Michael Chiorean, MD, on Therapeutics for Managing Ulcerative Colitis

In this video—part 1 of a 2-part discussion—Dr Chiorean reviews recent progress in therapeutics for treating ulcerative colitis and Crohn disease and strategies for further improving outcomes in inflammatory bowel disease management.

Michael Chiorean, MD, is director of the IBD Center of Excellence at Virginia Mason Medical Center in Seattle.

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Transcript: Hello, my name is Dr. Michael Chiorean. I'm a gastroenterologist at Virginia Mason Medical Center in Seattle. Thank you for joining us today.

I have reviewed the advances in inflammatory bowel disease and, in my previous talks, the current state of affairs in the field of therapeutics for inflammatory bowel disease, and more specifically for ulcerative colitis. Most of the lessons that I learned and that I'm going to discuss in the next few minutes truly apply to inflammatory bowel disease in general.

We made great strides in the last 20 years as far as therapeutics, with the advent of biologics and more recently small molecules, which are more or less targeted therapy with substantially improved efficacy, and even safety over what we used to call standard therapies, namely steroids, mesalamine, and the first-generation immunomodulators.

However, the other part that's apparent right now is that we have hit a ceiling with our therapeutics. And allowing for the differences in the study design, the control group, and perhaps baseline demographics of the patient population, I think, without being a statistician, people can very easily see how the response and readmission rates are very similar with the first-line drugs on patients who are relatively treatment-naïve—so no prior biologic or small molecule experience.

The results are within the ballpark, and they're not great — 50% response, 20% to 30% remission. The tougher, the more stringent the goals when we're talking about endoscopic remission, histological remission, obviously, the lower the results.

The silver lining there, or the glass half full, is obviously the placebo rates are now looking miserable. If you look at the placebo rates for the most recent clinical trials in the last 5 years vs placebo rates in the first decade after the 2000s, essentially the decade that belongs to anti-TNF agents, their quantum, they're degrees less in magnitude.

We're talking single digits versus, frequently, 20% to 30% placebo response. That's a good thing because we truly are distilling the effect of the therapeutic. On the other hand, the true rates of response, the absolute difference rates, are now becoming a bit more sobering because, as I said, the more stringent the endpoint, a bit lower the results.

How do we break through this glass ceiling which we have with our present therapeutics? There are several strategies that are now in research. People are spending considerable effort and investment in those areas.

First, would be personalized therapy. Can we identify the right treatment for the right patient? That is the holy trail, in a way, of IBD. Even with a drug that you can say that, in the general population, has an efficacy of 30% or 40%, if you use it in the right patient efficacy numbers may increase to 80% or 90%.

How do we identify the most appropriate treatment for a particular patient? That is a complicated answer because it has to involve, most likely, host factors like genetic background and quite likely environmental factors. By that, I mean, microbiome or the level of immune dysregulation. Which pathway is the most important pathway for a specific patient with inflammatory bowel disease, so that we can trigger that?

Then we just have to keep our fingers crossed and say that pathway is a static process, which is probably not the case, as the immune system is very smart. It has tens of millions of years of history and learning. And it oftentimes adapts around the hurdles that we put in its way.

So it’s not uncommon to have patients losing response with appropriate drug levels. In other words, to have what we call a mechanistic failure or loss of response. Just by scratching the surface, you realize that this is a very complicated issue that certainly will see a lot of research. It will call for substantial resources, substantial investment of time, personnel, and financial resources.

The other approach is to say forget about individualized therapy. We're just going to turn up the fire on everybody and do something that, in a way, we have accomplished with proton pump inhibitors or with hepatitis C therapies more recently.

Rather than just breaking down by genotype 1, 2, 3, with hepatitis C, basically the drugs that were discovered recently are so effective regardless of the genotype. As far as I know, my colleagues in hepatology who treat hepatitis C don't really care so much about the genotypes, which were a very hot topic when I was a fellow.

If we somehow figure out a way to get to those effectiveness rates in the 80% to 90% then it probably wouldn't matter what is the dominant pathway in a specific host or whether there's a genetic or microbiome individuality, for a certain patient, because the average response and remission rates were will be in the 70% to 80%, hopefully, 90%.

One of the newer nuances in IBD or lessons that we learned in the last decade is that we win and lose this battle in induction. I firmly believe that we win and lose our battles in IBD mostly during induction. I'm not saying maintenance therapy is easy, but it's relatively easier once you brought the patient to shore. Thank you very much for your attention.