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Remicade® (Infliximab): 20 years of contributions to science and medicine

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On August 24, 1998, Remicade® (infliximab), the first tumor necrosis factor-α (TNF) inhibitor, received its initial marketing approval from the US Food and Drug Administration for the treatment of Crohn's disease. Subsequently, Remicade was approved in another five adult and two pediatric indications both in the USA and across the globe. In the 20 years since this first approval, Remicade has made several important contributions to the advancement of science and medicine: 1) clinical trials with Remicade established the proof of concept that targeted therapy can be effective in immune-mediated inflammatory diseases; 2) as the first monoclonal antibody approved for use in a chronic condition, Remicade helped in identifying methods of administering large, foreign proteins repeatedly while limiting the body's immune response to them; 3) the need to establish Remicade's safety profile required developing new methods and setting new standards for postmarketing safety studies, specifically in the real-world setting, in terms of approach, size, and duration of follow-up; 4) the study of Remicade has improved our understanding of TNF's role in the immune system, as well as our understanding of the pathophysiology of a range of diseases characterized by chronic inflammation; and 5) Remicade and other TNF inhibitors have transformed treatment practices in these chronic inflammatory diseases: remission has become a realistic goal of therapy and long-term disability resulting from structural damage can be prevented. This paper reviews how, over the course of its development and 20 years of use in clinical practice, Remicade was able to make these contributions.
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REVIEW
Remicade
®
(iniximab): 20 years of contributions
to science and medicine
This article was published in the following Dove Press journal:
Biologics: Targets and Therapy
Richard Melsheimer
1
Anja Geldhof
1
Isabel Apaolaza
1
Thomas Schaible
2
1
Medical Affairs, Janssen Biologics BV,
Leiden, the Netherlands;
2
Medical Affairs,
Janssen Pharmaceuticals, Horsham,
PA, U S A
Abstract: On August 24, 1998, Remicade
®
(iniximab), the rst tumor necrosis factor-α
(TNF) inhibitor, received its initial marketing approval from the US Food and Drug
Administration for the treatment of Crohns disease. Subsequently, Remicade was
approved in another ve adult and two pediatric indications both in the USA and
across the globe. In the 20 years since this rst approval, Remicade has made several
important contributions to the advancement of science and medicine: 1) clinical trials
with Remicade established the proof of concept that targeted therapy can be effective in
immune-mediated inammatory diseases; 2) as the rst monoclonal antibody approved
for use in a chronic condition, Remicade helped in identifying methods of administer-
ing large, foreign proteins repeatedly while limiting the bodys immune response to
them; 3) the need to establish Remicades safety prole required developing new
methods and setting new standards for postmarketing safety studies, specically in
the real-world setting, in terms of approach, size, and duration of follow-up; 4) the
study of Remicade has improved our understanding of TNFs role in the immune
system, as well as our understanding of the pathophysiology of a range of diseases
characterized by chronic inammation; and 5) Remicade and other TNF inhibitors have
transformed treatment practices in these chronic inammatory diseases: remission has
become a realistic goal of therapy and long-term disability resulting from structural
damage can be prevented. This paper reviews how, over the course of its development
and 20 years of use in clinical practice, Remicade was able to make these
contributions.
Keywords: Remicade, iniximab, monoclonal antibody, immune-mediated inammatory
disease, TNF inhibition, Crohns disease, rheumatoid arthritis
Plain language summary
Prompted by the recent twentieth anniversary of the rst approval of Remicade
®
(iniximab; Janssen Biotech, Inc., Horsham, PA, USA), a rst-in-class monoclonal
antibody tumor necrosis factor α(TNF) inhibitor, the authors have written this review
in order to recognize the drugs contributions to science and medicine. Remicadesrst
therapeutic indication, Crohns disease, was followed by another ve indications, all of
which are immune-mediated inammatory diseases (IMIDs). A common factor in these
diseases is increased expression of the cytokine TNF, which drives the underlying
inammation causing them. Through inhibition of TNF, this chronic inammation can
be suppressed and the disease successfully treated. In the course of Remicades devel-
opment and its use in clinical practice, several important rsts were achieved. Remicade
established the proof of concept that targeted therapy (ie, blockade of a single inam-
matory mediator) can be a successful treatment approach for IMIDs. It demonstrated
Correspondence: Richard Melsheimer
Medical Affairs, Janssen Biologics, BV,
Einsteinweg 101, Leiden 2333 CB,
Netherlands
Tel +3 165 533 2947
Email rmelshe1@its.jnj.com
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that there is a role for monoclonal antibodies in the treatment
of chronic diseases. The need to establish its safety prole led
to the development of new methods and standards for post-
marketing commitment studies. Studies in current indications,
in indications where it was not efcacious, and of its safety
prole have taught us much about the immune system and
greatly improved our understanding of the pathophysiology of
several IMIDs. Lastly, the availability of Remicade and other
TNF inhibitors has transformed the practice of medicine in
these diseases, where more ambitious goals of therapy are
now possible. Each of these advancements has helped to bring
about a revolution in medicine that is still ongoing today.
Introduction
On August 24, 1998, the monoclonal antibody (mAb)
Remicade
®
(iniximab; Janssen Biotech, Horsham, PA,
USA) received approval from the US Food and Drug
Administration (FDA) for the treatment of Crohnsdis-
ease (CD), thereby becoming the rst tumor necrosis
factor-α(TNF) inhibitor available for use in clinical
practice. In the ensuing years, this initial indication
was followed by approval in another ve adult and
two pediatric chronic inammatory conditions both in
the USA
1
and around the globe (Figure 1). Beyond
TREAT (CD Registry)43 – 1999 to 2012
Remicade first approval RA,18
First approval AS,28
First approval PsA,28 Phase III ASPIRE (MTX-naïve RA),30
First approval PsO,28 Phase II IMPACT and Phase III
IMPACT II (PsA),32 Phase III ASSERT (AS),33 Phase III ACT I
and II (UC),34 Phase III EXPRESS (PsO),35 First approval UC18
Millionth patient treated with Remicade,a
JRA trial,37 Phase III EXPRESS II (PsO)38
Phase III ACCENT II (Fistulizing CD maintenance)31
Phase II CHF trial failed29
First approval CD maintenance,18
1999
1998
2002
2001
2000
2006
2009
2010
2012 2013
2018
2019
2011 2016
1994
1992
1993
1991 1995
1990
1989
1975
1984 1986
1975 1980 1990 2000 2010 2020
1997
2003
2004
2005
2007
Phase III ATTRACT (RA),19
Phase II (Present) Fistulizing CD,20
Phase III ATTRACT (RA) structural damage data21
Remicade first approval CD,16
KEY
Remicade Milestones
Related Milestones
Phase II
Braun (AS),25
Phase III
ACCENT I (CD
maintenance),26
Phase II
Targan
(CD),15
Phase II
sepsis trial
failed9,10
First
Phase II
CD trial14
Demyelinating
disorders
identified
as TNFi risk24
TB identified as
TNFi risk22,23
HSTCL
identified
as TNFi risk,36
First approval
pediatric CD18
Barkham
study
(Early
axSpA)39
SONIC (AZA-naïve CD)40
RESPOND
(MTX-naïve
PsA)41
First approval
pediatric UC18
PREVENT
(Post-operative CD)42
2 millionth
patient
treated with
Remicadea
3 millionth
patient treated
with Remicadea
20 Year
Anniversary
of first approval
of Remicade16
First Phase II RA trial,13
cA2 mAb developed8
First use
in CD12
First use
in RA11
Enbrel (etanercept) first approval (RA)17
Rituxan/
Mabthera
(rituximab)
approval
(NHL)6
Humira
(adalimumab)
first approval
(RA)27
ReoPro (abciximab) approval6
Central role of
TNF in RA
reported7
Identification of TNF,2
Köhler and Milstein
describe mAb
technology3
OKT3
(muromonab)
approval6
Chimeric
mAbs first
described4,5
Company-
owned
registries
Remicade
postmarketing
commitments
(PMCs)
Independent
registry
studies
and other
ENCORE (CD Registry)47 – 2003 to 2013
OPUS (UC Registry)48 – 2007 to 2016
PSOLAR (Psoriasis Registry)49 – 2007 to 2022
DEVELOP (Pediatric IBD Registry)50 – 2007 to 2039
Rheumatology (6 studies)51–56 – 1999 to 2021
Psoriasis (3 studies)a,57,58 – 2007 to 2014
HSTCL (3 studies)a,59,60 – 2009 to 2019
BeSt (RA Treatment Strategies Trial)61 – 2000 to 2016
Nordic Pregnancy Registry44 – 2000 to 2016
RemiTRAC (Remicade Registry,
all indications)45,46
BioTRAC (Rheumatology Registry)45,46
– 2002 to 2018
Figure 1 Key milestones in the development of Remicade.
Note:
a
Janssen, data on le.
Abbreviations: AS, ankylosing spondylitis; axSpA, axial spondyloarthritis; CD, Crohns disease; CHF, congestive heart failure; HSTCL, hepatosplenic T-cell lymphoma; IBD,
inammatory bowel disease; JRA, juvenile rheumatoid arthritis; MTX, methotrexate; mAb, monoclonal antibody; NHL, non-Hodgkins lymphoma; PBO, placebo; PsA,
psoriatic arthritis; PsO, psoriasis; RA, rheumatoid arthritis; TB, tuberculosis; TNF, tumor necrosis factor; TNFi, TNF inhibition; UC, ulcerative colitis.
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offering a welcome new treatment option for patients, it
has contributed to several important advances in science
and medicine, which will be the focus of this review.
Remicades approval represented the culmination of two
independent sets of research that began in 1975 when both
TNF and hybridoma technology, the method for producing
monoclonal antibodies, were rst described in the
literature.
2,3
Subsequent research on TNF identied its
role not only in host response, but also in the pathophysiol-
ogy of a number of immune-mediated inammatory dis-
eases (IMIDs), such as CD and rheumatoid arthritis (RA).
This observation led to the question of whether blockade of
TNF could serve as a treatment for these diseases. At the
time, conventional treatments for IMIDs, such as immuno-
suppressants and corticosteroids, treated symptoms of dis-
ease, but not the underlying pathophysiology, and were
associated with both limited efcacy and side effects.
However, the feasibility of targeted therapy in this setting
was unknown. In a complex network of inammatory med-
iators with pleiotropic, sometimes overlapping functions,
could inhibiting a single cytokine such as TNF suppress
inammation in a clinically meaningful way? How could
such a cytokine be inhibited? Because of their high ligand
specicity and afnity, mAbs were obvious candidates, but
had not met expectations as therapeutics. Could they achieve
their potential? These questions were rst answered in 1992
when Remicade, then known simply as cA2, was used to
conrm the hypothesis that the inammation driving RA is
mediated by TNF and can be suppressed by its blockade.
11
The development of Remicade up to that point and since
then has been a classic example of how an improvement in
understanding of pathophysiology can lead to a therapeutic
breakthrough, which in turn leads to a deeper understanding
of pathophysiology. Each new learning led to another ques-
tion to be answered, which has resultedin the development of
asignicant body of scientic and medical research: a litera-
ture search for the word iniximabtoday reveals more than
13,000 publications, a number that approaches 50,000 when
including other TNF inhibitors such as etanercept (Enbrel
®
;
Immunex Corporation, Thousand Oaks, CA, USA) and ada-
limumab (Humira
®
; AbbVie, North Chicago, IL, USA).
Many of the learnings are now common knowledge, but in
1992 were hypotheses. It is only with hindsight that we can
put them into perspective (Figure 1).
This article reviews these learnings as they developed
over time: the discovery of TNF; Remicades clinical devel-
opment, primarily in RA and CD, which are its earliest and
most prominent indications; its evaluation in other diseases;
the establishment of its safety prole; and its role in chan-
ging clinical practice. It is important to note that the parti-
cipants in this scientic journey were not only Janssen and
its commercial partners and local distributors (Merck, Sharp
and Dohme [MSD] in Europe, Turkey, and Russia, and
Mitsubishi Tanabe Pharmaceutical Corporation in Japan,
Taiwan, and Indonesia), butalso a large number of indepen-
dent researchers. Their collective work demonstrates that
the learnings from a drug do not stop at the end of its formal
development, but can continue for years afterward.
With the recent 20-year anniversary of Remicadesrst
approval in 1998, it is tting to reect on its contributions
to science and medicine.
TNF is a key driver of inammation
In 1975, Carswell et al described an experiment in which
tumor regression was observed in mice injected with endo-
toxin from the pathogenic bacterium Serratia marcescens.
They isolated a substance in the serum of these mice that
led to this regression and named it tumor necrosis factor
(TNF).
2
In 1985, Beutler et al studied a factor which
caused cachexia, a wasting syndrome, by acting on lipo-
protein lipase and other metabolic pathways.
62
This factor,
which they called cachectin, was later found to be TNF.
Simultaneously, Dayer et al, while searching for a factor
that mediated shock, isolated a substance from cells of
monocytic lineage which was also found to be TNF.
63
These three independent discoveries of TNF in separate
elds of research display vividly the central and complex
role that it plays in the immune system. It is a key driver
and regulator of the bodysinammatory response
64
and is
involved in immune surveillance and homeostasis.
65,66
TNF is not usually detectable in healthy populations,
but is increased in both serum and tissue under inamma-
tory and infectious conditions, and after tissue injury.
67
It
is one of the rst cytokines to appear in the blood after
injury or stress and does so within minutes,
65
secreted
primarily by macrophages and monocytes, but also by
other immune cells, eg, neutrophils, T cells, and natural
killer (NK) cells, as well as non-immune cells.
67
The
concentration of TNF in serum correlates with the severity
of infection. Other pro-inammatory cytokines, such as
interleukin (IL)-6 and IL-1, appear later and are at least
in part dependent on prior release of TNF.
65
The 24-kDa
membrane-bound form of TNF (tmTNF) is cleaved by a
metalloproteinase enzyme, TNF-α-converting enzyme
(TACE), to release a 17-kDa soluble form (sTNF). Both
forms are biologically active.
67
They mediate their effects
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through binding to either of two receptors, TNFR1 (p55)
or TNFR2 (p75). TNFR1 is expressed on most cell types
and is generally activated by sTNF, while TNFR2 is
expressed primarily on immune, specically T-regulatory,
and endothelial cells and is preferentially activated by
tmTNF.
65,68,69
TNFR1 seems to be primarily involved in
the inammatory response and mediating apoptosis while
TNFR2 appears to be important for tissue repair, immune
modulation, and homeostasis.
65,69
TNF exerts its pleiotropic effects via a number of
mechanisms, such as macrophage activation, differentia-
tion and phagosome formation,
64
activation of neutro-
phils and NK cells, and promotion of cell adhesion,
apoptosis, and cellular proliferation.
70
These mechanisms
contribute to the bodys common manifestations of
inammation, eg, fever, vasodilation/edema, sleep dis-
ruption, regulation of coagulation and tissue degenera-
tion, as well as to the manifestations of downregulation
of the inammatory response, eg, promotion of immune
modulation, tissue regeneration, formation and mainte-
nance of granulomas, immune surveillance, and
homeostasis.
66,67
TNFs functions are seemingly contra-
dictory: it plays a role in both tissue degeneration and
tissue repair, cellular proliferation and apoptosis, and has
anti-tumor and tumor pro-growth properties.
65
These
functions are, in fact, complementary. Succinctly stated,
in a time- and context-dependent manner, TNF drives a
rapid and vigorous inammatory response triggered by
infection or injury (primarily via sTNF/TNFR1), and also
functions to limit the extent and duration of this inam-
matory response when the trigger has been resolved (pri-
marily via tmTNF/TNFR2).
69
These dual roles will, in
part, explain later observations in patients treated with
TNF inhibitors.
Studies in the 1980s and 1990s showed that levels of
TNF were increased in a number of pathophysiological
conditions. In patients with sepsis, elevated levels of TNF
appeared to correlate with mortality. Moreover, peak ele-
vation in monocyte TNF expression correlated with septic
episodes.
71
Overexpression was also observed across see-
mingly unrelated conditions, often in the absence of infec-
tion. Elevated levels were present in the mucosa and stools
of patients with inammatory bowel disease (IBD), and
mucosal cells expressing TNF had been detected in
patients with CD.
72
Pro-inammatory cytokines such as
TNF and IL-1 were detected in the synovial uid of
patients with RA, and TNF surface receptors were found
to be upregulated in active RA tissues.
73
These ndings led to the question: if TNF is a driver of
inammation and these conditions are primarily diseases
of chronic inammation, could blockade of TNF be a
successful treatment strategy in these conditions?
Two key proofs of concept are
established with Remicade
Would blocking a single cytokine be
effective in these complex immune-
mediated diseases? How could such a
cytokine be blocked?
The advent of monoclonal antibodies
Traditional development of pharmaceuticals in the past
had been empirical, where potential agents were not tar-
geted to a specic mediator of disease and their mechan-
ism of action was not precisely understood.
65
In IMIDs,
while conventional drugs such as steroids and immuno-
suppressants are benecial, they have broad unspecic
effects and are characterized by limited efcacy in itself
or efcacy constrained by unacceptable toxicity. A deeper
understanding of the pathophysiology of disease would
have offered the possibility of testing a new approach to
pharmaceutical development, where targeting specic
mediators of disease provides benet with fewer toxicities.
In the 1980s and 1990s, the most readily available
approach to targeted therapy was through the use of
mAbs, the largest class of therapeutic proteins derived
from recombinant DNA techniques, known as biologics.
However, 1020 years after the publication of Köhler and
Milstein rst describing them,
3
they had not met expecta-
tions as therapeutics.
74
The mAbs available at that time
were fully murine and were associated with a number of
limitations. As foreign proteins, they were immunogenic
and associated with high anti-drug antibody (ADA) rates,
which resulted in both safety implications and a negative
effect on pharmacokinetics (PK). In addition, murine
mAbs were poor at inducing antibody effector function
in humans. As late as 1993, only one mAb had received
regulatory approval for clinical use, Janssens muromonab,
also known as OKT3, for short-term use in transplant
rejection with concomitant immunosuppression, a setting
in which ADA risk was limited.
6
Yet, advances in mAb technology were coming to
fruition at that time. Under the assumption that replacing
the murine content of mAbs with human equivalents
would both reduce the risk of ADA and improve effector
function, researchers used new molecular biology
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techniques to develop chimeric mAbs, which are produced
from genes whose DNA sequences are approximately 75%
human, where only the DNA sequence for the variable
domain within the antigen-binding fragment (Fab) remains
murine.
46
The assumption proved correct and in 1994,
Janssens abciximab (ReoPro
®
; Janssen Biotech, Horsham,
PA, USA), a Fab fragment, became the rst chimeric mAb
to receive regulatory approval, for the prevention of plate-
let-mediated thrombosis during angioplasty.
6
The rst
whole chimeric mAb to receive regulatory approval was
rituximab (Rituxan
®
; Genentech, South San Francisco,
CA, USA; MabThera
®
; Roche Registration GmbH,
Grenzach-Wyhlen Germany) in 1997 for use in lymphoma.
Both were approved for single or short-term use, leaving
questions about long-term use of mAbs unanswered.
6
In the early 1990s, Janssens Immunology unit (then
known as Centocor) developed the chimeric anti-TNF
mAb, cA2.
8
Based on data showing that TNF blockade
prevented septic shock in animals given a lethal dose of
endotoxin,
71,75
Janssen selected sepsis as the initial focus
for the clinical development of cA2. Sepsis was an
obvious candidate for targeted therapy with mAbs because
of its high rate of mortality, which increased the accept-
ability of possible adverse drug reactions (ADRs), and the
need for short-term therapy, limiting the possibility of
immunogenicity as a concern. However, in the preliminary
clinical study, there were no differences in patterns of
cytokine activation or mortality with cA2 relative to
placebo,
9,10
and the program was discontinued. Most
researchers in the eld concluded that TNF inhibition
failed in sepsis because blocking a single cytokine could
not work in diseases characterized by a complex mixture
of redundant inammatory mediators.
76
Based on these
results, the expectations for targeted therapy in other
inammatory conditions were low.
Proof of concept in RA and CD
However, in parallel to the research in sepsis, Ravinder
(Tiny) Maini and Marc Feldmann at the Kennedy Institute
in London had completed research suggesting that block-
ade of a single cytokine could reap therapeutic benetin
an IMID. When evaluating a batch of synovium samples
from patients with active RA, they observed elevated
levels of pro-inammatory cytokines in all of them.
65
This was striking, since such cytokines are usually pro-
duced for short periods only (hours to 2 days), and sug-
gested that in RA their production was continuous. The
key breakthrough came in 1989, when Brennan et al
suggested for the rst time that TNF may be a pivotal
cytokine in the pathophysiology of RA.
7
Their study, in
which several pro-inammatory cytokines (TNF, IL-1, IL-
6, granulocyte-macrophage colony-stimulating factor)
were neutralized one by one, revealed that blocking TNF
in synovial culture led to the inhibition of the others. This
was consistent with the observation that TNF is one of the
rst cytokines to appear after injury or stress and led to the
concept of a pro-inammatory cascade at work in RA,
with TNF at its beginning.
Based on these observations, in 1993, Elliott et al of
the same group in London conducted a proof-of-concept
study in humans, where 20 patients with severe RA were
treated with either two 10 mg/kg or four 5 mg/kg infusions
of cA2, given 2 weeks and 4 days apart, respectively.
11
Positive clinical improvements, as measured by swollen
and tender joint counts and pain, and biochemical
responses, as measured by reduced levels of inammatory
mediators, were observed in all patients, providing the rst
evidence that TNF blockade reduced inammation and
improved symptoms in RA. The effect faded after a few
weeks.
Elliott et al proceeded to conduct a 73-patient rando-
mized, placebo-controlled trial of a single infusion of two
doses (1 mg/kg and 10 mg/kg) of cA2 in RA.
13
Both doses
proved highly effective (combined dose groups with a 61%
clinical response [Paulus 20%] vs 8% for placebo at week
4, P<0.001), but the maximal improvement and its duration
were dose dependent. The rate of adverse events was simi-
lar across the cA2 arms and the placebo group. As found in
the rst study, the benets disappeared within a few weeks.
In a rst exploration of retreatment, several initial respon-
ders from the rst study were given cA2 for up to three
additional cycles administered upon relapse.
77
The patients
regained their responses, but they were again temporary,
and the time to relapse generally shortened with each suc-
cessive cycle, raising concerns about ADAs developing
over time (four of seven patients were ADA positive).
Gastroenterologists, who had observed increased levels
of TNF in patients with CD, also explored its blockade as
a possible treatment. In 1993, the group of Sander van
Deventer at the Academic Medical Centre in Amsterdam
reported on a female patient, age 12 years, with CD who
was non-responsive to conventional therapies and received
cA2 as a compassionate-use treatment.
12
She received two
infusions of cA2 10 mg/kg 2 weeks apart and responded
immediately after the rst dose. Clinical and endoscopic
remission was observed, but, as with RA, this was
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temporary, with symptoms returning after 3 months. Van
Dullemen et al from the same group in Amsterdam then
conducted an open-label proof-of-concept study of a single
dose of cA2 (10 mg/kg or 20 mg/kg) in 10 patients with
steroid-non-responsive CD.
14
Within 4 weeks, eight
patients showed normalization of their Crohn's Disease
Activity Index (CDAI) scores and near-complete healing
of mucosal ulcerations, images of which merited display
on the cover of the journal in which the data were pub-
lished (Figure 2). The average duration of response after a
single infusion was 4 months, and cA2 was well tolerated
among all patients.
This small, uncontrolled study supported the hypoth-
esis that TNF was a major contributor to the pathophysiol-
ogy of CD and paved the way for Targan et al to conduct a
12-week multicenter, double-blind, placebo-controlled
trial in 108 patients with treatment-resistant CD.
15
In
1997, they reported that 65% of patients receiving a single
dose of cA2 (5, 10, or 20 mg/kg) had a clinical response
by week 4 compared with 17% of placebo-treated patients
(P<0.001). The rates of adverse events were similar among
treatment groups. Rutgeerts et al explored retreatment in
this trial, where patients with an initial response to cA2
were given an additional four open-label infusions of 10
mg/kg every 8 weeks (q8w) beginning 12 weeks after the
initial infusion.
78
Similarly to the previous experience in
RA, they found that the initial benet of cA2 could be
regained and, owing to the regular q8w retreatment sche-
dule rather than waiting for relapse, it was also sustained
for the duration of the study. cA2 was well tolerated and
the rate of immunogenicity was low (10%).
These studies showed that blocking one cytokine, TNF,
could have profound, if temporary, clinical benets in both
RA and CD. The benet observed in both conditions was
profound and rapid. Moreover, the lack of signicant
safety issues despite these benets was encouraging.
While the cause of the TNF-driven inammation was
still unknown, and its blockade was not a cure, a possible
method to suppress it had been found, suggesting potential
for clinical use. However, for this therapeutic strategy to
work, it was clear that sustained TNF blockade would be
necessary. Initial experience with retreatment was positive,
but would it work in the long term?
How can dose and concomitant
medications inuence the rate of efcacy
and immunogenicity? Phase II trial in RA
The possibility of long-term TNF blockade with cA2 as a
treatment strategy for chronic inammatory diseases raised
three fundamental questions: 1) Could mAbs be adminis-
tered repeatedly as long-term therapy? Immunogenicity
was the primary concern as it could be associated with
ADRs (eg, allergic or hypersensitivity reactions) or limits
on efcacy (neutralization and clearance of the mAb); 2)
Would long-term TNF blockade succeed, or would the
disease circumvent this blockade and restore the chronic
inammation via another pathway? 3) Would long-term
TNF blockade be associated with an unacceptable safety
risk? Given the function of TNF, infections and malignan-
cies were of particular concern. Clinical development in
RA and CD proceeded, starting with the rst of these
questions, immunogenicity.
The relationship between dose, PK, efcacy, safety,
and immunogenicity of cA2 was rst studied in a phase
II, double-blind, placebo-controlled RA trial, conducted in
19951996, evaluating cA2 alone or in combination with
methotrexate (MTX), an immunomodulator and the gold-
standard conventional synthetic disease-modifying anti-
rheumatic drug (csDMARD) in RA.
79
In the trial, 101
patients with clinically active disease despite receiving
MTX were randomized to receive cA2 at 1, 3, or 10 mg/
kg, with or without MTX, or placebo plus MTX, at weeks
0, 2, 6, 10, and 14, and were followed through week 26.
The rationale for an induction regimen at weeks 0 and 2
followed by 4-week intervals thereafter was two-fold: 1)
that high-dose induction would suppress inammation
rapidly and profoundly, and 2) that early, high systemic
exposure of the immune system to an antigen, in this case
cA2, could result in increased tolerance, thereby reducing
immunogenicity.
AB
Figure 2 Healing of colonic ulcerations in a Crohn's disease patient (A) before
treatment and (B) 4 weeks after a single infusion of Remicade 10 mg/kg.
Notes: Gastroenterology by American Gastroenterological Association. Reproduced
with permission of W.B./Saunders Co., from Treatment of Crohns disease with anti-
tumor necrosis factor chimeric monoclonal antibody (cA2). van Dulleman HM, van
Deventer SJ, Hommes DW, et al. Gastroenterology, volume 109, issue 1, 1995.
14
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Approximately 60% of patients in all dose groups had
respondedby week 2, but the degree and duration of response
varied by dose and MTX use. Patients receiving cA2 1 mg/kg
without MTX experienced a rapid decline in response, while
patients receiving 3 or 10 mg/kg without MTX showed
sustained responses. In all three dose groups, the response
was longer in duration when combined with MTX. Serum
cA2 concentrations were stable in patients receiving 3 or 10
mg/kg alone or in combination, though consistently higher in
those receiving MTX. In contrast, patients receiving 1 mg/kg
without MTX showed an elimination of cA2 in the serum by
the end of the 4 weeks, whereas stable, albeit low, levels were
maintained in patients receiving MTX. On the important
question of immunogenicity, there were two key observa-
tions: rates of ADA were lower for all doses when combined
with MTX and were inversely related to cA2 dose adminis-
tered (Figure 3).
These ndings demonstrated not only that retreatment
with TNF blockade could be effective in sustaining the
initial treatment benet, but also how immunogenicity of
mAbs could be reduced: a high-dose induction regimen
was associated with tolerance to cA2, levels of immuno-
genicity were inversely proportional to dose, and co-
administration with MTX both reduced immunogenicity
and improved the PK of cA2.
First approval of Remicade: CD
Despite the initial proof-of-concept study of targeted TNF
blockade with cA2 being conducted in RA, CD was
selected as the rst indication for commercial development
because it was believed to have a more expedited path to
regulatory approval owing to its severity in patients not
responding to conventional therapies.
Having completed the Targan study in luminal CD,
15
the next trial was conducted in stulizing CD, a debilitat-
ing complication observed in as many as 20% of CD
patients where no therapy had been shown to be effective.
Present et al evaluated the efcacy of cA2 to close drain-
ing stulas in 94 patients randomized to receive an induc-
tion dose at 0, 2, and 6 weeks of placebo, or 5 or 10 mg/kg
of cA2, and then followed through week 18.
20
The primary
endpoint was closure of 50% of stulas for at least two
consecutive visits 4 weeks apart. The response rate was
26% in placebo patients compared with 68% (P=0.002)
and 56% (P=0.02) in the 5 and 10 mg/kg groups, respec-
tively. The safety results were consistent with those
observed in the initial studies.
The Targan and Present studies thus demonstrated the
safe and effective use of cA2 in treatment-resistant, mod-
erate-to-severe CD, and were the basis for its rst regula-
tory application. The FDA granted accelerated review and
approved cA2, renamed Remicade (iniximab), on August
24, 1998.
16
Approval by the European Medicines Agency
(EMA) in Europe was granted a year later, followed by
approvals in Brazil (2000), Canada (2001), Japan (2002),
and over 100 other countries (Janssen, data on le).
Importantly, the FDA and other health authorities
granted approval for single treatment with Remicade, but
recognized the need for maintenance treatment in CD and
required that Janssen study it in the phase III setting as a
condition of approval.
Can long-term blockade of TNF lead to
sustained suppression of inammation?
Phase III trials in RA and CD
Maintenance treatment was rst studied in the phase III
ATTRACT trial, which evaluated Remicade over a 2-year
period in moderate-to-severe RA despite treatment with
MTX.
19
Patients, all of whom remained on stable doses of
MTX, were treated with an induction regimen (infusions at
weeks 0, 2, and 6) of either placebo or Remicade 3 or 10
mg/kg, followed by infusions of the same dose administered
every 4 weeks (q4w) or q8w thereafter (with placebo infu-
sions as needed to maintain the blind). The clinical effects
of all four Remicade groups were superior to placebo and
similar to each other at the primary endpoint, the proportion
of patients who achieved 20% improvement in the
60
53
21
7
15
7
0
50
40
30
20
10
0n = 15 14
Remicade without MTX
Incidence of ADA (%)
Remicade 1 mg/kg Remicade 3 mg/kg Remicade 10 mg/kg
Remicade with MTX
15 14 1415
Figure 3 Incidence of ADAs in a phase II trial of MTX-refractory RA patients, by
Remicade dose and use of concomitant MTX. ADAs were measured by a drug-
sensitive immunoassay.
Note: Data from Maini et al.
79
Abbreviations: ADA, anti-drug antibody; MTX, methotrexate; RA, rheumatoid
arthritis.
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American College of Rheumatology response criteria
(ACR20) at 6 months (50.0% in the 3 mg/kg q8w group
[standard approved dose] vs 20.0% in the placebo group,
P<0.001), and were sustained through the 2-year duration of
the trial with a mild dose response.
80
This dose response,
combined with another trial evaluating dose escalation for
Remicade in RA, START,
81
led to the approval of dose
increase above 3 mg/kg in RA for lack of initial response or
later loss of response.
In CD, maintenance treatment with Remicade was
studied in the phase III ACCENT I and II trials for luminal
and stulizing disease, respectively.
26,31
Both trials had a
randomized withdrawal design, where all patients were
initially treated with Remicade, after which responders
were randomized either to Remicade maintenance therapy
(5 or 10 mg/kg in ACCENT I or 5 mg/kg in ACCENT II)
or placebo maintenance q8w for 1 year. Patients who lost
response to treatment crossed over to a dose of Remicade
5 mg/kg higher than their randomized dose. In ACCENT I,
at crossover, the dose was administered upon symptom
return, allowing the evaluation of episodic use of
Remicade. In ACCENT II, the regular q8w maintenance
schedule was continued after crossover. Both studies met
their primary endpoints, which were clinical remission and
time to loss of response at week 30 in ACCENT I and
median time to loss of response (50 reduction in number
of draining stulas) in ACCENT II. In both studies, the
initial Remicade induction response waned in patients
randomized to placebo maintenance, while the benets
were largely sustained in patients randomized to continue
Remicade (with a dose response in ACCENT I).
Moreover, dose escalation resulted in regaining response
in patients who lost their initial response.
82
Episodic
retreatment with Remicade in ACCENT I revealed impor-
tant lessons. While response was regained, outcomes were
generally worse and led to higher levels of ADA than in
patients who maintained a regular q8w maintenance
schedule.
83
In both ACCENT studies (as in ATTRACT),
ADA development was associated with an increased risk
of infusion reactions and subsequent loss of response.
26
These observations, conrmed independently,
84
provided
support to the then novel, now accepted, hypothesis of an
important dynamic of immunogenicity and serum drug
levels: not only do ADAs lead to low serum levels of
drug, but low serum levels lead to increased ADAs.
85
It
is now well understood that maintaining target levels of
the drug is important to minimize the development of
ADAs.
Thus, the phase II/III program had answered all three
initial questions about long-term TNF blockade with
Remicade: 1) mAbs could be administered repeatedly as
maintenance therapy, and several strategies were identied
to reduce the risk of ADA; 2) sustained TNF blockade could
result in long-term suppression of disease; 3) to the degree
that the safety prole of a drug could be assessed with fewer
than 2,000 patients treated for 2 years, and considering the
efcacy observed, the overall benetrisk prole was con-
sidered acceptable (see Establishing the safety prole of
Remicade, later in this review). On the basis of the results
of the ATTRACT and ACCENT I/II trials, Remicade was
approved as induction and maintenance therapy for RA in
1999 and as maintenance therapy for CD in 2003.
Is TNF blockade disease-modifying?
At the time of the initial approvals in CD and RA, it was
not known whether TNF blockade would be disease-mod-
ifying and thereby inhibit the progressive, irreversible
structural damage caused by these diseases. This question
was rst answered in RA, where joint destruction is a
hallmark of the disease and a predictor of poor functional
outcome and disability. The ATTRACT study was the rst
to show that progression of joint damage could be inhib-
ited with TNF blockade. The mean increase in radio-
graphic progression score at 1 year (using the Sharp/van
der Heijde score [SHS]), the co-primary endpoint of the
trial, was 0.6 for Remicade across all doses versus 7.0 for
the MTX group (P=0.001), indicating inhibition of joint
damage progression in the majority of Remicade-treated
patients, which was unprecedented for any therapy at that
time (Figure 4).
21
This effect was sustained through to the
end of the 2-year trial.
80
Importantly, the inhibition of
progression was observed regardless of whether patients
had a clinical response to Remicade or not. Further sub-
group analysis showed that inhibition of joint progression
occurred in patients with early disease as well as those
with established disease, another important nding.
Analogous work was done in the CD clinical trials, where
the endpoints studied included the effect of Remicade on
mucosal healing and the need for surgery. The original obser-
vation by Derkx et al
12
and van Dullemen et al,
14
that
Remicade healed the mucosa in CD patients, was conrmed
in ACCENT I, where the healing (dened as the absence of
mucosal ulcerations in all segments where they had been
observed on endoscopy at baseline) was observed as early as
the end of induction and was sustained through to the end of
the trial: 50% of initial responders receiving q8w maintenance
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therapy had complete mucosal healing at 1 year compared
with only 7% of initial responders receiving episodic main-
tenance therapy (P=0.007).
82
In addition, in both ACCENT I
and ACCENT II, Remicade maintenance therapy was asso-
ciated with a reduced rate of hospitalizations and
surgeries.
89,90
The inhibition of joint destruction and the mucosal heal-
ing effects with Remicade in patients with RA and CD
demonstrated that TNF blockade was not just an effective
agent on clinical symptoms, but was also disease-modifying,
implying an impact on the course of the disease. Research
into the exact mechanism of Remicades effect followed.
What is Remicades mechanism of action?
Analyses from RA and CD clinical trials
It was of interest to determine whether the TNF-dependent
inammatory cascade observed in the initial synovial cell
culture experiments77 occurred in vivo. In RA patients
receiving Remicade, rapid decline in serum IL-6 levels on
the day of treatment conrmed that a TNF-dependent cyto-
kine cascade was indeed occurring.
91
Reductions in other
pro-inammatory mediators and chemokines were also
observed.
10
Similarly, C-reactive protein (CRP, a serum
marker of systemic inammation) was observed to decline
rapidly after administration of Remicade.
19
Detailed
mechanistic studies were performed, and multiple aspects
of the disease were found to improve, including immune
function, joint function and hematological parameters.
65
Immunohistological studies were conducted to investigate
changes in the synovium, where reductions in the expres-
sion of adhesion molecules and in cell inltration were
observed, as were reductions in angiogenic factors and
angiogenesis.
10
Taylor et al demonstrated in a neutrophil
radiolabeling study that the inux of granulocytes was
reduced by approximately 50% in the joints within 2
weeks of a single dose of Remicade, indicating that reduced
recruitment of these and other leukocytes to the joints is an
important aspect of the mechanism of anti-TNF therapy.
92
Similar mechanistic studies were performed in CD. As
with RA, Remicade treatment of CD patients was asso-
ciated with a rapid reduction of CRP.
15
Histological eval-
uation of colonic biopsies revealed a reduction in
detectable TNF after treatment and provided evidence of
reduced inltration of inammatory cells and other inam-
matory markers at these sites. Analysis of lamina propria
mononuclear cells of the intestinal mucosa showed that
Remicade treatment caused a reduction in the number of
cells capable of expressing TNF and interferon-γ.
93,94
As an antibody, Remicade functions in two ways: it
binds directly to s/tmTNF via its Fab (antigen-binding)
region and has a functional Fc (constant) region.
Through both, its possible mechanisms of action of TNF
inhibitors generally fall into two categories: 1) blockade of
TNF-receptor-mediated signaling through neutralization of
sTNF and tmTNF; and 2) removal of TNF-expressing cells
by induction of Fc- or tmTNF-mediated effector mechan-
isms, such as antibody-dependent cellular cytotoxicity
(ADCC) and apoptosis (Table 1). The relative contribution
of these mechanisms to Remicadesefcacy remains
uncertain and possibly differs by disease. For example,
the role of anti-TNF-induced apoptosis of immune cells
in reducing inammation in RA synovial tissue is unclear,
10
8
6
4
2
0
-2
n = 64
Placebo
+ MTX
Remicade
3 mg/kg
q8w + MTX
Mean change from baseline in SHS
Remicade
3 mg/kg
q4w + MTX
Remicade
10 mg/kg
q8w + MTX
Remicade
10 mg/kg
q4w + MTX
71 77 66
-0.7
0.2
1.6
1.3
7.0
P<0.001 P<0.001 P<0.001 P<0.001
71
Figure 4 Progression of structural damage in RA at week 54 in the ATTRACT trial.
Notes: Data from Lipsky.
21
P-values vs placebo + MTX arm.
Abbreviations: MTX, methotrexate; q4w, every 4 weeks; q8w, every 8 weeks; SHS, Sharp/van der Hejde score.
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while evidence exists for such a process in the bowel
mucosa in IBD.
Early clinical evidence that the mechanism of action of
anti-TNF therapy in CD differs from RA was the observa-
tion that etanercept, a p75(TNFR2)-IgG Fc receptor fusion
protein, did not show efcacy in CD.
95
Certolizumab
(Cimzia
®
; UCB, Smyrna, GA, USA), a PEGylated IgG
Fab fragment, demonstrated efcacy in CD, but seemingly
less so than Remicade and adalimumab (both of which are
full antibodies), especially in induction of clinical response.
96
A comparison of the differing characteristics of the TNF
inhibitors tested in CD provides insight into possible expla-
nations for these differences. All TNF inhibitors bind to both
sTNF and tmTNF, but the nature of this binding differs
between them. Remicade and adalimumab, as full antibodies,
are bivalent; ie, capable of binding two molecules of TNF
simultaneously, enabling them to form complexes.
97
Certolizumab and etanercept are both monovalent.
Remicade, adalimumab, and certolizumab have high afnity
for tmTNF, while etanercept has lower afnity for tmTNF
than the antibodies.
94
Remicade and adalimumab have fully
functional Fc fragments, while etanercept has lower Fc activ-
ity than the full mAbs and certolizumab has no Fc fragment
at all.
94
Together, this evidence suggests that in CD, in
addition to the neutralization of TNF, one or more effector
mechanisms are involved in the resolution of inammation
and mucosal healing (Table 1). Research continues today to
determine exactly which mechanisms contribute to the ef-
cacy of these agents.
The results of mechanistic studies of TNF inhibitors com-
bined with their demonstrated efcacy conrmed the role of
TNF in the pathogenesis of both RA and CD. The next ques-
tion was whether TNF inhibition would be an effective ther-
apeutic strategy in other conditions characterized by TNF
elevation.
TNF elevation does not always
mean TNF mediation
Is TNF blockade effective in diseases
beyond CD and RA?
Remicade approval in additional IMIDs
The rst evidence of efcacy of TNF blockade beyond RA
and CD came from anecdotal reports in clinical practice, in
which patients treated with Remicade for CD experienced
improvements in extraintestinal manifestations of their
disease, specically ankylosing spondylitis (AS)
98
and
psoriasis (PsO).
99
These ndings led to clinical develop-
ment in these indications. Psoriatic arthritis (PsA) and
ulcerative colitis (UC) were also studied owing to their
related pathogenesis to RA and CD. Health authority
approvals for AS, PsA, PsO, and UC were received
between 2003 and 2006, followed by pediatric CD
(2006) and pediatric UC (2011).
18
The efcacy of Remicade in each of these conditions was
comparable with that seen in RA and CD (Figure 5), and these
results brought new insights to the understanding of the patho-
genesis of each. For instance, effective treatment of UC,
Table 1 Possible mechanisms of clinical efcacy of TNF blockade with Remicade
Mechanism of action RA, AS, PsA,
and PsO
IBD
(CD and UC)
Mechanisms involving the Fab (antigen binding) region
Blocking TNFR1 and TNFR2 activity via binding and neutralization of s/tm TNF √√
Reverse (outside-to-inside) signaling via binding to tmTNF
Apoptosis of lamina propria activated T cells
Suppression of cytokine secretion
Mechanisms involving the Fc (constant) region
Induction of CDC on tmTNF-expressing target cells (via C1q binding)
Induction of ADCC on tmTNF-expressing target cells (via FcγRIIIa binding expressed
on effector cells)
Induction of regulatory macrophages in mucosal healing
Abbreviations: ADCC, antibody-dependent cellular cytotoxicity; AS, ankylosing spondylitis; CD, Crohns disease; CDC, complement-dependent cytotoxicity; IBD,
inammatory bowel disease; PsA, psoriatic arthritis; PsO, psoriasis; RA, rheumatoid arthritis; sTNF, soluble TNF; tmTNF, transmembrane TNF; UC, ulcerative colitis.
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Trial (Indication)
Odds ratio and 95% Cl
Primary endpoint
Placebo
(%)
Trial DesignaPopulation Primary endpoint
Remicadea
(%)
Odds ratio
(95% Cl) P-value
Targanb,15 (CD) 16.7
20.9
30.0
30.0
25.8
19.4
37.2
29.3
20.5
25.5
53.6
8.6
19.2
9.6
11.0
2.6
1.9
81.5
38.9
56.8
44.4
67.7
36.3
69.4
64.5
50.0
58.0
62.4
52.9
61.2
65.4
58.0
80.4
75.5
< 0.001
0.003
< 0.001
0.006
< 0.002
0.009
< 0.001
< 0.001
< 0.001
< 0.001
0.028
< 0.0001
< 0.001
< 0.001
< 0.001
< 0.0001
< 0.001
22.0 (5.2, 93.6)
2.4 (1.3, 4.4)
3.1 (2.0, 4.9)
1.9 (1.3, 2.9)
6.0 (2.0, 18.2)
2.4 (1.2, 4.6)
3.8 (2.2, 6.5)
4.4, 2.6, 7.5
3.9 (2.0, 7.6)
4.0 (2.9, 5.6)
1.4 (1.04, 2.0)
14.2 (3.6 ,55.4)
6.6 (3.5, 12.4)
17.9 (6.0, 52.5)
11.2 (5.3, 23.5)
153.8 (36.7, 644.6)
120.6 (43.6, 334.2)
0.1 1
Placebo
better
Single infusion PBO vs single infusion CD Clinical response at Week 4
Clinical remission at Week 30
Corticosteroid-free remission at Week 26
50% reduction in number of draining fistula
for 2 consecutive visits
Absence of draining fistula at Week 54d
Clinical response at Week 8
Clinical response at Week 8
ACR20 at Week 30
ASAS20 at Week 24
ACR20 at Week 16
ACR20 at Week 14
75% improvement in PASI score at Week 10
75% improvement in PASI score at Week 10
ACR20 at Week 22d
ACR20 at Week 54d
50% improvement in BASDAI at Week 12
CD
AZA-naïve CD
Fistulizing CD
Fistulizing CD
UC
UC
MTX-IR RA
MTX-IR RA
MTX-naïve RA
AS
AS
PsA
PsA
PsO
PsO
3 yrs duration
Remicade 5 mg/kg
PBO vs Remicade 5 mg/kg in responders to
PBO vs Remicade 5 mg/kg in Remicade 5 mg/kg
PBO vs Remicade 5 mg/kg
PBO + MTX vs Remicade 3 mg/kg + MTX
PBO + MTX vs Remicade 3 mg/kg + MTX
PBO + MTX vs Remicade 3 mg/kg + MTX
PBO vs Remicade 5 mg/kg
PBO vs Remicade 5 mg/kg
PBO vs Remicade 5 mg/kg
PBO vs Remicade 5 mg/kg
PBO vs Remicade 5 mg/kg
PBO vs Remicade 5 mg/kg
PBO vs Remicade 5 mg/kg
single infusion of Remicade 5 mg/kg
induction responders
Induction PBO vs induction Remicade 5 mg/kg
PBO + AZA vs Remicade 5 mg/kg + AZA
PBO + AZA vs Remicade 5 mg/kg + PBO capsulesc
Remicade
better
10 100 1000
ACCENT Ib,26 (CD)
SONIC (combo)b,40,86 (CD)
(mono)b,40,86 (CD)
Presentb,20 (Fistulizing CD)
A
CCENT IIb,31 (Fistulizing CD)
ACT Ib,34 (UC)
ACT IIb,34 (UC)
ATTRACT19 (RA)
STARTb,87 (RA)
ASPIREb,30 (RA)
Braunb,25 (AS)
ASSERTb,32 (AS)
IMPACTb,33 (PsA)
IMPACT IIb,35 (PsA)
EXPRESSb,38 (PsO)
EXPRESS IIb,40 (PsO)
Targanb,15
ACCENT Ib,26
SONIC (combo)b,40,86
(mono)b,40,86
Presentb,20
ACCENT IIb,31
ACT Ib,34
ACT IIb,34
ATTRACT19
STARTb,87
ASPIREb,30
Braunb,25
ASSERTb,32
IMPACTb,33
IMPACT IIb,35
EXPRESSb,38
EXPRESS IIb,40
Figure 5 Efcacy of Remicade in pivotal phase II/III clinical trials in adult indications: odds ratio of primary endpoint.
Notes:
a
Most trials evaluated multiple doses of Remicade. In the treatment arms shown (the generally approved doses), the Remicade dosing regimen tested was induction
(infusions at weeks 0, 2, and 6) followed by q8w maintenance, with the exceptions of the Targan and Present studies, where single infusion and induction only, respectively,
were tested, and of the AS trials (Braun and ASSERT), where induction followed by q6w maintenance was tested.
b
Janssen, data on le.
c
PBO of AZA.
d
Major secondary
endpoint. The primary endpoint was a continuous variable for which an odds ratio was not calculated.
Abbreviations: ACR20, American College of Rheumatology 20% response; AS, ankylosing spondylitis; ASAS20, Ankylosing Spondylitis Activity Score 20% response; AZA,
azathioprine; BASDAI, Bath Ankylosing Spondylitis Disease Activity Index; CD, Crohns disease; MTX, methotrexate; MTX-IR, methotrexate inadequate responders; PASI
75, Psoriasis Area and Severity Index 75% reduction; PBO, placebo; PsA, psoriatic arthritis; PsO, psoriasis; q6w, every 6 weeks; q8w, every 8 weeks; RA, rheumatoid
arthritis; UC, ulcerative colitis.
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previously viewed to be a Th2-mediated disease, with the
blockade of TNF, a cytokine associated with Th1-mediated
diseases such as RA, CD, and psoriasis, contributed to a
reassessment of the Th1/Th2 paradigm in the pathogenesis of
IBD.
100
Treatment of PsA with Remicade demonstrated that
TNF drives the inammation not just in joint-related signs and
symptoms and structural damage,
101
but also in its other major
clinical manifestations, such as PsO, enthesitis, and
dactylitis.
32
In AS, TNF inhibition demonstrated efcacy on
signs and symptoms of disease, but, in contrast to RA and PsA,
it had no apparent effect on structural damage in clinical trials,
despite a reduction in bone/spinal inammation as measured
by magnetic resonance imaging (MRI). Later non-randomized
studies suggested that TNF blockade reduces progression of
structural damage in the long term (2 years).
102,103
In psor-
iasis, two targeted therapies (alefacept, an anti-CD2 agent, and
efalizumab, an anti-CD11 agent) were approved by the FDA
and the latter by the EMA, but had modest efcacy, and in the
case of efalizumab, emerging safety issues in the
postmarketing setting. They were later removed from the
market.
104106
In contrast, TNF inhibitors provided evidence
that targeted systemic therapy could have both proven efcacy
and acceptable safety in the setting of psoriasis.
Unsuccessful clinical indications of TNF blockade
In addition to the approved indications, both Janssen and
independent investigators have evaluated Remicade in
other disorders associated with elevated TNF, including
both other IMIDs, such as asthma and multiple sclerosis
(MS), and diseases not generally characterized as IMIDs,
such as infectious diseases, cancer, and cardiovascular
conditions (Table 2). In each of these disorders, there
were mechanistic, in vitro and/or animal data supporting
the hypothesis that TNF blockade could be benecial. In a
few, such as systemic lupus erythematosus (SLE) and
cancer, there was reason to believe that TNF blockade
could either exacerbate the disease or treat it, reective
of the multiple functions of TNF. However, even in these
Table 2 Diseases beyond approved indications where Remicade was studied as treatment
IMIDs Non-IMIDs
Alcoholic hepatitis
107
Infectious disease
Atopic dermatitis
108
Hepatitis C
132
Asthma
a
(Janssen, data on le) HIV/AIDS
133
Autoimmune hepatitis
109
Behcets disease
110,111
Sepsis
a,9,76
Malignancy
Giant cell arteritis (GCA)
a
(vasculitis, Wegeners Ovarian cancer
134
disease, polymyalgia rheumatica)
112114
Renal cancer
135
Graft versus host disease
115
Myelodysplastic syndrome
136
Hydradenitis suppurativa
116
Non-small cell lung cancer (weight loss)
137
Juvenile rheumatoid arthritis
b,37
Pancreatic cancer (cachexia)
a,138
Kawasaki disease
117,118
Prostate cancer (pain, biomarkers)
139
Multiple sclerosis
a,119
Cardiovascular disease
Pemphigus vulgaris
120
Congestive heart failure (CHF)
a,29
Polymyositis
121
Hypertension
140
Primary sclerosis cholangitis (PSC)
122
Mental health
Sarcoidosis
a,123,124
Depression
141
Scleroderma
125
Bipolar disorder
142
Sjogrens syndrome
126
Endocrinology
Systemic lupus erythematosis (SLE)
127129
Metabolic syndrome
143
Type 1 Diabetes
130
Other
Uveitis
a,111,131
Age-related macular degeneration
144
Chronic obstructive pulmonary disease (COPD)
a,145
Endometriosis (pain)
146
Sciatica
147
Notes:
a
Janssen-sponsored study.
b
A randomized, placebo-controlled trial was conducted to evaluate Remicade plus MTX for the treatment of polyarticular-course juvenile
rheumatoid arthritis (JRA). While Remicade produced an important, rapid, and durable clinical effect in children with JRA at 1 year, the difference between Remicade and
placebo was not statistically signicantly different at the primary endpoint, ACR Pediatric 30 criteria at week 14, and thus regulatory approval was not obtained. Of note, the
sample size was reduced, as one site of this trial was excluded owing to potential patient unblinding.
37
Abbreviation: IMID, immune-mediated inammatory disorder.
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conditions, the unmet medical need and the potential ben-
et justied testing TNF blockade as a treatment.
In several of the IMIDs, efcacy was observed in
initial clinical studies, but for various reasons full devel-
opment did not follow. Based on small studies, Remicade
received regulatory approval in Japan for two rare diseases
prevalent in the Japanese population, Behҫets and
Kawasaki disease.
110,111,11 7,118
In hidradenitis suppurativa
and uveitis, initial studies suggesting efcacy with
Remicade led to the development and approval of other
TNF inhibitors in these indications.
116,131,148
In autoim-
mune hepatitis and SLE, efcacy was observed in proof-
of-concept studies, but was outweighed by the negative
safety prole,
109,127129
and in sarcoidosis and asthma,
only marginal benet was observed in formal phase II
trials and development was discontinued.
123
In the remain-
ing IMIDs evaluated (Table 2), Remicade showed no or
only short-term clinical benet. In all non-IMIDs studied,
TNF blockade with Remicade proved ineffective or insuf-
ciently effective to justify further clinical development.
In two instances, unexpected safety signals arose in
clinical studies with Remicade. Despite preclinical evi-
dence that TNF blockade improved an animal model of
MS,
119
two patients with rapidly progressive MS treated
with Remicade in a phase I safety trial experienced a
transient increase in the number of gadolinium-enhancing
lesions and other signs suggestive of immune activation
and increased disease activity.
119
A similar worsening of
symptoms was found in a double-blind placebo-controlled
study in MS with another TNF inhibitor, lenercept,
149
and
in clinical practice TNF inhibitors have been associated
with cases of new onset and exacerbation of central and
peripheral nervous system demyelinating disorders, such
as optic neuritis and GuillainBarré syndrome.
150
In the second situation, preclinical and early clin-
ical data suggested that TNF played an important role
in the pathogenesis and progression of congestive heart
failure (CHF). Yet in the phase II ATTACH study of
150 patients with stable class III or IV CHF, short-term
TNF blockade with Remicade showed no clinical ben-
et,andhighdoses(10mg/kg)wereassociatedwith
an elevated risk of death or hospitalization.
29
Poor
outcomeswerealsoobservedwithetanerceptinclin-
ical trials of patients with CHF, conrming that TNF
blockade is not an effective strategy in the treatment of
moderate-to-severe CHF.
151
What are the possible reasons for failure
of TNF blockade?
Two possible explanations for the lack of demonstrated
benet of Remicade in these indications, both related to
trial design, are that the dose or duration of treatment was
not sufcient or that, as proof-of-concept studies, the trials
were underpowered and unable to detect a benet.
However, given the general understanding of Remicade
dosing, and the consistency of results across multiple trials
with other TNF inhibitors, it seems more likely that TNF
blockade is simply not the right treatment strategy in these
diseases. But why not?
In the non-IMID indications, investigators identied
two main possible explanations for lack of effect of TNF
blockade. First, the inammation in these diseases is pos-
sibly not driven by TNF, but rather the high production of
TNF could be a downstream effect. Alternatively, the
inammation, even if TNF driven, is just one of several
ongoing pathologies such that suppressing it does not have
an impact on the disease as a whole.
It is less clear why TNF blockade works so effec-
tively in some IMIDs with elevated TNF, but is ineffec-
tive or leads to worsening in others. It is possible that
the timing of treatment with respect to disease course or
the selected patient population was not optimal.
Sarcoidosis, similar to CD, is both granulomatous in
nature and mediated by Th1. Theoretically, TNF block-
ade should have been effective, yet the phase II trial
showed only marginal benet with Remicade. The
investigators noted that one possible explanation for
the trials results is that it included patients with stable
disease, which may have diminished a possible response
to Remicade, owing to a lack of inammation and/or
high levels of brosis, which TNF blockade would not
treat. An exploratory subgroup analysis revealed that
patients with severe disease were more likely to benet.
Janssen subsequently conducted another phase II trial
with a follow-up TNF inhibitor, golimumab (Simponi
®
;
Janssen Biotech, Horsham, PA, USA), enrolling speci-
cally this severe population, and yet again only marginal
benet was observed.
152
The sarcoidosis experience
emphasizes the challenge of identifying a suitable popu-
lation for a targeted treatment (eg, patients with TNF-
driven disease) even when a sound understanding of the
disease pathophysiology is present.
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Another possible explanation for the lack of benetin
IMIDs treated with TNF blockade is that the ongoing inam-
mation is not TNF-driven, not solely TNF-driven, or not
TNF-driven at each stage of disease, ie, where drivers of
inammation change over time or in different circumstances.
It is known that the inammation in IMIDs has different
etiologies, mediated by Th1, Th2, and/or the more recently
discovered Th17 responses. Elevated levels of TNF are asso-
ciated with diseases thought to be driven by Th1 and/or Th17
responses, such as RA and CD. A number of the diseases
where Remicade failed to work are thought to be Th2-
mediated, including asthma (Janssen, data on le) and
scleroderma,
125
where TNF, although elevated, is possibly
not central to the underlying inammation. In others, multi-
ple pathways could be active. For instance, in view of the
negative results with Remicade in Sjögrens syndrome
126
and
atopic dermatitis,
108
investigators speculated that TNF block-
ade could have shifted the balance of Th1/Th2-mediated
inammation in favor of Th2. Whereas recent research has
shown that some diseases, such as PsO and CD, can be
effectively treated by blockade of cytokines elevated in either
the Th1 or Th17 pathway,
35,40,153,154
others perhaps require
blockade of both. One analysis, for instance, suggested that
the inammation in giant cell arteritis (GCA) is driven by
cytokines from both the Th1 and Th17 pathways and suc-
cessful treatment will require blockade of both.
155
Several hypotheses have been proposed for worsen-
ing disease with TNF blockade. In the MS trials, inves-
tigators identied possible mechanisms by which TNF
blockade could lead to further immune activation con-
tributing to the diseases pathogenesis or to interruption
of TNF-mediated tissue repair via TNFR2.
150,156
In
CHF, disease worsening occurred despite decreases in
both CRP and IL-6 with Remicade treatment. This led
the investigators to propose that cytokine activation,
including TNF, was benecial, serving as part of the
bodys adaptive response to CHF, and that blocking it
disrupted this response.
29
It is clear that despite an improved understanding of
the immune system, there are still many unknowns. The
learnings from these trials have demonstrated that TNFs
effect and, by extension, those of TNF blockade, are
context driven and are difcult to predict. Remicade is
effective in a number of IMIDs with a TNF-driven
inammatory component. In the other diseases where
Remicade was studied, the results have provided useful
insights into their pathophysiology and helped research-
ers in the search for new therapeutic targets.
Establishing the safety prole of
Remicade
As Remicade was both the rst TNF inhibitor and the rst
mAb to be used in chronic diseases, there was little pre-
cedent to draw upon, leaving researchers to hypothesize on
its safety prole. Given the physiological role of TNF in
host defense and immune surveillance, Remicade was
expected to be associated with an increase in infections
and, over the long term, malignancy, specically lym-
phoma. As a foreign protein, Remicade also brought con-
cerns of immunogenicity and consequent allergic and
hypersensitivity reactions. Finally, as with any new drug,
but in particular with this new form of targeted therapy,
there were concerns about unforeseen risks.
The process of fully dening Remicadessafetyprole
took years and is still ongoing (Tabl e 3). It has required
Janssen to use a combination of data sources: phase II/III
clinical trials, routine pharmacovigilance, postmarketing
studies, large clinical databases, and independent research.
Depending on the frequency of a given ADR, eg, common,
uncommon, rare, and unexpected, different data sources and
methods of analysis have been utilized. Several examples
are described in this section to demonstrate how this was
done.
What could the phase II/III program tell us?
The number of patients exposed to Remicade across the
trials completed at the time of initial approval was not
large (<200 patients in CD, approximately 500 across all
clinical trials), yet based on this limited experience, the
observed prole was aligned with expectations of TNF
blockade. In Remicade-treated patients across all trials,
ADAs were observed in 28.3% of patients. One or more
infusion reactions occurred in 15.9% of patients (in 7.6%
of infusions) (Janssen, data on le), most of which were
mild to moderate in severity. Other than infusion reactions,
allergic/hypersensitivity reactions were infrequent.
Infections, including serious infections, occurred at a
higher rate in patients treated with Remicade than with
placebo (21.0% vs 11.0% for infections and 2.4% vs 1.8%
for serious infections, respectively) (Janssen, data on le).
Malignancies, including lymphomas, were observed, but
were too infrequent to assess any possible association with
Remicade (seven malignancies, of which ve were lym-
phoid). One unexpected phenomenon, an increase in the
risk of autoimmunity, was identied. In Remicade-treated
patients, there was a net increase in new anti-nuclear
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Table 3 Overview of Remicades safety prole
Adverse event Role of TNF/immune pathways
Acute and delayed hypersensitivity reactions Infused proteins generate acute infusion reactions via unclear mechanisms.
Most are mild to moderate
45,157,158
Allergic and (delayed) hypersensitivity reactions are also possible
45,157,158
Serious infections, including opportunistic infections, TB, and
hepatitis B reactivation
Serious infections, including tuberculosis, bacterial infections, including
sepsis and pneumonia, invasive fungal, viral, and other opportunistic
infections have been observed in patients treated with TNF
inhibitors
70,159,160
TNF is critical for the clearance of intracellular pathogens
93
Immune responses against viral pathogens can be also mediated by TNF
93
Neutropenia may occur after TNF inhibitor administration, increasing risk
of opportunistic infections
64
TNF helps form and maintain granulomas in TB and induces apoptosis of
TB-infected cells
161
Malignancy, including lymphoma, leukemia, Merkel cell carcinoma,
melanoma, cervical cancer, HSTCL, and pediatric malignancy
Malignancy, especially lymphoma, is a known risk of immunosuppression
162
Mechanistic studies have also shown that TNF has tumor-promoting
potential under certain conditions
163
Postmarketing surveillance suggests that there is relatively low risk of
malignancy with TNF inhibitor treatment
55,164
SLE and lupus-like syndrome Lupus-like syndrome has been observed in patients treated with TNF
inhibitors
70
TNF inhibition has been associated with the formation of anti-nuclear
antibodies (ANA), anti-DNA antibodies, anticardiolipin antibodies, and
antihistones
70
Increased cell lysis in patients treated with TNF inhibitors may lead to
exposure to self-antigens
165
Hematologic reactions Pancytopenia, leucopenia, neutropenia, and thrombocytopenia have been
reported in patients receiving TNF inhibitors
166
Demyelinating disorders TNF inhibitors have been associated with cases of new onset or exacer-
bation of CNS demyelinating disorders, including multiple sclerosis, and
peripheral demyelinating disorders, including Guillain-Barré syndrome
150
The role of TNF in demyelinating disorders are still under investigation
150
TNF has pleiotropic functions at different stages of autoimmune demyeli-
nation that may promote neuronal damage or potentially provide protec-
tive functions during CNS pathogenesis
150
Congestive heart failure Clinical trial data evaluating TNF blockade as a treatment for heart failure
have shown a worsening of disease in patients with NYHA class III-IV
CHF
167
There have been postmarketing reports of worsening and new-onset CHF
in patients receiving TNF inhibitors
167
Compromised myocytes express TNF on their membranes and TNF
inhibitors might kill those cells through apoptosis or CDC
165
Hepatobiliary events and hepatotoxicity In clinical trials, sporadic two- to three-fold liver function test elevations
have been observed in patients treated with TNF inhibitors
166
Isolated cases of hepatic failure have been reported in patients treated
with TNF inhibitors
168
Genetically susceptible individuals may generate an idiosyncratic (rare and
unpredictable) immune response after inhibition of the TNF pathway
169
Abbreviations: CDC, complement-dependent cytotoxicity; CHF, congestive heart failure; CNS, central nervous system; HSTCL, hepatosplenic T-cell lymphoma; NYHA,
New York Heart Association; SLE, systemic lupus erythematosus; TB, tuberculosis; TNF, tumor necrosis factor.
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antibodies (ANA) of 12% (from 24% to 36% of
Remicade-treated patients), and anti-dsDNA antibodies
developed in 9% of patients (from 0% to 9%). Isolated
cases of (reversible) lupus-like syndrome were observed
(Janssen, data on le). Viewed in the context of moderate-
to-severe CD unresponsive to conventional therapies, this
benetrisk prole was viewed as positive, and Remicade
received approval for CD.
As clinical development in additional indications pro-
ceeded, the phase II/III/IIIb trial database increased in size
and had, by the end of development in 2016, grown to over
10,000 patients in more than 50 trials conducted across the
globe in the six approved adult indications, and included
pediatric populations in RA, CD, and UC (Janssen, data on
le). While this was a much larger data set than was avail-
able at the time of initial approval, it was still not sufcient
to fully establish Remicadessafetyprole, a situation
typical of clinical development programs. Clinical trials
enroll a highly selected patient population and are not
designed to detect rare safety events or events with long
latency periods. To remedy this, manufacturers employ
routine pharmacovigilance activities to monitor a drugs
safety prole in clinical practice, the key part of which
includes analysis of safety events reported to the company
and in the medical literature.
What was the scale of the challenge of
dening Remicadessafetyprole?
Common, uncommon, rare, and
unexpected adverse events
Considering that a number of foreseeable risks needed
further quantication and qualication, routine pharmacov-
igilance activities were not sufcient to dene Remicades
emerging safety prole. For this purpose, postmarketing
commitment (PMC) safety studies were agreed with or
required by the health authorities for each new indication
as it was granted. (In this manuscript, the term PMCs will
be used collectively to refer to all studies agreed with or
required by health authorities as a follow-up measure to
provide additional data on safety or efcacy in the post-
approval setting, known as postmarketing requirements
[PMRs] and postmarketing commitments [PMCs] for the
FDA, and postapproval measures [PAMs] for the EMA.)
The primary goals of the PMCprogram were to evalu-
ate Remicades long-term safety, specically infections
and malignancies, and its safety in vulnerable populations
where it was expected to be used, specically, pediatric
patients and women exposed during pregnancy. The pro-
gram was also to serve as a data source and hypothesis-
generating tool for other possible adverse events.
A major consideration for the health authorities
when determining the scope of the PMC program was
the estimation of how broadly Remicade was to be
used. It was indicated for six different diseases,
which were serious but not generally regarded as life-
threatening in nature. Moreover, their collective preva-
lence consisted of millions of patients. Given that the
indicated diseases themselves differed in demo-
graphics, background safety risks, comorbidities, and
conventional therapies, key safety questions would
sometimes need to be evaluated separately by thera-
peutic area, ie, rheumatology, gastroenterology, and
dermatology, and occasionally for each individual indi-
cation, ie, CD and UC. With the need to study
Remicade in multiple diseases, as well as in demogra-
phically and geographically diverse populations, the
PMC program needed to include tens of thousands of
patients and would take years to execute.
The majority of the Remicade PMCs have sourced
data from prospective, observational registries of speci-
c diseases. Registries, while neither randomized nor
containing the level of detail collected in controlled
clinical trials, have the advantages of large size, long
duration of patient treatment and follow-up, and inclu-
sion of a broad population reecting real-world use.
Where registries already existed, Janssen initiated colla-
borations to meet its PMC requirements. When such
independent initiatives were not sufciently available,
de novo disease registries were set up by Janssen and
its commercial partners.
In total, the Remicade PMC program in approved
indications consisted of seven company registries, 12
registries studies (ie, those based on analyses from inde-
pendent registries), and three additional studies addressing
specic safety topics (Table 4). Of the registries/registry
studies, one included patients across all indications, seven
included patients with rheumatic diseases, ve were in
IBD, including two pediatric registries, four were in PsO,
and two evaluated Remicade in pregnancy across multiple
indications. All seven company registries were designed
and recruited by Janssen or its partners specically to
address Remicade PMCs. In general, the registry-based
PMCs had two key design features: 1) they followed
Remicade patients as well as comparator cohorts, includ-
ing those receiving conventional therapies, and later, when
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Table 4 Remicade postmarketing commitment program
Study name Indication Study title Location No.
Remicade
patients
a
No. total
patients
a
Patient fol-
low-up time
Registries/ registry studies
RemiTRAC
45
All Remicade Treatment Registry Across Canada Canada 1,632 1,632 Until last infusion
TREAT
43
CD The Crohns Therapy, Resource, Evaluation and Assessment Tool Registry USA,
Canada
3,440 6,273 Med 6.36 years;
max 12.54 years
ENCORE
47
CD Crohns Disease European National Registry. A Prospective, Observational, Postmarketing Safety
Surveillance Registry of Patients Treated with REMICADE or Standard Therapy
EU 1,839 2,662 5 years
OPUS
48
UC Ulcerative Colitis European Registry. A Prospective, Observational, NonInterventional,
Postmarketing Safety Surveillance Program
EU 1,355 2,239 5 years
DEVELOP
50
Ped IBD A Multicenter, Prospective, Long-term, Observational Registry of Pediatric Patients with
Inammatory Bowel Disease
Global 4,107 6,070 20 years
PedIBD
Registry
170
Ped IBD The Pediatric Inammatory Bowel Disease Collaborative Research Group Registry USA,
Canada
568 1,736 Mean 2.4 years
(Remicade), max
8.3 years
BioTRAC
Rheumatology
46
RA, AS, PsA Biologic Treatment Registry Across Canada Rheumatology Canada 1,390 1,390 As long as
exposed to
Remicade
CORRONA
51
RA, PsA Consortium of Rheumatology Researchers of North America USA,
Canada
6,669 35,350 Up to 8 years
NDB
52
RA, PsA, AS National Data Bank for Rheumatic Diseases Iniximab Study USA 9,055 23,394 5 years
ARTIS
53
RA, PsA, AS Antirheumatic Therapies in Sweden Sweden 2,898 9,139 Min 5 years
BIOBADASER
54
RA, PsA, AS Spanish Registry of Adverse Events of Biological Therapies in Rheumatic Diseases Spain 3,204 6,754 Min 5 years
BSRBR
55
RA, PsA, AS British Society of Rheumatologists Registry of anti-TNFαTreated Patients and Prospective
Surveillance Study for Adverse Events Surveillance of Iniximab
UK 4,837 8,611 Min 5 years
RABBIT
56
RA, PsA, AS Long-term Observation of Treatment with Biologics in Rheumatoid Arthritis Germany 610 5,263 5 years
PSOLAR
49
Psoriasis A Multicenter, Open Registry of Patients with Extensive and/or Disabling Plaque Psoriasis Who
Are Candidates for Systemic Therapy Including Biologics
Global 2,360 12,090 8 years
(Continued)
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Table 4 (Continued).
Study name Indication Study title Location No.
Remicade
patients
a
No. total
patients
a
Patient fol-
low-up time
PsoBEST
57
Psoriasis Observational, Noninterventional, Postmarketing Safety Surveillance Program in Psoriasis Germany 107 2,272 5 years
BADBIR
58
Psoriasis British Association of Dermatologists Biological Interventions Register UK 151 1,580 5 years
NPTR (Janssen,
data on le)
Psoriasis Nordic Psoriasis Tumor Registry Sweden,
Denmark
892 25,936 Max 5 years
C0168T71
44
All
(Pregnancy)
Exposure to REMICADE (Iniximab) During Pregnancy in Patients with Inammatory Bowel
Disease, RA, PsA, AS and PsO: A Review and Analysis of Birth Outcomes from the Swedish,
Danish, and Finnish Medical Birth Registries
Sweden,
Denmark,
Finland
270 7,636
b
2,155,535
c
1 year
PRIORITY
(Janssen, data on
le)
IBD
(Pregnancy)
Pregnancy and Infant Outcomes Research Initiative Utilizing Data from the United States Based
PIANO Registry on Inammatory Bowel Disease
USA 248 641 1 year
Total: all registries/registry studies 43,632 160,668
Total: including T71 pregnancies from the general population 2,308,567
Other PMCs
HSTCL-
PALGA
59
All A Retrospective Review of Reports of Hepatosplenic T-cell Lymphoma in the Dutch National
Database of Pathology (Pathologisch-Anatomisch Landelijk Geautomatiseerd Archief [PALGA]),
a Database of Pathology Results for The Netherlands
Netherlands 0 12 13 years
HSTCL-Kaiser
Permanente
60
All Epidemiologic Study of Hepatosplenic T-cell Lymphoma USA 1 150 N/A
HSTCL-Biobank
(Janssen, data on
le)
IBD A Research Study to Bank Samples for Future Evaluation to Identify Biomarkers that Predispose
Patients with Crohns Disease and Ulcerative Colitis to Develop Hepatosplenic T-Cell Lymphoma
(HSTCL)
USA,
Canada
Ongoing Ongoing N/A
Notes:
a
Patient numbers reported in this table might differ from those provided in the cited publication, as patients continued to enroll post-publication.
b
Including patients in study with anti-TNF-indicated diseases exposed to
Remicade, other TNF inhibitors, or non-biologic conventional treatments.
c
Including all pregnancies in the national databases, ie, including the general population.
Abbreviations: AS, ankylosing spondylitis; CD, Crohns disease; EU, European Union; IBD, inammatory bowel disease; N/A, not applicable; ped, pediatric; PMC, postmarketing commitment; PsA, psoriatic arthritis; RA, rheumatoid
arthritis; TNF, tumor necrosis factor; UC, ulcerative colitis.
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they became available, those exposed to other biologics;
and 2) Janssen committed to long-term patient follow-up,
ranging from 5 to 20 years. The three additional studies
were designed specically to evaluate the risk of hepatos-
plenic T-cell lymphoma (HSTCL) with Remicade.
To date, approximately 44,000 patients exposed to
Remicade and 117,000 patients in the comparator cohorts
have been included in the PMC program, a gure which
does not include patients followed in local post-approval
safety monitoring programs, such as those required in
Japan. From the beginning of each PMC through study
closure, health authorities worldwide receive comprehen-
sive reports on a regular basis providing updated analyses
of key safety risks to support the prescribing information.
Several of these PMCs are still ongoing today.
How can registries inform us about
common adverse events?
The major common adverse event to be studied in the
PMC program was infection, including the subgroup of
serious infections. TREAT, a US-based Janssen registry in
CD started in 1999, is a good example of the scale and
design needed for this purpose. Over 5 years it enrolled
two cohorts, those receiving treatment with Remicade and
those receiving conventional therapies, and followed them
until it was closed in 2012. It was the largest registry in
IBD at the time, enrolling more than 6,000 patients with a
median follow-up time of 6.36 years.
43
Importantly, TREAT served as a data source also
for studying the risks in conventional treatments. At
the time of initiation of the program, thorough under-
standing of the risk of serious infection with conven-
tional medications (specically corticosteroids,
analgesics, and the immunosuppressants thiopurines
and MTX) was lacking. It was necessary in the
RemicadePMCregistriestogainanunderstandingof
the background risks of these conventional agents as
Remicade itself, used mostly after or in combination
with these therapies, could not be judged in the
absence of such knowledge. Similar understanding on
the interactions between certain disease characteristics,
such as severity and the risk of infection, was also
required to understand the risks of Remicade and was
also obtained from TREAT.
Analyses in TREAT conrmed the increased risk of
serious infections with Remicade observed in the phase
II/III program (unadjusted rates: 2.04 and 1.00 per 100
patient-years for Remicade and conventional therapies,
respectively; adjusted HR=1.43, 95% CI 1.11 to 1.84,
P=0.006).
171
Further analysis revealed that other signi-
cant predictors of serious infection were older age, use of
prednisone, narcotic analgesics, moderate/severe disease,
colonic disease, and disease duration at enrollment. The
ENCORE and OPUS PMC registries in Europe for CD
and UC, respectively, yielded conrmatory results to these
ndings and showed that results were generalizable for
patients treated in clinical practice across geographic
borders.
47,48
In rheumatology, data from several biologics regis-
tries in the USA and Europe were published indicating
a similar association between TNF inhibitors and ser-
ious infection risk to that found in CD,
172,173
with
similar additional risk factors for serious infection
such as disease severity. It was also established that
there is a time-dependent increase in serious infection
risk, where the maximum risk is reached within the
rst 6 months of therapy, with a gradual decline
thereafter.
159,174,175
Can registries inform us about
uncommon events?
TREAT also demonstrated how registries can be used
to better characterize the risk of uncommon events, for
example lymphoma, for which they are often not ade-
quately powered despite their size and duration. During
the 13 active years of TREAT, just 15 cases of lym-
phoma were reported, evenly distributed between the
Remicade and conventional therapy cohorts.
43
Owing
to this limited number of cases, predictors associated
with the risk of lymphoma could not be further esti-
mated in regression models. This low rate of lym-
phoma was also an occurrence in registries across the
other indications.
48,55,175178
Although an increased
risk in patients treated with Remicade could not be
excluded with these limited numbers, they suggested
that there was a relatively low rate of lymphoma with
TNF blockade, and that this rate did not differ from
that observed with conventional therapies or from the
background rate in these diseases. Additional studies,
especially meta-analyses including population-wide
data, suggested that an increased risk is associated
with profound persistent immunosuppression, eg, com-
bination therapy with thiopurines and TNF inhibitors,
and with cumulative disease activity.
162,179181
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