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European Biopharmaceutical Review
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Genetic, environmental and clinical factors combine to pose challenges
in drug discovery for respiratory, inflammatory and autoimmune diseases.
While progress is being made, there is a clear unmet need for
therapeutic monoclonal antibodies in the field.
Immune-mediated inflammatory diseases (IMIDs) are a group of over 80
chronic diseases that share common inflammatory pathways and are caused
by dysregulation of our immune system. IMIDs result from uncontrolled
immune responses against self antigens or foreign antigens: T cells or
antibodies produced either mistakenly or to unusually low levels of
antigen (hypersensitivity) trigger the production of cytokines,
including interleukins (ILs) such as tumour necrosis factor alpha (TNFα)
and interferon gamma (IFNγ) (see Figure 1). While genetic factors play
an important role in the development of IMIDs, the onset of clinical
symptoms is often preceded by an infection, exposure to sensitising
foreign antigens, or trauma. The chronicity of IMIDs, such as in
autoimmune diseases, is attributed to the inability to eliminate or
ignore triggering self antigens. Host defence against foreign pathogens
can turn into autoimmunity and inflammation against the body under
mechanisms which are not fully understood. Inflammation cascades are
complex and self-amplified if not properly regulated by inhibiting the
key cytokines in the diseases. IMIDs can affect almost any organ system;
Table 1 lists the most prevalent conditions.
IMIDs represent a major healthcare and economic burden. It is estimated
that five to seven per cent of the population in the western world have
been diagnosed with an IMID (1-3). The estimated direct and indirect
costs associated with treating IMIDs in the US alone run into millions
of dollars (2).
Historically, treatment for IMIDs involved suppression of the immune
response, typically with corticosteroids, to relieve symptoms without
addressing the underlying cause of the disease. However, when used
long-term and at high doses, corticosteroids may increase susceptibility
to infection and cause metabolic, dermatological, gastrointestinal and
cardiovascular complications, which can be serious and result in the
discontinuation of treatment. The introduction of mAbs in the late 1990s
revolutionised the treatment of rheumatoid arthritis (RA) and Crohn’s
disease. The success of mAbs in the treatment of major IMIDs is
underscored by their rapid uptake and increasing dominance among
top-selling pharmaceuticals.
A number of mAbs have been introduced for conditions in the respiratory,
inflammatory and autoimmune (RIA) cluster of diseases. In particular, a
choice of therapies is available for RA, psoriasis and Crohn’s disease
(see Table 2, page 46). Progress in introducing biologics in other
important RIA conditions, such as severe asthma, COPD, SLE and
scleroderma, which are poorly controlled by existing medications, has
been slow. However, a robust pipeline of attractive drug candidates is
being tested in various stages of clinical development. Some of them are
likely be approved in order to provide more effective treatment options
for these diseases.
This article discusses why mAbs are so valuable in the RIA settings, the
challenges of developing products for these conditions and what new
entrants can offer to patients. It also looks at four mAbs in detail, as
examples of where drug development is heading in the future.
Advantages of mAb Therapy in RIA Diseases
Monoclonal antibodies work by inhibiting disease-causing targets in the
body. Once the target has been identified, the mAb can be generated and
designed to be equipped with high potency against its target, so that it
rapidly and efficiently inhibits the harmful effects of the target
antigen (4). For example, effective treatment of exacerbations in severe
asthmatic patients can not only prevent disease progression and adverse
outcomes, but also averts the need for costly hospitalisation and
disruption of work and daily life. For mAbs that target key
disease-causing cytokines, they can provide significant benefits to the
patients, such as improved lung function in asthma, healing of eroded
joints in RA and inflamed skin in psoriasis, and prolonged recovery of
fistulae in Crohn’s disease. These disease-modifying benefits will
ultimately improve patients’ quality of life and a reduction in their
dependence on other medications such as high-dose corticosteroids.
The selectivity of mAbs has the unique advantage of being more likely to
achieve on-target clinical activities over other non-selective
medications, such as those immunosuppressive drugs. mAb therapy, when
used in select patients, has fewer and more manageable adverse effects
that can be monitored closely before and during the course of the
treatment. Therefore, mAb therapy can deliver a favourable benefit:risk
ratio to the patients.
Developing New Medicines for RIA Conditions
The complex interactions between genetic, environmental and clinical
factors in RIA conditions make it exceptionally challenging to
accurately define the underlying disease mechanisms and to select the
most important targets for drug intervention (see Figure 1). The
heterogeneity of pathogenic mechanisms of each disease among patient
subgroups poses immense challenges when selecting the right patients for
a particular mAb therapy for maximal clinical benefits and fewer
unwarranted side effects. The chronicity of these diseases also poses
significant challenges to the clinical development process and the use
of clinically meaningful endpoints. The physicochemical differences
between antibodies and small-molecule drugs present their own challenges
in terms of costs of treatment, routes of drug delivery, patient
preference and compliance.
Multiplicity of Targets
Although some cytokine targets are associated with more than one
disease, some RIA conditions are linked to more than one diseasecausing
target.
The combination of these targets can vary between patients.
Significantly, it may also mean that treatment with a single mAb may not
be adequate for improving patient outcomes. Therefore, genomics and
proteomics research used in discovery also needs to generate biomarkers
of disease control or progression and a means of identifying patients
through a diagnostic test most likely to benefit from a particular
treatment in clinical trials and postmarketing. Advances have been made
to generate new mAb antibody constructs with multi-specific binding
capacities to more than one target. This opens up the possibility to
maximise clinical benefits for diseases with heterogeneous disease
mechanisms. Taken together, better understanding of the biology of the
disease and characteristics of patient subgroups is central to design
the best treatment strategies for each disease.
Multiplicity of Actions of a Target
In addition to understanding how the mAb interacts with the cytokine
(binding kinetics) and the nature of the interaction (such as blocking
activity, preventing signalling), it is necessary to establish the full
function of any cytokine targeted for mAb therapy. Studies in multiple
sclerosis (MS) found that mAbs that blocked TNFα caused an increase in
disease activity because, in addition to its role in the infl ammation
cascade, TNFα also promotes the growth of myelinproducing cells (5,6).
Chronicity of RIA Conditions
Trial designs in chronic diseases such as RIA conditions must take into
consideration repeated, long-term exposure to the treatment mAb. With
mAbs, immunogenicity to the construct, acute toxicity such as
hypersensitivity and clinical sequalae due to immune complex
accumulation in circulation and tissues, and continuous immune
suppression may all entail compromise to the host’s defence against
infections and malignancy in some patients. These risks can be mitigated
by closely monitoring patients’ responses to the therapy. Dose
adjustment or termination of treatment should be exercised if needed.
Antibody Treatment and Delivery
Monoclonal antibodies are most easily delivered by intravenous infusion
administered in clinics by professionals. Monoclonal antibodies can now
be engineered to extend their biological halves, which make them
amenable for subcutaneous, low-dose regimens with less frequent
administration, which could be given by the patients themselves.
Currently, it is not possible to combine several individual mAbs in a
treatment regimen, and this remains an unmet clinical need, particularly
in RA where multiple targets are more common (7).
Early mAb Entrants into the RIA Market
Table 2 lists early mAb entrants into the RIA market. Of the 10 mAbs
that have been introduced for RIA conditons, six are indicated for RA.
In fact, RA was the first RIA condition to benefit from mAb therapy with
the introduction of chimeric anti-TNFα mAb, infliximab in 1998.
Available antibodies cover the whole range of construct versions, from
chimeric (human/mouse) whole antibodies and humanised fragment antigen
binding to human whole antibodies.
Infliximab, adalimumab, tocilizumab, certolizumab pegol, golimumab, and
ritiximab are approved for use in combination with methotrexate in
adults with moderate to severe active RA who have had an inadequate
response or intolerance to other disease-modifying anti-rheumatic drugs
(DMARD). Adalimumab, tocilizumab and certolizumab may also be used as a
monotherapy. Infliximab and golimumab may be used in patients naïve to
methotrexate. X-ray evidence confirms that in combination with
methotrexate, these drugs reduce the rate of progression of joint damage
and improve physical function. Adalimumab and tocilizumab are also
approved as monotherapies or in combination with methotrexate in
children with idiopathic juvenile arthritis. Infliximab, adalimumab and
golimumab are also approved in patients with severe ankylosing
spondylitis with an inadequate response to conventional therapy.
Psoriasis and Psoriatic Arthritis
Three of the mAbs currently approved for psoriasis and psoriatic
arthritis target TNFα and one targets IL12/23. Infliximab, adalimumab
and golimumab are approved in patients with psoriatic arthritis when
DMARD therapy has proved inadequate or intolerable. Infliximab and
golimumab may be used in monotherapy or in combination with DMARDS. All
have been shown to improve physical function in patients with psoriatic
arthritis, and to reduce the rate of progression of peripheral joint
damage.
Infliximab and adalimumab are also indicated as monotherapy in patients
with moderate to severe psoriasis who fail to respond to other forms of
treatment, including phototherapy.
Ustekinumab is approved for patients with moderate to severe plaque
psoriasis. Ustekinumab blocks IL-12 and IL-23. It binds to the p40
subunit, common to both IL-12 and IL-23, which prevents these cytokines
from binding to the cell surface receptors of Th1 and Th17 cells,
thereby blocking the inflammatory cascade of these T helper cells.
Crohn’s Disease
Adalimumab, infliximab and certolizumab are indicated for use in
patients who have not responded to treatment with corticosteroids or
other immunosuppressants. It should be noted that the EMA refused a
licence for certolizumab, although the FDA approved it. Infliximab was
the first mAb to be approved in Crohn’s disease and is approved for all
three forms of the disease. Treatment success has been shown to be
maintained in the longterm. Infliximab is also approved in children aged
six years or older who have failed on conventional therapy.
Infliximab and adalimumab are also approved for use in patients with
ulcerative colitis and who have not responded adequately to, or who are
intolerant of, conventional treatment.
Asthma
Omalizumab, which inhibits immunoglobulin E (IgE) from binding to its
receptors on mast cells, basophils and dendritic cells, is the only mAb
approved for use in allergic asthma. Its high cost means that its use is
limited to adults and children (aged six years or older) with moderate
or severe asthma (despite the use of daily high-dose inhaled
corticosteroids and long-acting beta-agonists) and proven atopy. Lack of
long-term safety data and the need for doctors to administer doses
seems to be hampering its market uptake.
System Lupus Erythematosus
Belimumab is a B-cell activating factor which has recently been
introduced for patients with SLE. It is the only mAb approved for use in
SLE and was approved as an add-on to conventional therapy when the
response is inadequate. In the US, belimumab was the first anti-SLE
therapy to be approved since 1955.
Conclusion
The evidence from more than 10 years of experience in RA and psoriasis
suggests that patients with RIA can benefit greatly from the specificity
and fast onset of mAb therapy – particularly in rescue treatment.
However, mAb therapy is currently only available for a few of the more
than 80 diseases that make up this category, leaving millions of
patients to cope with suboptimal treatment. Even in conditions covered
by mAb therapy, not all patients are able to tolerate the available
drugs and others are resistant to them. There is a clear unmet need for
an expansion of mAb therapy in RIA conditions. Despite the challenges
involved in discovering and developing new biologics, a variety of new
mAbs are in development, including for asthma, COPD and SLE, for which
little or no choice in mAb therapy currently exists.
References
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diseases (IMIDs) and biologic tharapy: a medical revolution, Postgrad
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healthcare spending, AARDA, 2011
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and control of chronic respiratory diseases: A comprehensive approach,
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