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Gaining ground

Biological therapies are gaining a foothold in the treatment of inflammatory bowel disease

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Inflammatory bowel disease is a general term for idiopathic, chronic inflammatory disorders of the gastrointestinal tract and the most common forms of this disease are Crohn's disease and ulcerative colitis.

In the UK, both Crohn's disease and ulcerative colitis affect around 60,000 and 120,000 individuals, respectively. The number of new cases diagnosed each year ranges from 3,000 to 6,000 for Crohn's disease and 6,000 to 12,000 for ulcerative colitis, according to 2004 figures from the National Association for Colitis and Crohn's Disease.

Although both conditions are related, they differ in terms of the location of the affected areas, histological patterns of inflammation, and their intestinal and extra-intestinal manifestations. Crohn's disease can affect multiple distinct segments of bowel tissue in any area of the gastrointestinal tract from the mouth to the anus. In contrast, ulcerative colitis is restricted to the epithelial lining of the colon and anus.

Symptoms of inflammatory bowel disease vary in severity and can include abdominal pain, diarrhoea, haematochezia, fever, loss of appetite, weight loss, anaemia, intestinal complications (such as bowel perforation, bleeding ulcers, strictures, obstruction, fistulae, perianal disease, toxic megacolon and malignancy) and extra-intestinal complications of the joints, eyes, skin and liver.

Both Crohn's disease and ulcerative colitis are characterised by periods of disease flares (ie, active disease) punctuated by intervals of remission. Management of inflammatory bowel disease is contingent on symptom severity and prognosis, and therapies include, modification of diet, medication and surgery.

Since there is no pharmacological cure for inflammatory bowel disease, drugs are aimed at inducing and maintaining remission. This is achieved by targeting the abnormal inflammatory response in the intestine with:

  • aminosalicylates: sulfasalazine, olsalazine, balsalazide, mesalazine
  • corticosteroids: prednisone, budesonide, methylprednisone, hydrocortisone
  • immunomodulators: azathioprine, cyclo-sporine A, methotrexate, tacrolimus
  • antibiotics: metronidazole, ciprofloxacin
  • biological therapies: infliximab.

Although the aetiology of inflammatory bowel disease remains unknown, there is an increasing acceptance of the role of immunogenetics in disease pathogenesis.

Advances in understanding inflammation, and the importance of developing targeted therapies that minimise adverse effects have spurred the creation of new biological therapies. These novel agents target specific molecules such as tumour necrosis factor TNF-?, interleukins, adhesion molecules and colony-stimulating factors and include biological therapies such as, Cimzia, Humira, Tysabri, Nuvion, Alicaforsen and orally-administered autologous colon-derived antigens.

The cytokine TNF-? is instrumental in mediating pathological inflammation and Cimzia, originated by the Celltech Group (now UCB), is an anti-cytokine human monoclonal antibody fragment that binds with high affinity to both soluble and membrane-bound TNF-?. Manufactured by fermentation in E. coli and subsequently modified by pegylation, the final product (a pegylated Fab' fragment) has a prolonged half-life which permits less frequent dosing. Eliminating the Fc segment of the original monoclonal antibody ensures that the final product retains its efficacy without producing the cytotoxicity mediated by the Fc region.

Cimzia is in the pre-registration phase of development in the EU and US for the treatment of Crohn's disease. Launch is expected in the EU in the second half of 2007.

Regulatory filings included data from the PRECiSE (Pegylated antibody fRagment Evaluation in Crohn's disease: Safety and Efficacy) phase I and II trials of Cimzia in 1,130 patients with moderate-to-severe disease. The co-primary endpoints and clinical response (defined as a greater than or equal to 100-point reduction from baseline in the Crohn's Disease Activity Index scores) at weeks 6 and 26, were met and reached statistical significance. Furthermore, C-reactive protein status or prior treatment with anti-TNF agents did not affect the efficacy of Cimzia.

The first fully human TNF-? monoclonal antibody, Humira, originated by Cambridge Antibody Technology, is being developed by licensee company, Abbott Laboratories. In February 2007, it was approved in the US for the treatment of moderate-to-severe Crohn's disease which is intolerant or unresponsive to treatment with infliximab. It is awaiting approval in the EU for this indication. The ability to administer Humira as a subcutaneous injection provides an advantage over drugs (such as infliximab) which are administered as intravenous infusions.

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Lymphocyte-endothelial interactions (mediated by adhesion molecules) are important in leukocyte migration and recruitment to sites of inflammation. Hence, selective blockade of these adhesion molecules has been evaluated as a strategy to treat Crohn's disease. The humanised monoclonal antibody, Tysabri, that blocks ?4fl1 integrin-mediated leukocyte migration into inflamed tissue, is being developed by Biogen Idec and Elan.

It is the first ?4-integrin antagonist in a new class of compounds known as selective adhesion molecule (SAM) inhibitors. It is in the pre-registration phase of development in the EU and US for the treatment of moderate-to-severe active Crohn's disease.

The phase III trial ENACT-1 (Evaluation of Natalizumab in Active Crohn's disease Trial-1) failed to meet its primary endpoint (response defined as a 70-point decrease in the CDAI score). However, the primary endpoint of response maintenance was met in ENACT-2 (Evaluation of Natalizumab as Continuous Therapy-2), which evaluated the effect of Tysabri on duration of response and remission in 428 patients with Crohn's disease who had previously participated in ENTACT-1. All endpoints were met in ENCORE ñ a phase III, randomised, double-blind trial in 510 patients with moderately to severely active Crohn's disease.

Nuvion, an anti-CD3 monoclonal antibody, is undergoing development with PDL BioPharma for the treatment of steroid-refractory ulcerative colitis and Crohn's disease. It is currently in phase II development for ulcerative colitis in the US, Australia, Canada and Europe. Data from a phase I/II trial, in patients with ulcerative colitis refractory to IV steroids, revealed that the compound produced a rapid and sustained improvement in the majority of treated patients. Preliminary results of a phase I trial, presented at the Annual Digestive Disease Week in 2006, were promising in patients with moderate-to-severe, inflammatory, non-penetrating Crohn's disease.

Alicaforsen, administered as an enema, is a novel agent that inhibits the synthesis of intercellular adhesion molecule-1 (a surface glycoprotein that promotes leucocyte adhesion during immune and inflammatory responses). Originated by Isis Pharmaceuticals, phase II trials of alicaforsen for ulcerative colitis have been completed in the US and Europe. The results of four phase II trials (in more than 300 patients) showed the enema formulation produced significant and long-lasting clinical improvement and that all objectives were met.

Future development of alicaforsen will be carried out by Atlantic Healthcare.

Enzo Biochem is using its proprietary immune regulation platform to develop an individualised approach to treatment using a complex of orally-administered autologous colon-derived antigens for the treatment of inflammatory bowel disease. It is currently in phase II in the US for Crohn's disease.

In a 15-week, phase II, double-blind study, 26 patients with Crohn's Disease were randomised to oral administration of a protein-containing extract (manufactured from their colon tissue) or placebo, each with or without concomitant anti-inflammatory medication. Treatment was more effective than placebo in terms of measures of clinical response (as assessed by the Crohn's Disease Activity Index), and remission and improvements in quality of life (as assessed by the Inflammatory Bowel Disease Questionnaire).

Other drugs undergoing development for the treatment of Crohn's disease include rifaximin (Xifaxan; Salix Pharmaceuticals). This agent differs from other antibiotics in that it is not absorbed into the bloodstream and only affects the gastrointestinal tract. Alizyme is currently developing Colal-Pred (prednisolone metasulphobenzoate with a new delivery system that releases the medication only in the colon) for the treatment of ulcerative colitis. This novel delivery system helps reduce potential corticosteroid-related adverse events.

Increasing insights into the mechanism of inflammation and the benefits of targeted therapies have led to biological therapies gaining a foothold in the treatment of inflammatory bowel disease. Optimal regimens (in terms of timing and duration of treatment) and concomitant therapies are important factors that will need to be explored further by the pharmaceutical industry and could provide a valuable addition to pipelines and revenue streams in the future.

"Although the aetiology of inflammatory bowel disease remains unknown, there is an increasing acceptance of the role of immunogenetics"

Pipeline was written by Liana Siqueira of Adis International, using data derived from Adis Clinical Trials Insight and R&D Insight.

For further information on Adis services, please contact Camille Scot-Smith on 020 7981 0733

11th June 2007


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