IBD Drive Time: Gary Lichtenstein, MD, on the Best of ECCO

IBD Drive Time continues its coverage of the European Crohn's & Colitis Organization meeting as Dr Gary Lichtenstein shares his choices on the best abstracts with host Dr Raymond Cross.

Raymond Cross, MD, is a professor of medicine and director of the IBD Program at the University of Maryland School of Medicine in Baltimore. Gary Lichtenstein, MD, is a professor of medicine and director of the Inflammatory Bowel Disease Center at the Hospital of the University of Pennsylvania in Philadelphia, Pennsylvania.

TRANSCRIPT:

Welcome, everyone, to IBD Drive Time. I'm Raymond Cross from the University of Maryland School of Medicine, and I'm delighted to have a return guest, Gary Lichtenstein from University of Pennsylvania, and he's going to discuss some of the best abstracts from ECCO.

Gary, welcome back to IBD Drive Time.

Dr Lichtenstein: Thank you, Ray. I look forward to our discussion. There's some exciting abstracts. and papers that were presented, so I think it's worthwhile to discuss these and explain them.

Dr Cross: Gary and I were fortunate enough to attend ECCO, which for the listeners that have not been there at this phenomenal conference, we got to see Stockholm, which is quite nice, and Gary looked at novel molecules and diagnostics, and I think the first abstract Gary is going to talk about is an intestinal ultrasound study, which is very hot in both Europe and the US now. So Gary, take it away, tell us about that study.

Dr Lichtenstein: So the study, Ray, is a digital oral poster 07, if people want to look it up. It's intestinal ultrasound is a predictor of biologic treatment persistent in inflammatory bowel disease. And it's an interesting study.

The background is biomarker -based monitoring is limited in predicting the risk of biologic treatment failure in patients with inflammatory bowel disease. So this was a 1-year prospective observational cohort study on patients on biologics compared to an historic control where intestinal ultrasound was performed to predict treatment persistence to biologics, which is clearly very relevant. It would be nice to know which factors predict who's going to stay on a medicine once we start.

So it's not a large study, but it's a small study—77 patients had intestinal ultrasound performed. And more patients with the intestinal ultrasound performed who had endoscopic remission were persistent. So 87% versus 41% had no endoscopic remission. Better treatment persistence was observed in patients who had treatment and had the use of the ultrasound and had a total remission versus those who did not.

Fecal calprotectin was looked at directly as well as clinical response. And the cumulative survival showed longer treatment persistence for those that had overall the transmural remission, if you would, which is looking at the entire bowel to see that yield combined transmural remission and fecal calprotectin normalization and endoscopic remission. So this was a study that looked at patients that had been on different treatments—infliximab, adalimumab, golimumab, vedolizumab, and ustekinumab— sort of the standard therapy we might use in treating patients. And this alone, the intestinal ultrasound alone or combined with fecal calprotectin was comparable to endoscopy to identify patients with high biologic treatment persistence.

So one can envision doing this, and not necessarily colonoscopy or cross-sectional imaging. So being a noninvasive, patient-friendly, cost-effective modality, intestinal ultrasound has the potential to improve current clinical disease programs aiming to increase treatment persistence.

We'll talk about the importance of this, but this was very exciting because it is something that's used a lot in the EU and other countries, but little in the United States, it's gaining momentum now in the US.

Dr Cross: Yes. I think the intestinal ultrasound is super interesting, and as a clinician, I'm trying to figure out how this would be utilized. I still think we need a prospective study where we compare what we have now, which would be biomarkers and endoscopy, with ultrasound, with or without endoscopy, to see if the outcomes are different. And I would imagine—hopefully that's forthcoming, although maybe this will just get to the bedside without really validation.

But I think some of the challenges here are the training requirements to do this. It's approximately 4 weeks, so you have to take a faculty member or an advanced practice provider and take them out of clinic where they're generating revenue and train them. The equipment and the probe, I believe, is about $200,000. I think the reimbursement is being figured out, but how often you can bill payers for this is not clear to me. So if you look in your crystal ball, Gary, how do you think we're going be using this in 5 to 10 years? And what needs to happen to the technology to make it more available on a broader scale?

Dr Lichtenstein: I think it's like doing a calprotectin, if you will. Years ago, we never did that. Now it's part of standard procedure, but the reality is you can get the result immediately. And that's the beauty of this. The schedule in MR, you know, takes time and you know, it's semi-invasive. This is no contrast, no preparation and directly looks at the bowel. The issue is going to be to compare it to MRI enterography and see what's missed. Different sections of the bowel may be not as well visualized as others. You know, in an obese patient, are they going to be easy to see everything on? Is it going to be like the pancreas visualization? So I think those are areas that are being sorted out.

But in the crystal ball, Ray, I'd say a person started on a biologic, the biologic is initiated, you get a baseline and then you see them back and say 2 to 3 months in the office to see how they're doing. And you can really get a good idea if they're responding or not.

You need to up the dose, you need to get other parameters to look at, but your question is critical. How does this differ from our standard current practice and does it add any benefit? I foresee this as a more rapid idea as to what's going on and may save time.

It depends on your institution. If your institution you're at say in private practice or you know community practice or an academic center, if you can get an MRI scan within a day or 2 then I don't see that it saves much time, but it is a cost-saver as well, because an MRI may be $10,000 and intestinal sounds much less.

Dr Cross: Yeah I completely agree with you. I don't think this is going replace endoscopy. I think it's going be used postinduction to get a sense of whether you should adjust at that point in time. And we don't really do early, early endoscopy. And I think in the future, we need something, you know, a small probe that we could attach to our iPhone or whatever device you're using and put on the patient's abdomen and you get artificial intelligence to spit out a read that would be point of care, real-time with a patient.

I think at that point it would be used much, much more widely in the US, but I think that's probably coming in the future.

Dr Lichtenstein: One area I think Ray that might be of interest that has never been discussed is perhaps you go in the colon you do a colonoscopy, there's a stricture. Can you do an intestinal ultrasound in endoscopy itself to see if it looks malignant beyond that area? And that might be of interest that you could take the probe and just bring it into the endoscopy unit and say, hey, this is okay, or can we tell the length of the stricture itself and say this is worth doing a balloon dilation at this time?

Dr Cross: Absolutely, I think that's a great point. Before we get to the second abstract, I just want to remind the listeners that IBD Drive Iime is sponsored by the AIBD Network and we are now on Apple Podcasts and Spotify so you can subscribe to IBD Drive Time and that way you won't have to search for our episodes.

So Gary, I think the next abstract was going to top about a novel therapy guselkumab. So, why don't you tell us a little bit about that?

Dr Lichtenstein: Thank you, Ray. So what I'd like to talk about now is the QUASAR phase 3 study. This is a study that evaluated health-related quality of life and fatigue with the guselkumab induction in moderately to severely active ulcerative colitis. And just as a background, the guselkumab is an investigational agent. It's an P19 inhibitor, an IL-23 selective antagonist.

And this is a study that looked at patients that had active disease and it looked to see what effect this would have. This is a substudy of the large study, the registration studies. And they looked at fatigue and health-related quality of life.

And the importance of this is fatigue is a very common symptom that we see in patients, both with ulcerative colitis and Crohn’s. And many times we say, is this because of the disease, or do they have some comorbid condition or medication or disturbance, something such as a sleep disturbance that may be causing this? But regardless of such, the study design was this is a phase 3 double-blind randomized controlled trial in patients with moderately to severely active ulcerative colitis. There was 3-to-2 randomization to get the guselkumab 100 milligrams intravenously or 200 milligrams intravenously every 4 weeks, or placebo.

They were followed up to week 12 and they were assessed with regards to quality of life. The medication was given at 0, 4, and 8 weeks. So it was a large number of patients that were randomized—701 patients were randomized and treated. At week 12, the patients who were receiving guselkumab had higher health-related quality of life measures based upon standard measurements. The PROMIS fatigue scale was used in standard health -related quality of life and fatigue measures.

And what happened was the study looked at the secondary end point and found that individuals that had medical therapy had less fatigue. The other thing is the quality of life was better. But one would ask it's nice to have less fatigue when you're looking at a scale, but how many people had no fatigue? How many people had disease-related improvement such that they were in remission and still had fatigue? Is this a way to say it's not due to the disease? There are many questions that come up. I thought this is very clinically relevant because it's a difficult scenario when a patient comes in and says, "I feel great for my colitis, but I'm just tired. I can't function. What should I do, Dr. Litz?" And I'm sure you've seen similar patients.

Dr Cross: So what do you do, Gary? So that's probably, we see that a couple times a day in a session. So how do you address that with your patient? Well, I first ask them, are they tired when they go to sleep and are they tired when they wake up? And if so, it could be a sleep disturbance. It could be restless leg syndrome from iron deficiency anemia. It could be depression.

These are the things directly. If someone says I get tired as the day goes on, then you say, are they anemic? Could they have B12 deficiency? Are they on a medication? Sometimes, for example, a PPI can get people fatigued, or other medications.

And of course, we ask, do you have active symptoms? Is a disease active when we look at biomarkers, a calprotectin, the CRP, things of that nature, to give us a clue as to is the disease active directly? Sometimes it's just intravascular volume depletion and people aren't drinking enough fluids and they're fatigued or they're exercising too much and they're just tired. Or, you know, may be other, quote, idiopathic reasons that we're not aware of. But I think to try to parse it out in that scenario is often the goal.

You always want to give someone an answer before they leave the office or at least a method to approach this.

Dr Cross: Yeah, I agree. I approach it very similarly to you and I find in clinical practice that when you get to the point where you start talking about sleep disorders and depression, patients become somewhat unhappy because they want you to find something simple and easy to fix. And even sometimes those things don't really pan out. And often, one of the things that patients need to do is, you know, you need to force them to exercise. And there can be some cognitive behavioral mindfulness type things that you can do with psychotherapy to try to help, but this can be a real problem.

For the listeners that are familiar with the PROMIS measures, they're pretty interesting and widely available for clinical research. So these were validated through the NIH and are available free of charge. And the nice thing about these scales is they're normalized for healthy controls in the US and they typically set normal as 50. Sometimes if the numbers are higher, that means more of a symptom like anxiety, depression. Sometimes if the numbers are lower, like quality of life, it means your quality of life is decreased. But the bottom line is I agree with Gary that we want to look at percent normalization, percent improvement. But also you can look at those PROMIS scales and when the scales go down to around the 50 range, you basically normalize that to that of a healthy control.

So they're really cool PROs to use and we're seeing them use more and more in clinical trials. So Gary, anything else about this abstract before we move on to the next one?

Dr Lichtenstein: I should probably mention which one it is. Because it's 2 abstracts combined, Digital Oral Presentation 49 and 52 and the measures that they used was the PROMIS 29 at week 12 for the overall health-related quality of life and fatigue was the PROMIS SF7A which is a standard parameter to look at fatigue. These are used in other disease states and they're validated so they're very helpful to truly know.

The other thing is there's often depression that's unrecognized and every patient coming to see us fills out a depression questionnaire. And we pick up depression as one of the more common reasons that people have fatigue. So if it's found, key is to act upon it or at least to guide them to the right people who can assist them with such. So it's good screening.

Dr Cross: Agreed. Before Gary's last abstract I just want to remind the listeners that we are in regional AIBD season and our next regional AIBD will be June 21st to June 22nd in Houston, Texas. So I hope to see all many of you there.

Gary, the last abstract you're going to talk about is a novel JAK inhibitors or TYK2 inhibitors that were looked at in Crohn's was a very interesting study design. So why don't you tell the listeners about that abstract?

Dr Lichtenstein: Gladly. Very interesting abstract, and it's oral presentation 9, the pizzicato study. So as a background rate, oral ritlecitinib, which is one of the agents studied, and brepositinib was the other agents studied, were assessed in a 64-week phase 2A randomized study. Just as a background, ritlecitinib is a JAK3/TEC family kinase inhibitor, and brepositinib is a TYK-2/JAK 1 selective inhibitor. So, they're unique in their medicine. which makes it exciting, because we always like to see new agents brought to fruition.

And what they did is an induction double-blind, randomized induction-maintenance study, and it's a unique design, it's an umbrella study, and I'll talk more about that because this is something that is currently recommended by the FDA to do. And it was moderate to severely active Crohn’s in patients that had an inadequate response, a loss of response, or intolerance to steroids, immune suppressants, or biologics. And this is a 12 -week induction study that we looked at.

So let me elaborate on an umbrella study versus a basket study. The umbrella study is a type of clinical trial that tests new drugs or other substances that work in patients who have had the same type of cancer, but different gene mutations or biomarkers. So an umbrella trial is patients get treated based on a specific mutation or biomarker found, say in a cancer, might be one to think of. Whereas the difference between an umbrella and a basket study, a basket study is a targeted therapy evaluated in multiple diseases that have common molecular alterations. So the umbrella studies on the other hand evaluate multiple targeted therapies for a single disease that's stratified into subgroups based upon molecular alteration.

So the advantages of the umbrella study, and this is why the FDA has asked that large companies and others do this, is umbrella and basket studies give advantages over traditional clinical trial design because there's increased efficiency, reduced costs, faster drug development timelines, and the potential for more precise patient selection.

So that's important because it speeds the time with which an agent can get to the trial and complete the trial.

So back to the medicines at hand. So I'll talk a little bit about ritlecitinib. So this is an agent that's approved, it's on the market for alopecia areata, and it irreversibly binds JAK3 and the tyrosine kinase expression into a paticellular carcinoma kinase family by blocking ATP. It's been shown to inhibit signaling of immune receptors, including B cells and T cells, both dependent on the tech kinase family.

Brepocitinib on the other hand, selectively binds and inhibits the activation of TYK2 and JAK1, so it disrupts TYK2 and JAK1-dependent cytokine signaling, and it can reduce inflammatory responses and prevent inflammation damage caused by certain immunologic diseases. And I had recently checked at the time of the presentation—it's been evaluated in 14 completed phase 1 and phase 2 studies. So we've got a lot of data from the past, 5 placebo-controlled phase 2 studies, psoriatic arthritis, plaque psoriasis, ulcerative colitis, alopecia areata, hidradenitis suppurativa, and also a recently large study, a phase 3 study in dermatomyositis. I'm unaware of other studies in dermatomyositis.

All of the placebo-controlled studies phase 2 studies had significant and clinically meaningful results. So it was promising to say it may work in IBD. There's over a thousand exposed subjects in a database that they've published data on, and it's similar to the JAK inhibitors, the safety profile.

There's another agent, ropsacitinib that Pfizer had. It's a selective TYK2 inhibitor they gave to another company, Priovant. So we may hear more about that directly, but with regards to the study, there were adult patients with endoscopically active Crohn's by standard criteria. They were randomized to 200 milligrams once a day ritlecitinib for 8 weeks, then 50 milligrams for 4 weeks, and then placebo in a 2-to-1 ratio or brepocitinib 60 milligrams a day for 12 weeks in matching placebo and 2-to-1 ratio. So it's more in the active therapy. They continued on the agents, the ritlecitinib 50 or the brepocitinib 30 for 52 weeks, and then they combined the placebo arms for analysis. The overall benefits were positive. The SES-CD 50 went down, clinical disease activity, remission, and response, 100 points also improved in patients, and remission. Safety was also evaluated. So the majority of patients benefited with treatment, and as a result of that, this suggests that this these are potentially good agents to consider. And this is, remember, a phase 2 study. So it's not a proof of — it's more than a proof of concept because we have some data from before. But this will likely lead to a phase 3 study, which I believe is now undergoing assessment. And so this is exciting because multiple different mechanisms are being looked at as a consequence of the studies.

And I would say that ritlecitinib and brepocitinib offer novel mechanisms of action and clinical benefit during induction. And remember, these are only induction studies. So we have to look more at maintenance long-term. I'm sure that'll be forthcoming in patients with moderate to severe Crohn's when you compare it to placebo.

Dr Cross: Yeah, this I agree this is exciting and I guess one of the things, we're both busy clinicians, is it's so nice to have more therapies in different classes of therapies than what we had in 1998 which is basically steroids, 5-ASA, azathioprine, methotrexate, and infliximab. So it's nice to have more agents and we've certainly learned how to use them more effectively.

But as these newer drugs come to market, I guess what are we going to or what is the FDA… what are we going to be looking for as clinicians? So something with greater efficacy than what's available, better safety, it seems like most of our therapies are safer. How is this going to compare with another similar drug in class like upadacitinib? I don't know the answer to that, and I'll be interested to see your thoughts.

It seems like we don't need more “me too” drugs, but we need things that are better than what we have or safer or both. And maybe you were mentioning molecular biomarkers. I certainly think we need precision medicine with these therapies to help us find the right drug for the right patient at the right time. So what are your thoughts on that, Gary?

Dr Lichtenstein: Totally agree, Ray. I think the key is going to be when you have 8 or 9 or 10 different agents, which one's right? So we look. If the patient has a low serum albumin, for example, we're more prone to give a small molecule or high dose of a biologic; if they have extraintestinal manifestations, we want to use the right medicine that has extraintestinal manifestation coverage. If they're elderly, we don't want to use certain medications if they have prior malignancy, we might go more with something such as vedolizumab or the IL-23  -12/23 group, more so than an anti -TNF. If they are going to become pregnant, you know, a biologic is the way to go; the small molecules we often avoid in that scenario, because we have unknown safety signals associated with them and theoretically, there may be issues.

So I think the old, you know, statement that the juice has to be worth the squeeze. You know, as well, you said that we look at agents that are effective and we can look at network meta-analyses and try to stack these up one against each other and see which is the most effective.

Now that doesn't mean every patient is going to respond. I totally agree. We need to find ways to predict who will and won't respond. So I think it's a long-winded answer for something. We're learning a lot, but you have to pick the right patient for the medicine.

Dr Cross: Yeah, and the thing I was thinking about while you were talking, Gary, is that we only have one JAK inhibitor approved for Crohn's and that’s upadacitinib. And typically we think with the small molecules, if you get them into a deep remission, that it should be long term, you shouldn't have as great of loss of response because there's not immunogenicity, but you do still see it. And I think we're going to learn in clinical practice can you cycle to another JAK in that situation and if you had a drug like one of these could you cycle to that to recapture response. I don't know the answer to that yet. I have had previous tofa exposures that I gave upadacitinib and more than 50% have done well with that conversion over to upadacitinib but I think that's going from what we think is maybe a little less effective JAK inhibitor to a more effective one. So it'll be interesting to see how these are positioned.

So time for the fun question, and this is hard for you because you've already answered it once. Tell the listeners something about yourself that they may not know, something maybe that I don't even know.

Dr Lichtenstein: You know everything! Well I like fishing and went fishing with a colleague recently; we caught 35 fish between us.

Dr Cross: Wow! So we have to get you and Ed Barnes and Frank Farraye together to fish because you're now our third avid fisherman at least on IBD Drive Time.

 Dr Lichtenstein: I used to fly fish, I used to go on the water with hip boots when I was younger and go out deep sea fishing for a hundred miles out in South Jersey here. But there is something called work which gets in my way. It gives us less free time than we'd like to have, but that's okay. It's fun to get out and do it.

Dr Cross: All right, Gary, this has been wonderful. Thanks for doing this. I hope that you and I get to go to ECCO in 2025 in Berlin. That'll be fun and hope to have you back as a guest on IBD Drive Time.

Dr Lichtenstein: Thank you, Ray. I appreciate the opportunity.