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In the last decade, a dramatic
change has been witnessed in the treatment of rheumatoid
arthritis (RA). This was mostly due to an increased insight
into the cellular and molecular mechanisms involved. How
bright is the future for the 1% of the population with this
chronic degenerative disorder? Is there any hope of a cure?
RA treatment in 2002
Current conventional treatment
of RA consists of fast-acting ‘first-line drugs’, which
include non-steroidal anti-inflammatory drugs (NSAIDs),
such as aspirin, and corticosteroids (e.g. prednisolone),
and slow-acting ‘second-line’ drugs known as disease-modifying
antirheumatic drugs (DMARDs). These include gold salts,
hydroxychloroquine, sulfasalazine and azathioprine.
Although DMARD use decreases
markers of inflammation such as swollen joint counts, they
are unacceptable long-term, with a limited effectiveness,
poor tolerability and toxic effects, and an inability to
slow irreversible joint destruction and hence disease progression.
The use of methotrexate has signalled an improvement in
efficacy and tolerability, and with a response observed
in 50-80% of patients, it has become the most widely used
‘gold-standard’ DMARD, particularly in emerging combination
therapies.
There is now a better prognosis
for RA sufferers following a change in approach from a ‘softly
softly’ one whereby DMARD therapy is delayed until bone
erosions are present, to a more aggressive strategy of DMARD
administration before irreversible damage occurs. The limitations
of these non-specific therapies, however, remain.
Products on the horizon
RA affects
millions of individuals, and it is not surprising that there
are large numbers of RA therapeutics under active development.
A search for 'rheumatoid arthritis/active studies' on IMS's
LifeCycle R&Dfocus
database, which covers over 7,000 R&D programmes, produces
171 hits that can be subdivided as charted below.
RA therapies
- from preclinical studies to marketed drugs
Source: LifeCycle
Latest RA therapies
Increased insight into the causes
of RA has at last begun to yield results. Clearly the most
successful aspect of RA research so far has been in the
field of cytokine expression and regulation, which has led
to new rational therapies.
The 1999 approval of Immunex’s
Enbrel (etanercept) and Centocor’s Remicade
(infliximab) signalled a new concept in RA treatment: biological
response modifiers that specifically target an inflammatory
mediator overexpressed in RA, tumour necrosis factor alpha
(TNFalpha). Clinical trials were very successful, with 60-80%
of patients resistant to existing therapies responding to
these agents.
The anti-TNF biologicals relieve
symptoms of RA, and more importantly have the ability to
halt joint destruction. Another R&Dfocus search
shows there are a number of other TNFalpha inhibitors in
development, including two in Phase II trials, and three
at the Phase I stage of testing.
Perhaps spurred on by the success
of infliximab, a partly humanised mouse monoclonal antibody
directed against TNFalpha, a number of RA therapies exploiting
MAbs are under development:
RA MAbs in
development
|
Compound
|
Action
|
Phase
of Development
|
|
adalimumab
|
Anti-TNFalpha
|
III
|
|
MAb Fv,
cytokine
|
Anti-TNFalpha
|
II
|
|
clenoliximab
|
Anti-CD4
|
II
|
|
MAb, CD4
|
Anti-CD4
|
II
|
|
MAb, C5
|
Anti-C5
|
II
|
|
MAb, IL-6
receptor
|
Anti-IL-6
receptor
|
II
|
|
MAb, IL-8
|
Anti-IL-8
|
II
|
|
MAb, IL-12
|
Anti IL-12
|
II
|
|
MAb, IL-15
|
Anti-IL-15
MAb
|
II
|
|
MAb, cytokines
|
Anti-IFNgamma,
IFNalpha, TNFalpha
|
I
|
|
MAb, RA
therapy
|
Anti-VAP1
|
I
|
|
MAb, 6G5.1
|
Anti-CD4
|
I
|
|
MAb, Fc
antagonist
|
Anti-macrophage
Fc receptor
|
I
|
Source: LifeCycle R&Dfocus
Unfortunately the initial euphoria
associated with Enbrel and Remicade has been tempered with
concern following the development of rare infections, such
as Mycobacterium tuberculosis. It is not surprising
that altering inflammatory mediators can have such consequences.
The extent of these side effects needs to be determined
with careful monitoring.
The use of these compounds does
also not come cheaply; the estimated yearly costs of Enbrel
and Remicade therapy are $12,000 and over $9,000 respectively.
Their use is only recommended following the failure of conventional
therapy.
Aventis' DMARD Arava (leflunomide)
was also approved in 1999 and is an inhibitor of a metabolic
pathway active in inflammation. At an estimated $3,000 per
year it is considerably cheaper than the other two agents
and has an efficacy similar to methotrexate. A further biological
response modifier, Amgen’s Kineret (anakinra), an
IL-1 receptor antagonist, received FDA approval in November
2001.
NSAIDs rekindled
While traditional NSAIDs are
the most common treatment for pain and inflammation of RA,
they are estimated to cause about 100,000 hospitalizations
and around 15,000 deaths each year in the USA alone, due
to severe gastrointestinal side effects.
Two COX-2
inhibitors (coxibs), Pharmacia and Pfizer's Celebrex (celecoxib)
and Merck & Co's Vioxx (rofecoxib), marketed in the last
two years, are providing relief from pain and inflammation
equivalent to high-dose NSAIDs with reduced gastrointestinal
effects. Currently there are 17 coxibs under active development,
and both Pharmacia and Merck & Co have had second-generation
products (Bextra and Arcoxia) approved.
There is some concern, however,
that there was a link between coxib use and an increase
in the number of heart attacks seen in some clinical trials
- though this was most likely due to a reduction in aspirin
use.
Is the future bright?
At the 65th annual meeting of
the American College of Rheumatology, held in San Francisco
on November 10-15 2001, it was clear that there is a lot
of excitement for the future of RA treatment.
The general consensus is that
in ten years time, it will no longer be a question of, "What
is the next new therapy for RA?" but rather, "What
specific therapies are being developed for which RA subgroups?".
There are a number of therapies
in development that have specific targets in the inflammatory
pathways. If it becomes possible to identify the particular
pathways playing a role in individual patients, the most
appropriate therapy could be decided on a patient by patient
basis.
An example of this is the adenosine
to guanine polymorphism 308 nucleotides upstream from the
transcription start site in the TNF promoter, known to be
associated with elevated TNF levels. It is possible that
TNF inhibitors could be effective in RA patients with this
A to G SNP.
RA drug development
by mechanism of action
|
Action
|
No.
of Studies*
|
|
TNF inhibitor
|
15
|
|
Cytokine inhibitor/antagonist
|
12
|
|
Gene therapy
|
11
|
|
Signal transduction inhibitor
|
10
|
|
Proteinase inhibitor
|
7
|
|
Vaccine
|
7
|
|
Angiogenesis inhibitor
|
6
|
|
Chemokine inhibitor/antagonist
|
5
|
|
Peptide
|
5
|
|
Complement inhibitor
|
3
|
|
VLA-4 inhibitor
|
2
|
|
Cell adhesion inhibitor
|
1
|
|
Integrin antagonist
|
1
|
|
VCAM-1 inhibitor
|
1
|
|
OTHER
|
59
|
*Note: Active studies from preclinical
to pre-registration
Source: LifeCycle R&Dfocus
Will insight into RA genetics
lead to new therapies?
RA is an oligogenic multifactoral
disease caused by both genetic and environmental factors.
As the genetics behind RA are delineated, this will hopefully
result in novel specific treatments, easier diagnosis, and
provide methods of detecting predisposition to the disease
allowing for early targeted treatment.
In the 1970s Stasny first described
an association between RA and a specific genetic sequence,
the ‘shared epitope’, which is part of the peptide-binding
groove of HLA-DR allele subtypes. Therapies targeting this
region are already being developed: AstraZeneca is developing
peptidomimetics in preclinical studies. These products are
designed to block the presentation of antigens from these
RA-associated HLA-DR molecules.
This susceptibility locus mapping
to the MHC region only accounts for 30-40% of the total
genetic component to RA susceptibility. As recently as December
2001, the first non-HLA gene with significant linkage to
RA was mapped by Roche and deCODE genetics. This and the
revealing of further susceptibility loci brings the promise
of genetic screening and the use of specific therapies ever
closer, but whether pharmaceutical companies believe targeting
therapies to individual
patients is
economically feasible remains to be seen.
Will there be a cure for RA?
Possibly the best chance of a
cure for RA is gene
therapy. Advances in
the understanding of the pathophysiology of RA have led
to the characterisation of several proteins with anti-arthritic
properties; however, the availability of these therapeutic
proteins in patients for extended periods is problematic.
Gene therapy could solve this problem with the capacity
to deliver multiple therapeutic proteins locally.
Stem cell transplantation
Another research area with exciting
prospects is stem cell research, and the ability of stem
cells and growth factors to engineer tissue repair. In particular,
studies of mesenchymal stem cells that can differentiate
into connective tissues are likely to be rewarding.
Preclinical studies of stem cell
transplantation have shown sustained remissions in models
of autoimmune disease and pilot studies with autologous
stem cells are under way, but it is unlikely that this type
of therapy will be available for the general RA population;
the consensus is that it will only be appropriate for patients
with aggressive disease that have failed other available
therapies.
Unanswered questions
The last few years have provided
many answers to the mystery of what causes RA, but there
are still numerous unanswered questions.
- How is tissue destruction
activated and upregulated? Why is T cell function abnormal
in RA patients?
- What are the key arthritogenic
antigens, epitopes and key angiogenic factors?
- What are the other RA susceptibility
genes?
The answers to these questions
should bring forth many new avenues of treatment for RA
sufferers in the future.
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