N E W S & A N A LY S I S

FRESH FROM THE PIPELINE

Abatacept
Larry Moreland, Guy Bate and Peter Kirkpatrick

Abatacept

In December 2005, abatacept (Orencia;

Bristol-Myers Squibb), a fusion protein
that selectively modulates a costimulatory
signal necessary for T-cell activation, was
approved by the US FDA for the treatment
of patients with rheumatoid arthritis who
have had an inadequate response to other
drugs. It is the first selective costimulation
modulator to be approved.

MTX, patients received either abatacept

(parenterally administered; dose based on
weight range) or placebo while continuing
to receive their stable dose of MTX for 12
months5. Patients receiving abatacept showed
greater improvement in all ACR response
criteria through 12 months than placebotreated patients5. For example, after 12
months, for the patients receiving abatacept,
the ACR70, ACR50 and ACR20 response
rates were 29%, 48% and 73%, respectively,
compared with 6%, 18% and 40%, respectively,
for the patients receiving placebo5. Abatacept/
MTX also slowed the progression of structural
damage (assessed radiographically) compared
with placebo/MTX, and patients receiving
abatacept showed greater improvements
in physical function compared with those
receiving placebo5.
In another study involving 369 patients
with an inadequate response to a TNFblocking agent (with the TNF-blocking agent
discontinued prior to randomization; other
DMARDs were permitted), patients received
either abatacept (parenterally administered;
dose based on weight range) or placebo for
6 months5. Patients receiving abatacept
showed greater improvement in all ACR
response criteria through 6 months than
placebo-treated patients5. For example, after
6 months, for the patients receiving abatacept,
the ACR70, ACR50 and ACR20 response
rates were 10%, 20% and 50%, respectively,
compared with 2%, 4% and 20%, respectively
for the patients receiving placebo5.

Rheumatoid arthritis is a chronic

inflammatory disease that leads to progressive
joint damage and disability, and consequent
reduction in quality of life1. Non-steroidal
anti-inflammatory drugs can alleviate
disease symptoms, but do not retard the
disease process, whereas disease-modifying
antirheumatic drugs (DMARDs) such as
methotrexate (MTX) interfere with the
underlying immuno-inflammatory events
and retard joint destruction1.
In the past decade, biological DMARDs
that block the activity of pro-inflammatory
cytokines in particular, tumour-necrosis
factor- (TNF), which is important in the
pathogenesis of rheumatoid arthritis have
had a major impact on disease treatment1.
Nevertheless, a substantial proportion
of patients do not respond to, or have an
unsustained response to, currently available
DMARDs, underlining the need for further
therapeutic strategies1.
Basis of discovery
Activated T cells are thought to have a major
role in rheumatoid arthritis1. To become fully

Abatacept
CD80/86

APC

CD28

T cell
MHC II

Cell
proliferation,
generation
of effector
and memory
cells

T-cell receptor

Figure 1 | Activity of abatacept. By binding

to CD80 and CD86 on antigen-presenting cells
(APCs), CTLA4Ig (abatacept) blocks the
costimulatory interaction with CD28 on T cells,
thereby inhibiting optimal T-cell activation,
which is thought to be important in the
pathogenesis of rheumatoid arthritis1,2,5.

activated, T cells require at least two signals

from antigen-presenting cells (APCs)2. The
first signal is antigen-specific, and results
from engagement of the T-cell receptor with
an immunogenic peptide bound to the major
histocompatibility complex (MHC) on an
APC. The second signal results from the
binding of a costimulatory receptor on the
T cell to a ligand on the APC; the interaction
of CD28 on T cells with CD80 or CD86 on
APCs is a key example of a costimulatory
signal2 (FIG. 1).
Following their activation, cytotoxic
T-lymphocyte-associated antigen 4 (CTLA4)
is expressed on the surface of T cells.
CTLA4 has a higher affinity for both CD80
and CD86 than CD28, and its natural
function might be to terminate T-cell
activation2,3. The potential for CTLA4 to
interrupt the delivery of the second signal
required for full T-cell activation was
harnessed by fusing the extracellular domain
of human CTLA4 to the modified Fc (hinge,
CH2 and CH3 domains) portion of human
immunoglobulin G1 (IgG1), to give a
soluble fusion protein, CTLA4Ig, which is
now known as abatacept25.
Drug properties
Abatacept binds to CD80 and CD86 on
APCs, preventing these molecules from
binding to CD28 on T cells and thereby
inhibiting optimal T-cell activation by
blocking the costimulatory signal25. In vitro,
abatacept decreases T-cell proliferation and
inhibits production of TNF, interferon-
and interleukin-2, and showed promising
activity in the rat collagen-induced arthritis
model5,6, prompting its evaluation in
several clinical trials in patients with
rheumatoid arthritis5,79.
Clinical data
Abatacept has been evaluated in five
randomized, double-blind, placebocontrolled trials in patients 18 years
old with active rheumatoid arthritis
diagnosed according to American College
of Rheumatology (ACR) criteria5, who had
inadequate responses to DMARDs such
as MTX and TNF-blocking agents5.
In one study involving 638 patients
who had an inadequate response to

NATURE REVIEWS | DRUG DISCOVERY

Indications
Abatacept is approved by the FDA for
reducing signs and symptoms of rheumatoid
arthritis, inducing major clinical response,
slowing the progression of structural
damage, and improving physical function
in adult patients with moderately to severely
active rheumatoid arthritis who have had
an inadequate response to one or more
DMARDs, such as MTX or TNF antagonists5.
Abatacept may be used as monotherapy or
concomitantly with DMARDs other than
TNF antagonists5. Abatacept should not
be administered concomitantly with TNF
antagonists, and is not recommended for use
concomitantly with the interleukin-1
receptor antagonist anakinra5.

VOLUME 5 | MARCH 2006 | 185

2006 Nature Publishing Group

N E W S & A N A LY S I S
ANALYSIS | DRUGS FOR RHEUMATOID ARTHRITIS
Analysing clinical issues in the treatment

of rheumatoid arthritis is Larry Moreland,

M.D., Professor of Medicine in the Division of
Clinical Immunology and Rheumatology at the
University of Alabama at Birmingham, USA.
In many well-controlled trials and postmarketing studies (for example, REFS 1012),
there is clear evidence that agents that inhibit
the action of tumour-necrosis factor (TNF)
etanercept, infliximab and adalimumab
have revolutionized physicians ability
to modulate the pain and suffering of many
rheumatoid arthritis patients. However, there
remain some limitations with the use of
TNF inhibitors. Emerging data show some
clear associations of adverse events, such as
increased risk of routine bacterial infections
in addition to opportunistic infections (for
example, tuberculosis), as well as some adverse
events that have been reported but not yet well
substantiated, such as central nervous system
demyelination. A further obstacle for many
patients is the cost of anti-TNF therapies.

With regards to efficacy, most of the clinical

trials have shown that 6070% of patients will
show a significant improvement while receiving
anti-TNF therapy, and 2030% of patients will
fulfill the criteria that have been used to define
very significant positive clinical response for
remission. However, in addition to the patients
who do not have such a response, an area that
is not yet well defined is the number of patients
who initially respond to these therapies and
then lose that response after several months.
There are some data suggesting that perhaps
up to 50% of patients are no longer taking antiTNF therapies after 5 years.
Other unanswered questions relate to
the biology of patients who do not respond
initially to anti-TNF therapies and why
patients who initially respond then lose
that response. Specifically, do they develop
antibodies to the administered protein?
Alternatively, perhaps the immune system has
developed other ways to circumvent anti-TNF
agents (for example, by expressing other proinflammatory mediators). Indeed, emerging

Box 1 | Rheumatoid arthritis market

data suggest that patients who have failed one

anti-TNF therapy may respond to another
agent, and the three current agents might have
different mechanisms of action, especially if
they have different pharmacokinetics.
Clinical data now indicate that other
biological response modifiers, including
abatacept and rituximab, may be effective in
the treatment of rheumatoid arthritis. There
have been several randomized, placebocontrolled studies evaluating abatacept in
rheumatoid arthritis patients5,79, as described
on the previous page. On the basis of the
results of these trials, abatacept represents a
therapeutic option for patients with rheumatoid
arthritis who have failed methotrexate and
those who have been treated with anti-TNF
therapies and were treatment failures or
discontinued owing to adverse events.
Larry Moreland is at the Department of Medicine,
University of Alabama, 1717 6th Ave South,
Birmingham, Alabama 35294-7201, USA. Guy Bate is
at IMS Health, 7 Harewood Avenue, London NW1 6JB,
UK. Peter Kirkpatrick is at Nature Reviews Drug
Discovery, UK. e-mails: Larry.Moreland@ccc.uab.edu;
gbate@uk.imshealth.com; p.kirkpatrick@nature.com
doi:10.1038/nrd1989

Analysing the market for disease-modifying antirheumatic drugs (DMARDs) is Guy Bate, Ph.D.,
Principal, Product & Portfolio Development, IMS Consulting & Services, IMS Health, London, UK.

DMARD market. Abatacept will compete mainly with other DMARDs. This market is dominated by
the tumour-necrosis factor- (TNF) antagonists adalimumab (Humira; Abbott), infliximab (Remicade;
Johnson & Johnson/Schering-Plough) and etanercept (Enbrel; Amgen/Wyeth). Etanercept is a fully
human TNF soluble receptor whereas the other two agents are monoclonal antibodies against
TNF. We estimate from company data and SEC filings that the worldwide pharmaceutical market
for TNF antagonists was worth more than US$6 billion in 2005, growing approximately 30% during
2004. Infliximab and etanercept have similar sales, taking ~40% of the TNF antagonist market each
in 2005. However, etanercept showed much stronger growth compared with infliximab (we estimate
35% versus 17%) and looks set to overtake it in 2006. The TNF blocker market could soon be boosted
by the arrival of certolizumab pegol (Cimzia; UCB), which is currently in Phase III trials for rheumatoid
arthritis. The agent is a PEGylated fragment of a TNF monoclonal antibody and this could improve
the convenience of dosing versus current TNF blockers.
Other important DMARDs are leflunomide (Arava; Sanofi-Aventis), a tyrosine kinase and dihydroorotate dehydrogenase inhibitor, and methotrexate, an antimetabolite. Leflunomide has around
one-tenth the worldwide sales of etanercept. Methotrexate, a genericised molecule, is a standard treatment for rheumatoid arthritis, and agents such as TNF blockers are often used in combination with it.
Abatacept. Abatacept can be used as monotherapy or in combination with other DMARDs (excluding
biological DMARDs). It will compete with the anti-TNF agents for patients who respond inadequately
to methotrexate and will also capture patients who fail to respond to anti-TNF therapies (with or
without methotrexate). This latter pool presents a significant market opportunity, as up to 30% of
patients fail with anti-TNF agents.
However, abatacept is administered by intravenous infusion, which might reduce the convenience
of administration and increase risk of infection, perhaps affecting the willingness of some physicians
to prescribe the product. Infliximab, which is also infused intravenously, has underperformed relative
to adalimumab and etanercept, which are both administered by single injection. Nevertheless,
analysts estimate that abatacept sales could reach US$ 1 billion by 2009/2010.
A supplemental Biologic License Application for rituximab (MabThera/Rituxan; Biogen Idec/
Genentech/Roche) for the treatment of rheumatoid arthritis patients who respond inadequately to
anti-TNF therapy was submitted in 2005. Rituximab might beat abatacept to the market if BristolMyers Squibb delays launch until after FDA approval of a secondary manufacturing facility.

186 | MARCH 2006 | VOLUME 5

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