IBD Drive Time: The Best of Digestive Disease Week Part 2

Drs Raymond Cross and Millie Long continue their discussion about the best abstracts on inflammatory bowel disease presented at the Digestive Disease Week conference in May.

Raymond Cross, MD, is a professor of medicine and director of the IBD Program at the University of Maryland School of Medicine in Baltimore. Millie Long, MD, is a professor of medicine, vice chief of education and director of the fellowship program in the Division of Gastroenterology and Hepatology at the University of North Carolina at Chapel Hill.

TRANSCRIPT:

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

Raymond Cross:

Welcome everyone to IBD Drive Time. I'm Raymond Cross from the University of Maryland School of Medicine and my cohost, as usual, is Millie Long from the University of North Carolina. This is part 2of the best of DDW for IBD Drive Time. I'd like to remind everyone that we are sponsored by the Gastroenterology Learning Network and Advances in IBD. Also, a reminder that we're now on Apple Podcasts, Spotify, and you can search for us on the Gastroenterology Learning Network.

Last announcement is that there is an in-person regional Advances in IBD coming up in Chicago July 21st to July 22nd. Both Millie and I will be there as speakers, and as you know, these regional AIBD courses are wonderful. So Millie, now with those announcements, why don't we talk about your top three abstracts?

Millie Long:

Absolutely. So one of the things I had the pleasure of doing at DDW was moderating the clinical trials session for IBD, and so I selected 3 of the abstracts from that session. Randomized controlled trials can be great for looking at effectiveness of interventions. They're great for shorter-term outcomes. I think you talked to us a little bit more about some longer-term outcomes, but I think that there were three that could potentially influence the way we manage ulcerative colitis and Crohn's disease.

The first one I wanted to talk about , it was actually an Australian study, that looked at withdrawal versus continuation of a thiopurine in vedolizumab-treated patients with ulcerative colitis. And this was a multicenter randomized controlled trial. And I think that many of us know as background that vedolizumab really has low immunogenicity, so you don't really develop antibodies to this drug.

So when you're using a thiopurine, it's probably not influencing things from an immunogenicity standpoint. So this trial went about to assess is there something different in terms of efficacy in those who are continued on thiopurine. And interestingly because it was set in Australia, they have some step guidance where kind of everyone has to go through a thiopurine to get vedolizumab. So this was a logical question, as they move through and someone stays on the thiopurine if they're randomized to that versus withdrawal immediately. And so this was a prospective study and they actually enrolled 62 consecutive patients either to withdrawal, that was 42, or continue the thiopurine. And the randomization was very balanced. And what they looked at is they looked at a number of different outcomes, kind of histologic activity, they looked at rates of relapse and additionally they looked at fecal calprotectin. So kind of both a clinical outcome of kind of relapse or these biologic outcomes that I think of as a little bit harder, kind of the inflammatory type components.

And what they found is that the thiopurine itself, when it was withdrawn, there was no difference in vedolizumab levels. So that's good to know. It doesn't really affect the level. But among those that had thiopurine withdrawal, they had increased calprotectin and increased histologic and histo- endoscopic activity in ulcerative colitis. And in those patients with histologic activity, despite deep remission, the thiopurine withdrawal significantly increased the instance of disease relapse, meaning the return of clinical symptoms. So I think that this is actually pretty important saying that among those individuals who had been on a thiopurine, adding vedolizumab, if they still have histologic activity or some degree of activity at baseline, when you're starting this, that group in particular, if you withdraw the thiopurine, they may have a higher incidence of relapse.

And so I think this is really important and I think what it tells me is that, and I think I've thought this for a long time, is that the thiopurines are probably independently helping with inflammatory activity. There's a group of patients that are going to do great on vedolizumab monotherapy, but that in addition, there is a group where if you withdraw the thiopurine, they can have a clinical relapse and return of other biological markers and using some markers to help us to understand that, meaning if they're on both and they still have some degree of histologic activity, even though they're feeling okay, that's probably not a good patient to withdraw the thiopurine. So again, just a clue that there may be another role for thiopurines other than just immunogenicity.

Raymond Cross:

So really interesting Millie, and I don't like Venn diagrams, but this is probably one of the areas where Venn diagrams are helpful in that we all have patients that need 2 separate MOAs to control their disease. And we think of combination therapy as combining advanced therapies, but that can include immunosuppressants as well. And I'm going to ask you how you would tease this out in clinical practice. So if you had a step therapy person that was doing well on vedolizumab and biomarkers were good and mucosa looked good, when if at all, would you have a conversation about withdrawal? And second part of that would be how would you tease out whether it's safe to withdraw drug? And then lastly, I know 3-part questions are terrible, but how would you monitor them moving forward?

Millie Long:

Yeah, exactly. And I look at this as kind of parallel to how we practice with other meds as well, whereas if I had someone on both of these drugs, it was really kind of the histologic activity at baseline that predicted this disease relapse. And so if they're in remission and they're in it and biologic markers are down, they don't have a significant histologic inflammation, of course I'm going to give them a trial at removing that thiopurine. But I think we have to keep in mind that the thiopurine does something. And whenever we're removing a drug like that, we have to really think about what's our exit strategy. Are we going to add it back? What are we going to do? And then if someone was feeling well but had Mayo 1 disease throughout and still some active inflammation on both, I wouldn't withdraw the thiopurine. So I think that is something that would change my practice. And these data and others kind of tell me that it's probably both. It's not just that the thiopurine does immunogenicity alone, it's probably doing something else in helping to control some of the inflammation, so.

Raymond Cross:

I wonder if a patient told you or I that they had absolutely no response at all to the thiopurine and/or if they had a subtherapeutic drug level, if that would help us in some way? And then I think how I would do this in practice is I'd probably get an early fecal calpro within 60 to 90 days of withdrawing and probably plan for a scope 6 to 12 months to re-look with. And that's my standard with my therapies.

Millie Long:

That's my standard anyway.

Raymond Cross:

So I think you want to try to pick up recurrence at the earliest possible time point before they go into a rip-roaring flare.

Millie Long:

No, I agree. And well, frankly, that's what I do, too. I think that I'm a big believer in combination therapy with anti-TNFs and thiopurines, but I don't keep them on it forever, either. You get them into a deep remission, meaning biologic remission, where their calpro is normal, they have endoscopic healing, and those are the folks that I then withdraw with a backup plan should they relapse and kind of a monitoring plan to recheck fecal calprotectin, recheck their anti-TNF drug level after I've withdrawn the combo therapy. So it's the same thing with this. We can't just drop it and forget it because I do think the thiopurine has an independent effect, but we need to choose the right patients and we need to monitor. So it's kind of the same message. But I do think it's interesting to show that the thiopurines don't affect vedo levels, but yet when you stop them, there is an increased risk of relapse in UC on vedo, so important.

Raymond Cross:

It's a very important clinical message. How about your second?

Millie Long:

So my second one, and so kind of keeping on the theme of these randomized control trials, I want to talk to you a little bit about the POWER trial. So this is the reason I like this is that it's a study of kind of what I do at practice, and now there's some data that helps me to understand, which is that this was the efficacy and safety of IV ustekinumab reinduction therapy in Crohn's disease patients with secondary loss of response to ustekinumab maintenance. And these are week 16 results from the POWER trial. And so in clinical practice, I think many of us, when we use ustekinumab, we feel that someone who's initially done well and then lost response, these are people where we might need a boost to their drug level to help them to recapture response. And there are kind of 2 ways of going about doing that.

One is dose titration of the subQ, meaning go from every 8 weeks to every 4 or 6 weeks. And the other is to give them an IV reload. And at least in my practice, it can be very difficult to get the shortened subQ interval because that's really expensive from an insurance perspective. But because the IV is less expensive, I actually am able to get some reinduction with IV. So I think these are actually very important data to help us to understand what does this do. And I actually add some safety data as well. And so this was again a randomized controlled trial. And again, among those who had secondary loss of response, and there were 215 patients included. About 108 got the IV reload versus the 107 that did not, they actually got placebo, and they looked at outcomes in both arms. They looked at not only adverse events, but they looked at normalization of fecal cal, normalization of CRP, endoscopic remission and improvement, and improvement in IBDQ score.

So lots of different measures, and essentially, let me get the safety out of the way. It's perfectly safe. There was no difference in adverse events. So that's really helpful from that perspective. And when they looked at the Crohn's disease activity index, which is as we know kind of a little bit of an arbitrary index, but what is used in all of our clinical trials, and when they looked at this primary endpoint at week 16, this was not met. So there was not a significant difference. However, the patients in this population who received the IV reinduction really did show clinically meaningful improvements at week 16 compared to those who did not for some of the objective endpoints, so inflammatory biomarkers and endoscopic outcomes. And so while it didn't meet CDAI, this is telling me that biologically this is helping and we have some data on it, really improving inflammation from that perspective. And so this seems like a viable option if someone does have secondary loss of response prior to changing drug class. You really may be able to recapture in a reasonable percentage with this. And in fact, when you look at the difference specifically in fecal cal, it did actually show an improvement associated with this and then CRP normalization as well.

Raymond Cross:

So it's really interesting, and I think you and I saw this before it was published in abstract form as part of an advisory board. And if I remember the numbers right, what was really interesting was in the group that just stayed on their therapy that got to placebo, I think it was like 40% or something clinically did well. So the message I took home there was, okay, IV reinduction is better, but if you just stay the course, sometimes things will settle out, at least clinically. Now whether those patients going out to a year or a year and a half would still be doing well, perhaps if biologic signature is not good, perhaps those patients aren't going to do well in the long term. But it also suggests sometimes that there are ebbs and flows in symptoms and activity. And with some patients, patients can often settle out. But I think there's no harm in giving the IV reinduction. I agree our experience has been, it's pretty easy to get, and this study would support it, probably going to help justify it if we have issues with the insurance companies.

Millie Long:

And the numbers were pretty impressive. So for the IV, they had a clinical response in 49% as compared to 37% for subQ. That just missed statistical significance. And then when you look at clinical remission even, it was 33% versus 27%. And when you looked at CRP normalization, I mean again, yet again, you're seeing these rates of like 16% for ustekinumab versus 10%, that's just with 1 dose. And then most impressively I thought , they looked at over 25% improvement in SES-CD from baseline. And for IV that was 40% as compared to 15% for the subQ. So again, we're seeing a sign here that this can have certainly endoscopic and biologic benefits.

Raymond Cross:

So don't give up on the drug,

Millie Long:

Don't give up on the drug. Don't switch too quickly. There really may be a role for continuation, whether just continuing the drug as you mentioned, a reasonable percentage will recapture response on their own or kind of an IV load like this. Or you could argue these data don't support it, but you could consider even a dose titration subcutaneously if you could get it.

Raymond Cross:

All right. So last one-

Millie Long:

All right, so my last one is an easy one because it has a good take-home message, which is on subcutaneous infliximab. This is maintenance therapy for Crohn's disease, a phase 3 randomized placebo controlled study. It was called the Liberty Crohn's Disease Study. And the reason I bring this to you, and I'm just going to give you the take-home point, is this is coming and I think that we all need to be comfortable and familiar with it. Subcutaneous infliximab has been available in Europe for some time. And there it's easily accessible, it's easily used by patients. And this is something that I suspect we're going to have an option for soon here in the US. So this required, unlike biosimilars, this actually required full registry trials as any other agent. And so the product, which is CTP 13, the subQ was more effective than placebo for all of its outcomes, including clinical remission, endoscopic response, clinical response, and clinical remission, endoscopic remission and corticosteroid-free remission at week 54.

And there were no new safety concerns. And so this becomes a great option for patients when you are using, wanting to use infliximab, particularly for patients that travel a great deal or may have issues with infusions. I think we can be confident that it went through the same registry process as the initial infliximab had to go through. This wasn't approved on a biosimilar paradigm where it just has to show it in 1 disease state. This actually showed effectiveness in Crohn's disease. So I think this is a viable option and I'll be using it on my patients when we're able to have it here in the US.

Raymond Cross:

Millie, 3 quick questions. I mean, obviously this is so applicable. We have patients that have been on infusions for years and years and years. Some of them are losing venous access, and this would be a really nice alternative for those patients as well as new starts. Just remind me, was this the study at DDW that used the pooled placebo rates from other trials as the comparator, so everyone got drug or am I not remembering that correctly?

Millie Long:

So no, they enrolled a total of 396 patients, 343 were randomized and they had 231 in the active drug arm and 112 in the placebo arm. So they actually did have a placebo arm for a comparison.

Raymond Cross:

I can't remember what drug that was that was used to pool placebo rates.

Millie Long:

Yeah, there have been some really novel study designs where they used kind of the prior placebo arm of other registry studies, pool data, which is a really interesting statistical technique. I think it's still a little new and I think a little bit more...or not as robust. So just because we don't have as much experience with that and whether this will ultimately if you kind of see in the real world, you know, what we see similar response differences, but here they actually did have the traditional placebo arm.

Raymond Cross:

But very obviously that approach is very patient-centric for and with patients enrolled in trial.

Millie Long:

Oh, absolutely, very patient-centric. It's always, yeah.

Raymond Cross:

And then just to follow up, from my memory, the clinical, the PROs, the clinical outcomes numerically just looked really, really good, better than what you'd expect for intravenous. And if I remember right, the drug levels, the PK of this drug was phenomenal.

Millie Long:

The PK was phenomenal. So I think the argument is you may get a more steady PK by doing the subQ infliximab. So there's actually, it's not, I think there are many of us that, there's the thought in the US that, oh, subQ may not be as good as IV, but I think that is definitively not the case here. So the coprimary endpoints, clinical remission, active drug, 62%. That's pretty good as compared to 32% placebo for endoscopic response, 51% active drug as compared to 17.9% placebo, all with a really good area under the curve for the drug level. So I feel like we might be getting kind of a, I won't say more sustained, but a very well sustained drug level throughout the dosing period by using the subQ approach.

Raymond Cross:

So you think you need to use combination therapy with the subQ, given how good that PK is?

Millie Long:

That we don't know, and that this study did not tell us. So it is an interesting thought. Will we see less immunogenicity over the long term? We don't know, but you could argue that there's the potential for that.

Raymond Cross:

I'm sure that data's available in the real world, right? Because they've been using the subQ for a while. I don't know it, but I'm sure that it has to be available.

Millie Long:

They've been using it for a long time in Europe. But remember in Europe they have a step-through with thiopurine, so they're often continued on the thiopurine, so we just may not have as much of the data as we'd like. I'm sure we will get it here in the US as we start using this.

Raymond Cross:

All right. Super interesting abstracts. Any parting thoughts, Millie, before we end? 

Millie Long:

No, just that I do hope people will consider the regional AIBD series and we'll keep talking about more of these interesting abstracts, et cetera. Looking forward to our next meeting review, which will be I guess UEG, maybe in the fall?

Raymond Cross:

Maybe.

Millie Long:

Well, thanks to our listeners. This is the end of Drive Time.