IBD Drive Time: Ed Barnes, MD, on Novel Therapeutics

Dr Barnes reviews key abstracts from ECCO 2023 on novel therapeutics for inflammatory bowel disease with hosts Drs Raymond Cross and Millie Long.

Edward Barnes, MD, is an assistant professor of medicine and associate director of the Gastroenterology and Hepatology Fellowship Program at the University of North Carolina School of Medicine at Chapel Hill, North Carolina.

TRANSCRIPT:

Dr Raymond Cross: Welcome everyone to IBD Drive Time. I'm Raymond Cross from the University of Maryland School of Medicine, and I'm here with my co-host Millie Long from UNC. And we're delighted to have a return guest, Ed Barnes from UNC who's going to talk about best of ECCO in the category of novel molecules. Ed, welcome back to IBD Drive Time.

Dr Ed Barnes: Thanks so much, Ray. I'm really, really a pleasure to be here and talk about some really exciting data that was presented at ECCO this year.

Dr Cross: Great. And before we go into that first set of studies you're going to talk about, I want to remind the listeners that IBD Drive Time is now on Apple Podcasts and Spotify. To find us, type in, Gastroenterology Learning Network, and then the IBD Drive Time are part of that. So we're very excited about that.

So Ed, let's jump right in and talk about upadacitinib, which of course is available for UC but not yet available for Crohn's. So what did we learn about upadacitinib for Crohn's at ECCO?

Dr Barnes:  Thanks, Ray. So one of the things that as you just nicely pointed out is that we don't yet have upadacitinib approved for Crohn's disease. And one of the abstracts that I thought really highlighted how we should potentially think about using upadacitinib in the treatment of Crohn's disease was Digital Oral Presentations 38, and this was titled UPCI Therapy Reduces Crohn's Disease Symptoms Within The First Week of Induction Therapy. If we just parallel UC therapy with upadacitinib and Crohn's disease therapy, one of the real calling cards or hallmarks of using upadacitinib and ulcerative colitis is this rapidity or onset of action when we think about how quickly patients get better when we think about using upadacitinib. And this has been a signal that's been present from the early days of when we first saw that clinical trial program.

Those initial results that were presented in abstract form, where we saw separation within the first few days among patients treated with upadacitinib and those patients treated with placebo. So this is a signal that's been present that we've been aware of for a long time, and I think that's a signal that at least in my practice has been translated into the real world. When I've been treating patients within clinic, patients get better within the first week or the first couple of weeks when they're treated for ulcerative colitis. This was an abstract that I was really excited to see presented at ECCO because this gave us the first chance to mirror and see will we have the same type of results in the treatment of patients with Crohn's disease. Now, just to remind you, the induction study design for patients with upadacitinib Crohn's disease was a 12-week protocol entitled U-EXCEL and U-EXCEED, where patients were randomized to receive either upadacitinib in 45 milligrams or a placebo.

And obviously they follow these patients for 12 weeks. But again, we're really worried about what happens in the first several days or the first 15 days of those patients that were treated with upadacitinib. And what they found is actually reassuring, if you want to think about it in the way that I was just laying it out, is that patients actually did get better within the first few days compared to placebo when they were treated with upadacitinib 45 milligrams, in terms of symptomatic scores and stool frequency and abdominal pain scores. When we think about symptomatic remission scores, patients started to get better as early as day 3 and certainly showed a sustained response in terms of those symptomatic remission scores by day 5 or day 6, and that continued out through the first 15 days of that window of the induction period.

But I think what's also important is obviously this was a large clinical trial program, so they continued to follow those patients beyond that, and once you saw those early separations, they actually continued to separate and continue to further widen all the way out to the first 100 days, and they didn't ever show any normalization back to any normal period.

So this is, I think, a reassuring abstract because we know that upadacitinib works for ulcerative colitis and we hope this is going to work just as well for Crohn's disease. When we think about anchoring those discussions with patients, setting expectations for patients when we start a new therapy. This provides important information for when patients can get better and for what they should expect in terms of the rapidity of onset set of action. So I was excited to see these data presented.

Dr Cross:  Yeah, I'm not going to ask you a 3-part question because I hate those, but I guess first question I could think of related to this, Ed, is did they show this based on bio-naive or bio-exposed and was there any difference? So the more treatment exposed patients, was it less quick response? I'm not sure. I can't recall if they showed that or not.

Dr Barnes: So to date, they have not broken that down in those terms. I think some of the other data they presented later on in terms of bio-naive and bio-exposed patients in terms of overall remission and overall response in terms of the entire induction period at week 12 mark. And I think in some ways, obviously we saw a little bit of a step-down in terms of when patients were able to achieve response and during that induction period if you were bio-naive or bio-exposed, but in terms of the first few weeks of therapy or that first 15 days in this abstract, they did not break it down in that granularity.

But I think it's an excellent question because obviously, the more refractory patients, again, we don't want to correlate the two disease stakes between ulcerative colitis, but we know even in this protocol, even though patients got better within potentially the first 3 to 6 days, they also had this, I don't want to call it an escape arm, but they had an extended induction period that was built into the clinical trial program. So I don't think they were expecting every patient to get better within the first 6 days either. There was an opportunity that you could stay on 45 milligrams beyond that first eight to 12 weeks of induction. So that's similar to what they did in the ulcerative colitis protocol as well. And so I think they realized there were some patients that may not get better so soon. So it's a great question.

Dr Cross: Yeah, I guess I've had the same clinical experience as you. I just saw a patient in the office on Friday who had not responded to an anti-TNF or UC, and within a couple of doses of upadacitinib, went into complete remission. This is someone who didn't really respond very well to steroids either. So it can be quite dramatic.

I guess with Crohn's, these patients to be in the trials are not going to be allowed to have a symptomatic stricture. But I just wonder what the structural damage with Crohn's that might this take longer, but certainly we're going to, I'm sure, identify subsets that you're going to see this perhaps colonic disease or ileocolonic as opposed to isolated ileo, but I'm sure they'll tease it all out. Upadacitinib is definitely coming to us for Crohn's. We're going to see it. So how is this going to affect your clinical practice when we have this available? So who are you going to position upadacitinib for in Crohn's?

Dr Barnes: I think it's a great question and I'm going to answer your question about positioning, but I would say the one thing that's really interesting when you think about using symptomatic data for Crohn's disease compared to symptomatic data for ulcerative colitis, thinking about that abdominal pain score. I could be wrong and you can please correct me if I'm wrong, but I don't think we understand the pathophysiology of abdominal pain as well as we do something like rectal bleeding, for instance. It's wise to think about that process of healing rectal bleeding and onset of efficacy in terms of healing rectal bleeding. So your point is a very good one about why this is occurring, and how this is occurring, and how patients get better. I think we could probably do better as far as physicians understanding that.

That being said, to answer your question about positioning, I think that this, presuming that the label looks the same for everything else we know about JAK inhibitors and the treatment of ulcerative colitis thus far, I would imagine that I would use this and I would position this immediately after a patient that has failed an anti-TNF therapy; I would be rushing to use this in a patient that is relatively refractory. We don't have a lot of data obviously about perianal disease, although there have been protocols looking at JAK inhibitors in perianal disease specifically with other mechanisms, not necessarily upadacitinib. We don't have a lot of those data. So I think it's still going to be a little bit more nuanced than it is in ulcerative colitis, but I think I wouldn't have a lot of hesitancy to use this after an initial anti-TNF failure. And that's how I would think about this. The same way I think about a lot of our other emerging mechanisms that seem to be designed, their clinical trial programs have been designed for a refractory population in mind.

Dr Cross: And I think JAKs and anti-TNFs potentially have some competitive advantage for the patients with prominent extraintestinal manifestations. So these would be good therapies there. Before we go on to another class of drug, I just want to remind our listeners that IBD Drive Time is sponsored by the Gastroenterology Learning Network and Advances in IBD. And speaking of Advances in IBD, we have an in-person regional Advances May 19th and May 20th in Boston coming up. So still plenty of time to register and attend that wonderful course.

So Ed, we've talked a bit on this podcast about S1P modulate receptor modulators and there's a new kid coming for UC, etrasimod. So what did we learn about etrasimod during ECCO?

Dr Barnes: So etrasimod is obviously, as you said, one of the new mechanisms that's coming. And one of the things of the abstract that was presented that I think really lays out several different aspects of the etrasimod program that I think can put sort of a bow on a lot of different abstracts that were presented is Digital Oral Presentation 42, which was the Efficacy of Etrasimod on Symptomatic Relief in Patients With Ulcerative Colitis, which was an analysis of the phase 3 ELEVATE UC 52 at ELEVATE UC 12 trial programs.

Now, just as a reminder for those of you that are not familiar with the way that the etrasimod trial programs were set up, etrasimod actually used a treat-through design on their ELEVATE UC 52, which was that patients were started on induction therapy and then continued on the same therapy, randomized either to receive a etrasimod or placebo and continued on that therapy for a 52-week period of time.

Now, they also had ELEVATE UC 12, which was a separate 12-week induction therapy. So within that ELEVATE UC 52, obviously they looked at outcomes at the 12-week mark. So you have 2 induction periods, but rather than randomizing people at the end of that 12 weeks, they continued patients on the same treatment through that whole week 52 period of time.

Now, this is not obviously a novel trial design. This has been used in multiple other studies in the past, but I would say this is a little bit different from what we've seen most of our trial designs recently in ulcerative colitis and Crohn's disease. So you definitely want to reorient yourself to that when you're looking at some of the results.

That being said, one of the things that I think we just talked about with upadacitinib in terms of anchoring discussions with patients is how quickly the therapies work. And that's why I picked this particular abstract, because this can do a lot of expectation setting when we think about etrasimod, when etrasimod hopefully comes to market, because what they did is they looked at how quickly patients got better symptomatically in terms of their treatment of their ulcerative colitis in both the ELEVATE 12, the 12-week induction study as well, they as well as the 52-week treat-straight-through design study as well.

And what they found is that patients had symptomatic improvement in terms of their stool frequency and rectal bleeding scores as early as week 2, and certainly by week 4 in both these 12 week- and 52-week periods of time. And so the other thing is that they were maintained throughout the rest of the, certainly the induction periods, and then obviously they went on in the 52-week arm throughout the 52-week maintenance period as well.

So one of the major takeaways for me is that obviously S1P receptor modulators probably work a little bit less, I would say a little bit slower in action or a little bit less frequent in terms of the onset of efficacy compared to what we saw and we just talked about with the JAK inhibitors in upadacitinib. And I think this is something that's probably been established by other S1P receptor modulators that have come to market and specifically in ulcerative colitis in the form of ozanimod. That being said, you did see this clear separation for patients that compared to those patients treating with placebo as early as week 2, certainly by week 4, and that continued throughout the study period.

Now the other thing that was interesting, and I want to point out about this trial program, in addition to the treat-straight-through design, if you look at some of the other abstracts that were presented here, they actually aggressively recruited patients that had previously been exposed to both biologics and JAK inhibitors.

And so to your question earlier about upadacitinib, as far as efficacy of onset, they didn't look necessarily in this abstract at the efficacy of onset. But when we think about where those patients might be positioned to be on an S1P receptor modulator, I think some of our experience from ozanimod and from the ozanimod trials would say maybe S1P receptor modulators aren't positioned after patients have failed multiple biologics or small molecules. And I think that was some of the signals that came out from some of the other abstracts of with the etrasimod program.

The second thing that they did that was really interesting in my opinion, was that they also specifically recruited patients with proctitis. And if you look at some of their results, if you separate out the proctitis patients from those patients with more extensive disease, either fully left-sided colitis or extensive colitis, you actually see a pretty big delta. Now, these are all obviously post hoc analyses, but you see a much larger delta compared to placebo for those patients with isolated proctitis. And these are small numbers, but I think also when we think about efficacy of action, when we think about positioning, the proctitis population may be one that we want to watch as these etrasimod trial programs move forward. So I'll stop there, but those were my initial impressions from ECCO with the etrasimod.

Dr Cross: Yeah, mostly comments here. I was a little surprised at the ulcerative proctitis data because although in many ways we think that's a less severe subgroup of UC patients that are less likely to get colectomy and of course colon cancer, we also know as clinicians that these patients often have persistent troubling symptoms of urgency and maybe some tenesmus and it can be really hard to get complete healing of the rectum.

And so I agree, I was blown away by the magnitude of response in these patients. So kudos to them for including them. To my knowledge, they're excluded from all studies. And it seems like all of our pivotal clinical trials, and it seems to me like the S1P, maybe you could still use it after one advanced therapy fails, but probably once you get to second, third, until we have specific biomarkers, it's unclear how effective it'll be until we have these precision medicine tools.

The other thing that we've been saying for a long time is drugs that impact inhibit leukocyte traffic or affect leukocyte trafficking or slower onset and the VARSITY trial with vedolizumab, and now some of the subanalyses for ozanimod and etrasimod, would suggest that that's not the case. So this is interesting.

Lot of chatter when ozanimod was launched about safety, and in many ways, I think it wasn't based on the evidence. Any safety signal with etrasimod that was picked up here, Ed? Anything new or reassuring perhaps?

Dr Barnes: Yeah, I would say it more falls in the reassuring camp in the sense that in what was presented at ECCO at least, there were no new safety signals that were identified as far as what we know, to your point about S1P receptor modulators. They did several different safety analyses from both the week 12 induction studies, which obviously is a short window, but also through that 52-week treat-straight-through design, and there were no new safety signals that were identified, at least in what the abstracts that were presented at ECCO.

So I think this is more, I would say, again, in the reassuring side of the street than being more alarming or anything that was new data that were presented, given that obviously this is a new mechanism or a new drug, but that was nothing that was new that was presented about the overall S1P receptor modulator.

Dr Cross: Now I'm going to turn it over to my cohost, Millie Long, to talk about our last section.

Dr Long: Hey Ed, thanks so much for joining us, and I am thrilled to be here as well and learn from you guys. I didn't get a chance to attend ECCO, so this has been really great. My next set of questions has to do with a new IL-23 agent, mirikizumab, which is approved now in Europe, I believe, and still pending approval here in the US, but what did you learn from ECCO about mirikizumab?

Dr Barnes: Yeah, thanks, Millie. This is a really exciting area. Obviously, as you mentioned, given the anticipated pending approval in the United States with mirikizumab and the fact that mirikizumab is anticipated to be the first IL-23 approved for ulcerative colitis. We obviously have an IL-23 in the form the treatment of Crohn's disease in the form of risankizumab. But given that mirikizumab would be the first for ulcerative colitis, there's a lot of excitement about this.

As far as mirikizumab goes with in terms of data that were presented at ECCO, the abstract that I think was most enlightening in terms of how we might think about using mirikizumab in the treatment of ulcerative colitis in the very near future was actually a poster. It was poster 469. It was entitled, The Effect of Mirikizumab on Clinical and Endoscopic Outcomes Based On Prior Advanced Therapy Failure In Patients With Moderately to Severely Active Ulcerative Colitis.

Now, just to remind you, mirikizumab, the phase 3 trial program was entitled the LUCENT Program. You had LUCENT-1, which was the induction program, and then LUCENT-2, which was the maintenance studies. Mirikizumab overall seem to be quite effective in these trial programs. But what this poster really tried to drill down was if a patient had been tried on 1, 2 or 3, or 2 or more essentially of advanced therapies, how effective was this and was essentially was there a drop-off in the overall efficacy as you move through how exposed a patient had been to prior therapies?

The major take home, I think first off, is that over a third of patients that made it to the LUCENT-2 maintenance study had been biologic exposed. This is important I think, when we think about these new therapies coming to market, is that this is often where these therapies get used when new therapies are available because our patients that are coming to clinic often in tertiary centers are already bio-exposed.

They've been on multiple different advanced therapies, and this is often when we're looking to use new therapies. So obviously this is a clinical question of importance when we're thinking about using these therapies.

But to get to the actual results that were presented, first off, it shouldn't be surprising to anybody in the audience that's listening, the most effective way to use these medicines is in patients that are bio- or advanced-therapy-naive. That was where we saw the biggest delta compared to placebo. But what was really interesting is that if you looked at the individual sequence in both the induction as well as in maintenance in the LUCENT-1 and LUCENT-2 maintenance study, you didn't really see that great of a drop-off if patients moved from one advanced to multiple different advanced therapies in terms of the delta to placebo.

Now, the greatest terms of clinical remission was still among those patients that were advanced-therapy naive and those patients that had only received one advanced therapy. But the other thing that I think really stood out to me in this poster was you didn't see necessarily that a patient that had been exposed to say, vedolizumab, did better than a patient that had been exposed to an anti-TNF. And this was a question I think, Ray, you alluded to earlier in our session about upadacitinib, that generated a lot of discussion actually in the audience where patient said, "Did the efficacy of upadacitinib change if you had been exposed to an anti-TNF compared to an IL-12/23 or to vedolizumab, in the treatment of ulcerative colitis or Crohn's disease?"

You didn't really see this signal with mirikizumab, though. The bars look pretty similar compared to which individual agent a patient had been exposed to. Now, again, remember, these are post hoc data. These are really small numbers depending on which individual agent or which series of agents the patient has been exposed to. But I think they're important for us to understand as we think about this agent moving into clinical practice, because this is really where I think our gestalt and going to a question that Ray asked earlier about how do you use this medicine as it comes to market? I think this is where our clinical intuition is going to come into play about finding the right patient to use this medicine in. Obviously, the easy answer is a bio-naive patient, a patient that hasn't been treated with ulcerative colitis before, that's the ideal patient. But if you don't have that ideal patient, I think trying to parlay some of these numbers and seeing how this plays out in clinical practice is going to be really important.

Dr Long: Absolutely. Where it's a blessing and a curse that all of a sudden we have a lot of different therapies approved and ulcerative colitis and in Crohn's disease, in Crohn's disease more coming. But the idea of positioning, sequencing, becomes really important. And so I think what you're teaching me here is that the biggest drop-off is between naive and any prior exposure, but almost no matter what that prior exposure is, you're going to have the same effect if you do use mirikizumab and you do have an effect. It's just not as great an effect. So that does allow us to use this drug in the right way, I think in our patient populations. Now recently, I know this went before the FDA, do we know any kind of timeline about when we might have this in the US?

Dr Barnes: Yeah, I think that there's an anticipation that this is going to be forthcoming very soon with the recommendations from the FDA. My understanding is there's a little bit of holdup among the delivery mechanism of the drug itself. Again, this is to my understanding, there were no concerns about the actual clinical efficacy or the safety of the drug, which I think is really important for us to know as clinicians and as gastroenterologists. It was more about the delivery of the medicine itself. And so I think that when we think about all the work that goes into a large clinical trial program and the results that we just went through and parsing out where a medicine might be used in terms of positioning and sequencing, those are the things that you can't replicate very quickly. Hopefully things like how a drug is delivered can be fixed to the FDA's liking and that this could lead to approval. And to your point, we could have a new drug that's a available in the market for the treatment of ulcerative colitis, which I think is really good for patients as well.

Dr Long: Exactly. And then right now, from a UC perspective, we obviously have an IL-12/23, but we don't yet have a IL-23 agent, so it would be nice to have one in our arsenal, so to speak. Well, Ed, as we wrap things up, we always ask each of our guests to tell, and this is going to be a challenge for Ed because he and I are at the same institution, so I know him pretty well. I'm going to see if he can stump us here. But we ask, can you tell us something about yourself that our audience may not know and share that with us?

Dr Barnes: That's an excellent question. I would say that our audience probably doesn't know this, is that I came to UNC and Millie was my fellow when I was a visiting medical student. So I don't know if our audience knows that. Millie knows that, but I don't know if our audience knows that. And I'm very lucky to be sitting in this chair on the podcast talking to you guys today. And so who knows, if I hadn't done a GI consult rotation, maybe I would've been doing nephrology consults and I would be talking to you guys about glomerulonephritis—or I wouldn't be talking to you guys, I'd be talking to the nephrology podcast. So I'm very grateful that Millie was my fellow and that she very quickly became an attending and became my mentor. So that's probably something the audience doesn't know.

Dr Cross: Well, thank goodness you didn't do that, because IBD is a lot more exciting than nephritis.

Dr Long: A lot more fun! Well, thanks again for joining us, Ed, on this episode of IBD Drive Time. Yet again, fantastic updates from ECCO. One thing I've learned is that I need to go to ECCO. So thanks to all of our listeners.