Sara Horst, MD, on Real World Effectiveness and Safety of Ozanimod in IBD

In this episode of IBD Drive Time, Drs Millie Long and Raymond Cross talk to Dr Sara Horst about abstracts from the ECCO ’23 Congress on how best to utilize ozanimod to achieve optimum outcomes in inflammatory bowel disease.

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

Transcript

Hello, this is Millie Long. Welcome to IBD Drive Time. I'm so excited to introduce our topic and guest today. I think it's going to be a highly valuable 20 minutes as we're going to do our first of a 3-part series on the best of ECCO. So we're bringing the best abstracts and science from the ECCO meeting to you all, and it's going to be interpreted today by 2 guests. I have Dr. Sara Horst, who is associate professor of medicine and director of telehealth at Vanderbilt. And then I have my cohost as a guest today, Dr. Ray Cross, who is professor of medicine and director of the IBD Center at University of Maryland. And just as a plug for this podcast, I'd like to announce that finally, we are now available on Apple and Spotify. You can search for us under the Gastroenterology Learning Network.

And so with that, Sara, welcome. We're so pleased to have you as part of IBD Drive Time.

Sara Horst:

Thanks. I'm excited to be here.

Millie Long:

Well, we're excited to learn from you. I didn't get a chance to go to ECCO this year, so A, I'm jealous, but B, this is such a wonderful way for me to learn the best abstracts and science out of ECCO. So the questions I have for you today center around some abstracts dealing with small molecules that are currently approved. And so I'd love to start with our S1P inhibitor, ozanimod, because there was an abstract you selected that helps us to better understand potentially how to utilize this drug.

Sara Horst:

Yeah, I thought this was a really interesting abstract. ECCO was a fantastic meeting, so it was really fun to be there. But in particular, this study was an open-label extension study of ozanimod use in patients who had actually nonresponded at week 10, so we're trying to look at and see what happens to people if we keep them on drug a little bit longer.

So it was about 220 patients were included, and about half of them were bioexperienced. The study did divide the groups into bionaive and bioexperienced when they looked at outcomes. And when they looked at clinical symptom response, about 50% of patients in both groups, so both bionaive and bioexperienced, experienced clinical response with an additional 5 weeks of ozanimod. And then by week 10, so about 20 weeks on drug total, that clinical response rate went up to about 60%. And there was really no difference between bionaive and bioexperienced between the outcomes. And then in those who stayed on longer-term drug, they looked at these longer outcomes, last observed, carried forward data which showed a clinical remission about 20% to 30% rate, and then endoscopic improvement in about 35, 40%. Obviously that goes down when they look at the nonresponder imputation analysis.

So to me, this is really important. This shows that we might be able to capture some people if we keep patients on ozanimod for an additional 5 to 10 weeks, and really probably 5 weeks is the big bang for your buck. And it really didn't matter whether they were bionaive or bioexperienced, so I think this is pretty important.

Millie Long:

Yeah, that's really interesting. Recently, I guess probably last year, and I think it was at UEG, there was some data on upadacitinib, a JAK inhibitor, that also showed something similar. By extending that induction time, they were actually able to capture a significant proportion that then ultimately went on to do well. So it sounds that way with ozanimod, that extra 5 weeks may help us. Obviously, you don't want to have our patients waiting forever for a response, and so was there any glimpse of who those people were that did better with the 5-week extension?

Sara Horst:

Not with the analysis they did. I sort of assumed that maybe patients with bioexperience might do a little less well, and maybe a little bit, but not really. I mean, in the long-term data, there was really no difference between any of their outcomes. So I think that's a really important point. I'm not sure that we can necessarily tell who's going to do better or not, and unfortunately for some people it might be a little bit longer. I think the expectation managing is really important. So you're going to do this, maybe just an additional 5 weeks, we're not going to go further, to help patients understand how long we can really say before failure.

Ray Cross:

So they didn't present this at the meeting, but I think it was presented at UEG, which I attended virtually. I think it was at UEG, but they showed something very interesting. Obviously very few, if any, of these patients are going to have a rectal bleeding score of zero at baseline when they're enrolled in the study. But at week 10 when they were assessing response, about 20% of the patients that went into the open label had a rectal bleeding score of zero. So I wonder, as clinicians, if that significant reduction in rectal bleeding may be a sign that this is going to be a delayed responder. Now, they didn't break the data down like that, but I think it would be an interesting analysis as to whether that may be a signal that an extra 5 weeks is worth it.

Millie Long:

Yeah, that's interesting. Well those are certainly the people who you might hang on longer because if someone had really had no response in rectal bleeding, I'm probably not going to extend them by 5 weeks, but then at least you feel you've made some progress in something that is clearly inflammatory, the bleeding issue. So it's interesting. Yeah, it'll be nice if they break out the characteristics for us, but I think I hadn't thought about this in this way before. I certainly had thought about it with the JAKs because I'd seen the data about the extended induction, but I think this is just another way to try to make sure that, for the right patient, this could give them a good outcome in the end, extending some of the induction.

Sara Horst:

Well, I was just going to say, increasingly, it's not easy to get these medicines approved, so I think that's one of the other things you need to think about when you're going in this treatment process for patients. And it seems like a long time, but you've got a new drug on board. If an extra 5 weeks is going to get you where you need to go, it might be worth it.

Millie Long:

Absolutely. Absolutely. And so let's move on to talk about the JAKs. I think you selected one on upadacitinib and one on tofacitinib to discuss, and the upadacitinib one allowed us to focus on some other things of concerns to our patients, namely fatigue. I know this is sometimes the bane of our patients' existence. They feel somewhat better, but they still have this overwhelming fatigue. What did you learn from this particular abstract?

Sara Horst:

Yeah, so I really liked this abstract. I think, to me, this is the kind of thing that increasingly we're not going to need to be looking at given that we have a lot of options, so I was really excited to see this. So this was looking at secondary outcome of symptom resolution and fatigue resolution in patients with UC on upadacitinib in the induction and maintenance studies. Symptom resolution was no bowel urgency, no abdominal pain, and no other classic symptoms of UC, so this was a pretty hard endpoint.

I think probably one of the most important things of this study that I took away was looking at the baseline characteristics of the 2 groups. In the placebo group, there were about 300 patients, in the treatment group, there were about 650 patients, so there's a ton of UC patients. At baseline, 90% of these patients reported abdominal pain scores greater than zero and bowel urgency symptoms, and so I think the presence of abdominal pain in the vast majority of UC patients is really important. That was actually one of the big takeaways that I had from the study, actually baseline characteristics.

So then they looked at their outcomes. It was resolution of all of those symptoms I just talked about and no fatigue, so this is a really quite rigorous endpoint, and nobody met it at baseline, as you would expect. By week 8, about 25% of the upadacitinib group met that endpoint and only 6% of placebo met it. And by week 52, about 25% of the patients in upadacitinib 15 milligram group met it and then about 36% of the 30 milligram upadacitinib group met that endpoint compared to about 12% of patients in placebo.

So this is real-world outcomes. These are things our patients care about, especially the fatigue. It is important that only 40% of the patients met this really hard endpoint by week 52, so that's something we have to think about as clinicians. And I do think in the future when they're looking at this, I'd like to have a little bit more data on just fatigue and even just improvement in fatigue, so I hope they go into that more detailed because our patients care about that, we care about it, it's really hard to treat, and maybe figure out whose fatigue is going to get better versus not. So those are what I'm hoping to see in the future, but I think this was really important.

Millie Long:

Great. Yeah, no, I mean, I think that it's important for our patients, it's important for us, and I think it goes along with my gist about this class of drugs essentially, which is that they're pretty darn effective. Obviously they work fairly quickly, and it's nice to know that they alleviate a lot of these symptoms. It'll be interesting to see what symptoms persist. I bet there's some people who actually the inflammation may be better, but they may have some symptoms that persist, and so I think it's an interesting group to look at those that didn't meet this endpoint and how much of that was inflammatory versus not.

I mean, at least in my practice, I feel like some of the urgency we see is actually more related to accommodation and scarring from prior inflammation and may or may not actually get all the way better with anti-inflammatory medications. So I think there's a lot we could learn about the flip side too, the people that didn't meet the endpoint.

Sara Horst:

Absolutely. I think it's really ... What happens when somebody still has fatigue and you've got them in endoscopic remission? I think digging into that group is going to be really important to help us as clinicians understand it. But I also think it's important to help patients understand, "Listen, your fatigue could get a lot better by us using a JAK inhibitor," and if we see that differential benefit in one class of drugs over the other, boy, I think that's pretty important for patients.

Millie Long:

So tell us about the ORCHID study, which was tofacitinib versus steroids for inducing remission. This could be a game changer. We want a drug that works quickly and helps us to minimize steroids just given all of the known complications that we see associated with steroid use. What did you learn from this abstract?

Sara Horst:

Yeah, this was a really, really cool exploratory study. So it's a pilot study from India, and it looked at about 80 patients total who had moderate to severe disease. They had a total Mayo score of 6 to 9, so pretty significant with endoscopic disease, and randomized these patients to induction of remission with tofacitinib 10 milligrams twice daily or prednisone with a taper, so one or the other. They had a really firm primary endpoint, which was a total Mayo score of less than or equal to 2 with an endoscopic score of 0 and a fecal cal less than 100 by week 8. And then their secondary endpoints were clinical remission and clinical response. Now, there's no data about prior treatments in either group, so that, I think, is a limitation. I don't really know what these patients were on beforehand, if they'd been bioexperienced or anything like that.

But it was a really positive study for both treatment arms, both prednisone and tofacitinib. Both got better quick, so median time to symptomatic remission was about 10 days. I think the secondary endpoints are really important here. So the clinical remission by week 8 was about 40% in both groups, and clinical response in both groups was 65%. So a lot got better, both got better quickly, really no difference.

The primary endpoint was really rigorous, but about 16% of the tofacitinib group met that and 7% of the prednisone group met, not statistically significant. It's a small study, but there was really no safety signal. One patient in each stopped; tofacitinib, there was a case of tuberculosis, and a patient on prednisone got cystic acne, and there was one zoster case in the tofacitinib group, but it's a little bit of a smaller study. So I think this is great, really important, actually comparing prednisone to a small molecule and really seeing no difference in what we can do for patients as far as clinical response and remission.

Millie Long:

That's great. Ray, do you think that this might change your practice? Do you think you might try to avoid steroid induction when you're starting a JAK, whatever the JAK may be?

Ray Cross:

I was just going to pick on Sara and ask her that. So I think the easy answer here is if you have a patient who is sick enough that you're thinking about prescribing prednisone that would otherwise be a good candidate for a JAK, by giving a JAK, you don't need to give a prednisone bridge. So I think that's a no-brainer for this, but then I guess the question for us is in patients that may not be a great long-term candidate for a JAK, perhaps a 26-year-old woman who's thinking about conceiving in the next few years, can we post them with a JAK, bridge them to a novel biologic or another small molecule like an S1P and avoid prednisone? I think that's really intriguing. I haven't done that yet, but I could see that that would be a reasonable approach, particularly for someone who's a little less treatment-exposed.

Sara Horst:

Yeah, I agree.

Millie Long:

No, I think we need to learn more, but I think we're certainly understanding that this onset of action with the JAK class is quite good, and hopefully it'll help to minimize some of the complications that we see with steroids if we can minimize ... At the very least, we should be able to minimize some of the steroid use.

Sara Horst:

Yeah, I think this gives you some of the reasoning to not always pull out prednisone. This gives us a little bit of support for the-

Millie Long:

We will always need it, yes-

Sara Horst:

We need prednisone.

Millie Long:

... but perhaps we may be able to avoid some of it. So with that, I do want to switch topics here. And as a reminder to our listeners, this podcast is sponsored by the Gastroenterology Learning Network and the Advances in IBD meeting. And just as a reminder, we have an upcoming in-person regional May 19th and 20th in Boston, Massachusetts. So if you're in that area, please join us for a day and a half of outstanding IBD learning.

So as we shift gears, Ray's going to fill us in on some additional abstracts from ECCO that are centered around the theme of Crohn's disease and individuals with a prior surgery. So Ray, talk to us a little bit about the first abstract you selected, which had to do with long-term outcomes of surgery versus anti-TNF therapy.

Ray Cross:

Yeah, there was a lot of interest in surgery and really I would say putting surgery in a positive light as far as a treatment approach for Crohn's disease. The first one I'm going to go over was an oral presentation, OP11, and it was a population-based study using the Danish nationwide cohort and had looked at patients with ileal Crohn's from 2003 to 2018.

They had over 16,000 patients, but they were looking at patients that had surgery, so a classic ileocolic resection, or received an anti-TNF within a year of diagnosis, so that was only 4% of the population. They used a composite outcome, which included Crohn's-related hospitalization, systemic steroid exposure, Crohn's-related surgery, and development of a perianal Crohn's diagnosis, and they adjusted for a number of confounding variables.

The bottom line is when you look at the composite outcome, the resection group was about 33% less likely to encounter this composite outcome. It was primarily driven by surgery, but even steroids was reduced by about 30% and Crohn's-related hospitalizations by about 20%. Perianal Crohn's, it didn't make a difference. And importantly, when you followed these patients out over time, only 50% of these patients were on some type of immunosuppressive or biologic treatment 5 years out, suggesting that early surgery for patients with ileal Crohn's can be an effective option that puts people into a long-term remission.

Millie Long:

That's great. I have to admit, I have a few patients like this that got early surgery or frankly were in the PREVENT trial and ended up having been on placebo, and you realize that they've had 5 years with nothing. So gosh, wouldn't it be nice to help us to better understand who are those patients that will do well? That's what we need next, the ability to predict and understand who are those that will have that truly durable remission after earlier resection. I don't think we're there yet. This abstract didn't-

Ray Cross:

We learned this from LIR!C, too, that in a randomized controlled trial fashion, that it can be a useful alternative. Maybe someone who isn't interested in long-term medical therapy, maybe someone who's going to be going to college or is going to be away, work, travel for a period of time where this can buy them time before they start treatment.

Now, Sara and I were shoulder to shoulder listening to many of these abstracts, and there's something inherently biased when you include surgery as an outcome and the anti-TNF group isn't getting surgery right. There's got to be some lead time bias that disadvantages the anti-TNF group. But having said that, even looking at steroids and hospitalizations, there was still a reduction. So I don't think it's just some type of lead time bias. I think there is something real there, and it's probably because they're stricturing disease in the anti-TNF group and you can't overcome that with therapy would be my guess.

Sara Horst:

Yeah, I agree, Ray. I think that I was going to mention that idea of bias, but they do a good job. I think that's another important point of this. The people who they chose for surgery did really well. I think understanding who we should put on the postoperative biologic or whatever we're going to use, we'll talk about this, but that's to me the key, is to figure out who's going to need it afterwards and who's going to do the best with surgery up front. A lot of people will, so I think that's a good-

Millie Long:

Well, and your next abstract tried to get at this to some extent. Is that right, Ray? They tried to look at some of these predictive factors?

Ray Cross:

Yeah, well the next abstract's a little different because it's not looking at just newly diagnosed patients. The DOP77 looked at nearly 600 French patients who had a resection between 2013 and 2015, so a little bit more modern timeframe. But patients had to have 3 years of follow-up or more to be included, so that got to sample size down to just under 300. Their outcome was durable remission, which they defined as absence of a Rutgeerts endoscopic score of I2 or greater and/or absence of medical treatment initiation or intensification.

This paints a much less rosy picture. Only 20% of these patients met the criteria with up to 85 months of follow-up. Doing the math, that's about 7 years. So very few patients met that criteria when you include the endoscopy. And even more telling, I think, is of that 20%, 10% were on medical therapy, so they were on postoperative prophylaxis and they didn't progress on therapy. So you're now looking at only 1 in 10 patients that's going to have a Rutgeerts score of I0 or 1 and no initiation of treatment after surgery, which is different. I think this is more patients have longer duration of disease, you're getting them later in the disease course, some of these patients this isn't their first surgery, so I think the real truth probably lies somewhere in between for these patients.

Millie Long:

Mm-hmm. Yeah, no, I think that's fair. But hopefully we'll continue. I mean, that'll be the way of the future being able to have some sort of valid predictive markers, and we're just not there yet.

Ray Cross:

We keep saying that. They're not here yet.

Millie Long:

They're not here yet. Someday. But your last study I think was ... Well, not that the rest aren't important, but I think this one's really important because I deal with this really a lot in my clinical practice, which is obviously I have patients who've cycled through various medicines and they end up undergoing surgery, and I may or may not want to go back to a TNF in terms of postoperative prevention of recurrence. And so the REPREVIO trial was actually looking at vedolizumab to prevent postoperative recurrence in Crohn's disease. What did this show?

Ray Cross:

This was cool. This was a prospective randomized controlled trial. It was small, only 80 patients, but they were looking at the ability of vedolizumab to prevent postoperative occurrence compared to placebo. And these patients were higher risk, so they either were active smokers, they had 1 or more prior resections, surgery for perforating complication, or they included prior anti-TNF use as a high risk subset. Vedolizumab or placebo was started within a month. Now, there was no loading; they just went immediately to maintenance, and the primary outcome here was endoscopic recurrence at 6 months, not clinical recurrence. And then they looked at a number of other secondary endpoints, the severity of recurrence and clinical recurrence and so forth.

So there's a couple things to look at here. First of all, there's a fairly high rate of smokers. About a quarter to a third of the population were smokers. And about a third, this was their second, third, or later resection, about a third had surgery for perforating disease, and prior exposure to anti-TNF was about 50% of the population.

Millie Long:

So darn, these are sick patients.

Ray Cross:

Yeah, yeah. Indeed they are. And so if you really look at the high risk recurrences, the ones we really care about, so this is going to be the 2Bs and the 3s, only 23% of the vedolizumab-treated patients achieved that endpoint, that negative outcome, compared to 60% of the placebo. So it's really quite striking, and just over 40% of these patients had an endoscopic score of I0.

They also looked at each grade of recurrence, and there were 3 in the vedolizumab treated group that had a I4, but importantly, 2 of those patients were lost to follow-up and they were presumed to be I4, so it was really only 1 actually got to endoscopy and actually hit that endpoint. So my sense is that probably any biologic therapy and maybe in the future small molecules, if they're started after surgery, would be effective, but I think in absence of the best available data, if you have a clinical trial, this should guide our post-op management, right?

So the best evidence now is with an anti-TNF and an anti-integrin vedolizumab in preventing recurrence. So I think the provocative question maybe for you and Sara is based on this study in a patient who's been exposed to an anti-TNF before surgery, should we be using vedolizumab first line or should we continue an anti-TNF? How are we going to sort through that?

Millie Long:

Yeah, I think for me it would depend on when the TNF was started. If somebody already has complications of bad inflamed stenosis, already has a fistula, whatever it may be, and you start the TNF, try, but they ultimately go to surgery within that 6-month window or what have you, that's a person I would continue on the TNF.

But I think for someone who has truly mechanistically failed, where inflammation progressed and worsened all on the prior TNF, I think in those patients, I think these data are robust, and I think vedolizumab would be a good option, and I think the idea of it's different when it's early, it's different in prevention, I think. Vedolizumab is not my go-to drug for small bowel Crohn's disease in most instances, and so I think these data made me think that this drug probably is good when it's early. It's just a matter of timing of some of that. I don't know. Sara, what are your thoughts on that?

Sara Horst:

Yeah, I think what you said is very reasonable. I also think about the patient as a whole, their extraintestinal manifestations, do they have perianal disease, all of that would probably factor in. I think one important point about this study, and we also saw it was with PREVENT really, was that there was no difference in clinical symptoms in this group. Both of them had 20%. So they were having endoscopic recurrence way early and they weren't experiencing anything different. So to me, it's almost like just start something in this really high risk group, and you've got to do it early. I feel like that's the key in this really high risk patient population. 

Millie Long:

Absolutely.

Sara Horst:

This was 6-month follow up, endoscopic follow up. We can't delay this.

Millie Long:

Well, and actually when Ray presented the inclusion, who was included in this study, it made me kind of take pause thinking, "Gosh, with clinical equipoise, could I really give one of these patients placebo?" Just because they're sick, multiple failed mechanisms. I think we would all be lying if we didn't say that the biggest intervention you could do for this group if they're 30% smokers is get them to quit smoking because that astoundingly increased rates of postoperative recurrence, much more so than any drug can.

Ray Cross:

Millie, another interesting thing, and Sara, please correct me if I'm wrong, but it seems like that we saw an abstract somewhere where they talk about the percentage of patients that start postoperative prophylaxis, and it's way, way higher in the US than it is in Europe. These patients, we would all agree, are super high risk. Someone who's already had a prior surgery or 2 surgeries or more, to me, that's a no-brainer. But the patient who has had disease for 8 years and has a 10-centimeter resection, does that patient need to be on a post-op biologic or can you monitor that patient to look for recurrence?

And as I've gotten older, I'm actually less likely to use treatment, particularly now that we have more therapies available, and just do that 3-month calprotectin and do the scope at 6 months and treatment based on what I see. But I'm not ... Again, it's probably the real truth should be somewhere in between, right? Maybe we should use a little less, they should use a little more. I think that that's fair. These patients though, I think the majority of experts would treat them.

Millie Long:

Yeah, absolutely. Well, wow! I didn't get a chance to go to ECCO, you all did, and now I feel like I have. I've learned some great pearls today. And thank you so much for both of my guests, Dr. Horst and Dr. Cross, for joining us for IBD Drive Time today. Stay tuned. This was segment one, but we're going to learn much more about our Best of ECCO series, including information on novel mechanisms as well as information on diagnostics, so we're looking forward to those next sessions, and thanks again, Sara and Ray.

Ray Cross:

Great. Thanks, Millie.

Sara Horst:

Thank you.