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European Biopharmaceutical Review

Hitting the Target


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

  1. Kuek A, Hazleman BL and Östör AJK, Immune-mediated inflammatory diseases (IMIDs) and biologic tharapy: a medical revolution, Postgrad Med J 83: pp251-260, 2007
  2. American Autoimmune and Related Diseases Association (AARDA), The cost-burden of autoimmune disease: The latest front in the the war on healthcare spending, AARDA, 2011
  3. Bousquet J and Khaltaev M (eds), Global surveillance, prevention and control of chronic respiratory diseases: A comprehensive approach, World Health Organization, 2007
  4. Waldman TA, Immunotherapy: Past, present and future, Nat Med 9: pp269- 277, 2003
  5. van Oosten BW, Barkhof F, Truyen L, Boringer JB, Bertelsmann FW, von Blomberg FM, Woody JN, Hartung HP and Polman CH, Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2, Neurology 47: pp1,531- 1,534, 1996
  6. Wiendl H and Hohlfeld R, Therapeutic approaches in multiple sclerosis: lessons from failed and interrupted treatment trials, Biodrugs 16: pp183- 200, 2002
  7. Campbell J, Lowe D and Sleeman MA, Developing the next generation of monoclonal antibodies for the treatment of rheumatoid arthritis, Br J Pharmacol 162: pp1,470-1,484, 2011
  8. Papp JA, Leonardi C, Menter C, Ortonne JP, Krueger JG, Kricorian G, Aras G, Li J, Russell CB, Thompson EH and Baumgartner S, Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis, N Engl J Med 366: pp1,181-1,189, 2012
  9. Burmeister GR, Feist E, Sleeman MA, Wang B, White B and Magrini F, Mavrilimumab, a human monoclonal antibody targeting GM-CSF receptor-α, in subjects with rheumatoid arthritis: a randomised, double-blind, placebocontrolled, phase I, first-in-human study, Ann Rheum Dis 70: pp1,542-1,549, 2011




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Zhengbin (Bing) Yao is a Senior Vice President of R&D and Head of the Respiratory, Inflammation and Autoimmunity (RIA) Innovative Medicines (iMED) unit at MedImmune, leading a cross-functional team dedicated to the prioritisation and advancement of the company’s RIA portfolio. An accomplished executive and scientist with more than 19 years of experience in the biotechnology and pharmaceutical industry, Bing has over 20 granted patents and applications and has more than 50 peer-reviewed scientific publications to his name.
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