IBD Drive Time: Upadacitinib Therapy for Crohn’s Disease

Dr Edward Loftus reviews details of the pivotal trial where upadacitinib emerged a superior alternative to placebo for induction and maintenance therapy among patients with moderate-to-severe Crohn’s disease.

Edward Loftus, MD, is a professor of medicine at the Mayo Clinic in Rochester, Minnesota. Raymond Cross, MD, is a professor of medicine and director of the IBD Program at the University of Maryland School of Medicine. Millie Long, MD, is an associate professor of medicine and director of the Gastroenterology and Hepatology Fellowship Program at the University of North Carolina at Chapel Hill.

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TRANSCRIPT:

Speaker 1:

Any views and opinions expressed are those of the authors and/or participants, and do not necessarily reflect the views, policy, or position of the Gastroenterology Learning Network, or HMP Global, its employees and affiliates.

Millie Long:

Hi, this is Millie Long from University of North Carolina, and joining me today is my cohost for IBD Drive Time, Ray Cross, from University of Maryland. And we're excited to welcome our guest, Ed Loftus, who's professor of medicine at Mayo Clinic in Rochester, Minnesota. Welcome, Ed.

Edward V. Loftus Jr:

Thanks for having me, guys.

Millie Long:

Oh, yeah. We're thrilled to talk to you about this topic, which is upadacitinib in Crohn's disease. Obviously, this has been recently approved, and many of us are gaining familiarity with it in practice, and we know you are involved in the pivotal trials, so we'd love to pick your brain a little bit on upa, and how it's being used in Crohn's disease.

Edward V. Loftus Jr:

Sure, I'm happy to help out. I was lucky enough to be involved in the Phase II CELEST trial, starting way back when, I think, in like 2014 or 2015. So I've been involved in the development program for, gosh, 8 years now.

Millie Long:

Well, we'd love to lean on that experience, and what you've learned through, not only the pivotal trials, but through your use in practice. Let's just start with, could you just give us a high level summary of the pivotal trial results for upa in Crohn's?

Edward V. Loftus Jr:

So the trial design was very similar to the Phase III U-ACHIEVE program in ulcerative colitis. So there were 2 induction trials, induction cohorts, that were 12 weeks long, and then the responders in those 2 cohorts fed into the maintenance cohort. And then, that was roughly, a year long.

So the 2 cohorts, the 2 induction trials, only differed in that, one of the cohorts, I believe it was U-EXCEL, was all patients. Well, it was about roughly half of the patients were bio-naive, and then, the other half had been bio-exposed. Of the ones that were bio-exposed, it was roughly, a third had failed 1, a third had failed 1, and a third had failed 3 or more. The other induction trial, U-EXCEED, was all bio-failures. So that was a little bit more refractory of population.

The other interesting nuance in that trial was that, steroid taper was mandated starting at week 4. And there was a steroid schedule, such that, ideally, all patients should have been off steroids by week 12, which was the time of the induction endpoint.

And so, there was a clinical remission endpoint, and then there was an endoscopic response endpoint. The clinical remission endpoint was defined by the CDAI. There was also a European stool frequency, and an abdominal pain-based clinical endpoint. And then, the endoscopic response endpoint is the usual decrease in the SES-CD score by 50%.

So at the end of 12 weeks, in the U-EXCEL trial, which was the ones with half bio-naive, about 50% of the patient had met clinical remission if they were on 45 milligrams of upadacitinib, versus about 30% in placebo. So the delta there was about 20%. And then in U-EXCEED, which included all bio-refractory patients, those numbers were like 39% and 21%. So it was like an 18% delta. For endoscopic response, the deltas were about 31, 32%. So again, for a week-12 trial, I think, the endpoint, those were pretty significant.

And then in the U-ENDURE, which was the maintenance trial, at the end of that trial, roughly 38% of patients on 15 milligrams, 48% of patients on 30 milligrams, versus 15% of patients on placebo, were in clinical remission. So those deltas are between 23 and 33%. And then for endoscopic response, it was 28% at the 15 milligram dose, 40% at the 30 milligram dose, and 7% for placebo. So those deltas were anywhere between 21 and 33%. So pretty good results for a fairly refractory population overall.

Millie Long:

No. And I think that's what struck me too is, we're so used to seeing these 10% deltas, that all of a sudden, these are pretty high deltas in a population that you described to us, that really has failed a lot of therapies and has pretty refractory disease. Is that what you think we should take from these data, that the efficacy is pretty impressive with this agent?

Edward V. Loftus Jr:

Yeah. I think that's one of my main takeaways is, not only the efficacy, but I think the speed to onset. It works fairly rapidly, and we saw that in the ulcerative colitis trials.

I've also been impressed by the tolerability of the drug, and really, the overall safety. And so, overall, I mean, my experience has been very favorable. And again, it's not just being involved in the trials. Because during the trials, we probably treated over the last 8 years, probably 50 patients. And so it's funny, the irony is that, last year, when we were having some trouble onboarding Skyrizi, building up the Epic infusion therapy sets, everyone was like, "Oh, we don't care, because we'll just use off-label upadacitinib." And that's how comfortable the group felt, because everybody had been exposed to it who had been seeing any of the trial patients.

Millie Long:

And you mentioned something that we were going to talk about later on, but since you mentioned it, I think we might as well have the conversation now. Which is that, in your experience, you've seen these drugs to be quite safe. And frankly, this is my experience as well. We also participated in CELEST and enrolled a number of patients. I've been using this drug for a long time now, almost 10 years, through the trials and in practice, and I've been impressed by that too. Obviously, there's some data, particularly the ORAL surveillance study, that has made us question some of the safety of JAK inhibitors. How do you reconcile those data? How do you talk to a patient about safety, and do you have concerns about this drug or this class in Crohn's disease?

Edward V. Loftus Jr:

Well, I mean the question is, ORAL surveillance was done with a different drug, in a different disease, with a different study design. And I know that sounds like fancy smart, but in many ways it's all true. And I think it's hard to extrapolate the results, when we're talking about, literally, a different drug and a different disease. And so, I've also been reassured by the subanalyses in the rheum literature that have been coming out on ORAL surveillance. And basically, in ORAL surveillance, if you were in the younger part of that cohort, and didn't have known coronary disease and weren't a smoker, your risk of these adverse events was actually fairly low. And it was interesting, the cancer and malignancy events kind of tracked together. So the people that were not having the cardiovascular events generally weren't having the malignancy events as well. So I think, you can really make that distinction. If you have an IBD patient, they don't have known coronary disease and they're not a smoker, I think it's a pretty safe drug.

Millie Long:

No, very fair. And I think that's a great point. This ORAL surveillance study, and obviously I think our listeners are aware, was done in an RA population of individuals over the age of 50, many who smoked, who had cardiovascular risk factors, who are also on methotrexate, who are using tofacitinib. So I think that's a lot of extrapolation. And we certainly need to counsel our patients on this, but it's not necessarily something that has made me not use this drug. I do like you, and just try to understand the individual risk factors for the patient.

Ray Cross:

Millie, I think it's also important to point out to patients, and after I do the counseling, that I'm sure we all do it fairly similarly, that the risk of having poorly controlled disease is not insignificant when you're thinking about clots and cardiovascular events. And then likewise, what are the risks associated with a tapering course of prednisone? So when I'm thinking about upa, I'm also thinking about prednisone and vice versa. And if I'm thinking about prednisone, I'm like, "What the heck? I might as well give upa, because it's safer than prednisone." So I've been using a lot more for that reason, because despite the safety concerns, everything we give is safer than prednisone.

Millie Long:

Yeah.

Edward V. Loftus Jr:

Yeah. And the steroid-free remission rates, even as early as week 12, were fairly impressive, with deltas of 22 to 27%. So again, that net benefit of getting off the steroids may actually be clinically relevant, I think.

Millie Long:

Absolutely. And it seems like, we always think of, or at least I do, of Crohn's as potentially taking a little bit longer to heal. It may take longer to have a remission, potentially, than UC, but really at week 12, those were pretty impressive. So even in Crohn's, I would argue that this is a pretty rapid therapy. That even with the mandated steroid taper, I mean, this was steroid-free, as you mentioned, so pretty impressive. Do you think about it that way too, Ed? Do you think that it may take a little longer in Crohn's than you see?

Edward V. Loftus Jr:

Yeah, I do. I think it does take a little bit longer. But having said that, having treated some refractory patients, and also seeing some pretty dramatic endoscopic responses, I think it's definitely in our armamentarium. I think right by the nature of the label, we're not going to be using this as a first-line therapy. We have lots of other options for that, but this is a great sort of second, third-line therapy. It's a nice ace to have in the hole, I think, for our patients.

Millie Long:

Well, let me follow up with one last question before turning it over to Ray. One of the things that in Crohn's in particular we see, are kind of some of these special populations, where patients may have perianal involvement, or they may have quite significant extraintestinal manifestations. Were any of these populations studied in the pivotal trials, and what data do we have on upa in these type of scenarios?

Edward V. Loftus Jr:

Yeah. And actually, we do. And if you recall, in the case report forms for this study, at every study visit you were sort of required to do a perianal exam, and record the number of fistulas and fissures, and draining fistulas. And so, there was prospectively collected data. Maybe not to the same degree as was seen in the old infliximab studies like ACCENT II, but still pretty robust data. So it turns out, and these data were presented by Jean-Fred Colombel, I think at ECCO, and then at DDW, about 14% of the whole study population had fistulas at baseline. And for fistula closure, the rates were 21% with upa, and 6% with placebo. And for resolution of draining, it was 47% versus 9%. And so, those are pretty good numbers. So there is definitely a sense that... And I think that's true with any effective agent. If you can reduce inflammation, you're going to probably heal some fistulas. So I think good numbers.

And then for EIMs, so EIMs were actually, resolution of EIM symptoms was actually listed in the maintenance trial U-ENDURE, as the last sort of prelisted, key secondary endpoint. They did not make the cut on that, that the treatment difference was about 9 to 11%. And so, there was a signal, it just wasn't statistically significant. And recall, that since only a percentage of the patients had EIMs, really, the study wasn't adequately powered to see. So I think there is a signal there, it just wasn't powered adequately.

Also, that's all EIMs. And I think we know from the RA studies that it's effective in RA. So like for purely for spondyloarthritis or spondyloarthropathy symptoms, I think this drug is effective. And I know in my head now, when I see a patient with active IBD and active spondyloarthropathy symptoms, I'm thinking usually either an anti-TNF or a JAK inhibitor, specifically this one.

Millie Long:

No, I agree with you, Ed. I practice similarly. The other thing that I have found upa in particular and JAK to be great with is pyoderma, believe it or not. With refractory pyoderma, we've often already tried TNF, we've already tried IL-23 type agents. And the JAKs in my practice have actually been kind of a game changer there as well. So I'd be interested to see future data surrounding pyoderma as well.

Edward V. Loftus Jr:

Yeah. I think that's a good point. It'd be nice to break out that data separately, see what that looks like.

Millie Long:

Well, wonderful. Well, as we break and turn things over to Ray, I wanted to remind our listeners that IBD Drive Time is sponsored by the Gastroenterology Learning Network, and Advances in IBD. And there is an upcoming regional, that is all virtual, September 14th and 15th for our Advances in IBD regional series. So please join us for that in the future. And now, turning it over to Ray.

Ray Cross:

Thanks, Millie. And Ed, I just wanted to follow up on a couple questions regarding the clinical trial. And one is, I was listening to you nicely summarizing the results and the deltas between the active drug and placebo. And I think what is striking is, that you don't really... Typically, we see a fairly significant drop off in the biologic experienced patients, but you don't seem to see that with upadacitinib. Is that your impression as well?

Edward V. Loftus Jr:

Yeah. I mean, maybe the top, in terms of the top line, the top line numbers, they're a little bit lower, but the deltas are actually pretty similar. So I think, right, just by the nature of a bio-refractory patient, but the absolute number may not be as good, but they're still pretty good efficacy. And again, you saw that both for the clinical remission and for endoscopic response in the induction trials, that regardless of the underlying population, the deltas were fairly similar.

Ray Cross:

In the maintenance arm, it seemed to me, that there's a pretty clinically relevant difference between the 30 and the 15 milligram dose for maintenance. I think you agree with that. But then, when you do get someone well on this drug, we get pressure at times to dose reduce because of the concern about safety. What dose are you using for maintenance? And are you dose reducing anyone? If so, who would that be?

Edward V. Loftus Jr:

When I first go to maintenance, I'm almost always doing the 30 milligram dose. I suppose, if you run into a specific issue, there's definitely, I mean you should be checking a CBC and LFTs probably every 3 months. You do see a little bit of noise around that. And so, sometimes you have to dose reduce on that basis. And occasionally, you'll see a patient, maybe an older patient or a frailer patient where they express concerns, and so selectively, I might consider reducing the dose. But again, I've been struck. The more I look at the safety data, I've been struck that it's not a major concern here.

Ray Cross:

And I think that Millie and I had looked at the RIVETING study with tofacitinib, and understanding it's different drug, but what was really concerning there, is about 20 to 30% of people relapse on the lower dose, and they weren't able to recapture everyone. I don't know if that will be the same for upa, but if we're using this for really refractory patients, is it that safety improvement, if there even is one, is it really worth it to take that risk of relapse and loss of recapture? I say no, and I think Millie agrees with that.

Edward V. Loftus Jr:

Yeah. I agree with it. And we always case by case, so you've got to look at your individual patient. But chances are, if you're going with upa, chances are you're using this in a patient who's already failed at least one advanced therapy, and often more than one. And so, you got to look at that risk benefit equation, and oftentimes, I think the benefit far outweighs that risk.

Ray Cross:

Ed, in real life, how are you positioning this? So which patients with Crohn's are you using this in?

Edward V. Loftus Jr:

I think, I mean literally, you can use it in anybody beyond second-line, I guess. Okay. So who wouldn't I use it in? Maybe a patient with a recent history of a malignancy, maybe I would say, "Okay, well maybe we can try something that has a perceived better safety profile." There are very few patients that wouldn't be eligible for this. Obviously, just because of the FDA restrictions, you're not going to use it in the anti-TNF naive population.

Ray Cross:

I caught you on that. So are you a purist, do they have to fail an anti-TNF, or can it just be, they haven't responded to an advanced therapy? Purist or practical?

Edward V. Loftus Jr:

I think you have to be practical. We're all pushing the envelope on this. And so, I think we're still honing our dark art of insurance denial appeals with upadacitinib. We all have our little means of doing it, and we're still working through that. But yeah, I think it's reasonable in a bio-failure to consider it.

Now, are you going to get it approved? Maybe not. But certainly, in an anti-TNF failure, it's definitely up for discussion. I mean, you have to talk to your patient, right? And I always talk about the patient who's driven by efficacy versus the patients who are driven by risk. And I think sometimes at our centers, we see more of those risk-averse patients sometimes. But if they're efficacy-driven, for sure, this should be introduced earlier in the algorithm, I think, than maybe how we're using it, right? Anytime a new drug comes out, we're using it in fourth-line, but as we get more comfortable with this, it's moving up the algorithm, I think.

Ray Cross:

Yeah, I completely agree. I practice very similarly. We're talking about Crohn's, but Crohn's patients can have severe acute colitis in the hospital, and we know that our UC patients do. Is there a role for this drug off-label in those patients?

Edward V. Loftus Jr:

There may be. It's just that we don't have a lot of data, and I've heard people talking about using either a 30 BID dose in the hospital, or 45 BID. We haven't been doing it yet at Mayo. There's some kinks we have to work out. I mean, part of the issue is, can you get samples? Are you allowed to use samples? And some of our centers maybe don't necessarily allow samples, and then that makes it a little bit harder to pull off such a protocol. But I think it'll be interesting to see the data come out on this. And I think it's a reasonable consideration.

Ray Cross:

Anecdotally, we've done it. My partner has gotten a cohort of 13 patients, I believe, between our site and NYU, where we've induced, and the results are pretty good. And we always assume that high dose is better. We've just been giving the 45 milligram, and I think patients do pretty well. And it's certainly easier than cyclosporine and hyperbaric oxygen to give people, if they've been on infliximab before. And so, I think it's going to be in our algorithm at some point someday. I don't know how much data we're going to need for that, but I think it's going to have a role.

Hey, before I ask you the fun question, Ed, I just want to remind our listeners that we are on Spotify and Apple Podcasts, so you can find us easily there now and subscribe, and we hope that you do.

So. Ed, the fun question. Can you tell the listeners something about yourself that they may not know? Maybe even something that Millie and I wouldn't know about you.

Edward V. Loftus Jr:

Yeah. So it's funny that you mentioned Spotify, because that's sort of how this happened. I grew up in this, I was in high school in the 70s, so at that time, I was into music, like Led Zeppelin, and then I got into U2, and a little bit of Bruce Springsteen. And then I had this weird thing. I've kind of gotten into Britpop bands from the 90s, especially Oasis, and I'm kind of obsessed with Oasis. And so, at the end of the year in Spotify, they tell you what you listen to, and I was off the charts percentile about how many Oasis songs I'd listen to. And it's kind of like, the backstory of them is just fascinating. These two guys who grew up in basically low-income housing in Manchester. Their parents had immigrated from Ireland, and they were basically on the dole, and they kind of formed one of the biggest bands in the UK, and it's kind of an interesting story. And yet, now they hate each other, they don't talk to each other. It's a big soap opera. So I'm kind of obsessed with them, kind of a little.

Ray Cross:

I thought you were going to tell me about your interest in Abraham Lincoln, history. I thought that's where you were going to go with that.

Edward V. Loftus Jr:

I have that too. But yeah, we went, during the pandemic, my wife and I did a road trip to Springfield, Illinois, and saw the museums, and libraries, and stuff like that. It was a lot of fun.

Ray Cross:

So any questions about British Pop and Abraham Lincoln, the listeners know where to go.

Edward V. Loftus Jr:

Yeah.

Ray Cross:

This has been great. Thank you so much for doing this, and we hope to have you back another time.

Edward V. Loftus Jr:

All right. Thank you so much for having me, guys.

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