Therapy of Inflammatory Bowel Disease: What to Expect in the Next Decade

David A. Leiman; Gary R. Lichtenstein

Disclosures

Curr Opin Gastroenterol 

In This Article

Chemokine Antagonists

Novel oral agents also may be available for patients with Crohn's disease in the future based on early research on the blockade of certain chemokines. Chemokines bind to G-protein-coupled transmembrane receptors and are involved in the recruitment and migration of leukocytes into intestinal mucosa under both normal and inflamed conditions;[27] they also play a role in the pathogenesis of IBD.[28] Aberrant expression of the chemokine receptor 9 is found in the small intestine and may be expressed in the colon as well, suggesting a potential target for the therapy of Crohn's disease.

The orally administered inhibitor of chemokine receptor 9, CCX282-B or vercirnon, was evaluated in a randomized, double-blind, placebo-controlled study of 436 patients with large or small bowel Crohn's disease.[29] The study evaluated both induction and maintenance of remission, with primary end points of clinical response at weeks 8 and 52, respectively. The patients received doses of 250 mg daily, 250 mg twice daily, or 500 mg daily. During the 12-week induction period, the clinical response was highest in the group that was given 500 mg once daily at 61 versus 47% in the placebo group (P = 0.039). At the end of the maintenance phase (week 52), 47% of patients on CCX282-B were in remission, compared with 31% on placebo (P = 0.012). Although not statistically significant, the trend suggests that there may be a benefit in a subset of the population having Crohn's disease. Ongoing phase III trials will aim to further evaluate this novel potential therapeutic.

Chemokine antagonists are also being explored for use in ulcerative colitis. Indeed, interferon γ-inducible protein-10 (IP-10) is a chemokine that is involved with inflammatory cell migration and is overexpressed in colonic tissue and the plasma of patients with ulcerative colitis.[30] An 8-week phase II clinical proof-of-concept trial was carried out in 109 North American and European patients with moderately-to-severely active ulcerative colitis to test an inhibitor of IP-10 called BMS-936557 (formerly, MDX-1100). Patients were randomized to intravenous drug (10 mg/kg at weeks 0, 2, 4, and 6) or placebo and evaluated for induction of remission at day 57. No statistically significant difference was seen in clinical response, remission, or mucosal healing. However, in the patients achieving highest plasma concentrations, there was a statistically significant difference in all three end points (87.5% for the highest tertile versus 37.0% for placebo; P < 0.001),[31] reinforcing enthusiasm for further investigation of chemokine antagonists. Another molecule in this class to watch for in the future includes interferon-γ IP-10 (CXCL-10), which mediates T-cell recruitment and activity modulating other cell functions such as epithelial and endothelial cells.[32] However, it is likely that these agents will require significant further investigation before they will be readily available for use in the management of IBD.

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