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Emerging treatments for inflammatory bowel disease (IBD)

Posted on: 20 Feb 05

Summary

Ulcerative colitis and Crohn’s disease, known collectively as inflammatory bowel disease (IBD) currently affects 0.5-1% of the Western world’s population. This translates to over one million people in America (525,000 Ulcerative Colitis, 490,000 Crohn's Disease) and four million people worldwide. Sufferers experience a range of gastrointestinal symptoms, including diarrhea, rectal bleeding and abdominal pain resulting in weight loss as well as other extraintestinal manifestation such as skin and
Emerging treatments for inflammatory bowel disease (IBD) (Febuary, 2005- Source LeadDiscovery)

Ulcerative colitis and Crohn’s disease, known collectively as inflammatory bowel disease (IBD) currently affects 0.5-1% of the Western world’s population. This translates to over one million people in America (525,000 Ulcerative Colitis, 490,000 Crohn's Disease) and four million people worldwide. Sufferers experience a range of gastrointestinal symptoms, including diarrhea, rectal bleeding and abdominal pain resulting in weight loss as well as other extraintestinal manifestation such as skin and eye disorders. Children with IBD suffer delayed growth and sexual maturation. Ulcerative colitis is restricted to the colon and primarily affects the mucosa while Crohn’s disease can affect all regions of the gastrointestinal tract. Crohn’s disease extends across the full thickness of the intestinal wall causing either strictures resulting in obstruction or fistulas in which adjacent tissue become interconnected. Because IBD is chronic and typically has an onset before 30 years of age, patients generally require lifelong treatment. The market for treatment of IBD was $1.2 billion in 2002 and is projected to reach $2.3 billion by 2011. This growth is due to increasing numbers of patients presenting with IBD and also the introduction of biologics to supplement exisitng steroid and aminosalicylate based therapies.

For up to date information on IBD therapeutics & markets see: Inflammatory Bowel Disease -Efficacy and Compliance Key to Maximizing Patient Share as Novel Biologics Wait in the Wings

Uncontrolled response to intestinal pathogens gaining increasing attention in the etiology of IBD: IBD is a disease of complex etiology and its cause has long been incompletely understood. One concept that has emerged is that uncontrolled inflammation results from a inappropriate response of the intestinal mucosal immune system to otherwise innocuous luminal antigens in a genetically susceptible host. This is supported by the recent identification of a CD susceptibility gene in chromosome 16 that codes for the NOD2/CARD 15 protein, a cytoplasmic protein involved in the recognition of bacterial components. Thus, it is currently believed that loss of tolerance against the indigenous enteric flora is the central event in IBD pathogenesis. Various complementary factors probably contribute to the loss of tolerance to commensal bacteria in IBD. They include defects in regulatory T-cell function and excessive stimulation of mucosal dendritic cells. For a review of IBD immunology click here

Aminosalicylates and steroids as the basis of IBD therapeutics: Treatment regimens depend on the nature of the disease however aminosalicylates and, when required, steroid with immunosuppressants form the basis of IBD therapeutics. Aminosalicylates are the cornerstone of therapy for mild to moderate disease. Sulfasalazine, which consists of sulfapyridine bonded to 5-ASA, was the first agent in this drug category and was followed by the development of more tolerable sulphur-free aminosalicylate (mesalamine) preparations. Corticosteroids are frequently used however adverse effects and efficacy issues limit their use to active disease. The development of budesonide, a newer corticosteroid with a lower systemic bioavailability than the previous corticosteroids does offer improvements with respect to toxicity. Immunomodulators such as azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate and cyclosporine are sometimes used, albeit in a limited fashion. The non-specificity of early immunomodulators and consequent toxicity has driven the development of various biologic therapies that act to modulate the immune response. This emergence of biologic therapies shares similarities with other inflammatory disorders and indeed the indications of many such therapeutics have the potential to expand across a spectrum of disorders during their life cycle.

Maintained remission is the goal for IBD patients: IBD is characterized by flare-ups separated by periods of remission. Remission is generally induced in patients with active ulcerative colitis or Crohn’s disease through the use of either oral or rectal aminosalicylates. although effective in Ulcerative colitis, inducing remission in 40-80% of patients. Long-term remission is achieved in 54-88% of these patients. Aminosalicylate induction efficacy is more controversial in Crohn’s disease. If remission is not induced by aminosalicylates, steroids are used, while third line approaches depend on cyclosporine. Cyclosporine is a more rapidly acting therapeutic option for severe IBD, not responsive to conventional therapy; however, its use is restricted to experienced centers equipped to monitor blood levels because it is associated with significant toxicities. AZA, 6-MP and methotrexate are also used to induce remission in severe and refractory Crohn’s disease. Aminosalicylate treatment is continued to maintain remission in ulcerative colitis patients. Corticosteroids are ineffective for maintenance therapy and once these agents have been tapered off AZA or 6-MP may be necessary to maintain remission. Aminosalicylates are less successful in maintaining remission in Crohn’s disease patients however this class of drug is still used to prevent relapse. Some patients with Crohn’s disease require prolonged steroid treatment to maintain clinical well-being and despite control of symptoms these steroid-dependent patients are not considered to be in remission. This cohort is usually treated with methotrexate despite its side effects.

Individualized therapeutic strategies contribute to patient compliance and clinical outcome: Although the classes of treatment used in IBD have remained largely unchanged for many years (ie aminosalicylates & steroids) there are many therapeutic agents in both classes. Individual agents have distinct side-effect profiles and can be administered orally or topically. Because of these options, clinicians can tailor treatments to patients’ unique needs and preferences. Patients with IBD require management throughout their lifespan and individualizing treatment is therefore important in order to encourage adherence. This is particularly significant given that non-adherence may result in relapse; furthermore ongoing adherence provides a prophylactic effect against colon cancer.

The pharmaceutical industry plays a major role in adherence. Those involved in drug development need to fully understanding the factors that impact on adherence. Factor include convenience (including frequency of dosing and number of pills), formulation (including mode of delivery and pill size), and cost (which may prevent patients from being able to purchase medication) however most important is tolerability.

Physicians underestimate significantly non-compliance rates in IBD. Patients with IBD are more likely to take medications when moderately ill, and often discontinue them when the disease is quiescent. Adherence often decreases dramatically after 1or 2 years. Non-adherence may take any of several forms, including failure to fill a prescription, consumption of too much or too little medication, alteration of dosing regimens, or incorrect self-administration especially with topical therapies. Healthcare providers should be encouraged to provide education regarding the correct use of medication and also the consequences of non-adherence.

Developing a relationship between the pharmaceutical sector and physicians is important in the field of IBD. Noncompliance reflects major loss of revenues for companies in the IBD field, particularly if noncompliant patients do not fill prescriptions. Furthermore if physicians are unaware of non-compliance amongst their patients they are likely to equate poor clinical response to the efficacy of IBD drugs rather than how well patients are adhering to them.

Biologics enter the fray: The value of biological drugs indicated for autoimmune diseases was roughly $6.8 billion in 2003. Biologics are no doubt transforming the treatment of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis and psoriasis. In 2003, Centocor’s Remicade (Infliximab) became first biologic to be approved by the FDA for the treatment of IBD. At the time of writing this editorial Remicade continues to hold this distinction. Remicade is a neutralizing anti-TNF alpha antibody approved for the treatment of fistulous Crohn’s disease and also for reducing the symptoms of the disease as well as inducing and maintaining its clinical remission. The use of Remicade is however associated with several risks. As of June 2001, 84 cases of tuberculosis were reported in connection with infliximab, and invasive fungal and other opportunistic infections have also been described. Infliximab has been implicated in causing demyelinating central nervous system lesions and activating latent multiple sclerosis.

Building on the successes of Remicade: Remicade is a mouse/human chimeric antibody to TNF and although it is an effective therapy for Crohn’s disease, it is immunogenic and leads to the formation of human anti-chimeric antibodies, which in turn lead to loss of efficacy, acute infusion reactions and delayed hypersensitivity. Abbott’s Humira (Adalimumab, phase III for Crohn’s disease), is a subcutaneously administered, monoclonal antibody to TNF. In contrast to Remicade which is a chimer (ie part human part mouse), Humira is full humanized. Humira has already been approved for the treatment of rheumatoid arthritis and data suggests that it may also be of benefit to patients with Crohn’s disease. Recent studies have demonstrated that Humira is well tolerated in patients with Crohn’s disease who had previously responded well to Remicade but who then either became intolerant or refractory to treatment. Data also demonstrates efficacy in these patients.

Celltech (now part of the UCB group) have used Nektar’s advanced PEGylation technology to develop a PEGylated form of anti-TNF antibody, CDP 870 (phase III for Crohn’s disease), with the aim of increasing the half-life and reducing the dosing frequency of the drug. CDP 870 consists of a humanized Fab antibody fragment to TNF that is linked to polyethylene glycol. A phase 2, placebo-controlled, dose-ranging study has investigated the effects of CDP 870 administered 3 times over 8 weeks to 292 patients with active Crohn’s disease. Efficacy was demonstrated, particularly in those patients with elevated C reactive protein, and hence those with the most severe inflammation. CDP 870 is now in phase III development for the treatment of both rheumatoid arthritis and Crohn’s disease. According to UCB, the recruitment of patients suffering from Crohn's disease in two pivotal registration studies has completed two months earlier than expected. The response rates in the open phase of one of these studies are in line with those achieved with Remicade.

More selective targeting of the immune system: The efficacy of Remicade in IBD and its approval for the treatment of Crohn’s disease has paved the way for the development of multiple biologics that target diverse components of the immune system. Remicade, Humira and CDP 870 are all antibodies to TNF. In other autoimmune diseases the development of TNF decoy receptors has been used an alternative approach to disease control. In contrast to, for example, rheumatoid arthritis, decoy receptors tested to date have been ineffective in IBD. One area that is however bearing fruit in IBD therapeutics focuses on the blockade of leukocyte adhesion molecules.

Biogen-IDEC’s Tysabri (Natalizumab; formerly known as Antegren) is the most advanced example of this approach. Tysabri, a humanized monoclonal antibody, is the first alpha-4 antagonist in the new selective adhesion molecule inhibitor class. The drug was designed to selectively inhibit immune cells from leaving the bloodstream and to prevent these cells from migrating into chronically inflamed tissue as occurs in a variety of inflammatory diseases. On November 23, 2004, The FDA approved Tysabri for the treatment of multiple sclerosis and this biologic has now been evaluated in a phase III trial for Crohn’s disease. Tysabri binds to the alpha4-subunit of alpha4beta1 and alpha4beta7 integrins expressed on the surface of all leukocytes except neutrophils, and inhibits the alpha4-mediated adhesion of leukocytes to their counterreceptor(s). The receptors for the alpha4 family of integrins include vascular cell adhesion molecule-1 (VCAM-1), which is expressed on activated vascular endothelium, and mucosal addressin cell adhesion molecule-1 (MadCAM-1) present on vascular endothelial cells of the gastrointestinal tract. Disruption of these molecular interactions prevents transmigration of leukocytes across the endothelium into inflamed tissue. ENACT-1, a phase II, 12-week trial of 248 patients with active Crohn’s disease demonstrated that two administration of Tysabri induced remission for at least 12 weeks. Tysabri was well tolerated with antibodies to Tysabri observed in 7% of patients. Results of this trial were comparable to those achieved in the initial infliximab study. A phase III maintenance study, ENACT-2, reported that monthly administration of Tysabri for 12 months produced a continued response in 61% of patients compared with 29% placebo-treated patients. Remission was maintained in 44% and the majority of patients were able to withdraw from corticosteroids.

Biologics spreading from Crohn’s disease to ulcerative colitis: To date biologics have been evaluated predominantly in Crohn’s disease. The approval and efficacy of Remicade has stimulated a growing number of ulcerative colitis trials although results have been mixed. Two phase III trials are currently underway. Top-line data from these trials are expected to be presented during the Digestive Disease Week meeting in Chicago in May 2005. In December, 2004 Centocor announced Remicade’s Fast Track Designation by the FDA for the treatment of active ulcerative colitis (press release).

Biologics being evaluated in phase II trials and earlier: Advanced development of monoclonal anti-TNF antibodies as well as Tysabri is being followed up by a diverse and rich early-stage pipeline. As well as further molecules targeting TNF and adhesion molecules, early stage candidates being investigated for the treatment of Crohn’s disease include inhibitors of Th1 polarization (anti-IL-12, anti-IL-18, anti-interferon-gamma), inhibitors of T cell activation (CD40 ligand), anti-CD4 therapy, growth hormone, immunostimulation therapy, and immunomodulators. Agents being investigated for the treatment of Crohn’s disease are gradually spreading over to ulcerative colitis. Other targets being evaluated for the latter include anti-IL-2 receptor antibodies and antibodies directed at the invariant CD3 chain of the T cell receptor, keratinocyte growth factor, and epidermal growth factor.

In conclusion the biologic era that is revolutionizing the treatment of inflammatory conditions such as asthma and rheumatoid arthritis is now creating a wave of hope destined to sweep through the field of IBD therapeutics. New therapeutics should supplement classic aminosalicylate- & steroid-based therapeutics offering greater opportunities to IBD sufferers.

For up to date information on IBD therapeutics & markets see: Inflammatory Bowel Disease -Efficacy and Compliance Key to Maximizing Patient Share as Novel Biologics Wait in the Wings

LeadDiscovery

Last updated on: 27/08/2010 11:40:18

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