David Rubin, MD, on JAK Inhibitors: Small But Mighty

Dr Rubin reviews his presentation from the Advances in Inflammatory Bowel Disease regional meeting on the latest information on the safety and efficacy of Janus kinase inhibitors for the treatment of inflammatory bowel disease.

David Rubin, MD, is the Joseph B Kirsner Professor In Medicine and chief of Gastroenterology, Hepatology and Nutrition at the University of Chicago School of Medicine.

TRANSCRIPT:

David Rubin:

Hi, it's David Rubin from the University of Chicago. I'm at one of the regional AIBD meetings. And today, I presented on JAK inhibitors for the patients who have Crohn's disease and ulcerative colitis. The most recent advances in managing IBD have included a number of synthetic targeted small molecule therapies. And I reminded our audience, and I'll share with you, that small molecules are by definition small enough to be absorbed through the lining of the small intestine.

So the advantage of them is not just that they can be absorbed through the small bowel and therefore delivered orally, but also, we get a very predictable PK from these therapies so we don't have to worry about some of the challenges we face with our monoclonal antibody and protein-based therapies.

So there's a very attractive consideration for small molecules in patients who have large burdens of inflammation related to Crohn's and ulcerative colitis and the potential that they may also be leaking proteins. When you use a small molecule, we avoid all of those considerations and concerns.

I spoke about the JAK inhibitors, and we now have two JAK inhibitors available in the US market and approved by the FDA. Tofacitinib is approved for moderately to severely active ulcerative colitis and has been available to us for a number of years, and we've become comfortable and understand how to use it. And more recently, upadacitinib has been approved by the FDA for moderately to severely ulcerative colitis last year, and more recently for moderately to severely active Crohn's disease.

These therapies all work similarly and that they inhibit the effects of a specific enzyme called Janus kinase. There are 4 types of Janus kinase enzymes. These transmural enzymes activate the inflammatory pathways along a number of different pathways and also give us consideration for how we might impact immune-based diseases. What we've learned from these therapies is not only how well they can work for our patients with IBD, but they've also been approved in other disease states, most notably rheumatological conditions involving the joints, psoriatic arthritis as well, and with upadacitinib, atopic dermatitis.

Tofacitinib is considered a pan-JAK inhibitor. It actually has an effect on Janus kinase 1, 2, and 3, as well as TYK2. Upadacitinib is selective to JAK1 with a little bit of off-target TYK2 inhibition. And therefore, we can think about these therapies in slightly different ways. In addition to the fact that upadacitinib now has an approval in Crohn's, both therapies can be used in ulcerative colitis, but there may be some differences in the way we see them affect our patients and the way we consider them going forward.

It's important to think about who are the right patients for these therapies. The therapies have been approved to be used in our patients with moderate to severe disease after they've been exposed to or have not responded to or have lost response to anti-TNF therapies. They were positioned that way after a phase 4 safety study was performed with tofacitinib in patients with rheumatoid arthritis who had pre-existing cardiovascular disease.

And in that study, the patients who received tofacitinib had a higher rate of unexpected venous thromboembolic complications in major adverse cardiovascular events. It led the FDA to suggest that we should make sure we know if our patients who are going to receive this therapy and subsequently other JAK inhibitors have a risk for venous thromboembolic complications or known or risks for cardiovascular disease before we treat them.

In the experience we've had with these therapies in the IBD population, we have not seen these risks appear both in the clinical trials with longer term follow-up safety as well as in the real world experience. And we've also learned that IBD is a risk for venous thrombolic complications. So what we've suggested is that if a JAK inhibitor like tofacitinib or upadacitinib was actually prothrombotic, we might have expected to see it already in our patients with moderate to severe Crohn's and moderate to severe ulcerative colitis, and that has not been the case.

So we're left with interpreting a phase 4 safety study in a rheumatology patient population with known heart disease. And the other caveat that all the patients in the rheumatology study were treated with methotrexate plus the JAK inhibitor or methotrexate with an anti-TNF, and that's different than what we look at when we use JAKs in the IBD population where they are used as monotherapy.

Now, in addition to putting that in context for the audience and discussing what we know and trying to reassure us based on what we're learning regarding the safety of using these therapies, I emphasized another important point. They're fast acting, and they work extremely well, not just in symptomatic improvement in our patients, but in the objective measures of endoscopic improvement, endoscopic remission, even in Crohn's, and, of course, improvement in the symptoms our patients have like urgency in the ulcerative colitis population as well as stool frequency and rectal bleeding.

In fact, I made the case that these therapies work so fast that if you know a patient's going to receive them, you can avoid corticosteroids altogether because within days of starting, most patients who are going to respond will notice that it's working, and we can avoid all the different consequences of being exposed to steroids and then figuring out a steroid taper and all the other things that we've become used to and probably do much too much in the IBD world. So that's of great interest.

In the Crohn's population, upadacitinib has demonstrated nice efficacy, but we've also looked at a couple of other interesting and important endpoints. One of them was patients with Crohn's disease who had draining fistulas or fissures on entry into those studies. And upadacitinib demonstrated a significant and impressive improvement in draining fistulas and healing of the fissures, which is something that I think is worthy of more study and certainly good to know.

As all of you know, if you're treating a patient with Crohn's disease who has known perianal disease, understanding what your treatment options are is a very important component of management, and knowing that JAK inhibitors and specifically upadacitinib may work in that setting is very reassuring and gives us another tool to help these patients.

I'll also add, interestingly, that in the upadacitinib UC and upadacitinib Crohn's studies, they also looked at fatigue. Fatigue, as you know, if you take care of IBD, is ubiquitous. Patients describe this all the time, and there are many reasons patients with inflammatory bowel disease may experience fatigue. The first one, of course, is if they're inflamed, but also if they're anemic. And then we start thinking about other things like, "Are they having sleep disorders because of their inflammation, and is that contributing to their fatigue?"

And it's a hard problem to solve. We routinely check thyroid, although that's rarely the actual cause, but we're always looking for ways to try to help our patients feel better. Well, in the upadacitinib Crohn's and upadacitinib UC studies, they assessed fatigue and demonstrated rapid response and good effect and resolution of the fatigue in almost half the patients who received active therapy compared with placebo.

So here's a new piece of information for us. When we see a patient who's experiencing fatigue from their IBD, this treatment may work specifically by controlling the inflammation in their bowel. But perhaps, there's something more about circulating cytokines and systemic inflammation contributing to fatigue that this might address as well. So I'm happy that this has advanced our understanding in that way, and it's added to the way I think about treating these patients in my own practice.

I'll end with one more point, which is that I think the use of the JAK inhibitors, whether it's tofacitinib or upadacitinib, is something that will transform how we think about the phases of management going forward. One of the audience members asked a question about how we might use these in combination or in new ways, and I think that because we don't worry about immunogenicity because they work so rapidly, we can start thinking about, number one, that of course these are effective induction therapies. But in maintenance phase, when we move into that and if we use the maintenance dosing or a lower dose in maintenance, what might we do for patients who relapse?

Can we go up on the dose for a little while, and then drop back down? Can we combine it with other therapies, or even in future studies, consider using a JAK inhibitor for induction of a patient who's acutely inflamed, and then something else in maintenance phase that might be better tolerated or have a longer and more convenient safety profile?

So there's a lot for us to consider. I've provided some updates for the audience today, and I hope that you will take away from this, that these therapies are very effective and, I believe, safe options in the right patients. Thank you.