Michael Chiorean, MD, on Therapeutics for Managing Ulcerative Colitis: Part 2

Dr Chiorean offers part 2 of his review of therapeutic agents for ulcerative colitis and Crohn disease and how best to position them to achieve and maintain remission among patients with inflammatory bowel disease.

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

TRANSCRIPT

Hello, my name is Dr. Michael Chiorean. I'm a gastroenterologist at Virginia Mason Medical Center in Seattle. In the first part of this conversation, I was telling you about one way to improve therapeutic efficacy, and breakthrough the ceiling of effectiveness and medical therapy for inflammatory bowel disease, which was finding the right drug for the right patient, based on mechanism of action and predictors of disease response. The second strategy that I would like to talk to you about, which is developing in parallel with the first strategy, is combining mechanism of action in order to get the benefit of two different pathways or two different drugs.

One plus one equals more than one. Such attempts include a combination of a biologic and an immunomodulator. Now, by this I don't mean an anti-TNF agent. As I appear in which is a benefit, that probably derives primarily from improved immunogenicity.

I'm talking here about a biologic and a small molecule. Two biologic agents targeting two different pathways, or even potentially two small molecule or broader coverage small molecules that target multiple pathways involved in inflammatory bowel disease.

Let's look at a little bit what do we have so far in terms of evidence for this. We do have bi-specific monoclonal antibodies that block two different pathways, specifically IL-12, and IL-23. The results haven't been quite so fantastic in that regard, perhaps because we learned that blocking diet, the IL-12.

The interleukin 12 is not so important for modulating the immune response in patients with IBD as well as other immune-mediated conditions. Therefore IL-23, or at least tampering with the IL-23 pathways seems to be far more important and effective.

On the other hand, there is some evidence from retrospective case series, observations, and even small prospective studies, about combining two monoclonal antibodies with different mechanism of action in the same patient. Again, allowing for the anecdotal quality of the evidence.

Obviously, low quality of evidence for now. There have been some fairly promising results, which I believe deserve further research. However, that has to be done in a rigorous fashion, as we've done with every other therapeutic that we're currently using for IBD, randomized clinical trials, and so on, so forth.

Lastly, or additionally, the advantage of small molecules in certain classes, specifically JAK inhibitors is, they can be truly tailored to the target of interest. Instead of just blocking one pathway, these agents can be designed to block multiple pathways at the same time, or something that's sometimes called pan-JAK inhibitors.

Obviously, the question there is about safety as it is in general with combining mechanism of action, and that has to be addressed adequately. What's the duration? How long can we continue such combination therapy? Whether it's with one agent, with a very broad spectrum of action, or with multiple agents that are combined to cover multiple mechanism of action.

Importantly here though, we have to keep in mind that in terms of treating IBD, overall induction is very important. I believe that we win and lose the fight with IBD during induction. I'm not saying that maintenance therapy is easy, but it's relatively easier compared to inducing response and remission. That's something to keep in mind.

Also, last but not least, cost. At the current rate, very few healthcare systems, if any, can actually afford a combination therapy of this source, specifically when we're talking about two monoclonal antibodies without outside of a research program or clinical trial. That's another issue that needs to be tackled long term.

However, the advantage of such pathway is, it doesn't require the preclinical and individual analytical research that is necessary to identify predictors of disease response. Conceptually, it's a little bit easier to understand.

As with other conditions, for instance, with reflux if you find an agent that's very effective for the majority of patients, you don't really care about identifying sub groups or sub types of patients that do better or worse. There are advantages to this pathway, but there are also disadvantages.

Among the disadvantages, certainly safety and cost. Among the advantages is that the research is intuitively a little bit easier, and the studies are easier to conduct. Somewhat low risk, high reward from that balance standpoint. Thank you very much for your attention.