This is the text of a video summarizing the current state of IBD treatment from a recent GI convention.
"I'm Steve Hanauer from the University of Chicago. I'm here in New Orleans at Digestive Disease Week. I'd like to give you some updates regarding the clinical field of inflammatory bowel disease [IBD] from this year's meeting.
I'd like to say that there were some breakthroughs in clinical IBD this year, but I'm afraid I can't go that far. Rather, I see this year as more evolutionary in our understanding of endpoints in particular and how to use our current therapies to their optimal effect in both ulcerative colitis and Crohn's disease.
As far as disappointments are concerned, I'd have to say that one of the true disappointments is the lack of benefit of T-cell therapies in both ulcerative colitis and Crohn's disease. We've seen this coming with prior treatments, but there was a lot of hope for abatacept [Orencia®], which is an agent that prevents activation of T cells, that is effective in rheumatoid arthritis. Previously, a trial in ulcerative colitis turned out to be negative, and unfortunately, I'm going to be reporting on a negative trial with abatacept in Crohn's disease this year.[1]
Changing Clinical Endpoints: Mucosal Healing
On the other hand, instead of that negativity, what we really do see is an evolution of how we are treating patients with both ulcerative colitis and Crohn's disease. We've identified that our endpoints for clinical trials that use subjective criteria in both ulcerative colitis and Crohn's disease have not really represented a change in the management of patients. Rather, when we look at more stringent endpoints in both diseases, we find that when we can completely heal the mucosa, we end up with better long-term outcomes.
We saw this previously in clinical trials that looked at biologic therapies (such as the anti-TNFs [tumor necrosis factor]). When we did achieve clinical remission or mucosal healing in clinical trials, this translated into better long-term outcomes, with reductions in surgeries and hospitalizations. We're beginning to take this a bit further. It turns out that when we treat mucosal healing with any of the anti-TNF agents, and this is what's been looked at in clinical trials and reported this year, that we're actually finding better long-term outcomes and better sustained remissions in patients than when we use clinical outcomes alone.[2,3]
Optimizing Biologic Therapy
At the same time, we're trying to identify ways to optimize therapy with the biologic treatments. We are beginning to identify correlations of mucosal healing and serum blood levels of monoclonal antibodies. It turns out that monoclonal antibody trough levels do correlate with mucosal healing. There is a wide variation among patients. In the past, we've been using serum antibody levels to determine why patients have lost response, in particular, to infliximab.
We are now learning that we can also use trough serum levels to help predict patterns of mucosal healing that are going to ultimately translate into longer-term remissions and hopefully aspects of disease modification such as improved outcomes, fewer hospitalizations, and certainly fewer surgeries.
Along these lines, we've been looking at a variety of different anti-TNF agents that are now on the marketplace in inflammatory bowel disease, which of course, include infliximab, adalimumab, and certolizumab pegol.[4]
While patients may initially prefer therapy with the injectable agents, sometimes we're finding that their therapeutic outcome may not be as optimal as with the intravenous agents. For instance, at this year's meeting, the results of a clinical trial with adalimumab in ulcerative colitis were presented.[5] While the investigators did identify meeting their primary endpoints, which were improved clinical remissions compared with patients treated with placebo, these outcomes did not seem as great as we've seen with the injectable anti-TNF agent infliximab. So we need to identify whether there is actually a difference in blood levels attributed to this better or apparent better response with infliximab than with adalimumab or whether [the outcomes are related] to different mechanistic issues.
Of course, it's not fair to compare agents across clinical trials, but I would say that the results with adalimumab are not quite what we expected and not quite as good as the results we've seen with infliximab in clinical trials in ulcerative colitis.
Summary
To summarize what we're learning: the key points coming out of these meetings are that we are beginning to anticipate more stringent hard endpoints for clinical trials and for clinical practice, such as mucosal healing. We definitely need some surrogate markers so we don't need to scope all these patients to identify whether or not they've achieved mucosal healing. Whether other surrogates such as calprotectin or other eventual markers are going to become available remains to be determined.
We're also recognizing an important factor of treatment with monoclonal antibodies, which is that we must anticipate adjusting doses between and even within individuals. It's not "one-stop shopping" where one dose fits everybody. We need to identify appropriate dosing to optimize [outcomes] and that may be according to blood levels in the future. We need to move again toward these stringent endpoints, and we think that's going to make a better overall improvement in long-term outcomes for our patients."
References
1. Hanauer SB, Sandborn WJ, Sands BE, et al. A randomized placebo-controlled trial of abatacept for moderately-to-severely active Crohn's disease (CD). Program and abstracts of Digestive Disease Week (DDW) 2010; May 1-5, 2010; New Orleans, Louisiana. Abstract 649.
2. Rutgeerts PJ, Reinisch W, Thakkar R, et al. Early mucosal healing status predicts long-term clinical benefits for adalimumab-treated patients with moderate to severe Crohn's disease. Program and abstracts of Digestive Disease Week (DDW) 2010; May 1-5, 2010; New Orleans, Louisiana. Abstract 644.
3. Van Moerkercke W, Ackaert C, Compernolle G, et al. High infliximab trough levels are associated with mucosal healing in Crohn's disease. Program and abstracts of Digestive Disease Week (DDW) 2010; May 1-5, 2010; New Orleans, Louisiana. Abstract 405.
4. Van Assche GA, Vermeire S, Ballet V, et al. Switch to adalimumab in patients with Crohn's disease controlled by maintenance infliximab. The prospective randomized switch study. Program and abstracts of Digestive Disease Week (DDW) 2010; May 1-5, 2010; New Orleans, Louisiana. Abstract 645.
5. Reinisch W, Sandborn WJ, Hommes DW, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis. Program and abstracts of Digestive Disease Week (DDW) 2010; May 1-5, 2010; New Orleans, Louisiana. Abstract 847t.
"I'm Steve Hanauer from the University of Chicago. I'm here in New Orleans at Digestive Disease Week. I'd like to give you some updates regarding the clinical field of inflammatory bowel disease [IBD] from this year's meeting.
I'd like to say that there were some breakthroughs in clinical IBD this year, but I'm afraid I can't go that far. Rather, I see this year as more evolutionary in our understanding of endpoints in particular and how to use our current therapies to their optimal effect in both ulcerative colitis and Crohn's disease.
As far as disappointments are concerned, I'd have to say that one of the true disappointments is the lack of benefit of T-cell therapies in both ulcerative colitis and Crohn's disease. We've seen this coming with prior treatments, but there was a lot of hope for abatacept [Orencia®], which is an agent that prevents activation of T cells, that is effective in rheumatoid arthritis. Previously, a trial in ulcerative colitis turned out to be negative, and unfortunately, I'm going to be reporting on a negative trial with abatacept in Crohn's disease this year.[1]
Changing Clinical Endpoints: Mucosal Healing
On the other hand, instead of that negativity, what we really do see is an evolution of how we are treating patients with both ulcerative colitis and Crohn's disease. We've identified that our endpoints for clinical trials that use subjective criteria in both ulcerative colitis and Crohn's disease have not really represented a change in the management of patients. Rather, when we look at more stringent endpoints in both diseases, we find that when we can completely heal the mucosa, we end up with better long-term outcomes.
We saw this previously in clinical trials that looked at biologic therapies (such as the anti-TNFs [tumor necrosis factor]). When we did achieve clinical remission or mucosal healing in clinical trials, this translated into better long-term outcomes, with reductions in surgeries and hospitalizations. We're beginning to take this a bit further. It turns out that when we treat mucosal healing with any of the anti-TNF agents, and this is what's been looked at in clinical trials and reported this year, that we're actually finding better long-term outcomes and better sustained remissions in patients than when we use clinical outcomes alone.[2,3]
Optimizing Biologic Therapy
At the same time, we're trying to identify ways to optimize therapy with the biologic treatments. We are beginning to identify correlations of mucosal healing and serum blood levels of monoclonal antibodies. It turns out that monoclonal antibody trough levels do correlate with mucosal healing. There is a wide variation among patients. In the past, we've been using serum antibody levels to determine why patients have lost response, in particular, to infliximab.
We are now learning that we can also use trough serum levels to help predict patterns of mucosal healing that are going to ultimately translate into longer-term remissions and hopefully aspects of disease modification such as improved outcomes, fewer hospitalizations, and certainly fewer surgeries.
Along these lines, we've been looking at a variety of different anti-TNF agents that are now on the marketplace in inflammatory bowel disease, which of course, include infliximab, adalimumab, and certolizumab pegol.[4]
While patients may initially prefer therapy with the injectable agents, sometimes we're finding that their therapeutic outcome may not be as optimal as with the intravenous agents. For instance, at this year's meeting, the results of a clinical trial with adalimumab in ulcerative colitis were presented.[5] While the investigators did identify meeting their primary endpoints, which were improved clinical remissions compared with patients treated with placebo, these outcomes did not seem as great as we've seen with the injectable anti-TNF agent infliximab. So we need to identify whether there is actually a difference in blood levels attributed to this better or apparent better response with infliximab than with adalimumab or whether [the outcomes are related] to different mechanistic issues.
Of course, it's not fair to compare agents across clinical trials, but I would say that the results with adalimumab are not quite what we expected and not quite as good as the results we've seen with infliximab in clinical trials in ulcerative colitis.
Summary
To summarize what we're learning: the key points coming out of these meetings are that we are beginning to anticipate more stringent hard endpoints for clinical trials and for clinical practice, such as mucosal healing. We definitely need some surrogate markers so we don't need to scope all these patients to identify whether or not they've achieved mucosal healing. Whether other surrogates such as calprotectin or other eventual markers are going to become available remains to be determined.
We're also recognizing an important factor of treatment with monoclonal antibodies, which is that we must anticipate adjusting doses between and even within individuals. It's not "one-stop shopping" where one dose fits everybody. We need to identify appropriate dosing to optimize [outcomes] and that may be according to blood levels in the future. We need to move again toward these stringent endpoints, and we think that's going to make a better overall improvement in long-term outcomes for our patients."
References
1. Hanauer SB, Sandborn WJ, Sands BE, et al. A randomized placebo-controlled trial of abatacept for moderately-to-severely active Crohn's disease (CD). Program and abstracts of Digestive Disease Week (DDW) 2010; May 1-5, 2010; New Orleans, Louisiana. Abstract 649.
2. Rutgeerts PJ, Reinisch W, Thakkar R, et al. Early mucosal healing status predicts long-term clinical benefits for adalimumab-treated patients with moderate to severe Crohn's disease. Program and abstracts of Digestive Disease Week (DDW) 2010; May 1-5, 2010; New Orleans, Louisiana. Abstract 644.
3. Van Moerkercke W, Ackaert C, Compernolle G, et al. High infliximab trough levels are associated with mucosal healing in Crohn's disease. Program and abstracts of Digestive Disease Week (DDW) 2010; May 1-5, 2010; New Orleans, Louisiana. Abstract 405.
4. Van Assche GA, Vermeire S, Ballet V, et al. Switch to adalimumab in patients with Crohn's disease controlled by maintenance infliximab. The prospective randomized switch study. Program and abstracts of Digestive Disease Week (DDW) 2010; May 1-5, 2010; New Orleans, Louisiana. Abstract 645.
5. Reinisch W, Sandborn WJ, Hommes DW, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis. Program and abstracts of Digestive Disease Week (DDW) 2010; May 1-5, 2010; New Orleans, Louisiana. Abstract 847t.
