Expert Review of Clinical Immunology

ISSN: 1744-666X (Print) 1744-8409 (Online) Journal homepage: https://www.tandfonline.com/loi/ierm20

A randomized study comparing the

pharmacokinetics of the potential biosimilar
PF-06438179/GP1111 with Remicade® (infliximab)
in healthy subjects (REFLECTIONS B537-01)

Ramesh Palaparthy, Chandrasekhar Udata, Steven Y. Hua, Donghua Yin,

Chun-Hua Cai, Stephanie Salts, Muhammad I. Rehman, Joseph McClellan &
Xu Meng

To cite this article: Ramesh Palaparthy, Chandrasekhar Udata, Steven Y. Hua, Donghua Yin,
Chun-Hua Cai, Stephanie Salts, Muhammad I. Rehman, Joseph McClellan & Xu Meng (2018)
A randomized study comparing the pharmacokinetics of the potential biosimilar PF-06438179/
GP1111 with Remicade® (infliximab) in healthy subjects (REFLECTIONS B537-01), Expert Review
of Clinical Immunology, 14:4, 329-336, DOI: 10.1080/1744666X.2018.1446829

To link to this article: https://doi.org/10.1080/1744666X.2018.1446829

View supplementary material Published online: 12 Mar 2018.

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EXPERT REVIEW OF CLINICAL IMMUNOLOGY, 2018
VOL. 14, NO. 4, 329–336
https://doi.org/10.1080/1744666X.2018.1446829

ORIGINAL RESEARCH

A randomized study comparing the pharmacokinetics of the potential biosimilar

PF-06438179/GP1111 with Remicade® (infliximab) in healthy subjects (REFLECTIONS
B537-01)
Ramesh Palaparthya, Chandrasekhar Udataa, Steven Y. Huaa, Donghua Yina, Chun-Hua Caib, Stephanie Saltsa,
Muhammad I. Rehmanc, Joseph McClelland and Xu Menga
a
Pfizer Inc, San Diego, CA, USA; bPfizer Inc, Groton, CT, USA; cPfizer Inc, Andover, MA, USA; dPfizer Inc, New York, NY, USA

ABSTRACT ARTICLE HISTORY

Background: To demonstrate pharmacokinetic (PK) similarity of PF-06438179/GP1111, a potential Received 11 December 2017
biosimilar to Remicade®, to Remicade® sourced from European Union (infliximab-EU) and United Accepted 26 February 2018
States (infliximab-US), and of infliximab-EU to infliximab-US. KEYWORDS
Methods: In this phase I, parallel-group, three-arm trial, healthy adult subjects were randomized to Pharmacokinetics; biosimilar;
receive a single 10-mg/kg intravenous infusion of PF-06438179/GP1111, infliximab-EU, or infliximab- infliximab; safety;
US. PK, and safety and immunogenicity evaluations were performed over 8 and 12 weeks, respec- immunogenicity
tively. PK similarity was established if the 90% confidence intervals (CIs) of the test-to-reference ratios
for PK parameters, Cmax, AUCT, and AUCinf, were within the 80.00–125.00% pre-specified equivalence
window.
Results: Of 151 subjects randomized, 146 received study treatment; 130 were eligible for PK similarity
assessment. Serum concentration–time profiles were similar across the three treatments. The 90% CIs
for test-to-reference ratios for Cmax, AUCT, and AUCinf were within 80.00–125.00% for comparison of
PF-06438179/GP1111 to infliximab-EU and infliximab-US, and of infliximab-EU to infliximab-US. Similar
numbers of subjects across treatment groups experienced adverse events. Anti-drug and neutralizing
antibody profiles were largely similar among groups.
Conclusions: This study demonstrated PK similarity of PF-06438179/GP1111 to infliximab-EU and
infliximab-US, and of infliximab-EU to infliximab-US. All three products displayed comparable safety
and immunogenicity profiles.
Trial registration: CT.gov identifier NCT01844804

1. Introduction functional characterization and proceeding to animal studies

(toxicity, pharmacokinetics [PK], pharmacodynamics [PD], and
The term ‘biosimilar’ refers to a biologic product that is devel-
immunogenicity) and human studies (PK, PD, immunogenicity,
oped to be highly similar to, and treat the same conditions as,
and comparative clinical safety and effectiveness) intended to
an existing licensed or approved biologic product [1–4].
support demonstration of biosimilarity [1–4].
Biosimilar is a regulatory term that is only applied if the
Remicade® (Infliximab; Janssen Biologics B.V., Leiden, The
biologic has been reviewed and approved through defined
Netherlands, and Janssen Biotech, Horsham, PA, USA) is a
and stringent regulatory processes that follow the World
recombinant human-murine immunoglobulin G1κ monoclonal
Health Organization, US Food and Drug Administration, and/
antibody directed against tumor necrosis factor-α (TNFα) [5].
or European Medicines Agency principles [1,3,4]. Biosimilars
Infliximab neutralizes the biological activity of TNFα by bind-
have the potential to increase patient access to biologic thera-
ing to the soluble and transmembrane forms of TNFα and
pies throughout the world. Unlike small-molecule drugs, bio-
inhibiting binding of TNFα with its receptors [5]. Infliximab is
logics are large, structurally complex molecules, and minor
approved for the treatment of Crohn’s disease, pediatric
changes in the manufacturing process can produce differ-
Crohn’s disease, ulcerative colitis, pediatric ulcerative colitis,
ences that may impact their safety, immunogenicity, and
rheumatoid arthritis (RA) (in combination with methotrexate),
potency [3,4]. Thus, biosimilars are not considered generic
ankylosing spondylitis, psoriatic arthritis, and plaque psoria-
equivalents to the licensed or approved biologic product,
sis [5,6].
and the regulatory process for biosimilar approval is different
PF-06438179/GP1111 is being developed as a potential
from the approval process of small-molecule generic medi-
biosimilar to Remicade® for use in all of the indications for
cines [3,4]. Regulatory decisions for approval of biosimilars
which Remicade® is licensed or approved, in accordance with
are based on the totality of evidence generated from a step-
current global regulatory guidance documents for biosimilars
wise approach, starting with comparative structural and

CONTACT Ramesh Palaparthy ramesh.palaparthy@pfizer.com Pfizer Inc, 10777 Science Center Drive, CB1/2103, San Diego, CA 92121 USA
Supplemental data for this article can be accessed here.
© 2018 Informa UK Limited, trading as Taylor & Francis Group
330 R. PALAPARTHY ET AL.
[1–4]. PF-06438179/GP1111 and Remicade® have an identical
primary amino acid sequence and are similar with respect to
their structural, in vitro functional, and nonclinical PK pro-
files [7].
After confirmation of biosimilarity using nonclinical assess-
ments, the next step in biosimilar development is to demon-
strate similarity in PK profile by a head-to-head comparison
(via a comparative clinical study) with the licensed or
approved reference product. The most sensitive population
in which to demonstrate similarity in PK is in healthy subjects
[8]. However, there are limited published data available about
the variability in area under concentration–time curve (AUC)
and maximum serum concentration (Cmax) of Remicade® in
healthy subjects after a single dose [9] to determine the
appropriate study sample size. In addition, information is lack-
ing about the possible interference between the bioanalytical
measurements for PK and immunogenicity profiling to define
the relevant sampling intervals. For this reason, a phase I,
single-arm, single-dose, open-label, pilot PK variability study
of Remicade® sourced from the European Union (infliximab-
EU), administered intravenously (IV) to healthy male and
female subjects, was conducted. The findings from the pilot
PK study were used to guide the design (including dose,
sampling duration, and PK variability) of the PK similarity
study (ClinicalTrials.gov identifier: NCT01844804), comparing
PF-06438179/GP1111 and infliximab-EU and Remicade®
sourced from the United States (infliximab-US). Safety and
immunogenicity of PF-06438179/GP1111, infliximab-EU, and
infliximab-US were also evaluated.
2. Methods
2.1. Study population and design
A total of 151 healthy male and female subjects, aged
18–55 years, were enrolled in this phase I, randomized, paral-
lel-group, single-dose three-arm trial (Figure 1). To be included
in the trial, a body mass index of 17.5–32.0 kg/m2 and a total
body weight >50 kg was required. Females had to be post-
menopausal or have undergone hysterectomy and/or bilateral
Day 0 Days 1–8
PF-06438179/
GP1111 Confined to unit
n=49
Randomization
Screening
Day 1
Infliximab-EU
n=48 Study drug
administration
Infliximab-US
n=49
†
Day 1 2 3 4
Hour 0†, 2, 4 24 48 72
Figure 1. Study design. *Pharmacokinetic sample was also collected at Day 85. †Time/day on which samples were collected for ADA; samples were collected at all
times shown. ‡Subjects with an unresolved AE were to be followed up until the AE or its sequelae resolved or stabilized per the Investigator’s assessment. If the
unresolved AE was considered by the Investigator as possibly related to or associated with ADA formation, the subject was to be asked to return for additional drug
concentration and ADA/NAb blood sampling at up to 3-month intervals until the AE or its sequelae resolved or stabilized at a level acceptable to the Investigator,
and the Sponsor concurred with the Investigator’s assessment, up to 6 months from the Day 85 visit or the day of early withdrawal. ADA: antidrug antibodies; AE:
adverse event; mo: months; NAb: neutralizing antibodies; PK: pharmacokinetic.
oophorectomy. Key exclusion criteria included history of sig-
nificant clinical disease or evidence thereof at screening, clini-
cally significant abnormalities in laboratory test results,
previous history of cancer other than adequately treated
basal cell or squamous cell carcinoma of the skin, previous
exposure to monoclonal antibodies, or current use of biologic
drugs. All subjects provided informed written consent. The
study was conducted in accordance with the ethical standards
of the institutional and/or national research committee, and
with the Declaration of Helsinki and its later amendments, or
comparable ethical standards.
Subjects were randomized in a 1:1:1 ratio to treatment
arms, with a single 10-mg/kg dose of PF-06438179/GP1111,
infliximab-EU, or infliximab-US administered by IV infusion
over a period of not less than 2 h. Although 3- or 5-mg/kg
doses are used in various treatment regimens, the 10-mg/kg
dose was chosen for this study because this dose was admi-
nistered to patients and healthy subjects in prior clinical stu-
dies and is also used in some therapeutic settings [5,6]. In
addition, studies have suggested that higher doses (e.g.
10 mg/kg) are associated with a lower incidence of detectable
antidrug antibodies (ADA) and therefore minimize the con-
founding effect of ADA formation on evaluating intrinsic PK
properties [10]. The sample size was estimated to ensure that
at least 120 subjects (40 per arm) completed the study proce-
dures and had evaluable PK data for the PK similarity assess-
ment. A total of 150 (50 per arm) subjects were enrolled to
account for attrition.
The power calculation was based on variability of AUC data
obtained from a prior phase I, single-arm, single-dose, open-
label, pilot PK variability study of infliximab-EU in healthy
subjects (n = 20). This pilot study used a single IV dose at
10 mg/kg and a sampling duration of 6 weeks; infliximab-EU
showed relatively low PK variability. The coefficient of varia-
tion (CV) values using the McKay’s confidence interval (CI)
(two-sided 80% CI) were 16.1% (13.4–20.8), 16.2% (13.5–20.8),
and 20.3% (16.9–26.3) for Cmax, AUC from time 0 to the last
time point with measureable concentration (AUCT), and AUC
from time 0 to infinity (AUCinf), respectively. Based on these
findings, with a sample size per arm of 40 subjects and
Extended
Follow-up
Days 9–57 Day 85 (≤6 mo)‡
Outpatient visits
Day 8
Visit days
Discharge
from unit 15, 22, 29, 36, 43, 50, 57, 85
Primary PK Assessment (8 weeks)*
ADA Assessment (12 weeks)
5 8 15† 22 29† 36 43† 50 57† 85†
96 168 336 504 672 840 1008 1176 1344 2016

assuming the ratio in each mean PK parameter (untrans-
formed) of PF-06438179/GP1111 versus either infliximab-EU
or infliximab-US = 1.05 or 0.95, the two comparators were
assumed equal (ratio = 1.0), and alpha = 0.05, and the one-
sided 90% upper confidence limit of the CV for AUCinf was
0.26. With this sample size, the study had >90% power to
demonstrate PK similarity in PK parameters using pair-wise
comparisons and >80% power to demonstrate PK similarity
in PK parameters using three-arm comparisons.
2.2. Pharmacokinetic evaluations
Blood samples for determining concentrations of
PF-06438179/GP1111, infliximab-EU, or infliximab-US were
collected on Day 1 at 0 h (within 2 h prior to initiation of
the infusion), 2 h (within 5 min prior to end of infusion), and
4 h after the start of infusion and on Days 2, 3, 4, 5, 8, 15,
22, 29, 36, 43, 50, and 57. Serum samples were analyzed
using a validated enzyme-linked immunosorbent assay
(ELISA) with a lower limit of quantification (LLOQ) of
100 ng/mL. In this ELISA method, infliximab-EU, infliximab-
US, or PF-06438179/GP1111 in human serum samples was
incubated onto a 96-well microtiter plate coated with
recombinant human TNF, as capturing agent. The bound
infliximab-EU, infliximab-US, or PF-06438179/GP1111 was
detected with a Donkey Anti-Human IgG Peroxidase conju-
gate. A tetramethylbenzidine peroxidase substrate solution
was utilized for signal generation and colorimetric readout.
Standard non-compartmental PK data analysis was con-
ducted with the per-protocol population to characterize the
concentration data collected up to Day 57. Actual sample
collection times were used for the analysis. The drug concen-
tration–time data were analyzed using internally validated
software, eNCA (v2.2.3). The non-compartmental PK analysis
resulted in calculation of the PK parameters, including the
Cmax, AUCT, and AUCinf, as well as clearance (CL), volume at
steady-state (Vss), and terminal half-life (t1/2). Statistical analysis
of Cmax, AUCT, and AUCinf using the standard bioequivalence
testing procedure was performed for each pair-wise compar-
ison (PF-06438179/GP1111 vs. infliximab-EU, PF-06438179/
GP1111 vs. infliximab-US, and infliximab-EU vs. infliximab-
US). Estimates of the ratio of adjusted geometric means and
the 90% CIs for the ratios for Cmax, AUCT, and AUCinf were
obtained. PK similarity was considered demonstrated for a
given test-to-reference comparison if the 90% CI of the ratio
was within the 80.00–125.00% prespecified equivalence
acceptance window.
2.3. Immunogenicity
Blood samples for detecting ADA and neutralizing antibodies
(NAb) were collected on Days 1 (pre-dose), 15, 29, 43, 57, and
85. Two parallel electrochemiluminescence immunoassays
(ECLIAs) were developed and validated by ICON
Development Solutions, LLC (Whitesboro, NY, USA), utilizing
Meso Scale Discovery (MSD) technology, for detecting ADA
against infliximab-EU/infliximab-US and against PF-06438179/
GP1111. In the assays, ruthenylated and biotinylated forms of
the drug molecules were incubated with the samples, and
EXPERT REVIEW OF CLINICAL IMMUNOLOGY 331
ADA present in the samples was detected through formation
of the complex of ADA and the labelled drug molecules. The
plate cut-point factor values, for the assay against infliximab-
EU/infliximab-US and PF-06438179/GP1111, were 1.11 and
1.34, respectively. The drug tolerance was determined to be
as follows: up to 0.5 or 5 µg/mL (PF-06438179/GP1111); up to
1 or 5 µg/mL (infliximab-US), and up to 0.5 or 1 µg/mL
(infliximab-EU), with the positive control at 320 and 2560 ng/
mL, respectively.
Similarly, two parallel, cell-based assays were developed
and validated to detect NAb against PF-06438179/GP1111 or
infliximab-EU/infliximab-US. In the NAb assays, the ability of
infliximab-EU/infliximab-US or PF-06438179/GP1111 to block
the TNF-induced cell cytotoxicity was evaluated in the pre-
sence of serially diluted samples. Presence of NAb would
inhibit the effect of drug molecules to suppress the TNF-
induced cell cytotoxicity. The plate cutpoint factors for the
infliximab-EU/infliximab-US and PF-06438179/GP1111 NAb
assays were 0.62 and 0.54, respectively. The drug tolerance
was determined to be up to 0.1 µg/mL and up to 0.5 µg/mL
for PF-06438179/GP1111 and infliximab-US/infliximab-EU,
respectively, with the positive control at 2500 ng/mL.
The assays showed similar performance for positive and
negative controls during validation and were utilized follow-
ing a tiered approach of screening, confirmation, and titer.
Serum samples were first tested for ADA using the ECLIA
specific to the product administered. Confirmed ADA-positive
samples were then assessed for cross-reactivity using the
alternate ECLIA. Samples confirmed to be positive for ADA
were tested for NAb using cell-based assays. Positive NAb
samples were then assessed for cross-reactivity using the
alternate assay.
2.4. Safety evaluations
Safety was evaluated throughout the study in all enrolled
subjects who received the study drug (safety analysis set). All
observed or volunteered adverse events (AEs), including ser-
ious AEs, were recorded, as well as the investigator’s assess-
ment of causality and the severity of the events. Severity was
graded in accordance with the National Cancer Institute
Common Terminology Criteria for Adverse Events (NCI
CTCAE; v4.03) [11]. Physical and clinical evaluations included
laboratory analyses, vital signs, pulse oximetry monitoring,
continuous cardiac monitoring, and electrocardiograms
(ECGs). Subjects reached the end of the study on Day 85,
unless they had unresolved drug-related AEs. Subjects with
unresolved AEs were followed until the AE or its sequelae
resolved or stabilized per the Investigator’s assessment.
3. Results
3.1. Subject demographics and disposition
Overall, 146 (safety population) of the 151 randomized sub-
jects received the study treatment as assigned; of these, 130
subjects were evaluable for PK characterization (per-protocol
population; Figure 2). Of the 16 subjects excluded from the PK
analyses (n = 8, 3, and 5 in the PF-06438179/GP1111,
332 R. PALAPARTHY ET AL.

Enrolled
n=151

Randomization 1:1:1

Not treated Not treated Not treated

n=3 n=2 n=0

PF-06438179/GP1111 Infliximab-EU Infliximab-US

n=49 n=48 n=49

Safety population Safety population Safety population

n=49 n=48 n=49

Excluded Excluded Excluded

n=8 n=3 n=5
(incomplete (incomplete (incomplete
PK profiles) PK profiles) PK profiles)

Per-protocol population Per-protocol population Per-protocol population

n=41 n=45 n=44

Figure 2. Subject disposition. PK: pharmacokinetic.

infliximab-EU, and infliximab-US treatment groups, respec-
tively), 15 discontinued from the study prematurely between
Days 2 and 29 and consequently had an incomplete PK profile,
whereas the one remaining subject was excluded because of
an incomplete PK profile resulting from no measurable drug
concentrations from Day 29 onward. For this subject (from the
infliximab-US group), ADA first emerged on Day 29 and per-
sisted (testing positive on Days 43 and 57) until the last
sample collection on Day 85, with high titers. Given the
incomplete PK profile, potentially related to development of
ADA, the subject was excluded from the PK analysis according
to prespecified criteria for exclusion. The baseline demo-
graphics for the 130 subjects in the PK analysis were similar
among treatment groups (Table 1).
individual subject serum concentration–time data showed
that the three study drugs exhibited similar profiles
(Figure 3(a-c)). Figure 3(d) shows that the mean serum drug
concentration–time profiles between the study drugs were
superimposable.
The PK parameters evaluated (Cmax, AUCT, AUCinf, CL, Vss,
and t1/2) were similar in the mean values and the intersub-
ject variability across all treatment arms (Table 2 and
Figure 4). The CVs were 20–24% for Cmax, 21–25% for
AUCT, and 23–28% for AUCinf. The 90% CIs for the test-to-
reference ratios of Cmax, AUCT, and AUCinf were within the
pre-specified equivalence acceptance range of 80.00–
125.00% for the comparisons of PF-06438179/GP1111 to
infliximab-EU and infliximab-US and for infliximab-EU to
infliximab-US (Table 3).

3.2. Pharmacokinetics
Of the 130 subjects included in the PK evaluation, 41 3.3. Immunogenicity
received PF-06438179/GP1111, 45 received infliximab-EU,
and 44 received infliximab-US (Figure 2). Evaluation of Of the 146 subjects in the safety analysis population, 118 and 119
subjects completed ADA assessments through Days 57 and 85,
respectively. No subject tested positive for ADA prior to dosing.
Table 1. Baseline demographics of enrolled per-protocol population for phar- The three treatments had comparable ADA profiles, with a some-
macokinetic evaluation.
what lower incidence of ADA response in the PF-06438179/
PF-06438179/ Infliximab- Infliximab-
GP1111 EU US GP1111 group (Table 4). Six of 37 (16.2%), 14 of 43 (32.6%), and
n = 41 n = 45 n = 44 11 of 39 (28.2%) subjects in the PF-06438179/GP1111, infliximab-
Male, n (%) 39 (95.1) 43 (95.6) 39 (88.6) EU, and infliximab-US groups, respectively, tested positive for
Mean age ± SD, years 34.4 ± 10.0 30.6 ± 9.4 33.8 ± 9.4 ADA in this study. Of these 31 subjects, 26 did not have detect-
Race, n (%)
White 12 (29.3) 18 (40.0) 18 (40.9) able levels of ADA until Day 85. The remaining five ADA-positive
Black 29 (70.7) 26 (57.8) 26 (59.1) subjects had at least one sample that tested positive at an early
Other 0 (0.0) 1 (2.2) 0 (0.0) time point: three (n = 2 and 1, PF-06438179/GP1111 and inflix-
Mean weight ± SD, kg 83.4 ± 13.3 78.0 ± 11.5 84.6 ± 14.9
Mean height ± SD, cm 177.3 ± 8.5 175.3 ± 8.1 177.7 ± 9.1 imab-US, respectively) tested positive on Days 57 and 85; one
Mean body mass index ± SD, 26.5 ± 3.3 25.4 ± 3.2 26.6 ± 2.9 subject in the infliximab-US group tested positive on Days 43, 57,
kg/m2 and 85; and one subject in the infliximab-US group tested posi-
SD: standard deviation. tive on Days 29, 43, 57, and 85. The subject from the infliximab-
 EXPERT REVIEW OF CLINICAL IMMUNOLOGY 333

PF-06438179/GP1111 Infliximab-EU Infliximab-US Mean (SD)

500.0
500.0
500.0

500.0
a b c d

50.0
50.0
50.0

50.0
Concentration (µg/mL)

5.0
5.0
5.0

5.0

0.5
0.5
0.5

0.5 PF-06438179/GP1111
Median Median Median
ADA negative ADA negative ADA negative Infliximab-EU

0.1
0.1
0.1

0.1

ADA positive ADA positive* ADA positive Infliximab-US

0 500 1000 1500 0 500 1000 1500 0 500 1000 1500 0 500 1000 1500
Time (h) Time (h) Time (h) Time (h)

Figure 3. (a–c) Individual and (d) mean ± SD serum concentration–time profiles following a 10-mg/kg single intravenous dose in healthy subjects (per-protocol
population). *No subjects tested positive. ADA: anti-drug antibodies; SD: standard deviation.

Table 2. Mean ± standard deviation pharmacokinetic (PK) parameter estimates.

PF-06438179/GP1111 Infliximab-EU Infliximab-US
n = 41 n = 45 n = 44
Cmax, μg/mL 221.9 ± 43.8 202.7 ± 46.1 209.3 ± 50.5
AUCT, μg·h/mLa 56,960 ± 12,157 51,180 ± 12,868 53,010 ± 11,906
AUCinf, μg·h/mL 61,460 ± 14,386 56,130 ± 15,972 57,610 ± 14,334
CL, mL/h/kg 0.1725 ± 0.0456 0.1918 ± 0.0527 0.1855 ± 0.0521
Vss, mL/kg 79.58 ± 20.73 92.06 ± 25.85 84.92 ± 24.52
t½, h 344.5 ± 99.72 367.6 ± 106.7 335.1 ± 124.5
a
AUCT was ≥80% of the corresponding AUCinf in 127 of 130 subjects who were included for PK analysis.
AUCinf: area under the concentration–time curve from time 0 extrapolated to infinite time; AUCT: area under the concentration–time curve from time
0 to last time point of measurable concentration; CL: clearance; Cmax: maximum serum concentration; t½: terminal elimination half-life; Vss: volume
of distribution at steady state.

Cmax AUCT AUCinf

400

100 000

100 000
350
300

80 000

80 000
AUCinf (µg·h/mL)
AUCT (µg·h/mL)
Cmax (µg/mL)
250

60 000

60 000
200

40 000

40 000
150
100

20 000

20 000
50

PF EU US PF EU US PF EU US

Figure 4. Individual and mean estimates of PK parameters (Cmax, AUCT, AUCinf) with geometric mean estimates (per-protocol population). Open circles (o) represent
individual observations. Asterisks (∗) represent the geometric mean value of each group. AUCinf: area under the concentration–time curve from time 0 extrapolated
to infinite time; AUCT: area under the concentration–time curve from time 0 to last time point of measurable concentration; Cmax: maximum serum concentration;
EU: infliximab-EU; PF: PF-06438179/GP1111; PK: pharmacokinetic; US: infliximab-US.

US group had comparatively high ADA titers (4.92 on Day 85), study, and dropped below LLOQ before terminal disposition
experienced rapid decline in drug concentration early in the phase could be characterized.
334 R. PALAPARTHY ET AL.

Table 3. Statistical comparison of pharmacokinetic exposure parameters between test and reference products.
Adjusted geometric mean
Test Reference Parameter Test Reference Ratio (%)a 90% confidence interval (%)
PF-06438179/ Infliximab-EU Cmax, μg/mL 217.4 197.6 110.03 101.32–119.49
GP1111 AUCT, μg·h/mL 55,600 49,650 111.98 102.85–121.92
AUCinf, μg·h/mL 59,750 54,080 110.49 100.67–121.28
PF-06438179/ Infliximab-US Cmax, μg/mL 217.4 203.1 107.05 98.53–116.31
GP1111 AUCT, μg·h/mL 55,600 51,640 107.67 98.85–117.28
AUCinf, μg·h/mL 59,750 55,810 107.06 97.49–117.58
Infliximab-EU Infliximab-US Cmax, μg/mL 197.6 203.1 97.29 89.72–105.50
AUCT, μg·h/mL 49,650 51,640 96.15 88.45–104.53
AUCinf, μg·h/mL 54,080 55,810 96.90 88.42–106.18
a
Test/reference ratio of adjusted geometric means.
AUCinf: area under the concentration–time curve from time 0 extrapolated to infinite time; AUCT: area under the concentration–time curve from time 0 to last time
point of measurable concentration; Cmax: maximum serum concentration.

Table 4. Number (%) of subjects testing positive for antidrug antibody (ADA) Table 5. Summary of adverse events (AEs) (all-causality; safety-analysis
during the study. population).
Time point PF-06438179/GP1111 Infliximab-EU Infliximab-US PF-06438179/ Infliximab- Infliximab-
Prior to dosing 0/49 (0) 0/48 (0) 0/49 (0) GP1111 EU US
Through Day 57 2/38 (5.3) 0/39 (0) 3/41 (7.3) n = 49 n = 48 n = 49
Through Day 85 6/37 (16.2) 14/43 (32.6) 11/39 (28.2) Subjects with AEs, n 17 21 18
Denominators indicate the number of subjects who completed the ADA Subjects with serious AEs, n 1 0 1
assessment. Subjects with AEs by grade, n
Grade 1 15 15 10
Grade 2 1 3 4
Grade 3 1 3 4
A majority (87%) of the 31 subjects who tested positive for Grade ≥4 0 0 0
ADA against the dosed study drug also tested positive in the Treatment-emergent AEs occurring in ≥5% of subjects, n (%)
Headache 3 (6.1) 3 (6.3) 4 (8.2)
ECLIA cross-reactivity assay on Day 85: PF-06438179/GP1111 Granulocytopenia 0 (0.0) 3 (6.3) 2 (4.1)
(n = 6/6), infliximab-EU (n = 10/14), and infliximab-US (n = 11/ Upper respiratory tract 3 (6.1) 2 (4.2) 0 (0.0)
11). This suggests that ADA were likely developed against infection
Aspartate aminotransferase 0 (0.0) 0 (0.0) 3 (6.1)
shared epitopes among the three study drugs. Of five subjects increased
who tested positive for ADA on Day 57 or earlier, four were Constipation 0 (0.0) 3 (6.3) 0 (0.0)
also in the per-protocol population and exhibited an altered No subjects discontinued permanently or temporarily or had dose reductions
PK profile with an accelerated terminal disposition phase due to AEs.
(Figure 3(a,c)).
Of the 31 subjects who tested positive for ADA, 26 tested
Overall, clinical laboratory results, vital signs, cardiac and
positive for NAb in the PF-06438179/GP1111 (n = 5/6), inflix-
pulse oximetry monitoring, and ECG data were unremarkable,
imab-EU (n = 12/14), and infliximab-US (n = 9/11) groups. Five
and no unexpected safety issues were identified. The number
subjects who tested negative for NAb did not test positive for
and percentage of subjects with laboratory test abnormalities
ADA until Day 85 and had generally low ADA titers.
appeared comparable among the three treatment groups. No
subjects experienced laboratory abnormalities meeting the
criteria for Hy’s Law for drug-induced liver injury.
3.4. Safety
Data from all 146 subjects who received treatment were eval-
4. Discussion
uated for safety. Similar numbers of subjects across treatment
groups experienced AEs (Table 5), and the most common PF-06438179/GP1111 is currently being developed as a poten-
treatment-emergent AEs were headache, granulocytopenia, tial biosimilar to Remicade®. The primary goal of this phase I
upper respiratory tract infection, increased aspartate amino- clinical study in healthy subjects was to demonstrate the PK
transferase, and constipation (Table 5). No grade 4 or 5 AEs similarity of PF-06438179/GP1111 to the Remicade® products
were reported. Although the frequency and type of AEs were approved in the European Union and licensed in the United
similar across all treatments, the number of treatment-related States. In addition, the PK similarity between the two mar-
AEs was lowest in the PF-06438179/GP1111 group (n = 7 vs. 13 keted Remicade® products was evaluated to provide bridging
and 18 in the infliximab-EU and infliximab-US treatment data justifying the use of a single reference product in sub-
groups, respectively). Two serious AEs were reported in the sequent comparative clinical trials. Since published details on
study: mental disorder experienced by one subject in the the PK of infliximab in human subjects are lacking [9], a pilot
PF-06438179/GP1111 group (considered not treatment PK variability study of infliximab-EU was conducted. The find-
related) and myalgia experienced by one subject in the inflix- ings were used to estimate the study sample size for the PK
imab-US group (considered treatment related). There were no similarity study of PF-06438179/GP1111 and infliximab-EU/
permanent discontinuations due to AEs, infusion-related reac- infliximab-US, as well as to obtain information about the
tions, or deaths reported. possible interference between the bioanalytical measurements
 EXPERT REVIEW OF CLINICAL IMMUNOLOGY 335

for PK and immunogenicity profiling, in order to define the conduct of a pilot PK study. The comparative study demon-
appropriate sampling duration. strated the PK similarity of PF-06438179/GP1111 to both inflix-
The similarity statistical comparisons of PF-06438179/ imab-EU and infliximab-US and of infliximab-EU to infliximab-
GP1111 to each of the reference products (infliximab-EU and US. Overall, the three treatment groups had a comparable
infliximab-US) were conducted according to prespecified ADA profile, with a possible exception on Day 85, where the
methods, without correction of protein content. The 90% CIs PF-06438179/GP1111 treatment group showed a somewhat
for test-to-reference ratios for the exposure parameters (Cmax, lower incidence of ADA compared with that for the inflixi-
AUCT, and AUCinf) were within the prespecified equivalence mab-EU or infliximab-US treatment groups. The majority of
acceptance range of 80.00–125.00% for the comparisons of the ADA-positive subjects also developed NAb. PF-06438179/
PF-06438179/GP1111 to infliximab-EU and infliximab-US and GP1111, infliximab-EU, and infliximab-US administered as a
of infliximab-EU to infliximab-US. single IV infusion were generally safe and well tolerated in
The nominal protein content in each administered drug this study conducted in healthy subjects. The PK similarity
product was 10 mg/mL. The measured protein content was results provide the critical evidence for continuing develop-
10.3, 9.5, and 9.7 mg/mL, for PF-06438179/GP1111, infliximab- ment of PF-06438179/GP1111 as a potential biosimilar to
EU, and infliximab-US, respectively (see Supplementary Remicade®.
Information). To evaluate whether this difference in the pro-
tein content among the products affected the PK similarity
conclusions, a supplementary PK similarity analysis was con- Key issues
ducted using protein-content corrected PK parameters. The
● PF-06438179/GP1111 is a potential biosimilar to Remicade®
results of this supplementary analysis showed that the 90%
(infliximab) that has been shown to have an identical pri-
CIs for the test-to-reference ratios for protein-content cor-
mary amino acid sequence and a similar structural, in vitro
rected Cmax, AUCT, and AUCinf between PF-06438179/GP1111
functional and nonclinical PK profile to the innovator
and infliximab-EU/infliximab-US and between infliximab-EU
product.
and infliximab-US were all within the 80.00–125.00% accep-
● Demonstrating similarity in PK profile by a head-to-head com-
tance criterion, further confirming the PK similarity among
parison of a potential biosimilar and the approved innovator
PF-06438179/GP1111, infliximab-EU, and infliximab-US (see
biologic product, typically in healthy subjects, forms a key
Supplementary Information). Together, these data demon-
component of the totality of evidence approach to biosimilar
strate that the PK data of PF-06438179/GP1111 were similar
approval, delineated by the US Food and Drug Administration,
to those of infliximab-EU and infliximab-US and that the PK
and European Medicines Agency.
data of the two marketed infliximab products were similar.
● The primary objective was to demonstrate PK similarity of
As with many biologics, immune responses against inflix-
PF-06438179/GP1111, infliximab-EU and infliximab-US, and
imab may develop. It should be noted that the primary objec-
of infliximab-EU to infliximab-US. Secondary objectives
tive of this single-dose study was to evaluate PK similarity and
included assessment of the safety and immunogenicity of
not immunogenicity. Specifically, a single-dose setting in
the three treatments.
healthy subjects with a limited sample size is not ideal for
● The 90% CIs for the test-to-reference ratios of the PK para-
evaluating and comparing immunogenicity between treat-
meters (Cmax, AUCT and AUCinf) for comparisons of
ment arms. Although the dose of infliximab-EU/infliximab-US
PF-06438179/GP1111 to infliximab-EU and infliximab-US,
and PF-06438179/GP1111 was chosen to minimize the impact
and of infliximab-EU to infliximab-US, were within the pre-
of immunogenicity on PK, the length of sampling duration is
specified equivalence acceptance window of 80.00–
one of the factors contributing to ADA occurrence. A majority
125.00%.
of ADA incidence in this study occurred after Day 85, when
● Similar numbers of subjects across treatment groups experi-
drug concentrations were lower. With these caveats, the inci-
enced adverse events. Anti-drug and neutralizing antibody
dence of ADA response was comparable across treatments,
profiles were largely similar among groups.
with a slightly lower incidence of ADA response observed in
● This study demonstrated the PK similarity of PF-06438179/
the PF-06438179/GP1111 group. In a later phase III study
GP1111 to both infliximab-EU and infliximab-US, and of
conducted in RA patients, the immunogenicity of
infliximab-EU to infliximab-US, with all three products dis-
PF-06438179/GP1111 and infliximab has been shown to be
playing comparable safety and immunogenicity profiles.
similar, after 30 weeks of treatment in patients with moder-
ately to severely active RA [12]. The majority of samples that
tested positive for ADA also tested positive for NAb. This study
also showed that the three products were generally safe and
Acknowledgments
well tolerated when administered as a single dose of 10 mg/kg The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT01844804).
in healthy subjects.

5. Conclusions
The design of the comparative, PK similarity study, including
dose, sampling duration, and study size, was informed by the
Author contributions
C-HC was involved in data collection and analysis. CU, RP, SYH, DY, MIR,
JM, XM, and SS were involved in the study design, data collection, and
data analysis. All authors were involved in manuscript writing and
approved the final manuscript.
336 R. PALAPARTHY ET AL.
Funding
This study was funded by Pfizer Inc.
Declaration of interest
Medical writing support was provided by Beth Sesler, PhD, Merry Saba,
PharmD, and Iain McDonald, PhD of Engage Scientific Solutions, and was
funded by Pfizer Inc.
C Udata, R Palaparthy, D Yin, CH Cai, S Salts, MI Rehman, and J
McClellan are employees of and hold stock in Pfizer Inc. SY Hua and X
Meng were employees of and held stock in Pfizer Inc. at the time the work
was conducted. The authors have no other relevant affiliations or financial
involvement with any organization or entity with a financial interest in or
financial conflict with the subject matter or materials discussed in the
manuscript apart from those disclosed.
References
Papers of special note have been highlighted as of considerable interest
(••) to readers.
1. European Medicines Agency, Committee for Medicinal Products for
Human Use (CHMP). Guideline on similar biological medicinal pro-
ducts containing biotechnology-derived proteins as active substance:
non-clinical and clinical issues [Internet]. London: European Medicines
Agency; 2014 Dec 18. [cited 2017 Sep 19]. Available from: http://www.
ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/
2015/01/WC500180219.pdf
2. Health Canada. Information and submission requirements for bio-
similar biologic drugs [Internet]. Ottawa, Ontario: Canada Minister
of Health, Health Canada Health Products and Food Branch; 2016
[updated 2016 Nov 14; cited 2017 Sep 19]. Available from: http://
www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/brgtherap/applic-
demande/guides/seb-pbu/seb-pbu-2016-eng.pdf
3. US Food and Drug Administration, Center for Drug Evaluation and
Research. Guidance for industry: scientific considerations in demon-
strating biosimilarity to a reference product [Internet]. SIlver Spring,
MD: US Department of Health and Human Services, US Food and
Drug Administration, Center for Drug Evaluation and Research (CDER),
Center for Biologics Evaluation and Research (CBER); 2015 [cited 2017
Sep 19]. Available from: http://www.fda.gov/downloads/Drugs/
GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.
pdf
4. World Health Organization, Expert Committee on Biological
Standardization. Guidelines on evaluation of similar biotherapeutic
products (SBPs) [Internet]. Geneva: World Health Organization;
2009 [updated 2009 Oct 19-23; cited 2017 Sep 19]. Available
from: http://www.who.int/biologicals/areas/biological_therapeu
tics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf
5. Janssen Biotech Inc. Remicade (infliximab) prescribing information
[Internet]. Horsham, PA: Janssen Biotech, Inc; 2017 Oct [cited 2018
Feb 14]. Available from: http://www.janssenlabels.com/package-
insert/product-monograph/prescribing-information/REMICADE-pi.pdf
6. European Medicines Agency. Remicade (infliximab) summary of
product characteristics [Internet]. European Medicines Agency;
2009 Jul 2 [cited 2017 Sep 19]. Available from: http://www.ema.
europa.eu/docs/en_GB/document_library/EPAR_-_Product_
Information/human/000240/WC500050888.pdf
7. Derzi M, Johnson TR, Shoieb AM, et al. Nonclinical evaluation of
®
PF-06438179: a potential biosimilar to Remicade (Infliximab). Adv
Ther. 2016;33(11):1964–1982. Epub 2016 Oct 28. PubMed PMID:
27585978; PubMed Central PMCID: PMC5083783.
•• Article describing the in vitro analytical characterization and
nonclinical in vivo data demonstrating the similarity of
PF-06438179/GP1111 to infliximab-US and/or infliximab-EU.
8. US Food and Drug Administration, Center for Drug Evaluation and
Research. Guidance for industry: clinical pharmacology data to support
a demonstration of biosimilarity to a reference product [Internet]. SIlver
Spring, MD: US Department of Health and Human Services, US Food
and Drug Administration, Center for Drug Evaluation and Research
(CDER), Center for Biologics Evaluation and Research (CBER); 2016
[Cited 2018 Feb 1]. Available from: https://www.fda.gov/downloads/
Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM397017.pdf
9. Klotz U, Teml A, Schwab M. Clinical pharmacokinetics and use of
infliximab. Clin Pharmacokinet. 2007;46(8):645–660. Epub 2007 Jul
28. PubMed PMID: 1765537.
10. Wolbink GJ, Aarden LA, Dijkmans BA. Dealing with immunogenicity of
biologicals: assessment and clinical relevance. Curr Opin Rheumatol.
2009;21(3): 211–215. Epub 2009 Apr 29. PubMed PMID: 19399992.
11. National Cancer Institute. Common terminology criteria for adverse
events (CTCAE); version 4.03 [Internet]. National Institutes of Health,
US Department of Health and Human Services; 2010. [updated 2015
Oct 21; cited 2017 Sep 19]. Available from: https://ctep.cancer.gov/
protocoldevelopment/electronic_applications/ctc.htm#ctc_40
12. Cohen S, Alten R, Kameda H, et al. A randomized, double-blind study
comparing PF-06438179/GP1111, a potential infliximab biosimilar,
and infliximab, both in combination with MTX, as treatment for
patients with moderate to severe active RA who have had an inade-
quate response to MTX therapy [abstract]. Arthritis Rheumatol.
2017;69(suppl 10).[Cited 2018 Mar 1]. Available from: http://acrab
stracts.org/abstract/a-randomized-double-blind-study-comparing-pf-
06438179gp1111-a-potential-infliximab-biosimilar-and-infliximab-
both-in-combination-with-mtx-as-treatment-for-patients-with-moder
ate-to-severe-active/
•• Double-blind, randomized, controlled trial highlighting the simi-
lar efficacy, safety, immunogenicity, and PK of PF-06438179/
GP1111 and infliximab-EU with or without dose escalation in
patients with moderate-to-severe active RA on background
methotrexate.