BioDrugs

DOI 10.1007/s40259-016-0193-2

ADIS DRUG EVALUATION

Infliximab Biosimilar (CT-P13; Infliximab-dyyb): A Review

in Autoimmune Inflammatory Diseases
Hannah A. Blair1 Emma D. Deeks1

Springer International Publishing Switzerland 2016

Abstract Infliximab biosimilar (CT-P13/infliximab-dyyb;
Remsima, Inflectra) is approved in several countries for
use in all indications for which reference infliximab
(Remicade) is approved, including rheumatoid arthritis
(RA), ankylosing spondylitis (AS), psoriatic arthritis, pso-
riasis, Crohns disease, and ulcerative colitis. Clinical data
contributing to the EU approval of infliximab biosimilar
were obtained from two pivotal double-blind clinical trials
in patients with AS (PLANETAS) or RA (PLANETRA).
Infliximab biosimilar demonstrated equivalence to refer-
ence infliximab in terms of its pharmacokinetic profile in
patients with AS, patients with RA, and in healthy volun-
teers, and in terms of its efficacy in patients with RA.
Clinical response rates in patients with RA or AS were
maintained over the longer term (up to 102 weeks). In
addition, the efficacy of infliximab biosimilar in patients
with RA or Crohns disease and ulcerative colitis [i.e.
inflammatory bowel disease (IBD)] has been demonstrated
in the real-world setting. Infliximab biosimilar was gener-
ally well tolerated, with a tolerability profile similar to that
The manuscript was reviewed by: S. Ben-Horin, Gastroenterology
Department, Sheba Medical Center and Sackler School of Medicine,
Tel-Aviv University, Tel Hashomer, Israel; K. Gecse, First
Department of Medicine, Semmelweis University, Budapest,
Hungary; W. Park, Inha University Medical School, Rheumatology,
Incheon, Republic of Korea; D. H. Yoo, Division of Rheumatology,
Hanyang University Hospital for Rheumatic Diseases, Seoul,
Republic of Korea.
& Hannah A. Blair
demail@springer.com
1
Springer, Private Bag 65901, Mairangi Bay, 0754 Auckland,
New Zealand
of reference infliximab. Switching from reference infliximab
to infliximab biosimilar had no detrimental effect on
efficacy, safety, or immunogenicity compared with con-
tinuous infliximab biosimilar therapy, according to the
extensions of PLANETAS and PLANETRA, and real-
world data in IBD. Current evidence therefore suggests that
infliximab biosimilar is a useful alternative to reference
infliximab in patients with autoimmune inflammatory
diseases.
Infliximab biosimilar: clinical considerations in
autoimmune inflammatory diseases
The first biosimilar monoclonal antibody to be
approved in the EU and in the USA
Approved for use in all indications in which
reference infliximab is approved (RA, AS, psoriatic
arthritis, psoriasis, Crohns disease, and ulcerative
colitis)
Equivalent to reference infliximab in terms of
pharmacokinetics in patients with AS, patients with
RA, and in healthy volunteers, and in terms of
efficacy in patients with RA
Effective in the induction and maintenance of
clinical remission in patients with IBD
Generally well tolerated, with a similar safety profile
to that of reference infliximab
Switching from reference infliximab has no negative
impact on efficacy, safety, or immunogenicity
Potentially cost saving to healthcare systems
 H. A. Blair, E. D. Deeks

1 Introduction and have been previously described in detail [18]. Briefly,

infliximab is a chimeric human-murine monoclonal anti-
body that specifically binds with high affinity to both sol-
Conventional synthetic disease-modifying antirheumatic
uble and membrane-bound TNF-a [1113], thereby
drugs (csDMARDs) such as methotrexate are commonly
preventing TNF-a receptor activation and neutralizing the
used in the management of autoimmune inflammatory dis-
biologic activity of TNF-a [16, 17].
eases such as rheumatoid arthritis (RA), psoriatic arthritis
In in vitro studies, infliximab biosimilar and reference
(PsA) and psoriasis [1]. The introduction of targeted biologic
infliximab demonstrated comparable binding affinities for
DMARDs (bDMARDs) has had a significant impact on the
soluble monomeric and trimeric forms of TNF-a, mem-
standard treatment of autoimmune diseases [1, 2]. First-line
brane-bound TNF-a, complement component C1q, and the
bDMARDs include tumor necrosis factor (TNF) inhibitors
Fcc receptors RI, RII, and Rn [16, 17]. Infliximab biosimilar
such as infliximab, which are widely used to treat RA [3, 4],
exhibited a lower level of afucosylated glycans than refer-
ankylosing spondylitis (AS) [5, 6], PsA [7], psoriasis [8],
ence infliximab, which translated into a lower binding
Crohns disease, and ulcerative colitis [i.e. inflammatory
affinity for FccRIIIa and lower antibody-dependent cellular
bowel disease (IBD)] [9, 10]. However, despite their proven
cytotoxicity in the most sensitive experimental assay
efficacy, the use of biologics is often hindered by the high
[16, 17]. However, this difference disappeared in the
costs associated with their development and production
physiologic environment (i.e. when serum was added), and
[1, 2]. It is expected that the availability of biosimilar ver-
was not considered to have any clinically relevant impact on
sions of established biologics may facilitate improved access
the efficacy and safety of infliximab biosimilar [16, 17, 19].
to therapy and reduce the economic burden on healthcare
As both infliximab and its biosimilar are biologic agents,
budgets through reduced drug costs [2].
antibodies can develop against them. Analyses of serum
CT-P13/infliximab-dyyb (Inflectra, Remsima), here-
samples taken from patients with rheumatic diseases [20]
after referred to as infliximab biosimilar, was the first
or IBD [21] showed that anti-drug antibodies (ADAs) to
biosimilar monoclonal antibody to be approved in the EU
infliximab in Remicade-treated patients were cross-reactive
and in the USA. Infliximab biosimilar is approved in a
with infliximab biosimilar, suggesting that reference
number of countries, including the EU [11, 12] and the
infliximab and infliximab biosimilar have similar
USA [13], for the same indications as reference infliximab
immunogenicity and shared epitopes. The development of
(Remicade): RA, AS, PsA, psoriasis, Crohns disease, and
ADAs against infliximab biosimilar is discussed in Sect. 5.
ulcerative colitis. A review of the results of a comparability
Although further studies are required, these results imply
exercise demonstrating the biosimilarity of infliximab
that loss of response and infusion-related reactions may
biosimilar to reference infliximab was published in
occur if ADA-positive patients are switched from reference
BioDrugs in 2014 [14]. Since then, additional clinical data
infliximab to infliximab biosimilar [20, 21].
have become available. This article provides an updated
review of the efficacy and tolerability of infliximab
biosimilar in patients with autoimmune inflammatory dis-
eases, with discussion focusing on recently published data. 3 Pharmacokinetic Properties
A brief overview of the pharmacologic properties of
infliximab biosimilar is also provided. The pharmacokinetic profile of infliximab biosimilar, as
assessed by the area under the concentration-time curve
(AUC) and the maximum serum concentration (Cmax), was
2 Pharmacodynamic Properties equivalent to that of reference infliximab in randomized,
double-blind trials conducted in patients with AS (PLANETAS;
Infliximab biosimilar is identical to reference infliximab in Sect. 4.2) [22], Japanese patients with RA receiving
terms of primary structure and highly similar to reference methotrexate (Sect. 4.1.1) [23], and healthy volunteers [24]
infliximab in terms of higher order structure, monomer and (primary endpoints).
aggregate contents, overall glycan type and distribution, The AUC and Cmax of infliximab increase in a dose-
potency, and binding affinity, according to comprehensive proportional manner following single intravenous infusions
physicochemical characterization studies [15]. Qualitative of 120 mg/kg [11, 12]. Distribution of the drug is mainly
and quantitative formulation studies demonstrated that intravascular [1113]. Infliximab is slowly cleared from the
infliximab biosimilar was adequately robust with regard to body, with a median terminal half-life of 7.79.5 days
product quality and stability [16, 17]. following single-dose administration (310 mg/kg) in
Infliximab biosimilar has the same pharmacologic patients with RA, plaque psoriasis, or Crohns disease [13].
effects as reference infliximab, which are well established After repeated administration [every 4 or 8 weeks in
Infliximab Biosimilar: A Review
patients with RA, or at 0, 2, and 6 weeks (induction phase)
in patients with fistulizing Crohns disease], there is some
accumulation after the second dose [11, 12]. Repeated
treatment does not lead to any further clinically relevant
systemic accumulation. In most patients with fistulizing
Crohns disease, serum concentrations of infliximab are
detectable for 12 weeks after repeated administration. The
drug is detectable in most patients for 8 weeks after a
recommended single dose. The elimination pathways of
infliximab are unknown; unchanged drug is not detected in
urine [11, 12].
The pharmacokinetics of infliximab have not been
assessed in elderly patients [11, 12] or in patients with
marked hepatic or renal impairment [13]. The pre-
scribing information states that there are no major
effects of age, bodyweight, or gender on the clearance
or volume of distribution of infliximab [1113]. How-
ever, a population pharmacokinetic study in patients
with Crohns disease [25] found that the clearance of
infliximab appeared to be influenced by bodyweight,
albumin, and the presence of antibodies against infliximab.
The pharmacokinetics of infliximab in pediatric patients
(aged 617 years) with Crohns disease were similar to
those in adults [13].
Because treatment with infliximab may normalize the
formation of cytochrome P450 (CYP) enzymes, therapeu-
tic monitoring should be considered when initiating or
discontinuing infliximab biosimilar in patients receiving
concomitant CYP substrates with a narrow therapeutic
index (e.g. warfarin, ciclosporin, theophylline) [13].
Plasma concentrations of infliximab may be increased by
concomitant use of immunomodulators (e.g. methotrexate)
in patients with RA, PsA or Crohns disease [11, 12].
Coadministration of corticosteroids does not appear to have
a clinically relevant effect on the pharmacokinetics of
infliximab [11, 12]. Serum concentrations of infliximab do
not seem to be affected by baseline use of corticosteroids,
aminosalicylates, or antibacterials [13].
4 Therapeutic Efficacy of Infliximab Biosimilar
The EU approval of infliximab biosimilar was supported by
the results of a clinical trial programme consisting of a
phase III study in patients with RA (PLANETRA; Sect. 4.1)
and a phase I study in patients with AS (PLANETAS;
Sects. 3 and 4.2). Comparability testing enabled extrapo-
lation of infliximab biosimilar approval to all other indi-
cations for which reference infliximab is approved,
including PsA, psoriasis, adult and pediatric Crohns dis-
ease, and adult and pediatric ulcerative colitis. Subsequent
to this approval, a large number of real-world studies
evaluated the efficacy of infliximab biosimilar in patients
with inflammatory arthritis (Sects. 4.1.2 and 4.4) and in
patients with IBD (Sects. 4.3 and 4.4).
4.1 In Patients with Rheumatoid Arthritis
The efficacy of infliximab biosimilar for the treatment of
RA was assessed in two randomized, double-blind, multi-
centre trials: PLANETRA [26] (the focus of this section)
and a small supportive Japanese phase I/II study (designed
primarily to assess pharmacokinetics; Sect. 3) with similar
inclusion/exclusion criteria and administration schedules as
PLANETRA [23, 27]. The studies enrolled patients aged
1875 [26] or 2075 [23] years with active RA and an
inadequate response to methotrexate (see Table 1 for
details). Concomitant use of oral glucocorticoids and non-
steroidal anti-inflammatory drugs (NSAIDs) was allowed if
dosages had been stable for C4 weeks prior to screening
[26]. Patients were randomized to receive infliximab
biosimilar or reference infliximab 3 mg/kg via 2-h intra-
venous infusion at weeks 0, 2, and 6, and then every
8 weeks up to week 30 [26] or 54 [23]. All patients
received methotrexate (12.525 [26] or 616 [23]
mg/week) and folic acid B5 [23] or C5 [26] mg/week
during the studies. Data from the Japanese study are dis-
cussed separately in Sect. 4.1.1.
At baseline, patients had a median age of 50 years and
the mean duration of prior methotrexate therapy was
93.6 weeks [26]. The primary endpoint was the American
College of Rheumatology 20 % (ACR20) response at
week 30 [26]. ACR responses were assessed in both the
intention-to-treat (ITT) and per-protocol (PP) populations
and all other endpoints were assessed in the PP population
unless otherwise specified.
In RA patients with an inadequate response to methotrex-
ate, the efficacy of adding infliximab biosimilar was equiva-
lent to that of adding reference infliximab in terms of
improving the signs and symptoms of RA, as the 95 % con-
fidence intervals for treatment differences for ACR20
response at week 30 were within the pre-specified equiva-
lence margin of 15 % in both the ITT and PP populations
(Table 1) [26]. The median time to onset of ACR20 was
99 days with infliximab biosimilar and 100 days with refer-
ence infliximab. ACR20 response rates with infliximab
biosimilar and reference infliximab did not appear to be
affected by baseline C-reactive protein (CRP) level, according
to an ITT post hoc sensitivity analysis (58.7 and 58.6 % in
patients with a baseline CRP level of[2 mg/dL, and 61.9 and
58.5 % in patients with a CRP level of B2 mg/dL) [26].
Other secondary endpoints demonstrated similar results
with infliximab biosimilar and reference infliximab [26].
For instance, ACR50 and ACR70 response rates at
week 30 were not significantly different between treatment
groups (Table 1). At week 30, 85.8 % of infliximab
 H. A. Blair, E. D. Deeks

Table 1 Efficacy of infliximab biosimilar compared with reference infliximab in patients with rheumatoid arthritis in the PLANETRA trial at 30
[26] and 54 [28] weeks
Tmt (no. of pts) Response (% pts) ACR/EULAR remission (% pts)
ACR20 ACR50 ACR70 Boolean-baseda Index-basedb

ITT population at week 30

INX biosimilar (n = 302) 60.9c 35.1 16.6 4.3 8.9
Reference INX (n = 304) 58.6c 34.2 15.5 4.6 7.2
Tmt difference (%) [95 % CI] 2 [-6 to 10] NR NR
PP population at week 30
INX biosimilar (n = 248) 73.4c 42.3 20.2 6.9 9.7
Reference INX (n = 251) 69.7c 40.6 17.9 6.8 9.6
Tmt difference (%) [95 % CI] 4 [-4 to 12] 2 [-7 to 10] 2 [-5 to 9]
ITT population at week 54
INX biosimilar (n = 302) 57.0 33.1 16.2 5.0 7.6
Reference INX (n = 304) 52.0 31.6 15.2 5.9 7.6
d
PP population at week 54
INX biosimilar (n = 225) 74.7 43.6 21.3 NR NR
Reference INX (n = 216) 71.3 43.1 19.9 NR NR
Pts had active disease for C1 year prior to screening, C6 swollen and C6 tender joints and C2 of the following: morning stiffness lasting
C45 min, CRP concentration of [2.0 mg/dL, and erythrocyte sedimentation rate of [28 mm/h despite methotrexate for C3 months
ACR American College of Rheumatology, ACR20, 50, or 70 20, 50, or 70 % improvement in ACR criteria, CRP C-reactive protein, EULAR
European League Against Rheumatism, INX infliximab, ITT intention-to-treat, NR not reported, PP per-protocol, pts patients, tmt treatment
a
Swollen joint count and tender joint count B1, CRP B1 mg/dL, and patient global visual analogue scale B1 using a 010 scale
b
Simplified Disease Activity Index B3.3
c
Primary endpoint. Equivalence of INX biosimilar with reference INX was shown, as the 95 % CI for the estimated tmt difference was within
the pre-specified equivalence margin of 15 %
d
Nonresponder imputation approach

biosimilar and 87.1 % of reference infliximab recipients
achieved a good or moderate European League Against
Rheumatism (EULAR) response (CRP) at week 30 (rela-
tive risk 0.98; 95 % CI 0.921.06) [26].
Infliximab biosimilar and reference infliximab also did
not significantly differ in terms of disease activity measures
at week 30, including improvements from baseline in
tender and swollen joint counts, Clinical Disease Activity
Index (CDAI), and Simplified Disease Activity Index
(SDAI) scores, or the proportion of patients who achieved
low disease activity or remission based on the Disease
Activity Score in 28 joints (DAS28)-erythrocyte sedimen-
tation rate (ESR; 26 vs. 24 %) or -CRP (41 vs. 39 %) [26].
Up to 10 % of patients in each group achieved remission,
as measured by ACR/EULAR criteria (Table 1), and few
patients required salvage therapy with a DMARD, NSAID,
or biologic (3.2 vs. 4.0 %) [26].
According to a post hoc subgroup analysis, there were
no statistically significant between-group differences in
ACR20, ACR50, ACR70, and EULAR responses and
DAS28 scores according to ADA status at week 30 [26].
A total of 455 patients in PLANETRA continued to
receive infliximab biosimilar or reference infliximab up to
week 54 [28]. Longer term, at week 54, the proportion of
patients achieving ACR20, ACR50, and ACR70 responses
continued to be similar in both treatment groups (Table 1)
and improvements in disease activity [as measured by
mean changes from baseline in DAS28 (ESR or CRP),
CDAI, and SDAI scores] were also maintained with each
regimen [28]. The efficacy of infliximab biosimilar was
maintained over up to 102 weeks of treatment in the
extension of this study (Sect. 4.4).
In a subgroup of patients who had radiographs at base-
line and week 54 (n = 336), joint damage progression
(assessed using the Sharp scoring system) was comparable
between infliximab biosimilar and reference infliximab
[28]. At week 54, the mean change from baseline in total
Sharp score (1.0 vs. 0.6), joint space narrowing score (0.4
vs. 0.7), and erosion score (0.7 vs. 0.0) was not signifi-
cantly different between treatment groups. In addition,
52 % of infliximab biosimilar and 51 % of reference
infliximab recipients had no radiographic progression in
total Sharp score (B0 units of change from baseline); the
between-group difference was not significant [28].
Infliximab biosimilar and reference infliximab recipients
reported improvements in measures of health-related
Infliximab Biosimilar: A Review
quality of life (HR-QOL) [Health Assessment Question-
naire (HAQ) and Short Form Health Survey (SF-36)] and
pain (visual analogue scale) at weeks 30 [26] and 54 [28],
with the difference between the two treatments not being
significant where specified [26].
4.1.1 In Japanese Patients
Support for the comparable efficacy of infliximab biosim-
ilar and reference infliximab in RA comes from a small
(n = 101 full analysis set) trial in Japanese patients [23].
ACR20 response rates at weeks 14, 30, and 54 were not
significantly different between infliximab biosimilar (74.0,
78.0, and 64.0 %, respectively) and reference infliximab
(70.6, 64.7, and 49.0 %, respectively). In addition, there
were no significant between-group differences in ACR50,
ACR70, or EULAR response rates at any timepoint, with
the exception of the ACR70 response rate at week 54
(42.0 % with infliximab biosimilar vs. 13.7 % with refer-
ence infliximab; p = 0.002). Improvements from baseline
in DAS28 (ESR or CRP), SDAI, CDAI, and HAQ Dis-
ability Index (HAQ-DI) scores were not significantly dif-
ferent between treatment groups, except for improvements
in DAS28-CRP and HAQ-DI scores at week 54, which
were significantly (p \ 0.05) greater with infliximab
biosimilar versus reference infliximab [23].
4.1.2 Real-World Experience
Data from a real-world RA setting were consistent with
those from clinical trials (Sects. 4.1 and 4.1.1), according
to an analysis of 98 patients from the prospective BIOPSY
registry in South Korea (available as an abstract) [29]. The
majority of patients were nave to biologic therapy. The
early DAS28-ESR remission rates 6 or 9 months after
starting infliximab biosimilar and reference infliximab
were 18.6 and 15.6 %, respectively. The change from
baseline in HAQ-DI scores was not significantly different
between treatment groups [29].
4.2 In Patients with Ankylosing Spondylitis
The efficacy of infliximab biosimilar in patients with AS
was investigated in the randomized, double-blind, multi-
centre PLANETAS trial [22]. While the primary endpoint of
the study was to demonstrate pharmacokinetic equivalence
between infliximab biosimilar and reference infliximab
(Sect. 3), efficacy endpoints were also assessed. Eligible
patients were aged 1875 years with active AS for
C3 months prior to screening (see Table 2 for details).
Concomitant treatment with oral glucocorticoids and
NSAIDs was permitted if dosages had been stable for
C4 weeks prior to screening. The median age at baseline
was 38 years, and 25 % of patients had a Bath Ankylosing
Spondylitis Disease Activity Index (BASDAI) score of
[810 (i.e. more severe disease). A total of 250 patients
were randomized to receive a 2-h intravenous infusion of
infliximab biosimilar or reference infliximab 5 mg/kg at
weeks 0, 2, and 6, and then every 8 weeks up to week 30
[22]. Of these, 210 patients completed 54 weeks of treat-
ment with infliximab biosimilar or reference infliximab [30].
Improvements in the signs and symptoms of AS did not
significantly differ between infliximab biosimilar and ref-
erence infliximab, as assessed by Assessment in Ankylos-
ing Spondylitis (ASAS) 20 and ASAS40 response rates
after 14, 30, or 54 weeks of treatment (Table 2) [22, 30].
There were also no marked between-group differences in
improvements in other efficacy measures assessing disease
activity (including Ankylosing Spondylitis Disease Activ-
ity Score-CRP and BASDAI), spinal mobility (Bath
Ankylosing Spondylitis Metrology Index), physical func-
tioning (Bath Ankylosing Spondylitis Functional Index), or
chest expansion (Table 2). At week 54, the proportion of
patients achieving ASAS partial remission was 19.8 % in
the infliximab biosimilar group and 17.6 % in the reference
infliximab group [30]. The efficacy of infliximab biosimilar
was maintained for up to 102 weeks in an extension of this
study (Sect. 4.4).
Infliximab biosimilar was associated with improvements
in HR-QOL, as measured by the SF-36 [22, 30]. SF-36
physical and mental component summary scores were
improved from baseline in both treatment groups at
weeks 14 and 30 [22], with the improvements maintained
at week 54 [30].
ASAS20 and ASAS40 response rates were not signifi-
cantly different between infliximab biosimilar and refer-
ence infliximab irrespective of ADA status at week 30
[22]. However, post hoc subgroup analyses demonstrated
that ADA-positive patients may have a less robust ASAS20
response to infliximab biosimilar or reference infliximab
than ADA-negative patients [22, 30]. For instance, at
week 30, the proportion of infliximab biosimilar recipients
achieving an ASAS20 response was 50.0 % in ADA-positive
patients, compared with 77.4 % in ADA-negative patients
[22]. Similar results were seen at week 54 (47.8 vs.
72.3 %, respectively) [30].
4.3 In Patients with Inflammatory Bowel Disease
Extensive real-world experience has demonstrated the
efficacy of infliximab biosimilar for the treatment of IBD,
including data from several studies (of prospective
[3134], retrospective [3537], or retrospective/prospec-
tive [38] design, where specified) conducted in Poland
[33, 36, 37], Portugal [38], Hungary [31, 34], Norway [32],
the Czech Republic [34, 39], and Korea [35, 40]
 H. A. Blair, E. D. Deeks

Table 2 Efficacy of infliximab biosimilar compared with reference infliximab in patients with ankylosing spondylitis in the PLANETAS trial at
14 [22], 30 [22] and 54 [30] weeks; analyses for the intent-to-treat population (missing equals excluded approach)
Tmt (no. of pts) Response (% of pts) Mean change from BLa [BL scores]
ASAS20 ASAS40 ASDAS-CRP BASDAI BASFI BASMI Chest
expansion (cm)

At week 14
INX biosimilar (n = 115) 62.6 41.7 -1.8 [3.8] -2.9 [6.7] -2.5 [6.2] -0.7 [4.0] ?0.4 [3.2]
Reference INX (n = 122) 64.8 45.9 -1.8 [3.9] -2.8 [6.6] -2.5 [6.2] -0.7 [4.1] ?0.7 [2.9]
OR [95 % CI] 0.91 [0.531.54] 0.85 [0.511.42]
At week 30
INX biosimilar (n = 112) 70.5 51.8 -1.8 [3.8] -3.0 [6.7] -2.6 [6.2] -1.0 [4.0] ?0.6 [3.2]
Reference INX (n = 116) 72.4 47.4 -1.7 [3.9] -2.7 [6.6] -2.5 [6.2] -0.9 [4.1] ?0.8 [2.9]
OR [95 % CI] 0.91 [0.511.62] 1.19 [0.702.00]
At week 54
INX biosimilar (n = 106) 67.0 54.7 -1.7 [3.8] -3.1 [6.7] -2.9 [6.2] -1.1 [4.0] ?0.7 [3.2]
Reference INX (n = 108) 69.4 49.1 -1.7 [3.9] -2.8 [6.6] -2.7 [6.2] -0.9 [4.1] ?0.9 [2.9]
OR [95 % CI] 0.89 [0.501.59] 1.26 [0.732.15]
Patients were required to have a BASDAI score of C4 and a visual analogue scale score for spinal pain of C4
ASAS20 or 40 improvement of 20 or 40 % in Assessment in Ankylosing Spondylitis International Working Group criteria, ASDAS-CRP
Ankylosing Spondylitis Disease Activity Score based on C-reactive protein level, BASDAI Bath Ankylosing Spondylitis Disease Activity Index,
BASFI Bath Ankylosing Spondylitis Functional Index, BASMI Bath Ankylosing Spondylitis Metrology Index, BL baseline, INX infliximab, OR
odds ratio, pts patients
a
No between-group statistical analyses were reported for the mean changes from BL

(n = 60210), some of which are available as abstracts
[33, 3639]. Efficacy (e.g. clinical remission/response) in
patients with Crohns disease was assessed using the
Crohns Disease Activity Index or Harvey-Bradshaw Index
(HBI) [3133, 35, 36, 38, 40], clinical, endoscopic, and
laboratory parameters [39], and (in patients with fistulizing
Crohns disease) fistula drainage/closure [31, 35, 40].
Clinical remission, response, and mucosal healing were
assessed by the Mayo score in patients with ulcerative
colitis [31, 32, 34, 35, 37, 39, 40].
Among the comparative studies (conducted in
TNF-inhibitor-nave patients, where specified [33, 38]), a
prospective trial demonstrated no significant differences
between infliximab biosimilar and reference infliximab in
rates of remission (43.8 vs. 43.1 %) or response (81.3 vs.
62.1 %) in patients with Crohns disease (n = 74) [33].
Comparative studies of retrospective (n = 176) [36] or
retrospective/prospective (n = 60) [38] design in this set-
ting support these findings. In the former study, for instance,
both infliximab biosimilar and reference infliximab signifi-
cantly (p \ 0.01) reduced disease activity (assessed by the
HBI) over 6 and 24 weeks [38], and there was no significant
difference between infliximab biosimilar, reference infliximab,
and adalimumab in CDAI scores after 1 year of treatment
[36]. In the latter study, clinical response/remission rates in
the respective treatment groups were 75.0, 66.2, and 63.8 %
at 1 year and relapse rates during 6 months of follow-up
were 13.0, 8.7, and 14.3 % [36].
The efficacy of infliximab biosimilar in patients with
Crohns disease was confirmed in several noncomparative
studies [31, 32, 35, 39, 40]. For example, in a prospective
cohort of TNF-inhibitor-nave (n = 93) and -experienced
(n = 33) patients, early clinical remission and response
rates at week 14 were 53.6 and 81.4 % [31]. Response
rates at week 6 and remission rates at week 14 were sig-
nificantly (p \ 0.05) greater in reference infliximab-nave
patients (87.3 and 60.9 %) than in reference infliximab-
experienced patients (51.7 and 35.7 %) [31]. Data from a
retrospective study support the longer-term efficacy of
infliximab biosimilar in TNF-inhibitor-nave patients
(n = 32) [35]. In this study, infliximab biosimilar was
associated with maintenance of clinical remission and
response rates at week 54 (75.0 and 87.5 %) [35].
A comparative study demonstrated the efficacy of rescue
therapy with infliximab biosimilar in patients with ulcera-
tive colitis (n = 67) [37]. After three induction doses, rates
of clinical response (79 vs. 68 %) and remission (24 vs.
29 %) were not significantly different between infliximab
biosimilar and reference infliximab. Two patients in each
group relapsed during the 6-month follow-up period [37].
Several noncomparative studies also demonstrated the
efficacy of infliximab biosimilar in patients with ulcerative
colitis [31, 32, 34, 35, 39, 40]. For instance, in a mixed
population of TNF-inhibitor-nave (n = 68) and experi-
enced (n = 16) patients, infliximab biosimilar was associ-
ated with early clinical remission and response rates of
Infliximab Biosimilar: A Review
58.6 and 77.6 % at week 14 [31]. Response rates at week 6
and remission rates at week 14 were significantly
(p \ 0.05) greater in reference infliximab-nave patients
(81.4 and 65.1 %) than in patients previously exposed to
reference infliximab (60.0 and 33.3 %) [31]. In a retro-
spective study of TNF-inhibitor-nave patients (n = 42),
rates of clinical remission and response were maintained
over the longer term (50.0 and 100 % at week 54) [35].
This study also demonstrated mucosal healing rates of
58.3 % at week 8 and 66.7 % at weeks 30 and 54 [35].
4.4 Switching from Reference Infliximab
to Infliximab Biosimilar
Switching from reference infliximab to infliximab biosim-
ilar was not associated with any negative effects on effi-
cacy in patients with RA or AS [41, 42]. Patients who
completed 54 weeks of treatment in PLANETRA
(n = 302) [42] and PLANETAS (n = 174) [41] entered
open-label, 48-week extension studies. Those receiving
reference infliximab at week 54 were switched to infliximab
biosimilar, while patients in the infliximab biosimilar group
continued to receive the biosimilar [41, 42]. In both stud-
ies, response rates were maintained and did not signifi-
cantly differ in the switch and maintenance groups through
102 weeks [41, 42]. In PLANETRA, 71.8, 51.4, and
26.1 % of patients in the switch group (n = 144) and 71.7,
48.0, and 24.3 % of patients in the maintenance group
(n = 158) achieved ACR20, ACR50, and ACR70 respon-
ses, respectively, at week 102 [42]. In PLANETAS, the
ASAS20 and ASAS40 response rates at week 102 were
76.9 and 61.5 % in the switch group (n = 86) and 80.7 and
63.9 % in the maintenance group (n = 88); corresponding
ASAS partial remission rates were 23.1 and 19.3 % [41].
Data from the prospective DANBIO registry provided
support for the efficacy of switching from reference
infliximab to infliximab biosimilar in patients with
inflammatory arthritis (available as an abstract) [43]. Data
were available for 647 patients with RA, PsA, or axial
spondyloarthritis. The duration of prior treatment with
reference infliximab ranged from &49 years; for the
majority (77 %) of patients, reference infliximab was the
first biologic they received. Three months after switching
from reference infliximab to infliximab biosimilar, disease
activity was largely unchanged in most patients [43].
Support for the efficacy of switching from reference
infliximab to infliximab biosimilar was also provided by
real-world studies in patients with IBD [35, 40, 4452],
some of which are available as abstracts [4447, 5052].
All studies demonstrated maintenance of clinical response
or remission after switching [35, 40, 4452]. In the largest
of these (PROSIT-BIO), 53 patients with Crohns disease
and 44 patients with ulcerative colitis were switched to
infliximab biosimilar after a mean of 18 previous infliximab
infusions; a further 450 patients receiving infliximab
biosimilar who were TNF inhibitor-nave (n = 311) or had
been previously exposed to C1 biologic (n = 139) were
also included in the study [44]. After 6 months follow-up,
89.7 % of evaluable patients who switched from reference
infliximab to infliximab biosimilar were responders, with
primary failure and loss of response seen in 1.0 and 15.6 %
of patients, respectively. Loss of response also occurred in
13.0 % of TNF inhibitor-nave patients and 16.5 % of pre-
exposed patients [44].
5 Tolerability of Infliximab Biosimilar
Infliximab biosimilar was generally well tolerated over up
to 54 weeks of treatment in patients with RA [26, 28] and
AS [22, 30], with a tolerability profile similar to that of
reference infliximab. Treatment-related adverse events
(AEs) occurred in 43.7 % of infliximab biosimilar recipi-
ents and 45.0 % of reference infliximab recipients in
PLANETRA [28] and 50.0 and 51.6 %, respectively, in
PLANETAS [30]. The majority of AEs were of mild to
moderate severity, with abnormal liver function tests,
infusion-related reactions (Sect. 5.1), latent tuberculosis
(TB), and upper respiratory tract infections (Sect. 5.2) the
most frequently reported (B5 % incidence) treatment-re-
lated AEs [28, 30]. Serious treatment-related AEs occurred
in 7.6 % of infliximab biosimilar recipients and 4.7 % of
reference infliximab recipients in PLANETRA [28], and
3.1 and 4.1 %, respectively, in PLANETAS [30]. None of
the deaths in PLANETRA (one in the reference infliximab
group) or PLANETAS (one in each treatment group) were
considered treatment related [28, 30].
The tolerability profile of infliximab biosimilar in patients
with IBD was consistent with that observed during RA or AS
trials, with no unexpected tolerability findings reported
[31, 32, 35, 37, 39, 40]. For instance, in an ongoing, open-
label, phase IV post-marketing study in which 173 patients
with Crohns disease or ulcerative colitis received infliximab
biosimilar (starting dose 5 mg/kg) for 30 weeks [40], treat-
ment-related AEs were reported in 10.4 % of patients, most of
which were mild or moderate in severity. The most common
treatment-related AEs were infusion-related reactions,
pyrexia, and pruritus. There were four serious treatment-related
AEs, three of which led to discontinuation of infliximab
biosimilar (infusion-related reaction, lung abscess, and
anaphylaxis); no deaths occurred [40].
Longer term, infliximab biosimilar continued to be
generally well tolerated in patients with RA or AS,
according to open-label extensions of PLANETRA and
PLANETAS [41, 42]. Switching from reference infliximab
to infliximab biosimilar at week 54 had no detrimental

effect on safety over a further 48 weeks of treatment
[41, 42]. Treatment-related AEs occurred in 18.9 % of
patients switched from reference infliximab to infliximab
biosimilar and 22.0 % of patients maintained on the
biosimilar in the PLANETRA extension [42], and in 39.3
and 22.2 % of patients in the switch and maintenance
groups of the PLANETAS extension [41]. Real-world
studies also showed that switching from reference infliximab
to infliximab biosimilar was generally well tolerated in
patients with IBD [4452].
As with all biologics, there are also warnings and pre-
cautions for infliximab relating to hepatitis B virus reacti-
vation, hepatotoxicity, hematologic reactions,
hypersensitivity, and neurologic reactions [13]; please see
local prescribing information for further details.
5.1 Immunogenicity and Infusion-Related Reactions
As with all therapeutic proteins, infliximab biosimilar has
the potential for immunogenicity. Indeed, a proportion of
RA or AS patients tested positive for ADAs after treatment
with infliximab biosimilar or reference infliximab in
PLANETRA [26, 28] (e.g. 41.1 and 36.0 % at week 54)
[28] and PLANETAS [22, 30] (e.g. 19.5 and 23.0 % at
week 54) [30]. Longer term, the proportion of ADA-positive
patients was 44.8 and 40.3 % in the switch and mainte-
nance groups of the PLANETRA extension [42], and 27.4
and 23.3 % in the respective groups of the PLANETAS
extension [41]. In both studies, the majority of patients who
were ADA-positive also had neutralizing antibodies
[28, 30, 41, 42]. In support of these findings, switching
from reference infliximab to infliximab biosimilar was not
associated with an increase in immunogenicity in patients
with IBD in real-world studies [47, 51, 53], including
children with Crohns disease [53].
Infliximab products have been associated with acute
infusion-related reactions during or after infusion [1113].
Infusion-related reactions (treatment related) occurred in
9.9 and 14.3 % of infliximab biosimilar and reference
infliximab recipients in PLANETRA [28] and 8.6 and
12.3 %, respectively, in PLANETAS [30]. When 30-week
data were assessed according to ADA status, the rate of
infusion-related reactions with infliximab biosimilar and
reference infliximab was 6.7 and 13.3 % in ADA-positive
patients and 4.2 and 2.8 % in ADA-negative patients in
PLANETRA [26], and 3.1 and 11.1 % in ADA-positive
patients and 3.4 and 2.2 % in ADA-negative patients in
PLANETAS [22]. In patients with IBD, there were 10.06
infusion-related reactions per 100 patient-years in the post-
marketing study [40], and a significantly (p \ 0.001)
greater incidence of infusion-related reactions with infliximab
biosimilar in patients who had previously received infliximab
compared with those who were infliximab-nave (27 vs.
H. A. Blair, E. D. Deeks
2.5 %) in a prospective cohort study [31]. Patients should
be observed for acute infusion-related reactions for at least
12 h after the infusion [11, 12]. Patients treated with
infliximab products may be pre-medicated with antihis-
tamines, hydrocortisone, and/or paracetamol [1113].
Severe or serious hypersensitivity reactions to infliximab
biosimilar should be treated symptomatically, and the drug
should be discontinued [1113].
5.2 Infections
Treatment with infliximab products is associated with an
increased risk of serious infections leading to hospitaliza-
tion or death, such as TB (including reactivation of latent
disease), invasive fungal infections, bacterial infections,
viral infections, and infections due to other opportunistic
pathogens [1113]. In the USA, infliximab biosimilar car-
ries a boxed warning regarding the increased risk of serious
infection [13]. The most common treatment-related infec-
tions (incidence C3 %) over 54 weeks in patients with RA
or AS in PLANETRA and PLANETAS were upper respi-
ratory tract infection, latent TB, urinary tract infection, and
lower respiratory tract infection [28, 30]; however, active
TB was uncommon with infliximab biosimilar and refer-
ence infliximab in PLANETRA (1.0 vs. 0 %) [28] and
PLANETAS (1.6 vs. 0.8 %) [30]. In patients with IBD in
the post-marketing study, there were 10.06 infections (re-
gardless of causality) per 100 patient-years, 1.11 active TB
events per 100 patient-years and no cases of pneumonia
[40]. All patients should be evaluated for infections before,
during, and after treatment with infliximab biosimilar, and
the drug should be discontinued if a patient develops a
serious infection or sepsis during treatment [1113].
5.3 Malignancies
Malignancies, some fatal, have been observed in clinical
trials and post-marketing surveillance in patients receiving
TNF inhibitors (including infliximab products) [1113]; a
boxed warning has been given for infliximab biosimilar in
the USA [13]. In PLANETRA, two patients receiving
reference infliximab discontinued treatment due to breast
cancer and cervical cancer [26]. During the PLANETRA
extension, three patients in the switch group and two
patients in the maintenance group developed malignancies
[42]. There was one serious case of basal cell carcinoma in
the infliximab biosimilar group in PLANETAS; this was
not considered to be treatment related [22, 30]. One serious
case of prostate cancer was reported in the maintenance
group during the PLANETAS extension and was consid-
ered to be unrelated to the study drug [41]. No cases of
malignancy occurred in patients with IBD during the post-
marketing study [40]. Caution is advised when considering
Infliximab Biosimilar: A Review
the use of infliximab biosimilar in patients with a history of
malignancy, or when continuing infliximab biosimilar
treatment in patients who develop a malignancy [1113].
6 Dosage and Administration
Infliximab biosimilar is approved in a number of countries,
including those of the EU [11, 12] and the USA [13], as a
biosimilar for use in all indications for which reference
infliximab is approved. Infliximab biosimilar is indicated
for the treatment of RA (in combination with methotrexate),
PsA (with or without methotrexate in the EU [11, 12]), AS,
psoriasis, Crohns disease, and ulcerative colitis in adults
[1113]. It is also indicated for the treatment of pediatric
(617 years) Crohns disease in the EU and USA [1113]
and pediatric ulcerative colitis in the EU [11, 12].
Infliximab biosimilar should be administered as an
intravenous infusion with weight-based dosing over 2 h in
the EU [11, 12] or C2 h in the USA [13]. Dosage regimens
differ between patient groups, countries, and indications;
please see local prescribing information for details.
In the EU, no dosage adjustment of infliximab biosim-
ilar is required in elderly patients (aged C65 years)
[11, 12]. However, caution is advised because of an
increased risk of serious infections [1113]. The use of
infliximab biosimilar has not been studied in patients with
renal and/or hepatic impairment [11, 12].
Owing to an increased risk of worsening heart failure
(which may lead to hospitalization or death) in patients
receiving infliximab, the biosimilar (at doses [5 mg/kg
[13]) is contraindicated in patients with moderate to severe
[New York Heart Association (NYHA) class III/IV] heart
failure [1113]; cautious use is advised in patients with
mild (NYHA class I/II) heart failure [11, 12]. Concomitant
treatment with tocilizumab [13], anakinra, abatacept, or
other biologics [1113] is not recommended due to an
increased risk of adverse events (e.g. serious infections).
Local prescribing information should be consulted for
comprehensive information regarding contraindications,
warnings, precautions, drug interactions, and use of
infliximab biosimilar in special patient populations.
7 Current Status of Infliximab Biosimilar
in Autoimmune Inflammatory Diseases
Current guidelines for the management of autoimmune
inflammatory diseases generally include the use of TNF
inhibitors and other bDMARDs [310]. For example, in
RA patients with an insufficient response to methotrexate
and/or other csDMARDs, the use of a bDMARD (a
TNF inhibitor, abatacept, tocilizumab, or rituximab) in
combination with methotrexate is recommended [3].
Treatment with a bDMARD (usually a TNF inhibitor) is
recommended in patients with PsA who fail to respond to
at least one csDMARD [7]. TNF inhibitors are also rec-
ommended for AS in patients with persistently high disease
activity despite conventional therapy [5], as second-line
induction and maintenance therapy for psoriasis [8], and in
patients with Crohns disease who fail to respond to con-
ventional therapy [9].
Infliximab biosimilar was the first biosimilar to be
approved in the EU for the treatment of autoimmune
inflammatory diseases. Approval was based on the results of
a comprehensive stepwise comparability exercise required
by the European Medicines Agency (EMA) to demonstrate
the biosimilarity of infliximab biosimilar to reference
infliximab [16, 17]. Two pivotal trials demonstrated the
pharmacokinetic and therapeutic equivalence of infliximab
biosimilar and reference infliximab in AS (Sect. 3) and RA
(Sect. 4.1) populations, respectively. Pharmacokinetic
equivalence was also demonstrated in Japanese patients with
RA and in healthy volunteers (Sect. 3). The comparative
efficacy of infliximab biosimilar and reference infliximab
was maintained over 54 weeks of treatment (Sects. 4.1 and
4.2); data collected up to week 102 demonstrated that the
efficacy of continued infliximab biosimilar therapy was
maintained over the longer term (Sect. 4.4). Real-world
data from the BIOPSY registry supported the efficacy of
infliximab biosimilar for the treatment of RA (Sect. 4.1.2).
Data from the comparability exercise provided the basis
for extrapolation of clinical data for infliximab biosimilar
from the key clinical trials in RA and AS to other approved
indications for reference infliximab, such as IBD
(Sect. 5.3). Concerns have been raised regarding the sci-
entific validity of indication extrapolation with respect to
biosimilars [2, 54]. Some learned societies recommend
against routine extrapolation of indications [5557], while
others generally endorse the process [58]. Studies con-
ducted in the real-world setting demonstrated that infliximab
biosimilar was effective in the induction and maintenance
of clinical remission in patients with Crohns disease or
ulcerative colitis (Sect. 4.3), providing some support for
the validity of indication extrapolation to IBD. However,
further data would be of interest. A randomized, double-
blind, phase III study is currently underway to assess the
non-inferiority of infliximab biosimilar versus reference
infliximab in [200 patients with active Crohns disease
(NCT02096861).
Infliximab biosimilar was generally well tolerated in
patients with RA or AS, with a similar safety profile to that
of reference infliximab (Sect. 5). In terms of immuno-
genicity, the proportion of RA or AS patients who devel-
oped ADAs against infliximab biosimilar or reference
infliximab did not markedly differ (Sect. 5.1). The

presence of ADAs appeared to be associated with a less
robust ASAS20 response to each of the infliximab agents in
patients with AS (Sect. 4.2) and a numerically higher
incidence of infusion-related reactions in some instances in
patients with RA and AS (Sect. 5.1), although the findings
of the latter subgroup analyses may have been confounded
by small patient numbers (n B 28) [22].
Thus far, the post-marketing safety evaluation of
infliximab biosimilar in patients with IBD has generally
been consistent with the clinical trial program in patients
with RA or AS (Sect. 5). Stringent pharmacovigilance is
particularly important in the biosimilars market, and risk
management plans are mandatory for all biosimilars
authorized by the EMA [59]. An extensive pharmacovigi-
lance program including post-marketing surveillance and
registry studies will provide long-term data on the safety of
infliximab biosimilar in IBD [2]. For example, an IBD
global registry is currently assessing the tolerability of
infliximab biosimilar in 500 patients with active Crohns
disease, fistulising Crohns disease, or ulcerative colitis
over 5 years (NCT02326155).
Considerable debate has existed regarding the efficacy
and safety of switching from the reference product to a
biosimilar [2, 60]. The EMA has stated that the issue of
interchangeability between the reference medicine and its
biosimilar is beyond the scope of their current guidelines
[61]. The general position of learned societies is that
switching between the reference product and a biosimilar
should occur only with consent of the prescribing physician
[5558, 62]. With respect to infliximab biosimilar, there
were no signs of altered efficacy, safety, or immunogenicity
after switching from reference infliximab to the biosimilar
(Sects. 4.4 and 5). However, it should be noted that the
PLANETRA and PLANETAS extension studies were not
designed or powered to assess the non-inferiority or equiv-
alence of switching from reference infliximab to infliximab
biosimilar versus continued treatment with infliximab
biosimilar [41, 42]. So far, almost one decade of experience
from clinical trials, post-marketing surveillance, and real-
world studies has provided reassuring data regarding the
efficacy and safety of switching from reference infliximab to
infliximab biosimilar [63]. The Norwegian government is
funding NOR-SWITCH, an ongoing study designed to
compare the efficacy and safety of switching from reference
infliximab to infliximab biosimilar in adults with RA,
spondyloarthritis, PsA, chronic plaque psoriasis, ulcerative
colitis, or Crohns disease (NCT02148640). Results from
this study are awaited with great interest.
In addition to CT-P13/infliximab-dyyb, another infliximab
biosimilar (SB2; Flixabi) has recently been approved in
the EU. A number of other biosimilars of infliximab are in
the pipeline, including several at the phase III stage of
development [64]. A biosimilar of etanercept has been
H. A. Blair, E. D. Deeks
approved in the EU, with several other etanercept
biosimilars currently undergoing development [65].
Biosimilar versions of adalimumab are also expected to be
available in the near future [59]. Given the high cost of
biologics, the availability of biosimilars is expected to
yield considerable cost-related savings [2, 59]. According
to modeled budget impact analyses in various EU regions,
and assuming CT-P13/infliximab-dyyb is priced 1030 %
lower than the reference product, the use of the biosimilar
is expected to offer cost savings over the next few years
[6670]. For instance, in an analysis over a 1-year time
horizon across all six licensed disease areas (RA, AS, PsA,
psoriasis, Crohns disease, and ulcerative colitis), cumu-
lative cost savings associated with the introduction of CT-
P13/infliximab-dyyb in Belgium, Germany, Italy, the
Netherlands, and the UK were projected to range from
25.8 million for the 10 % discount scenario to
77.4 million for the 30 % discount scenario [70]. Such
savings may result in improved access to biologic agents,
thereby reducing the burden on healthcare budgets [2].
To conclude, infliximab biosimilar has proven pharma-
cokinetic and therapeutic equivalence to reference infliximab,
with a similar safety profile, making it a useful alternative
in patients requiring treatment with infliximab for various
autoimmune inflammatory diseases.
Data selection sources: Relevant medical literature (including
published and unpublished data) on infliximab biosimilar
(CT-P13; infliximab-dyyb) was identified by searching databases
including MEDLINE (from 1946), PubMed (from 1946), and
EMBASE (from 1996) [searches last updated 6 Sep 2016], bib-
liographies from published literature, clinical trial reg-
istries/databases, and websites. Additional information was also
requested from the company developing the drug.
Search terms: CT-P13, Remsima, Inflectra, infliximab biosimi-
lar, biosimilar infliximab.
Acknowledgments During the peer review process, the manufacturer
of infliximab biosimilar was also offered an opportunity to review this
article. Changes resulting from comments received were made on the
basis of scientific and editorial merit.
Compliance with Ethical Standards
Funding The preparation of this review was not supported by any
external funding.
Conflict of interest Hannah Blair and Emma Deeks are salaried
employees of Adis/Springer, are responsible for the article content,
and declare no relevant conflicts of interest.
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