Final Progress Report

Proposal No. IBD-0171R
Principal Investigator:  Laura P. Hale, M.D., Ph.D.
Applicant Organization:  Duke University (Durham, North Carolina, U.S.A.)
Project Title: Therapy of inflammatory bowel disease using LMP-420
Period of Award:  March 1, 2006 – February 28, 2007

Lay summary of progress report

The drug infliximab (Remicade™) has revolutionized the treatment of IBD. Infliximab markedly decreases inflammation in both ulcerative colitis (UC) and Crohn’s disease (CD). However, infliximab treatment also has disadvantages. It is expensive, must be given by injection, and makes patients susceptible to serious infections. Infliximab is an antibody that binds to the inflammatory molecule TNF, preventing TNF from triggering inflammation. We have identified a small molecule drug called LMP-420 that prevents the body from making TNF and can be targeted to the intestine by supplying it orally. We thought that LMP-420 could potentially overcome many of the disadvantages associated with the use of infliximab and thus could represent a major advance in treatment of patients with IBD.

We showed that LMP-420 could be given in high doses to mice both orally and by injection without harming them. LMP-420 was very effective in preventing production of TNF. However, we found that using LMP-420 to decrease TNF production did not decrease the severity of colitis in 2 mouse models of IBD.  We showed that TNF levels decreased to normal levels as colitis continued, regardless of whether LMP-420 was supplied.

Our studies highlight the importance of having an animal model that closely resembles the human disease, something that our models approach but do not fully achieve. They also suggest that the benefits of inflixmab treatment may not be due simply to its preventing TNF from triggering inflammation. Infliximab has previously been shown to be able to kill cells that make TNF, and we believe that this property, rather than its effects on TNF itself, may be why it is such an effective treatment for IBD.