1 (25.3)
2.4 (2.4)
5.5 (1.1)
4.9 (1.1)
46 (88.5)
40 (76.9)
50 (96.2)
15 (10─15)
48 (92.3)
6 (4─8)
0.30
0.35
0.21
0.75
0.55
–
–
–
0.92
0.45
0.29
0.24
0.29
0.43
0.12
0.055
0.88
0.59
0.26
0.013
164 (82.4)
35 (17.6)
124 (84.4)
23 (15.6)
40 (76.9)
12 (23.1)
0.23
–
–
Data presented are mean (standard deviation), unless otherwise indicated
BMI body mass index, CCP cyclic citrullinated peptide, CRP C-reactive protein, DAS28 disease activity score in 28 joints, DMARD diseasemodifying antirheumatic drug, ESR erythrocyte sedimentation rate, IQR interquartile range
(p = 0.96; Fig. 1c). After 4 years’ follow-up, the retention
rate was 17.5% for CT-P13 and 33.6% for reference infliximab in the overall patient population. In patients receiving
first-line therapy, the retention rate was 15.7% for CT-P13
and 35.4% for reference infliximab.
3.3 Treatment Changes and Discontinuations
Reasons for changing to another agent or discontinuing treatment are presented in Table 2. Overall, the rate of treatment
changes or discontinuations was similar between the CT-P13
and reference infliximab groups (65.2% vs 69.6%, respectively). The most common reason for treatment changes or
discontinuations was lack of efficacy (CT-P13: 31.9%; reference infliximab: 34.8%). Treatment changes or discontinuations due to an AE were reported in 20.0% of patients in
the CT-P13 group and 23.9% of patients in the reference
infliximab group. A similar proportion of patients in the
CT-P13 group and reference infliximab groups changed
or discontinued therapy after achieving clinical remission
(3.0% and 4.3%, respectively).
A similar proportion of patients in each treatment group
changed biologic therapy (CT-P13: 43.7%; reference infliximab: 39.1%) or discontinued treatment (CT-P13: 21.5%;
reference infliximab: 30.4%; Table 2). Of those patients
who changed biologic therapy in the CT-P13 and reference
infliximab groups, the most commonly cited reason was
lack of efficacy (Table 2). AEs were the most commonly
cited reason for discontinuing treatment with CT-P13 or
reference infliximab (Table 2). AEs leading to treatment
discontinuation or changing to another biologic are shown
in Supplementary Table 2 (Online Resource 1). Infusionrelated reactions were the most common AEs resulting in
treatment changes (CT-P13: 12 events; reference infliximab:
two events) and treatment discontinuation (CT-P13: three
events; reference infliximab: three events).
Similar proportions of patients receiving first-line CT-P13
or reference infliximab changed biologic (44.2% and 42.9%,
CT-P13 Treatment of Rheumatoid Arthritis
93
Esmated probability
(a)
CT-P13
Reference infliximab
1.0
0.8
Log-rank p = 0.8382
0.6
0.4
0.2
0.0
0
1
Paents at risk, n
103
CT-P13 135
31
Reference 46
infliximab
2
3
4
5
Time (years)
76
25
60
22
50
18
29
14
20
13
6
8
2
4
0
1
–
0
Esmated probability
(b)
1.0
0.8
Log-rank p = 0.6609
0.6
0.4
0.2
0.0
0
Paents at risk, n
CT-P13 113
Reference 35
infliximab
1
2
3
4
3.4 Efficacy
5
Time (years)
89
25
65
21
53
18
45
15
27
11
18
10
5
6
1
4
0
1
–
0
(c)
Esmated probability
biologic by line of therapy are presented in Supplementary
Table 3 (Online Resource 1). Overall, 15 out of 22 patients
(68.2%) in the CT-P13 group and nine out of 11 patients
(81.8%) in the reference infliximab group changed or discontinued treatment during second-line or subsequent therapy.
The drugs received following treatment with CT-P13
and reference infliximab are summarized in Supplementary
Table 4 (Online Resource 1). Tocilizumab was the most
commonly substituted drug following first-line treatment
with CT-P13 and reference infliximab (34.0% and 73.3%,
respectively). Adalimumab was also commonly used following first-line treatment with CT-P13 (26.0%), but was not
substituted after first-line reference infliximab.
1.0
0.8
Log-rank p = 0.9552
0.6
0.4
0.2
0.0
0
Paents at risk, n
CT-P13 22
Reference 11
infliximab
1
2
3
4
5
Time (years)
14
6
11
4
7
4
5
3
2
3
2
3
1
2
1
0
0
–
–
–
Fig. 1 Drug retention in a all patients, b patients treated with firstline therapy and c patients treated with second-line or subsequent
therapy. Shading indicates 95% Hall-Wellner bands. + indicates censored patients
respectively) or discontinued treatment (20.4% and 22.9%,
respectively; Supplementary Table 3, Online Resource 1).
Reasons for discontinuing treatment or changing to another
CT-P13 demonstrated similar efficacy to reference infliximab with comparable improvements observed over time
(Figs. 2 and 3). Over the 4-year observation period, treatment with either CT-P13 or reference infliximab resulted
in a substantial reduction in disease activity from baseline,
assessed by DAS28-ESR and DAS28-CRP (Fig. 2). After
2 years of treatment with either CT-P13 or reference infliximab, DAS28-ESR and DAS28-CRP scores corresponded
to low disease activity/disease remission, and disease control was maintained up to 4 years after initiating treatment.
ACR20 response rates in the first year of treatment were
57.3% with CT-P13 and 45.8% with reference infliximab,
and increased in the second year of treatment (CT-P13:
82.1%; reference infliximab: 62.1%; Fig. 3). ACR50 and
ACR70 response rates showed a pattern consistent with
ACR20 responses, where the proportion of patients responding increased between the first and second years of treatment
and were numerically higher in the CT-P13 group compared
with the reference infliximab group (Fig. 3).
Table 2 Reasons for discontinuation of therapy or changing to another biologic
CT-P13 (N = 135)
Lack of efficacy
AE
Clinical remission
Other reasons
Unspecified
Total
Reference infliximab (N = 46)
Changed, n (%)
Discontinued treatment, n (%)
Total, n (%)
Changed, n (%)
Discontinued treatment, n (%)
Total, n (%)
35 (25.9)
18 (13.3)
–
6 (4.4)a
–
59 (43.7)
8 (5.9)
9 (6.7)
4 (3.0)
8 (5.9)b
–
29 (21.5)
43 (31.9)
27 (20.0)
4 (3.0)
14 (10.4)
–
88 (65.2)
14 (30.4)
4 (8.7)
–
–
–
18 (39.1)
2 (4.3)
7 (15.2)
2 (4.3)
2 (4.3)c
1 (2.2)
14 (30.4)
16 (34.8)
11 (23.9)
2 (4.3)
2 (4.3)
1 (2.2)
32 (69.6)
AE adverse event
a
Reasons include removal of prescription code for CT-P13 (n = 6)
b
Reasons include patient’s decision (n = 5), planning for pregnancy (n = 2) and scheduled surgery (n = 1)
c
Reasons include patient’s decision (n = 1) and planning for pregnancy (n = 1)
94
H.-A. Kim et al.
3.5 Safety
Overall, 19 grade 3 AEs were reported in the CT-P13 group
and eight in the reference infliximab group (Table 3). There
were four grade 3 AEs considered to be related to CT-P13
(one infusion/injection reaction; one infection, not specified;
one case of mononeuritis multiplex; and one case of skin
rash). No drug-related grade 3 AEs were reported with reference infliximab. Infusion-related reactions were the most
commonly reported AEs (CT-P13: 16 events; reference infliximab: seven events), followed by infection (CT-P13: 11
events; reference infliximab: four events). There were no
cases of tuberculosis reported with either treatment. Two
cases of malignant solid tumors (one case of malignant
(a)
CT-P13
Reference infliximab
DAS28–ESR
6
4
2
0
p-value
n
CT-P13
Reference n
infliximab
Baseline
Year 1
Year 2
Year 3
Year 4
0.07
147
52
0.74
133
46
0.33
66
29
0.92
36
17
0.61
6
11
(b)
DAS28–CRP
6
CT-P13
Reference infliximab
4
melanoma and one case of thyroid cancer) were reported
with CT-P13. Three cases of malignancy (one case of lymphoma and two cases of oral cavity mass) were reported with
reference infliximab. Of these malignancies, only lymphoma
was deemed related to treatment. One death was reported in
each group, due to pneumonia (CT-P13 group) and cardiac
arrest (reference infliximab group).
4 Discussion
This prospective, registry-based, observational study presents real-life data on the long-term retention, efficacy and
safety of CT-P13 compared with reference infliximab in
Korean patients with RA. Our analysis showed that drug
retention was comparable in patients treated with CT-P13
and reference infliximab, irrespective of treatment line.
CT-P13 provided similar long-term clinical benefit to reference infliximab. Treatment with both CT-P13 and reference
infliximab resulted in a substantial reduction in DAS28ESR and DAS28-CRP scores over the 4-year observation
period. Furthermore, DAS28-ESR and DAS28-CRP scores
Table 3 Summary of adverse events of interest
AE, number of events
CT-P13
(N = 147)
Reference
infliximab
(N = 52)
AE, grade 3
Drug-related AE, grade 3
Infusion-related reaction
Infection
Tuberculosis
Malignancy
19
4
16
11
0
2
8
0
7
4
0
3
2
0
p-value
n
CT-P13
Reference n
infliximab
Baseline
Year 1
Year 2
Year 3
Year 4
0.11
147
51
0.96
133
45
0.08
66
29
1.00
36
17
0.88
6
11
Response rate (%)
Fig. 2 Efficacy measured by a DAS28-ESR and b DAS28-CRP
scores. DAS28-CRP disease activity score in 28 joints–C-reactive
protein, DAS28-ESR disease activity score in 28 joints–erythrocyte
sedimentation rate
Year 1
100
CT-P13
Reference
infliximab
80
60
57.3
45.8
40
20
39.9
33.3
22.5
16.7
0
AE adverse event
Year 2
100
CT-P13
Reference
infliximab
82.1
80
62.1
60
59.7
37.9
40
20
34.3
13.8
0
ACR 20
ACR 50
ACR 70
ACR 20
ACR 50
ACR 70
n 138 48
Responders, n
79 22
138 48
55 16
138 48
31 8
67 29
55 18
67 29
40 11
67 29
23 4
Fig. 3 ACR response by duration of follow-up. ACR American College of Rheumatology, ACR20 20% response as defined by ACR, ACR50 50%
response as defined by ACR, ACR70 70% response as defined by ACR
CT-P13 Treatment of Rheumatoid Arthritis
corresponded to low disease activity/disease remission after
2 years of treatment with either CT-P13 or reference infliximab, and disease control was maintained up to 4 years after
initiating treatment.
For observational registries, drug survival may be
regarded as a reliable indicator of overall treatment effectiveness [25]. Registry-based studies in patients with RA
who received first-line reference infliximab, including the
Swedish Biologics Register ARTIS [26] and a local Italian
registry [25], have reported drug survival rates of 38–44.3%
after 5 years. The Danish DANBIO registry reported a drug
survival rate of 41% for reference infliximab after 2 years
[27]. The reference infliximab retention rates found in our
study were similar to previous reports, with a retention
rate of 33.6% in the overall patient population and 35.4%
in patients receiving first-line therapy, after 4 years’ follow-up. The main reason for drug discontinuation in the
observational registry studies was lack of efficacy and AEs
[25–27], which is consistent with our study. Our analysis
demonstrated that drug retention was comparable in patients
treated with CT-P13 and reference infliximab irrespective
of treatment line. This is consistent with the data reported
by Germain et al., who observed similar treatment retention rates among patients with rheumatic disease who had
switched from reference infliximab to CT-P13 (56%, median
follow-up 120 weeks), compared with a historic reference
infliximab cohort (67%, median follow-up 131 weeks;
p = 0.052) [14].
In the current study, the efficacy of CT-P13 and reference
infliximab (in combination with methotrexate) was comparable when measured using the continuous disease activity
measure of DAS28 and the dichotomous measure of ACR20
response in a patient population with highly active disease
of long duration. We observed 1-year ACR20 response rates
of 57.3% and 45.8% with CT-P13 and reference infliximab,
respectively. Similarly, the PLANETRA randomized controlled study showed that CT-P13 and reference infliximab were comparable in terms of efficacy, although higher
ACR20 response rates of 74.7% and 71.3% were achieved
after 54 weeks of combined treatment with methotrexate
plus CT-P13 or reference infliximab, respectively [7]. These
higher response rates may reflect the fact that clinical trials have strict inclusion criteria and enrolled patients may
not always be representative of the entire real-world patient
population. Indeed, analysis of data from the German RABBIT registry has shown that only 21–33% of patients with
RA treated with reference infliximab in RABBIT would have
been eligible for major trials, with ineligible patients having
lower response rates but similar absolute improvement [28].
CT-P13 was well tolerated during our study and displayed
a long-term safety profile consistent with that of reference
infliximab, with no clinically important differences. Consistent with the 54-week PLANETRA phase 3 clinical study [7],
95
infusion-related reactions were the most commonly reported
AEs in our analysis (CT-P13: 16 events; reference infliximab: seven events). Although it is established that patients
with RA are at an increased risk of lymphoma compared
with the general population, TNF inhibitor (TNFi) treatment
does not appear to increase lymphoma risk [29–31]. The case
of lymphoma deemed to be related to CT-P13 reported in
our analysis does not raise safety concerns due to the known
increased risk of lymphoma in patients with RA; however,
the incidence of lymphoma in patients treated with TNFis
should continue to be closely monitored. TNFis are associated with an increased risk of serious infections in RA [31],
and infections are the most common serious AEs associated
with CT-P13 and reference infliximab during post-marketing
spontaneous reporting [32, 33]. In the current study, one
serious infection was reported in the CT-P13 group (pneumonia). Reassuringly, this study reported no cases of active
tuberculosis infection with either infliximab product.
In addition to offering efficacy and safety comparable
with reference infliximab, the introduction of CT-P13 for
the treatment of RA offers the potential for substantial costsavings, given the high contribution of medication to overall
treatment costs for RA [34, 35]. Introduction of lower-priced
infliximab biosimilars, including CT-P13, might increase
patient access to treatment, particularly in those countries
where reference infliximab is not recommended due to cost
constraints [35–37]. In addition, the NOR-SWITCH study
has provided support for non-medical switching from reference infliximab to CT-P13 [11, 38]. In 2014, the Norwegian
health authorities recommended CT-P13 for patients initiating infliximab treatment; as a result, the cost saving in
Norway for CT-P13 versus reference infliximab increased
from 39% in 2014 to 69% in 2015 [11]. Such cost savings
could significantly impact CT-P13 uptake and, consequently,
healthcare budgets in many countries [11, 38]. Direct medical costs for both patients and the payer were reduced following the introduction of biosimilar infliximab in the South
Korean healthcare market, which could potentially be used
to increase patient access to biologics [39]. Moreover, the
introduction of infliximab biosimilars in the United Kingdom resulted in substantial cost-savings in the first 2 years
of use [40], and considerable budget reductions are predicted
for the roll out of infliximab biosimilars in other European
countries [35, 41]. While treatment with intravenous CT-P13
is effective and well tolerated, a subcutaneous formulation of
CT-P13 is being developed for self-administration [42, 43],
offering the potential for improved patient compliance and
reduced costs to healthcare systems [44].
Through the KOBIO registry, patients were managed
according to routine clinical practice, providing a comprehensive and accurate real-world assessment. Strengths of
our analysis include the prospective nature of data collection
in the KOBIO registry, the long follow-up period, and the
96
relatively large patient population. The main limitation of
the current study is related to its observational design, which
relies on passive reporting of safety events and may lead to
under-estimation of incidence. Few patients included in this
analysis received infliximab as second-line or subsequent
therapy, precluding analysis of the reasons for discontinuing
therapy in this population. Furthermore, the generalizability
of our results to other countries may be influenced by the
stringent Korean National Health Insurance reimbursement
criteria for TNFi eligibility [45]; hence, the patient population in this analysis may not be representative of patient
populations undergoing infliximab treatment in other countries and, subsequently, outcomes may vary.
5 Conclusion
In conclusion, long-term data from this nationwide cohort of
Korean patients with RA treated in routine clinical practice
showed that CT-P13 had a comparable drug retention rate
to reference infliximab, with similar efficacy and an acceptable safety profile. The proven comparability of CT-P13 and
reference infliximab safety, tolerability and efficacy, and the
lower price of CT-P13, offers the opportunity for substantial
cost-savings without compromising on quality of treatment
or patient outcomes.
Acknowledgements Medical writing support (including development
of a draft outline and subsequent drafts in consultation with the authors,
assembling tables and figures, collating author comments, copyediting,
fact checking and referencing) was provided by Julianna Solomons,
PhD, at Aspire Scientific (Bollington, UK), and funded by Celltrion
Healthcare Co., Ltd. (Incheon, Republic of Korea).
Author contributions HAK, EL, YNL, HJK, and KS made a substantial contribution to the conception or design of the study; and all
authors made a substantial contribution to the acquisition, analysis, and
interpretation of the data and manuscript development, and gave final
approval of the manuscript for submission.
Compliance with Ethical Standards
Funding This study was supported by Celltrion Healthcare Co., Ltd.
Conflict of interest Young Nam Lee and Hee Jung Kang are employees of Celltrion Healthcare Co., Ltd. Hyoun-Ah Kim, Eunyoung Lee,
Sun-Kyung Lee, Yong-Beom Park, and Kichul Shin have no conflicts
to declare.
Research including human participants The present analysis was conducted according to the principles of the Declaration of Helsinki. The
data collection form and study protocol were approved by institutional
review boards (Ajou University Hospital; AJIRB-MED-MDB-17-505)
or local ethics committees at each participating center.
Informed consent All patients provided written consent to participate
in the registry.
H.-A. Kim et al.
Data availability statement All available data are reported in the manuscript and supplementary file.
Open Access This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License
(http://creativecommons.org/licenses/by-nc/4.0/), which permits any
noncommercial use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the
source, provide a link to the Creative Commons license, and indicate
if changes were made.
References
1. European Medicines Agency. European Public Assessment
Report: Remsima. 2013. https ://www.ema.europ a.eu/docum
ents/asses sment -repor t/remsi ma-epar-publi c-asses sment -repor
t_en.pdf. Accessed 05 Feb 2019.
2. McKeage K. A review of CT-P13: an infliximab biosimilar. BioDrugs. 2014;28(3):313–21.
3. Becciolini A, Raimondo MG, Crotti C, Agape E, Biggioggero
M, Favalli EG. A review of the literature analyzing benefits and
concerns of infliximab biosimilar CT-P13 for the treatment of
rheumatologic diseases: focus on interchangeability. Drug Des
Devel Ther. 2017;11:1969–78.
4. Park W, Hrycaj P, Jeka S, Kovalenko V, Lysenko G, Miranda P,
et al. A randomised, double-blind, multicentre, parallel-group,
prospective study comparing the pharmacokinetics, safety, and
efficacy of CT-P13 and innovator infliximab in patients with
ankylosing spondylitis: the PLANETAS study. Ann Rheum Dis.
2013;72(10):1605–12.
5. Yoo DH, Hrycaj P, Miranda P, Ramiterre E, Piotrowski M, Shevchuk S, et al. A randomised, double-blind, parallel-group study
to demonstrate equivalence in efficacy and safety of CT-P13
compared with innovator infliximab when coadministered with
methotrexate in patients with active rheumatoid arthritis: the
PLANETRA study. Ann Rheum Dis. 2013;72(10):1613–20.
6. Park W, Yoo DH, Jaworski J, Brzezicki J, Gnylorybov A, Kadinov
V, et al. Comparable long-term efficacy, as assessed by patientreported outcomes, safety and pharmacokinetics, of CT-P13 and
reference infliximab in patients with ankylosing spondylitis:
54-week results from the randomized, parallel-group PLANETAS
study. Arthritis Res Ther. 2016;18:25.
7. Yoo DH, Racewicz A, Brzezicki J, Yatsyshyn R, Arteaga ET,
Baranauskaite A, et al. A phase III randomized study to evaluate
the efficacy and safety of CT-P13 compared with reference infliximab in patients with active rheumatoid arthritis: 54-week results
from the PLANETRA study. Arthritis Res Ther. 2016;18:82.
8. Yoo DH, Prodanovic N, Jaworski J, Miranda P, Ramiterre E, Lanzon A, et al. Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: comparison between
switching from reference infliximab to CT-P13 and continuing
CT-P13 in the PLANETRA extension study. Ann Rheum Dis.
2017;76(2):355–63.
9. Takeuchi T, Yamanaka H, Tanaka Y, Sakurai T, Saito K, Ohtsubo H, et al. Evaluation of the pharmacokinetic equivalence and
54-week efficacy and safety of CT-P13 and innovator infliximab
in Japanese patients with rheumatoid arthritis. Mod Rheumatol.
2015;25(6):817–24.
10. Tanaka Y, Yamanaka H, Takeuchi T, Inoue M, Saito K, Saeki
Y, et al. Safety and efficacy of CT-P13 in Japanese patients with
rheumatoid arthritis in an extension phase or after switching from
infliximab. Mod Rheumatol. 2017;27(2):237–45.
CT-P13 Treatment of Rheumatoid Arthritis
11. Jorgensen KK, Olsen IC, Goll GL, Lorentzen M, Bolstad N,
Haavardsholm EA, et al. Switching from originator infliximab to
biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. Lancet. 2017;389(10086):2304–16.
12. Abdalla A, Byrne N, Conway R, Walsh T, Mannion G, Hanly
M, et al. Long-term safety and efficacy of biosimilar infliximab
among patients with inflammatory arthritis switched from reference product. Open Access Rheumatol. 2017;9:29–35.
13. Avouac J, Molto A, Abitbol V, Etcheto A, Salcion A, Gutermann
L, et al. Systematic switch from innovator infliximab to biosimilar
infliximab in inflammatory chronic diseases in daily clinical practice: the experience of Cochin University Hospital, Paris, France.
Semin Arthritis Rheum. 2018;47(5):741–8.
14. Germain V, Scherlinger M, Barnetche T, Schaeverbeke T, Federation Hospitalouniversitaire Acronim. Long-term follow-up after
switching from originator infliximab to its biosimilar CT-P13: the
weight of nocebo effect. Ann Rheum Dis. 2018 (E-pub ahead of
print).
15. Glintborg B, Sorensen IJ, Loft AG, Lindegaard H, Linauskas
A, Hendricks O, et al. A nationwide non-medical switch from
originator infliximab to biosimilar CT-P13 in 802 patients with
inflammatory arthritis: 1-year clinical outcomes from the DANBIO registry. Ann Rheum Dis. 2017;76(8):1426–31.
16. Holroyd CR, Parker L, Bennett S, Zarroug J, Underhill C, Davidson B, et al. Switching to biosimilar infliximab: real world data in
patients with severe inflammatory arthritis. Clin Exp Rheumatol.
2018;36(1):171–2.
17. Nikiphorou E, Hannonen P, Asikainen J, Borodina J, Kokko A,
Paalanen K, et al. Survival and safety of infliximab bio-original
and infliximab biosimilar (CT-P13) in usual rheumatology care.
Clin Exp Rheumatol. 2019;37(1):55–9.
18. Kristensen LE, Alten R, Puig L, Philipp S, Kvien TK, Mangues
MA, et al. Non-pharmacological effects in switching medication:
the nocebo effect in switching from originator to biosimilar agent.
BioDrugs. 2018;32(5):397–404.
19. Kim SK, Choe JY, Lee SS, Shin K. Body mass index is related
with the presence of syndesmophyte in axial spondyloarthritis: data from the Korean College of Rheumatology BIOlogics
(KOBIO) registry. Mod Rheumatol. 2017;27(5):855–61.
20. Park DJ, Choi SJ, Shin K, Kim HA, Park YB, Kang SW, et al.
Switching profiles in a population-based cohort of rheumatoid
arthritis receiving biologic therapy: results from the KOBIO registry. Clin Rheumatol. 2017;36(5):1013–22.
21. Seoul National University Hospital. Korean College of Rheumatology Biologics Registry (KOBIO). 2018. https://clinicaltrials.
gov/ct2/show/NCT01965132. Accessed 05 Feb 2019.
22. Anderson J, Caplan L, Yazdany J, Robbins ML, Neogi T, Michaud
K, et al. Rheumatoid arthritis disease activity measures: American
College of Rheumatology recommendations for use in clinical
practice. Arthritis Care Res (Hoboken). 2012;64(5):640–7.
23. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College of Rheumatology. Preliminary
definition of improvement in rheumatoid arthritis. Arthritis
Rheum. 1995;38(6):727–35.
24. Hall WJ, Wellner JA. Confidence bands for a survival curve from
censored data. Biometrika. 1980;67:133–43.
25. Favalli EG, Pregnolato F, Biggioggero M, Becciolini A, Penatti
AE, Marchesoni A, et al. Twelve-year retention rate of first-line
tumor necrosis factor inhibitors in rheumatoid arthritis: reallife data from a local registry. Arthritis Care Res (Hoboken).
2016;68(4):432–9.
26. Neovius M, Arkema EV, Olsson H, Eriksson JK, Kristensen LE,
Simard JF, et al. Drug survival on TNF inhibitors in patients with
rheumatoid arthritis comparison of adalimumab, etanercept and
infliximab. Ann Rheum Dis. 2015;74(2):354–60.
97
27. Hetland ML, Christensen IJ, Tarp U, Dreyer L, Hansen A, Hansen
IT, et al. Direct comparison of treatment responses, remission
rates, and drug adherence in patients with rheumatoid arthritis
treated with adalimumab, etanercept, or infliximab: results from
eight years of surveillance of clinical practice in the nationwide
Danish DANBIO registry. Arthritis Rheum. 2010;62(1):22–32.
28. Zink A, Strangfeld A, Schneider M, Herzer P, Hierse F, Stoyanova-Scholz M, et al. Effectiveness of tumor necrosis factor
inhibitors in rheumatoid arthritis in an observational cohort study:
comparison of patients according to their eligibility for major randomized clinical trials. Arthritis Rheum. 2006;54(11):3399–407.
29. Mercer LK, Galloway JB, Lunt M, Davies R, Low AL, Dixon WG,
et al. Risk of lymphoma in patients exposed to antitumour necrosis
factor therapy: results from the British Society for Rheumatology
Biologics Register for Rheumatoid Arthritis. Ann Rheum Dis.
2017;76(3):497–503.
30. Mercer LK, Regierer AC, Mariette X, Dixon WG, Baecklund E,
Hellgren K, et al. Spectrum of lymphomas across different drug
treatment groups in rheumatoid arthritis: a European registries
collaborative project. Ann Rheum Dis. 2017;76(12):2025–30.
31. Ramiro S, Sepriano A, Chatzidionysiou K, Nam JL, Smolen
JS, van der Heijde D, et al. Safety of synthetic and biological
DMARDs: a systematic literature review informing the 2016
update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis. 2017;76(6):1101–36.
32. European Medicines Agency. Remsima Summary of Product
Characteristics. 2019. https ://www.ema.europ a.eu/docum ents/
product-information/remsima-epar-product-information_en.pdf.
Accessed 5 Feb 2019.
33. European Medicines Agency. Remicade Summary of Product
Characteristics. 2018. https ://www.ema.europ a.eu/docum ents/
product-information/remicade-epar-product-infor mation_en.pdf.
Accessed 13 Dec 2018.
34. Gulacsi L, Brodszky V, Baji P, Kim H, Kim SY, Cho YY, et al.
Biosimilars for the management of rheumatoid arthritis: economic considerations. Expert Rev Clin Immunol. 2015;11(Suppl
1):S43–52.
35. Brodszky V, Baji P, Balogh O, Pentek M. Budget impact analysis
of biosimilar infliximab (CT-P13) for the treatment of rheumatoid arthritis in six Central and Eastern European countries. Eur
J Health Econ. 2014;15(Suppl 1):S65–71.
36. Schulze-Koops H, Skapenko A. Biosimilars in rheumatology: a
review of the evidence and their place in the treatment algorithm.
Rheumatology (Oxford). 2017;56(suppl_4):iv30–iv48.
37. Yoo DH. The rise of biosimilars: potential benefits and drawbacks in rheumatoid arthritis. Expert Rev Clin Immunol.
2014;10(8):981–3.
38. Goll GL, Jorgensen KK, Sexton J, Olsen IC, Bolstad N, Haavardsholm EA, et al. Long-term efficacy and safety of biosimilar
infliximab (CT-P13) after switching from originator infliximab:
open-label extension of the NOR-SWITCH trial. J Intern Med.
2019;285(6):653–69.
39. Kim J, Ha D, Song I, Park H, Lee SW, Lee EK, et al. Estimation of cost savings between 2011 and 2014 attributed to infliximab biosimilar in the South Korean healthcare market: realworld evidence using a nationwide database. Int J Rheum Dis.
2018;21(6):1227–36.
40. Aladul MI, Fitzpatrick RW, Chapman SR. Impact of infliximab
and etanercept biosimilars on biological disease-modifying antirheumatic drugs utilisation and NHS budget in the UK. BioDrugs.
2017;31(6):533–44.
41. Jha A, Upton A, Dunlop WC, Akehurst R. The budget impact
of biosimilar infliximab (Remsima(R)) for the treatment of
autoimmune diseases in five European countries. Adv Ther.
2015;32(8):742–56.
98
H.-A. Kim et al.
42. Westhovens R, Yoo DH, Jaworski J, Matyska-Piekarska E, Smiyan
S, Ivanova D, et al. Novel formulation of CT-P13 for subcutaneous
administration in patients with rheumatoid arthritis: initial results
from a phase I/III randomised controlled trial. Ann Rheum Dis.
2018;77(THU0191).
43. Yoo D-H, Westhovens R, Ben-Horin S, Reinisch W, Schreiber
S, Ye BD, et al. Development of a subcutaneous formulation of
CT-P13 (infliximab): maintenance subcutaneous administration
may elicit lower immunogenicity compared to intravenous treatment. Arthritis Rheumatol. 2018;70(Abstract 2514).
44. Viola M, Sequeira J, Seica R, Veiga F, Serra J, Santos AC, et al.
Subcutaneous delivery of monoclonal antibodies: how do we get
there? J Control Release. 2018;286:301–14.
45. Hur JW, Choe JY, Kim DW, Kim HA, Kim SH, Kim WU, et al.
Rheumatoid arthritis patients fulfilling Korean National Health
Insurance reimbursement guidelines for anti-tumor necrosis factor-alpha treatment and comparison to other guidelines. Rheumatol Int. 2015;35(11):1817–23.
Affiliations
Hyoun‑Ah Kim1
Kichul Shin4
· Eunyoung Lee2,3 · Sun‑Kyung Lee4 · Yong‑Beom Park5 · Young Nam Lee6
1
Department of Rheumatology, Ajou University School
of Medicine, Suwon, Republic of Korea
2
Department of Biomedical Informatics, Ajou University
School of Medicine, Suwon, Republic of Korea
3
Office of Biostatistics, Ajou Research Institute for Innovative
Medicine, Ajou University Medical Center, Suwon,
Republic of Korea
· Hee Jung Kang6 ·
4
Division of Rheumatology, Seoul Metropolitan
Government-Seoul National University Hospital Boramae
Medical Center, Seoul, Republic of Korea
5
Department of Internal Medicine (Division
of Rheumatology), Yonsei University College of Medicine,
Severance Hospital, Seoul, Republic of Korea
6
Celltrion Healthcare Co. Ltd., Incheon, Republic of Korea