Biologic therapy of Crohn's Disease: Natalizumab, Vedolizumab, CCX282-B

Alvin Ru Tien Chung, Peter Raymond Gibson

Research output: Chapter in Book/Report/Conference proceedingChapter (Book)Researchpeer-review

Abstract

There is still an unmet need for new, safer, and more effective therapies in patients with Crohn’s disease. Adhesion molecules, which are involved in leukocyte recruitment, are a relatively new target for therapy in Crohn’s disease. Inhibition of leukocyte adhesion and migration would decrease the density of leukocytes within the gastrointestinal tract, reduce the secretion of proinflammatory soluble mediators, and diminish cellular immune events, which ultimately attenuates tissue inflammation.
Natalizumab is a monoclonal antibody against α4 integrin and inhibits the binding of α4β1 and α4β7 to their corresponding endothelial receptors, VCAM-1 and MAdCAM-1. As an induction agent, natalizumab is superior to placebo, but the magnitude of the effect is small. What is more impressive is its ability to maintain remission in patients in who responded initially to natalizumab. The major issue regarding the use of natalizumab in Crohn’s disease is the 1 in 1,000 risk of developing progressive multifocal leukoencephalopathy, a disabling neurological disease with a high mortality.
Vedolizumab is a highly selective adhesion molecule antagonist to α4β7 integrin. The results from a phase 2 induction study show significant benefit in the secondary endpoint of clinical remission but not the primary endpoint of clinical response. A phase 3 study is currently in progress.
CCX-282 (Traficet-En™) is an orally bioavailable antagonist to the chemokine receptor CCR9. The results of clinical studies, which have only been published in abstract form currently, suggest that CCX-282 is effective for induction and maintenance therapy in Crohn’s disease.
Lastly, alicaforsen is a first-generation phosphorothioate antisense oligodeoxynucleotide, which hybridizes selectively with messenger RNA encoding human intercellular adhesion molecule-2 (ICAM-1). Results of clinical studies show a lack of clinical efficacy of this class of medication in the management of Crohn’s disease.
There is currently insufficient data to recommend antiadhesion molecules as first- or second-line therapy in Crohn’s disease patients who have failed immunomodulatory treatment. Publication of further large randomized controlled trials is eagerly awaited.
Original languageEnglish
Title of host publicationCrohn's Disease and Ulcerative Colitis
Subtitle of host publicationFrom Epidemiology and Immunobiology to a Rational Diagnostic and Therapeutic Approach
EditorsDaniel C Baumgart
Place of PublicationNew York NY USA
PublisherSpringer
Pages441 - 452
Number of pages12
ISBN (Print)978-1-4614-0997-7
DOIs
Publication statusPublished - 2012

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