Video New Medical Therapeutics in IBD Play Pause Previous Next 1 of 200 slides Volume Quality 720P 540P 270P Fullscreen Captions Transcript Chapters Slides New Medical Therapeutics in IBD Overview Dr. Sakuraba, MD, PhD, Assistant Professor at the University of Chicago Medicine & Biological Sciences, discusses New Medical Therapeutics in IBD. [MUSIC PLAYING] ATSUSHI SAKURABA: So this is my disclosure slide. And here's a figure that describes the current available medical options for inflammatory bowel disease. On the right, you see ulcerative colitis, and we start with-- in mild cases, we start with 5-ASAs, mesalamine. And then if the patients don't respond, or if the patient has more moderate to severe disease, we give them corticosteroids. If the patient becomes steroid-dependent or steroid-resistant, we give them thiopurines or step up doing biologic agents, immunomodulator agents. And if, ultimately, the patient does not get better or will suffer from long-term steroid side effects, we need to consider surgery. It's quite similar in Crohn's disease, but the mesalamine 5-ASAs appear to have not such a strong role in Crohn's disease. And in addition to thiopurines, methotrexate is often used as an immunomodulator, too. And for biologic agents, in addition to the anti-TNFs, we have natalizumab, which is an anti-endocrine inhibitor available for Crohn's disease, too. And so this is a figure showing some mechanism-based treatment of inflammatory bowel disease. The precise mechanism of inflammatory bowel disease remains unknown, but we know it's a complex combination of genetic, environmental, and technological factors, and possibly also enteric abnormality and enteric flora. Microbiota plays a role, too. And antibiotics, probiotics, and possibly fecal transplant try to normalize the enteric flora. 5-aminosalicylates directly act through the intestinal inflammation and try to reduce inflammation. Surgery removes the inflamed portion of the intestine and might be a cure for ulcerative colitis but not so often for Crohn's disease, because inevitably, inflammation comes back in Crohn's disease. And corticosteroids, immunomodulators, and anti-TNF agents work on the immunological abnormalities, try to normalize the dysregulated balance, and also reduce intestinal inflammation and tries to help symptoms of IBD. So there are still a lot of issues with the current available options. So with the traditional therapies-- steroids, 5-ASAs, and immunomodulators-- steroids often work as an induction agent. The issue is that when the patients are taken off of the steroids, the inflammation symptoms come back. And 5-ASAs only work in mild cases, and the long-term outcome might not be very good. Immunomodulators often work very well, but there are high rates of intolerance with each of the agents-- azathioprine, methotrexate, cyclosporine. And the issues with biologics is that it's much more effective than the traditional therapies. The higher cost is an issue. And also, there are about 30% to 40% of patients who do not respond, which are called primary non-responders. And about 10 percent of those who initially responded lose response, which are called secondary loss of response. And this figure shows what we've recently learned about the immunological pathogenesis of inflammatory bowel disease. So in the intestine, the macrophages and dendritic cells capture the antigens that come through the intestinal layer. And then once they capture those, they upregulate pro-inflammatory cytokines such as IL-12, IL-23, and TNF-alpha. And once they upregulate those, together with those pro-inflammatory cytokines, they present the antigen to the naive T-cells. Once those naive T-cells are primed, stimulated by the macrophages and dendritic cells, they start producing pro-inflammatory cytokines like interferon gamma in Crohn's disease, IL-4, IL-5 in ulcerative colitis, L-17 and also TNF-alpha. Another characteristic is that when the naive T-cells are primed in the intestine, these macrophages and dendritic cells, they upregulate a marker called alpha 4 beta 7 on the cell surface. And this is like a hallmark of the gut-specific T-cells. So based on these immunological understandings, there have been recent advances in the therapies of inflammatory bowel disease. Natalizumab has been available since 2007, and it blocks a marker integrin called alpha 4. Vedolizumab has just been become available few months ago, and it blocks this gut-specific T-cell integrin, alpha 4 beta 7. And there are also several other anti-cytokine therapies that are currently being studied and are in the Phase II/Phase III status-- L-12, L-23 blocking agents, L6 blocking agents, and there's also a Janus kinase inhibitor that lots the production of various cytokines. And there's also a biologic that blocks the production of interferon-gamma-inducible proteins. So today I'd like to focus on the anti-integrin inhibitors. Just like I mentioned, natalizumab blocks alpha 4, and alpha 4 is actually expressed on the white cells that migrate back to brain, skin, which is non-specific. And also, it blocks the alpha 4 beta 7-expressing leukocytes which migrate back to the intestine. On the other hand, vedolizumab, which is the gut-specific agent, only blocks alpha 4 beta 7, and it only blocks the leukocytes from migrating back to the intestine. It does not block the leukocytes from going to the other organs. So natalizumab, as I mentioned, is an alpha 4 integrin inhibitor. It blocks alpha 4 beta 1 and alpha 4 beta 7. And it's non-organ-specific. Vedolizumab blocks alpha 4 beta 7, and it's gut-specific. And natalizumab was about was approved for multiple sclerosis, because it prevents the leukocytes from migrating back to the brain. It was approved for multiple sclerosis in 2006 and then for Crohn's disease in 2007. Because-- there's a scary risk of a condition, brain infection, called PML that's caused by the JC virus, and that's been a great, huge issue in multiple sclerosis. And we recently learned that the risk is as high as 11 out of 1,000 if the multiple sclerosis patient who is positive for JC virus has been treated for more than two years with natalizumab and has had a prior history of immunomodulator use. So since 2012, there's a test called JC virus antibody serology test available, and we can check this test prior to initiating natalizumab and only give natalizumab when the patient is JC virus-negative. And in addition to that, the patient needs to be registered on the Crohn's Disease TOUCH Program, which was initiated by the pharmaceutical company. And also, the patient needs to discontinue all immunomodulators, including biologics, prior to initiation of natalizumab, because it's a known risk factor for developing PML. And steroids are allowed in the beginning, but the patient needs to respond and they need to be in steroid-free remission after six months. On the other hand, vedolizumab was approved for Crohn's disease and ulcerative will colitis a few months ago. There's been no reported cases of PML so far, and you don't need to check JC virus antibody. And there's no restriction in giving concomitant steroid or immunosuppressives. And first, I'd like to go the results of the natalizumab clinical trials. And here is an induction trial with natalizumab and Crohn's disease. You can see that as early as week four, patients on natalizumab start to do better than the patients given placebo. That rate goes up at week eight. It reaches highest at week 12. So this is exactly the same as our clinical experience, where it takes about two or three months for patients to respond to natalizumab treatment. And this is the result of the maintenance-based study. And you can see that more than 50% of patients given natalizumab do well for more than 15 months. And this response appears to be durable and not wear off over a year period of time. And there's been also some post-hoc analysis from these clinical trials, and it seems that patients given natalizumab in combination with immunomodulators or without immunomodulators did similarly well. And also, it's been reported to be effective for patients who failed anti-TNFs, too. And next I'll move on to the vedolizumab clinical trial results. First, I'll start with ulcerative colitis. And this is the response rate in week six. Patients are given three doses of vedolizumab within a six-week period. And you can see that the clinical response rate is much higher than the placebo. Clinical remission rate is much higher than placebo, too. And at week six, nearly 40% of patients did achieve a condition called mucosal healing, which is when we do a colonoscopy, there's almost no inflammation at all. And the response seems to be a little bit better for patients who have never been on anti-TNFS, but it still worked much better than placebo or prior anti-TNF failure patients too. And this is the maintenance result of the vedolizumab study in ulcerative colitis. And when patients are evaluated at week 52, nearly half of the patients given vedolizumab every eight weeks or every four weeks did much better than the patients given placebo. And similarly to the prior slide, patients who were never treated with anti-TNF or who were anti-TNF failures, their rates were a little bit better was anti-TNF-naive patients. But still, patients who failed anti-TNFs still did very well at week 52 in ulcerative colitis. OK, next, I'll move on to the results with vedolizumab and Crohn's disease. And contrary to ulcerative colitis, at week six, the clinical remission rate was marginally significantly better than patients given placebo. But the clinical response rate was actually not significantly better than placebo. So it seems that in Crohn's disease, either it does not work well as in ulcerative colitis, or maybe patients need more time-- not week six, but similar to like natalizumab, maybe patients need two or three months to achieve remission. And the maintenance trial with vedolizumab and Crohn's disease-- the maintenance phase actually did pretty well, and nearly 50% of patients achieved clinical response at week 52. However, when we look at the results with combination therapy or anti-TNF failures in Crohn's disease, it seems that numerically, patients who were given concomitant immunomodulators did better than patients who were not on immunomodulators. And the response rate at week six on those who were anti-TNF failures was not significantly better than placebo, but only at week 10. So this further supports that maybe patients with Crohn's disease need a little bit more time with vedolizumab induction therapy. So my summary is that natalizumab is an effective and safe treatment for refractory Crohn's disease patients who have failed anti-TNF agents and/or immunomodulators. It can be given as monotherapy and is effective in nearly half of the patients who failed those agents. And nowadays, more recently, we can do risk stratification for PML based on checking anti-JC virus prior to and after initiation of therapy. And vedolizumab is a gut-specific anti-integrin inhibitor. It seems that it works better for ulcerative colitis than Crohn's disease. Possibly combination therapy is better than monotherapy. And it's a little bit unclear whether or how well it works for anti-TNF failures. And I didn't show any results, but there's no risk of serious infections compared to anti-TNF agents, and there's been no reported case of PML with vedolizumab. And my conclusion is that now we've reached an era of medical therapy for IBD that has changed from steroid refractory to anti-TNF refractory. Emerging evidence suggests that anti-integrin inhibitors, which have a different mechanism of action compared to anti-TNFs, are effective for Crohn's disease and ulcerative colitis. And also, novel agents targeted against non-TNF pathways are on the horizon and hold great promise. Thank you very much. [APPLAUSE] Published June 2, 2015 Created by
