Dr Abreu recaps her presentation on how to optimize the use of leukocyte trafficking agents in treating inflammatory bowel disease.

Maria T. Abreu, MD, is director of the Crohn's and Colitis Center, professor of medicine, and professor of microbiology and immunology at the University of Miami Miller School of Medicine, in Miami, Florida.

TRANSCRIPT:

My name is Maria Abreu. I'm at the University of Miami. I'm an IBD doc, and I just gave a talk in a wonderful session entitled optimizing therapies in our arsenal, and I was given the challenge of discussing leukocyte tracking. And you might be aware that, even as of a few years ago, if I was giving this, if I was going to give this talk, really, the only thing that we were talking about is vedolizumab because, again, you may be aware that other drugs or other biologics that work in that same mechanism actually really probably at least not anytime soon are going to see the light of day. I'm aware of other companies may be coming up with, small molecule inhibitors that will do something similar to vedolizumab, but that mechanism of action right now squarely is only with vedo. But now we have more to talk about. Right? Because we have S1P receptor agonists, which, as I'll share with you, in putting this talk together, I'm left wondering how much more interesting stuff is going to come out in the coming years about how these really work. And so what I reviewed, was that was, you know, this optimizing therapies, was to look at, how do we normally optimize therapy? So we'll start with vedolizumab. Right? We believe vedolizumab works by inhibiting or blocking T cells from getting into the intestinal mucosa by blocking alpha 4 beta 7 on the surface of activated t cells that are gut-homing alpha 4 beta 7, that heterodimer is one of the indications that a T cell is homing to the gut. So that's fine. And, we know of the study done by Andres Yarur, where he asked the question, okay, well, what if we try to optimize the dose of vedolizumab early on. Will that change the rate of response of a patient to, vedolizumab? And the answer was no.

We did a smaller study at the University of Miami led by one of my colleagues where he combined pentaxofilin, which we reasoned was kind of a poor man's anti TNF since it has a weak TNF inhibiting effect. And we gave patients with Crohn's disease who are about to start vedolizumab, pentoxifilin or not, or a placebo, and looked at how quickly they got better. We did see differences earlier on, like 4 to 6 weeks after starting them on pentaxofilin or the vedo. But at the at the initial, like, sort of primary time point of the study, those 2 groups seem to come together. So I think There probably are things that will jump start, you know, clinical efficacy. Maybe not clinical efficcacy, but, you know, having a patient become symptomatically and possibly endoscopically better faster when they start on vedolizumab but that hasn't been laid so bare.

A recent publication that you may be aware of is the EXPLORER study that combined vedolizumab with, adalimumab and methotrexate in a patient in patients with Crohn's disease and showed, you know, reasonably high levels of endoscopic improvement and clinical efficacy when you use those 3 together. And then, then adalimumab is pulled off and vedo is left behind. So suggesting that, you know, vedo, it is also not only effective on its own, but also effective in combination. On its own, I made the point that we know that vedo, at least in ulcerative colitis and patients that are mostly naive to therapy that vedolizumab was superior to adalimumab. And, of course, that's the basis for our use of vedolizumab as first line in ulcerative colitis patients.

There are clinical decision support tool developed by Parambir Dulai that are publicly available that help us to discern which patients are more likely to respond to vedolizumab and choosing vedolizumab perhaps over other forms of therapy, especially in in the context of Crohn's disease where we're lacking these head to head studies. And so those are very useful. And, actually, Interestingly, that clinical decision support tool doesn't seem to predict response to ustekinumab but does a good job of respond of helping to predict response to vedolizumab.

One of the things I think we're all kind of now evolving into is thinking through This issue of combination therapies. And, of course, vedolizumab is a lovely thing to contemplate in that context because it's a very safe therapy. It also works, again, in its own little bucket. And so therefore, one can imagine that it lends itself to combine with other therapies, especially very potent Induction therapies that might work rapidly, and then vedolizumab can can presumably maintain remission in patients that have had an initial response to whatever therapy you might choose, to think through. I think that's particularly true for any therapy that might have some toxicity. I'll pick cyclosporine and say ulcerative colitis or severe ulcerative colitis patient. You are unlikely to continue in thev cyclosporin indefinitely, but might the cyclosporin might be a bridge to something more sustainable like vedolizumab.

The S1P receptor agonists are themselves kind of interesting, and those therapies in more than in theory, trap lymphocytes in lymph nodes all over the body. It’s thought to have an effect that can be overcome by infection, and this we hypothesize is the case given that these therapies as a class are very safe and have no black box warnings. There is no increased rate of infection in patients that are on these therapies in spite of the fact that their lymphocyte counts can be quite low, at least a 50% drop in lymphocyte. And in fact, If you see a patient and they don't have, a low lymphocyte count, then you could assume that they're not telling the truth and they're not, taking their medication. That's how clear a pharmacodynamic effect of the drug is. So we're left to grapple with then, really, how is it having its biological effect, is that happening because it's trapping, certain T cells in these lymph nodes, or are there other mechanisms perhaps locally in the gut, you know, lymphatic tissue, for example, that might be mediating that effect. And, of course, that'll happen over time.

We don't yet have a really good way of predicting who's going respond to these S1P receptor agonists. Most medications, including vedolizumab, seem not to look as good when they're used as second and third line to other therapies, especially anti-TNFs, but really brought more broadly. And in fact, one of the interesting things with respect to that and the sequencing, if you will, of and that dimension of optimizing our therapies in terms of sequencing and what to do first is whereas if you use an anti-TNF first followed by vedolizumab, vedolizumab doesn't look quite as good. If you used vedolizumab first and then an anti-TNF, at least in, real world studies, the anti-TNF seems to work just as well as it would have as first line. In other words, you haven't burned any bridges when you do that. We don't yet know that, actually, for the S1P receptor agonists. If we start with an S1P receptor agonist, and you may know it's only approved for ulcerative colitis, so If it's if we used it for now, I know that they're working on they're busy doing clinical trials to see whether it works in Crohn's disease, that S1P receptors that are then followed by something else as a second line medication. My prediction would be that these others will work equally well, in spite of the fact that someone has been on a previous S1P receptor agonist. So I think that'll be interesting, because there is a kind of rationale for using something oral that you could know pretty quickly whether something whether it's working or not. And then if that's not working, then get out of Dodge and find something else, for that patient.

And like I said, I think that we'll make a lot of progress with respect to really what is the mechanism of action of these S1P receptor agonists because it seems to me that we're still sort of dealing with a bit of a black box. So stay tuned. Hopefully, that'll be my next AIBD, and I hope to see you there.