IBD Drive Time: Meena Bewtra, MD, on Top Abstracts From ECCO

In this episode of IBD Drive Time, guest Meena Bewtra, MD, joins hosts Raymond Cross, MD, from the University of Maryland and Millie Long, MD, from the University of North Carolina, to discuss top abstracts presented at ECCO on management of inflammatory bowel disease.

Meenakshi Bewtra, MD, MPH, is an assistant professor of medicine and epidemiology at the Hospital of the University of Pennsylvania in Philadelphia.

TRANSCRIPT:

Hi, this is Millie Long from University of North Carolina. And along with my cohost, Ray Cross from University of Maryland. Welcome to this edition of IBD Drive Time. And I'm thrilled to introduce our guest today, who is Dr. Meena Bewtra, who is Associate Professor of Medicine at Penn in their IBD center and also an epidemiologist and a researcher on her own right. So thank you so much, Meena, for joining us.

Dr. Bewtra:  No, thank you guys. This is awesome. I am really, really excited and honored.

Dr Long: Well, I want to jump into the data. So we have asked Meena to provide some highlights of recent abstracts that hopefully will be applicable for your clinical practice in terms of up and coming agents for the management of inflammatory bowel disease. And so the first one I'm going to ask her about is a drug that has recently been approved by the FDA, upadacitinib. This is a small molecule, it's a selective JAK inhibitor. And we're all kind of excited about this drug. I have to admit, I've tried to prescribe it, just getting a few patients started on it. But tell us about some of the most recent data? We've looked a little bit at the major approval data. But I know more recently, data were presented surrounding extraintestinal manifestations with upadacitinib?

Dr. Bewtra:  The 3 that I picked, I tried to pick 3 different classes of medications. Three completely different reasons, but the unifying theme being that there is some useful real-world information. Even in these new studies, these new drugs that we may be talking about. And so, this was an oral presentation looking at using upa for treatment of these extraintestinal manifestations. And the way that they set this up, the induction studies for upadacitinib were U-ACHIEVE and U-ACCOMPLISH. They were 8 weeks, randomized trials. Then the maintenance arm was ironically also called U-ACHIEVE, maintenance. Patients were rerandomized. During induction patients got upa 45, and then they were randomized to 15 or 30 or placebo in the maintenance arm.

During both the induction and the entire clinical trial, they noted the presence of extraintestinal manifestations. Now, we may have a little bit of qualms about what exactly constituted extraintestinal manifestations in this abstract. But they included peripheral and axial arthropathies, episcleritis, uveitis, erythema nodosum, pyoderma, Sweet syndrome, oral aphthous ulcers, PSC, autoimmune hepatitis, venous thromboembolism, COPD, bronchiectasis, kidney stones, and anemia. And so what they noticed, about a fourth of the patients in the entire study had at least one EIM. To be fair, the most common were anemia and the arthropathies, both the peripheral and the axial arthropathies.

At week 8, numerically more patients in the upa 45 induction arm had resolved their extraintestinal manifestations. So, this was 40% versus 33%. And then when they looked at the maintenance arm, at week 52, statistically significantly more patients who had gotten the upa 30 milligrams had resolved their extraintestinal manifestations. So 66% versus 45% with the 15 milligrams and 24% with placebo. Now obviously this, the study's not powered to look at extraintestinal. That was not the goal. This was part of the substudy of this randomized trial. And we can argue about whether some of these are actually intestinal, extraintestinal manifestations.

Dr Long: Right. Well, and a lot of them are complications of active disease, right?

Dr. Bewtra :  Absolutely.

Dr Long:  I mean you would expect anemia to get better, you would expect some of these things to get better. Erythema nodosum even, which is linked to active…

Dr. Bewtra: Absolutely.

Dr Long: …ongoing inflammation. So it also kind of supports the fact that the drug works, right?

Dr. Bewtra: Yeah.

Dr Long: People got better, and a lot of these extraintestinal manifestations got better?

Dr. Bewtra: Absolutely. And what I really liked about this, first of all, is that there was this dose response. And we see that in the real world, when we're treating our extraintestinal manifestations. That we do need that higher dose, and we need that longer amount of time. You were seeing that in this clinical trial, even though this was not the goal of that clinical trial. But also because so often this is not something that's even looked at in a clinical trial, right? Nobody is remarking, even measuring these extraintestinal manifestation, what happens with them? So we get all these drugs on the back end, and we don't know if they work.

And if you're like me, you call the dermatologist and say, "Hey, this is how this works. Do you think it'll work in this patient who's got bad pyoderma?" And you make a guess. A lot of times, we don't use certain drugs, because we don't believe that they will have any type of resolution of these extraintestinal manifestations. So I think it's really useful with these newer medications, these newer mechanisms of action that people look at this. Because it opens up the possibility of being able to utilize these in these refractory patients, who maybe had a bad reaction to an anti-TNF or developed drug antibodies and now we don't know what to do for them.

Dr Long: Well, and you would expect joints to be something. That it's particularly the peripheral joints, right? I mean so these are obviously JAKs, including upadacitinib, are approved in rheumatoid arthritis. Meaning that they are effective from that perspective.

Dr. Bewtra:  I would love to see a little bit more granularity on some of these more refractory ones. Saying the ones we really ... the pyodermas, the erythemas, those sort of things. So those are really tough to treat, and we typically think of using an anti-TNF. But what do we do, when we don't have an anti-TNF anymore?

Dr Long: Well, no, I will say anecdotally just in my practice ... not necessarily with upa, because I haven't really had access to that yet. But with tofacitinib, which is a little bit more of a pan-JAK, I have noticed anecdotally in my refractory pyoderma patients that I've had some benefit with it. I am interested to see if this holds out with upa.

Dr. Bewtra: With upa. Yeah. Yeah, absolutely. And so, I liked that this study took a look at this. Again, there's definitely limitations on how they did it, but I appreciate the effort.

Dr Long: And stay tuned, Cleveland Clinic is actually going to be leading a multicenter prospective cohort out of the Crohn's & Colitis Foundation Clinical Research Alliance. To really track and follow extraintestinal manifestations, particularly these joint manifestations to start, and really try to understand better which classes of drugs may have the most benefit. So I think we'll have more information, and this is a great start. Let's move on to your second abstract, which is another drug that I think many of us are excited about, which is risankizumab.

Dr. Bewtra: Yep.

Dr Long:  Which is an IL-23/p19 agent that is already approved in psoriasis, but is currently in phase 3 clinical trials of Crohn's disease. And hopefully, maybe even available as soon as this year, later in 2022. So, tell us about this abstract on risankizumab rescue therapy? Patients who may have relapsed it sounds like, during maintenance?

Dr. Bewtra: Yes, fingers crossed at this gets approved before the end of the year. Risankizumab had also 2 industry studies, this was ADVANCE and MOTIVATE and a 52-week maintenance study called FORTIFY. And just as a reminder for folks, these were really these sick patients. They had very elevated CRPs and fecal calprotectins, and over 50% had tried and failed at least 1 biologic. So, this was a pretty refractory group of Crohn's patients. And so during maintenance, patients were rerandomized to the sub-q risankizumab as either 180 or 360. They designed the study patients at week 16 who had an inadequate response— an inadequate response meant elevated daily stool, abdominal pain, CRP, fecal calprotectin, an SES-CD score. Or if they were on steroids, so if they had to increase their dose of steroids or if they had to start new steroids. These patients were able to get a single IV dose of 1,200 milligrams of risankizumab.

Then they automatically went to the sub-q, 360-milligram arm, and patients were allowed to get up to 2 of these rescue doses during the maintenance therapy. So when they looked at the results, all of the patients who required a rescue dose ... and this included patients who were randomized to the placebo, to the 160 ... to 180, sorry, or the 360 sub-q arm. Between 50% to 75% of them achieved a response in terms of stool frequency and abdominal pain. And 20% to 35% achieved a clinical remission of their stool frequency or abdominal, or an endoscopic response. And most patients only required 1 of these rescue visits. So now again, in terms of limitations, this was not part of the randomization. This was post-hoc analysis. It would definitely be helpful to know who were the patients who really did respond, were there any predictors of response?

But what I love about this is this happens to us in the real world, right? You have a patient who's doing okay on a drug, but maybe they haven't gotten completely better. Or maybe they miss a dose, or the insurance company is delayed in the approval and they start to feel a little bit crappy. Or they feel okay, but you do a scope and they have endoscopically active disease. And the question is, do we drop them to every 4 weeks? Do I give them a dose of steroids? Now I could give them one dose of IV and just increase the sub-q dose, and I could rescue about at least a third of these patients. That's a big deal for keeping our patients on their medications and avoiding steroids, which is fantastic.

Dr Long: No, absolutely. These are great data. And what's interesting is just again anecdotally in my clinical practice ... we obviously don't have access to the IL-23/p19s. But we do have access to an IL-12/23, ustekinumab. And there are some observational data about the same with ustekinumab, giving another IV load and potentially shortening the interval. At least in observational data, there can be some efficacy there as well. So overall, I think all of these IL-23 agents are probably dosed very effectively and they have very good pharmacokinetics. But I think understanding, like you said, who are those people that could benefit? As we learn more about those specific predictors I think it'll be, help us to individualize treatment for sure.

Dr Bewtra: Yeah. And to be able to use these medications longer and more effectively. Because it's great that there are these new medications, but there're not that many new meds. I mean, we really need something.

Dr Long: We need more. Uh-huh, for sure.

Dr Bewtra: Yes we do. We always need more.

Dr Long:  Well, I'm going to turn it over to my cohost, Ray Cross, who we will continue this discussion.

Dr Cross: Thanks, Millie. So I just want to remind the listeners that we are sponsored by Advances in IBD and the Gastroenterology Learning Network. And Meena and I covered these, covered ECCO for the IBD Education Group, of which MedEd Consultants is a parent company. So Meena, let's talk about the last study, a comparative efficacy and safety analysis of sub-q infliximab and vedolizumab in Crohn's and UC.

Dr Bewtra: So this, of course may not seem like a new emerging therapy. But if you're in the United States, the option to do a sub-q infliximab, at least to me feels like it would be a new and emerging therapy. And I think it's important to know that ... a little bit about it. Because I think it would be very, very useful.

So a little bit of background, CT-P13 I think is the first and only sub-q formulation, I will forever now call it sub-q infliximab. And what is really interesting is that the most recent United European Gastroenterology Week, UEGW, there was an oral presentation from the UK where they randomized patients who were on IV infliximab to get sub-q infliximab. They found patients maintained a stable remission. The vast majority, almost 90% were happier on their sub-q infliximab. But also, that the mean infliximab level was significantly higher in the sub-q group. It was actually 10 versus 15, 10 in the IV and 15 in the sub-q.

And so now getting to this abstract, this was actually a systematic literature review and meta-analysis looking at comparing the sub-q infliximab study with all the vedolizumab studies in Crohn's and ulcerative colitis. And so they looked at the 7 randomized trials and the sub-q infliximab study, all the studies you'd expect. GEMINI II and III and VISIBLE 2 for Crohn's, GEMINI I, VARSITY and VISIBLE 1 for ulcerative colitis. The results are what we would also expect, that infliximab was statistically significantly better in induction compared to vedolizumab, the sub-q formulation in Crohn's disease. Numerically better, although no statistical significance in the maintenance arm. In ulcerative colitis, they had similar efficacy, sub-q infliximab versus vedolizumab. Interestingly, a higher proportion of patients discontinue their vedolizumab. In Crohn's disease, it was 32% versus 5% for the sub-q infliximab. In ulcerative colitis, it was 15% versus 3% in the sub-q infliximab.

Now, the limitations are also I think the strengths of this. This is not a head-to-head comparison. But we're never going to get a head-to-head comparison probably of this, and this includes all the very rigorous randomized trials. So the best data we have on these meds, given lack of randomization, it's absolutely possible that baseline characteristics are not randomized. And additionally, this isn't real-world. We know we use these meds differently than a randomized trial would. But what I really ... there were 2 things I liked. First of all, that the outcomes were what we would expect in the way we use these medications, right? We get a little bit better with infliximab efficacy in Crohn's than we do with vedolizumab. And that I think there is always this feeling that IV is better. IV is faster, IV is better. If you have a really, really sick person we use IV.

And I think this is not just providers, but patients as well, a little bit of resistance to change. But at the same time when I talked to our European colleagues, during the pandemic, some of them were like, "We never prescribed an IV medication. Everything was sub-q." I think it's incredible to think about, that that could be our future. Making people feel a little bit more comfortable with having real-world evidence and data that says, "Look, this is not worse. This is at least as good and perhaps more efficacious, despite the fact that it's a sub-q formulation of a medication."

Dr Cross: And we all have these patients, right? That they have, venous access is a problem. So, do you do a nonmedical switch or do you put a port in?

Dr Bewtra: Yeah.

Dr Cross: People that are very busy and traveling, and it becomes difficult. Of course, we're forcing people out of our infusion centers and have to do home infusions, which many of us I think are still somewhat uncomfortable with. So, this would be a nice flexible option. And having the IV form also for our Medicare patients that can't get the copay assistance, the flexibility would be really nice.

Dr Bewtra: Yeah. And it's comforting to know that not only does it biologically seem to be the same levels, if not better, but that it is, that the data is very robust. In saying, "Hey, this is going to work. This is going to work for our patients."

Dr Cross:  What's interesting—Millie and I learned that the sub-q vedolizumab, the PK is actually modeled for 6-week dosing, not 8-week dosing. So they were smart when they designed this, they didn't want to have PK drop when they switched to the sub-q. And so, you could actually use that to your advantage a bit.

Dr Bewtra: Yeah.

Dr Long: Absolutely. I will say, interesting, I've had a couple patients recently who've moved to Europe and then come back, and sub-q infliximab is available in Europe.

Dr Bewtra: Yep.

Dr Long: I've had these patients switched over, and they've done well. They come back and they're like, "Can I stay on that sub-q?" I'm like, "Not here, sorry." Yeah, right? So, I think it will be a nice tool to have-

Dr Bewtra:  It will be a very nice tool.

Dr Long: In the toolbox.

Dr Bewtra: Yep.

Dr Cross: All right, Meena. I want to do a quick, a rapid fire. So I'm going to give you the drug, and you tell me the perfect patient for the drug.

Dr Bewtra: Oh, good Lord. Okay.

Dr Cross: All right? Short question, short answer. So, upadacitinib?

Dr Bewtra: Moderate-to-severe UC and who you need a fast onset of efficacy.

Dr Cross: And maybe with some EIMs?

Dr Bewtra:  Yes. Yeah. Hey, throw them in there.

Dr Cross: Okay. Risankizumab?

Dr Bewtra: Crohn's disease, moderate-to-severe. And that would be it.

Dr Cross: So any patient, moderate-to-severe?

Dr Long: Anyone.

Dr Cross: And then how about—

Dr Long: What about perianal fistula though, would you go a different route for that patient?

Dr Bewtra: I think that is an ... I think of perianal disease as a separate entity unto itself. And a tough, tough ... I don't know. If I did, it would be the higher dose. And really, I might consider giving that rescue dose of IV, just if they weren't getting better by about week 8 or week 16.

Dr Long: Yeah, I think that's tough. I think I'd want honestly more data. I know in their trial program they had patients with perianal fistula, and so I think we will be seeing more data and more observational data. But I think at this point, that's the one group where I would still use combo therapy upfront with TNF an immunomodulator.

Dr Bewtra: I like the ability to measure levels in that setting. Because I want to know that I am pushing everything to the maximum. Because these patients, just it's really hard and it's so devastating. So, you want to be aggressive.

Dr Cross: The only other group I'm thinking about is those with joint extraintestinal manifestations, we're not sure how they respond to treatment of the underlying gut disease. And if parallels are ustekinumab experience, these don't seem to work as well …

Dr Bewtra: No.

Dr Cross: … as the anti-TNFs and JAK-STATs. Having said that, if you had an incomplete response, you could add a COX-2 inhibitor. You could add sulfasalazine, you could add low-dose methotrexates. Or you could do them together in combination, of course. So, it doesn't mean you couldn't use it when it's someone with prominent joint symptoms.

Dr Bewtra: Yeah.

Dr Cross: Okay, who are you going to use sub-q vedolizumab on?

Dr Meena Bewtra: Everyone I possibly can.

Dr Cross: I think …

Dr Bewtra:  Really, I am super excited to move to sub-q. For both of-

Dr Cross: You're going to probably give 0, 2, 6, IV. And then …

Dr Bewtra: Then move them over to …

Dr Cross: … you'll get them set up for the sub-q maintenance.

Dr Bewtra: Yep.

Dr Cross:  For their first maintenance?

Dr Bewtra: Yep.

Dr Long:  Mm-hmm

Dr Bewtra: And what's really interesting is in, if you look carefully at some of the data on sub-q infliximab, even patients with antibodies were able to be ... back their antibodies on the sub-q formulations. So, I don't think that this is a situation where we need to think there's a special population that just needs the IV. I think for both of these drugs, we can flip it over. It'd be cheaper, it'll be easier. It arguably could be safer in certain situations. And I think patients are going to like it. We just need to make them feel comfortable, and I think that means making us feel comfortable with that thing we're …

Dr Cross: Given our, the nonsense with the insurance companies, at least given that it's dosed ... PK'd at every 6 weeks. So that'll be 1 group of patients we don't have to worry about fighting about their dosing, right?

Dr Long: Yes

Dr Bewtra: Exactly.

Dr Cross: Okay, the best question of all. So Meena, tell us something about yourself that the listeners would not know? Or maybe that Millie and I would not know?

Dr Bewtra: Ooh. Okay. So, I had 2 major career decisions before I decided to go into medicine. First, I decided, very sadly, in the sixth grade that I was not going to be an FBI spy posing as a bartender on a Carnival cruise ship. And then in my first year of medical school, I decided I was not going to quit medical school and become a chef. I was very seriously considering just, "This is it, I'm done. I don't like this anymore. I want to go and become a chef." And my girlfriend and I sat down one night, we planned out the entire restaurant. What it would look like, what we would serve, where we would ... how the whole layout out would be. Then decided we would proceed to continue to study for our anatomy exams. So I came this close, this close to …

Dr Long: There may be a restaurant still in your future, Meena.

Dr Cross: Yeah.

Dr Bewtra: I would love it. 

Dr Cross: Well, Millie and I are glad that you didn't drop out med school and I'm sure your patients are glad as well. So Meena, this has been wonderful. Thank you for joining us, and we hope to have you back again in the future for IBD Drive Time.

Dr Bewtra: I would love to. I love you guys. Thank you so much for having me, it was fun.