INFLAMMATORY BOWEL DISEASE

What is inflammatory bowel disease?

There are two major forms of inflammatory bowel disease (IBD): ulcerative colitis (UC) and Crohn's disease (CD). In about 10-15 per cent of cases, it may not be possible to distinguish between them with certainty. The main feature of IBD is inflammation of the lining of the intestine, leading to ulceration, pain, diarrhoea (containing blood in ulcerative colitis) and bowel obstruction (in Crohn's disease). Both diseases are long-term, non-infectious conditions with an unpredictable variation in symptoms over time. They are associated with the risk of anaemia, malnutrition, difficulty in maintaining body salt balance and an enhanced risk of developing bowel cancer. Irritable bowel syndrome is a quite different condition, with symptoms including pain and diarrhoea, in which the characteristic tissue damage of UC and CD is not seen.

The causes of IBD are not well understood. In both ulcerative colitis and Crohn's disease, the walls of the gut are found to be infiltrated by inflammatory cells, but the cause of this inflammation is not clearly established in either case. A genetic mutation has been found to markedly increase susceptibility to Crohn's disease (but not to ulcerative colitis). A protein product of this gene is involved in the recognition by cells in the gut of bacteria, and an inappropriate or ineffective immune response to gut bacteria, with migration of inflammatory white blood cells into the cells lining the gut, has been suggested as a cause of Crohn's disease. One bacterium that has been suggested to be involved is Mycobacterium paratuberculosis, found in cow's milk and known to cause a similar disease in sheep and cattle. However, the evidence for this infection as a cause of IBD is still unclear. The Australian company Giaconda has a proprietary combination of three antibiotics (Myoconda) in Phase 3 trial in Crohn's disease that may provide a definitive answer to this question. If this disease model were verified, it would be a striking parallel to the way stomach ulcers are caused by Helicobacter pylori.

Who gets ulcerative colitis and Crohn's disease and what does it cost?

Ulcerative colitis affects some 120,000 people in the UK and 6,000-12,000 new cases are diagnosed each year. About 60,000 people suffer from Crohn's disease, with 3,000-6,000 new cases a year. The most common age for diagnosis is between the ages of 15 and 25 (CD) to 35 (UC), and men and women are equally affected. No global figures are available for the cost of IBD, but a study found a wide variation in cost per patient. Over six months, the average cost of treating patients with ulcerative colitis was £1,256, while the figure for Crohn's was £1,652. Disease relapse was associated with a 20-fold increase in costs for those needing to be hospitalised.

Present treatments and shortcomings

Management of the acute phase of IBD commonly involves relief of symptoms with antidiarrhoeal medicines, nutritional support and the use of anti-inflammatory steroids, which result in complete or partial remission in about 80 per cent of cases. In addition, Schering-Plough has the anti-TNF-α monoclonal antibody infliximab (Remicade) for treatment of acute CD and for UC that is not controlled by steroids and/or immunosuppressants. In a recent analysis of over 200 patients with moderate-to-severe CD, infliximab treatment was found to be effective in about three quarters of cases, with nearly 80 per cent stopping or reducing steroid use and with a marked reduction in the need for hospital in-patient treatment.

Once acute symptoms have been controlled, the aim is to maintain remission through the use of 5 amino-salicylate derivatives, such as balsalazide (Colazide, Shire), mesalazine (Asacol MR, Procter & Gamble; Pentasa, Ferring, and others), sulphasalazine (Salazopyrin, Pfizer) and olsalazine (Dipentum, UCB). All are available for use in ulcerative colitis, and sulphasalazine and mesalazine are indicated for Crohn's disease as well. Salicylates may also be used for acute treatment in mild to moderate ulcerative colitis, but tend to be less effective than steroids. They can cause nausea, headache and rashes. A Granulocyte Monocyte Adsorption (GMA) apheresis system (Adacolumn, Otsuka) is also available for treating ulcerative colitis that does not respond to steroids. In severe IBD that does not respond to medicines, surgical removal of the diseased segment of the intestine may be necessary.

What's in the development pipeline?

IBD is a disorder in which inflammatory substances called cytokines, such as tumour necrosis factor alpha (TNF-α), interferon-gamma, interleukin-1 and interleukin-12 are overproduced and can give rise to local tissue damage (Figure 1). Several companies have recognised the potential this provides and the most popular targets for intervention have been TNF-α and IL-12.

UCB has a monoclonal antibody against TNF-α (certolizumab pegol) that is given by monthly subcutaneous injection. This route of administration would permit self-administration by patients whose disease was in a stable phase. In addition, Abbott has adalimumab (Humira) which has completed Phase 3 trials in CD. It has shown efficacy both in induction and maintenance of remission. This antibody is also given by subcutaneous injection.

Approaches targeting IL-12 are at an earlier stage. Abbott has a monoclonal antibody (ABT-874) in Phase 2 trial in CD, as does Centocor (CNTO-1275).

Alpha4-integrins are important in the adhesion of white blood cells to blood vessel walls and their subsequent migration into underlying tissue, where they can contribute to the inflammatory response seen in IBD. Elan has developed natalizumab (Tysabri) that inhibits alpha₄-integrin. Trials in people with Crohn's showed a marked decrease in disease activity and a positive response was seen as soon as two weeks after starting treatment. Another integrin inhibitor is in development by Ajinomoto (AJM300, Phase 2).

New formulations of salicylates and steroid derivatives also continue to be developed for IBD. Shire has developed SPD476, a formulation of mesalazine giving delayed and extended release for once-a-day use in mild-moderate ulcerative colitis. Alizyme's ATL- 2502 (Colal-Pred) uses a colonic drug delivery system to release the steroid prednisolone locally in the intestine, with the same objective of reducing side-effects. It has reached Phase 3 trial for ulcerative colitis.

The longer-term future

Many other approaches to IBD are in development. Agents under study for Crohn's disease include ChemoCentryx's CCX282 and epanova (Tillotts) at Phase 3, while AstraZeneca's AZD 9056 and teduglutide (NPS Pharma) are at Phase 2. Also at the same stage are EGS21 (Enzo Therapeutics), visilizumab (PDL BioPharma), which has reached Phase 3 in ulcerative colitis, and Teva's TV-5010.

Therapeutic targets in ulcerative colitis are equally diverse. Otsuka is developing tetomilast, which has reached Phase 3. Pfizer has a monoclonal antibody (PF-547,659) in Phase 2 trial, ISIS Pharmaceuticals has ISIS 2302 and sanofi-aventis has the NK₁ antagonist SR 140333 (nolpitantium besylate) at this stage. In addition, Millennium Pharmaceuticals has a monoclonal antibody (MLN02) in Phase 2 study and Medarex has a monoclonal antibody in Phase 1 trial.

Most of the agents mentioned seek to intervene in the immune/inflammatory reaction but the possibility of an infectious origin should not be forgotten. At the very least, with this great diversity of different targets under investigation, it can confidently be expected that management of IBD will improve further in the years to come.

FOR FURTHER INFORMATION CONTACT:

National Association for Colitis and Crohn's Disease
4 Beaumont House, Sutton Road
St Albans
Herts, AL1 5HH
Phone: 0845 130 3344 (Helpline)
Website: www.nacc.org.uk