IBD Drive Time: The Best of DDW with Dave Hudesman, MD

In this episode of IBD Drive Time, your hosts Drs Ray Cross and Millie Long discuss the best abstracts from Digestive Disease Week 2022 with Dr Dave Hudesman.

David Hudesman, MD, is co-director of the the Inflammatory Bowel Disease Center at NYU Langone and associate professor of medicine at NYU Grossman School of Medicine.

TRANSCRIPT

Ray Cross, MD:
Welcome, everyone, to IBD Drive Time. I'm Raymond Cross from the University of Maryland, and I'm delighted to have my colleague, Millie Long, from UNC, co-hosting. Today, we're going to do the best of DDW, and I'm very happy to have my friend and colleague, Dave Hudesman, from NYU, as our guest. So Dave, welcome to IBD Drive Time.

David Hudesman, MD:
Thanks. Thanks, Ray. Thanks, Millie. Looking forward to it.

Ray Cross, MD:
Awesome. So let's jump right in, so we're going to start with a couple of studies that we're looking, one was an existing therapy for Crohn's and UC, and the other is a therapy that's just approved for UC, but not yet for Crohn's. So Dave, let's start with A Randomized Trial of Vedolizumab Dose Optimization in Patients with Moderate to Severe UC Who Have Early Non-Response and High Drug Clearance, The Enterpret Trial. So why don't you let the audience know the general design of the study, the key findings, and then let's talk about how it's going to influence your practice.

David Hudesman, MD:
Yeah, so I really like this presentation at DDW because I think it definitely directly impacts our practice, and I think many of us know, for our biologic therapies, at least 30% of our patients are just not going to respond to the therapy that we pick. And a lot of times, especially with anti-TNFs, especially Infliximab, we're used to dose optimizing even early on if we're not seeing that response. We push that dose, whether we are using therapeutic drug monitoring or not. And especially, I think, we're all comfortable with anti-TNFs with reactive therapeutic drug monitoring, so if they're not doing well, their level is low, we'll increase the dose.

David Hudesman, MD:
So what this study was looking at was, what do we do with Vedolizumab? And I know prior to this study, in my practice, if the patient was slow to respond or not doing so well, I might push that dose or go right to every four weeks, but we really didn't have any data. So the design of this study was, this was an open label, phase IV study, and what they did was they took patients on with moderate to severe UC, where they had their typical induction with Vedolizumab at zero, two, and six weeks. And then the patients that did not respond at week five, so prior to that third infusion, and that had high drug clearance, so a low drug level. The cutoff they used was 50 at week five, I don't think that's as important, but if the level was a little bit low, they're not doing well, the patients were then randomized to standard dosing, which was your typical 300 milligrams every eight weeks, versus an accelerated dosing.

David Hudesman, MD:
And at this part, they broke it up based on drug levels. If your level was in a moderate range versus low range, again, the exact numbers I don't think are as important, but the two options were getting a double dose of 600 milligrams at week six, and then 600 milligrams every four weeks afterwards, out to about six months, versus 600 milligrams at week six, and then 300 milligrams every four weeks, depending on what your level was, with the primary endpoint of mucosal healing or a Mayo endoscopic sub score of zero one at 30 weeks.

David Hudesman, MD:
So this is something, again, I would do in practice, and they added the patients that were enrolled in the study, about a little over 50% of them responded to therapy. So then at about the half that did not respond, this group was randomized and this broke down to about a little over 50 patients per arm. And I think the bottom line was at week 30, whether you just continued Vedolizumab at 300 milligrams every eight weeks, or you did some sort of accelerated dosing at every four weeks, there was no difference. So there was no difference in mucosal healing, both arms right around 20%, there was no difference in clinical remission, both arms around 10%, and no difference in clinical response with both arms at around 30%.

David Hudesman, MD:
And why I think this is important, again, this is something I was doing for some of my patients that were more refractory, I thought were more refractory, they weren't responding early. Really what this shows is there's no difference, that we probably, if the patients aren't responding to Vedolizumab at all, just pushing the dose, giving every four weeks, probably isn't going to do much. However, Vedolizumab can take some time to work, so even the patients that didn't respond at week six, if you just gave it a little more time after standard dosing, again, you picked up another 30% of patients with the clinical response.

Ray Cross, MD:
So Dave, in my practice, I adopted a proactive drug monitoring approach with Vedolizumab, and I will acknowledge, I don't know if that was the right approach, but I would check a level at week six and if it wasn't in the mid thirties, I would try to guesstimate what their maintenance dose should be, whether it should be six weeks or four weeks, and then try to check another level and make sure it's in the teens. But after looking at this with really massive doses of Vedolizumab, it really didn't make a difference. So in my practice, I think I'm going to abandon that because I can't imagine that's really having a positive effect on our outcomes. Now, whether we should just abandon at week six or eight, or try a little longer, I think that's up for debate, maybe that depends on how treatment exposed they are. If they're relatively early and you don't think they're going to respond, you have good options, then maybe you'd move more quickly. What do you think?

David Hudesman, MD:
Yeah, I agree completely, and I did something similar initially. I'm a proactive believer, so I was doing that at week six, then I realized I don't know how much that matters. So in my more refractory patients, I was just going to every four weeks despite the level. But looking at this, it really doesn't seem like it matters. I think you give things a little more time, depending on that particular patient, how sick they are. And if you look at the predictors of non response in general, where typically what we see patients with higher biomarkers up front, pan colitis patients failed an anti-TNF in the past or another biologic in the past. So I think Vedo still plays best in that first line agent in that more moderate patient. I think in somebody that's a little more refractory, I think giving more time makes sense, as long as they're not worsening, but just pushing that dose, whether you're doing it empirically or whether you're checking a level, I don't really think makes much sense anymore, which I agree with you. And same for me, it would be a change in my practice.

Ray Cross, MD:
Great. I'm thinking about Crohn's disease where we don't use this as much. I think the results probably will be even worse with Crohn's, although maybe you get some later captures with Crohn's than you do in UC, perhaps.

David Hudesman, MD:
Yeah. And it's just to add on about the TDM, we've seen this with Vedolizumab and some other studies that just pushing that dose, or saturating those receptors, there hasn't been as good of a correlation as we've seen with some of the retrospective studies with anti-TNF agents.

Ray Cross, MD:
Yeah, like Ben Click says with the novel biologics, they're pretty much set it and forget it, so optimization with those drugs is a little less clear. So, let's move on to the second paper. It was entitled, Efficacy and Safety of Upadacitinib Induction Therapy in Patients with Moderately to Severely Active Crohn's Who Failed Prior Biologics, Results From a Randomized Phase 3 U-ACHIEVE study. So, take it away, Dave.

David Hudesman, MD:
Sure. So I think this was another key study presented at DDW. We've had, in the past year, a little over the year, two oral small molecules FDA approved for ulcerative colitis, but none for Crohn's, and the earlier data with [inaudible 00:07:25] for Crohn's, it was a negative study. So this is looking at Upadacitinib, the selective JAK1 inhibitor in moderate to severe Crohn's patients. And this was, they randomized, so they looked at about 500 patients, and these were all pretty refractory patients, they all had to fail at least one biologic in this study, about 60% failed two biologics, and about a third of the patients were on steroids going in.

David Hudesman, MD:
So a sicker Crohn's study, and pretty much they were looking at co-primary endpoints at week 12, and this is Upadacitinib, 45 milligrams once a day. Of clinical remission, they looked at both CDAI and PROs, or Patient Reported Outcomes, of abdominal pain and stool frequency, as well as an endoscopic response, so a drop in your endoscopic score by about 50%.

David Hudesman, MD:
And similarly to what we saw with ulcerative colitis, which were pretty impressive numbers, the study with Crohn's also was impressive as well. So the Delta, the difference between drug and placebo, for clinical remission, was about 20%. So depending on which indices you would use, about close to 40% of patients were in clinical remission at week 12, versus about 20% in placebo. And if you look at endoscopic response, that also was pretty impressive where just under 35% of patients at week 12 had an endoscopic response, and less than 4% of placebo patients had an endoscopic response at week 12. And again, these are refractory patients. They also looked at some secondary endpoints, just a couple to mention, steroid free remission at week 12 was also significantly better with Upadacitinib, as well as clinical response at week two.

David Hudesman, MD:
So I think something we're getting, we've seen with a lot of our JAK inhibitors and ulcerative colitis is that rapid onset, but we haven't seen as rapid onset, at least with some of our biologics and Crohn's. And this seems to have a pretty quick onset, at least from this study. So overall, a very positive study, very large treatment effects that we're not used to seeing with Crohn's disease, especially in this refractory population.

David Hudesman, MD:
Just to touch on safety, because I think that's a concern for our JAK inhibitors, are something we're always thinking about. So, in your typical clinical trials, more commonly with Upadacitinib, we're seeing headaches, nasal pharyngitis, URI. Specifically, serious infections where higher, so these are infections that would require antibiotics or hospitalization. They were higher in the Upadacitinib group, about 3% versus about 2% in placebo. There were higher rates of Zoster, but this is something we could deal with and vaccinate for Shingrix. No other adverse events of concern.

David Hudesman, MD:
But again, the infections are things that are popping up and we should be thinking about this. And I think, just to sort of sum this abstract up is, hopefully, if we look at the maintenance data that's positive as well, and we're seeing some early indication of that, this is another option for our Crohn's disease patients. I think this will be a good option for our moderate to severe patients that have failed in anti-TMF and have failed other biologics.

Ray Cross, MD:
So yeah, this was really, I thought, really impressive. And I know there is in Kisumab Crohn's data is pretty impressive as well, particularly for the treatment exposed. But I don't think even that study showed this degree of deltas in a treatment in refractory populations. I think we have a lot of therapies, but unfortunately none of them really work better than what we have, except perhaps this drug, and maybe Risankisumab seem to perhaps work better than what we have. So assuming this is approved, Dave, how are you going to use this in clinical practice? So we can't use it first line, so are you going to use this after a first biologic failure, or second biologic failure, or haven't thought that far ahead yet?

David Hudesman, MD:
Yeah. I think I'll probably end up doing something similar to ulcerative colitis, and I think this is where it gets a little more difficult is really risk stratifying your patient. So I think, this is going to have to follow an anti-TNF, but if this is a more moderate patient without complicating factors, is not anemic, doesn't have diffuse small bowel disease, I think this is where I'm still going to want to use, let's say Ustekinumab or possibly Risankinumab, if and when it's FDA approved, and anti-TNF. But in those patients with more severe disease, more refractory disease, those patients that I'm concerned about, I think this is something I'd probably move towards second line after an anti-TNF, and not use some of those other medications such as Vedolizumab and Ustekinumab. So I think it's just risk stratifying the patients, but I think my concern with the risks with these JAK inhibitors and what happened with Tofacitinib is these get pushed to third, fourth, fifth line. I don't think that's the right place for them.

Ray Cross, MD:
Yeah, and maybe move it up even earlier on those that have prominent joint extra intestinal manifestations where this drug probably works really well. So I want to bring Millie in, but before I do, just a reminder that IBD Drive Time is sponsored by the Gastroenterology Learning Network and Advances in IBD. And speaking of the latter, there's an in-person regional coming up, July 23rd in Chicago, so plenty of time to register and attend that excellent regional course. So Millie, I'm going to hand it off to you.

Millie Long, MD:
Great. Thanks so much, Ray. I always enjoy hearing about some of these newest trial data, and I'm excited about the new tools that we have in our toolbox. And David, thanks so much for explaining some of that UPA data to us. But I want to shift gears because, also at DDW, there are a number of different abstracts that actually focused on other aspects of IBD management, and even development of inflammatory bowel disease. So let me start with you describing to us a little bit about another randomized control trial, but instead of being on a therapeutic agent, this is actually on cognitive behavioral therapy and mindfulness intervention in patients with Crohn's. Would you mind telling us about this abstract?

David Hudesman, MD:
Yeah, sure, and I think this is a really important topic, and we really focus on, we've just been talking about mucosal healing, clinical remission, but improving the quality of life of our patient is just as important. And I think what's been nice is we've been seeing more awareness of these issues such as fatigue, pain, work productivity, and so forth. And we're starting to see in these clinical trials now, they're measuring this in questionnaires as sort of exploratory endpoints. Ray and I have done some work with some registry studies looking at patients with Crohn's disease and ulcerative colitis with work productivity and fatigue. And yes, when the disease is more severe, you have worse work productivity, but even in patients in remission or with mild disease, there is significant impact on work productivity and fatigue.

David Hudesman, MD:
So what this study was doing is a randomized control trial, looking at mild to moderate Crohn's patients, so not really sick patients, but mild to moderate based on the Harvey Bradshaw index. And as you said, Millie, they were using cognitive behavioral and mindfulness intervention. And it was about 120 patients, randomized to two groups, the group that got this therapy, it was pretty intensive therapy, it was seven 60 minute sessions over three months, versus your standard of care.

David Hudesman, MD:
And what you saw is in these mild to moderate patients, with this intervention, there was improvement in fatigue, improvement of their work productivity, and significant improvement in their pain. I think their pain, especially, to see a benefit of this, is so important, because as I said with this increased awareness, it's great, but a lot of times we're like, "Great, it's there. We know it's there, but what do we do about it?" Right? And how we can intervene. And I think across the board, showing this improvement, it was pretty impressive, even though it was a smaller study. And I think the next step to this bus is how do we scale this, right? How can we get this out to all of our patients? And I know there's a variety of different ways people are trying to think about this, but I think that would be the next step.

Millie Long, MD:
Right, and you would hope that with all we've learned about virtual care during this COVID pandemic that there may be ability to outsource this more broadly outside of tertiary care centers and have even a virtual intervention. It would be such a huge importance for our patients. So stay tuned, right? As we try to get access to cognitive behavioral therapy for more of our patients.

David Hudesman, MD:
There is some data looking at virtual hypnosis, virtual behavioral therapy. And I know, I think there's going to be other platforms that maybe people could do online and train themselves, so hopefully we'll see similar benefit with them.

Millie Long, MD:
I certainly hope so. Even in our online cohort, called IBD Partners, a few years ago, we actually did a virtual mindfulness intervention. And actually, even just with that, heavy mindfulness intervention as compared to just simple reminders, people did have improvement in outcomes as well. So I think it's something that we all need to embrace, this other side of treating the full patient.

Millie Long, MD:
So the other one that, actually, I mentioned to you that I missed at DDW, so I really want to hear the results of, was something called the GEM study that was presented that looked at environmental factors associated with a risk of Crohn's disease development. So what can you teach us about this abstract?

David Hudesman, MD:
Yeah, so this is interesting, probably one of the more common questions, if not the most common question, we get at an initial visit or a new diagnosis, "Why did I get this?" Right? And we give our typical general answer, but we don't have any great data to explain why somebody has this. So the GEM study, pretty much what they were doing was they were following first degree relatives of patients with Crohn's disease, so siblings or parents, and looking at genetic, environmental, and microbiome factors that possibly could have been triggers. And really the only data we have are really these cross sectional studies, which are associations, how long they've had this, these risk exposures or these factors, when do they have them is very unclear. So they would enroll these patients and then follow these patients, of a family member of somebody with Crohn's, they would take a detailed history of environmental risk factors. The ones they were looking at were dietary factors, whether they're drinking water, their family size, do they have a dog? And then they ask these questions every six months for up to five years.

David Hudesman, MD:
And they ended up putting together this cohort of just under 4,300 relatives, first degree relatives, of somebody with Crohn's disease. And just about 2% of this group, so about 89 patients, developed Crohn's disease within the next five years. And then they looked at some of these risk factors and these environmental factors, and the two factors that came up is, first, having a large family size, so more than three, early in life within the first year, protected you from getting Crohn's. And the other protective factor they found, which was interesting, was having a pet, so having a dog, within year two to four was another protective factor. We just did get a dog, I kid, I think was just outside that window, but it was another protective factor.

David Hudesman, MD:
And then they went in, interestingly, they were trying to see if they could find, mechanistically, why that might be. Any biomarkers, they looked at 16S sequencing of the stool. They looked at fecal calprotectin and they also did a surrogate marker looking at intestinal permeability. And actually, in first degree relatives that had a dog, that were protected from Crohn's, they had better intestinal permeability, or decreased intestinal permeability based on this factor, and this is just a urine study.

David Hudesman, MD:
So, pretty interesting stuff, I think this is the most rigorous study looking at these environmental factors, and I'm really looking forward to learning more about the environmental, how this plays with the microbiome, as well as the genetic analysis.

Millie Long, MD:
It's so interesting because I'm sure our patients read about this hygiene hypothesis, it's been floated out there for decades and decades and decades, that we can't put people in a bubble, that we need to expose them to bacteria, microbacteria, all of these factors, to help make sure they have a robust immune system. And so this dog thing may play in a little bit to that as we try to learn more in terms of exposure. And really interesting work where you actually have pre-samples as well as post, after development, and all of the environmental data, so I think this will be helpful. Obviously, what we're all looking for, ultimately, is a cure to Crohn's disease, but we really need to understand what are the risk factors, what is the ideology, before we can totally get there, so studies like this become really important.

Ray Cross, MD:
Is it the physical contact with the dog? Or is it the mind, body, and stress reduction associated with a dog? It's probably not exercise, but what do you think? I just find it so interesting.

Millie Long, MD:
Well, you do have to walk the dog. So, it could be a combination of all of these things, all of it, whether it's exercise, whether it's mental health. I have a large lab, and I love coming home and having the dog be so happy to see me, and all of this, it's nice, but I also have to walk him, and could that play a role? And I'm sure there's lots more bacteria in my house than someone who does not have a dog, but I don't think we can tell, but it's just a really interesting phenomenon.

David Hudesman, MD:
Yeah, I agree. I think it's a combination, but it was interesting, especially with the dog, depending on, no matter what age it was in, the intestinal permeability was improved at no matter what age. So I think part of that is, at different ages, kids will probably be walking the dogs more or less, but I think the combination. But I like Millie's concept about the hygiene hypothesis and just the dog being all over you and licking you and so forth.

Ray Cross, MD:
So your grandmother's always right, so rub some dirt on it, so that's the-

Millie Long, MD:
Yeah, exactly. Well, this was a great overview, Dave, but before we let you leave, we have a tradition here on IBD Drive Time where we ask you to let us know something about yourself that none of your colleagues or patients may know, that will help us to understand something unique about you.

David Hudesman, MD:
I guess the way I made some money in high school before going to college was, I was actually a bar mitzvah dancer. So nothing scientific at all, but a bar mitzvah dancer, it actually did pay pretty well. And so, yeah, I still try to do it on the side now and again for a little extra money, so.

Ray Cross, MD:
Is that better than Ben Click being a skateboarder with green hair, Millie? It might be.

Millie Long, MD:
It might be, you might win on that one, David. I think so.

David Hudesman, MD:
Oh, that's pretty close with the green hair, I didn't have that, but I did have a sequenced vest.

Ray Cross, MD:
All right, you win.

Millie Long, MD:
You win. You win, although photos will be necessary at the next DDW. So with that, we'll conclude this IBD Drive Time, and we will look forward to you hearing us for our next podcast. So thanks again, Dave.

David Hudesman, MD:
Thanks so much.