IBD Drive Time: David Rubin, MD, on Ozanimod for Treatment of Ulcerative Colitis

In this episode of IBD Drive Time, cohosts Raymond Cross, MD, and Millie Long, MD, interview Dr David Rubin, from the University of Chicago, on using newly-approved ozanimod in treating ulcerative colitis.

Raymond Cross, MD, is a professor of medicine and director of the IBD Program at the University of Maryland School of Medicine. Millie Long, MD, is an associate professor of medicine and director of the Gastroenterology and Hepatology Fellowship Program at the University of North Carolina at Chapel Hill.

David Rubin, MD, is Joseph B Kirsner Professor of Medicine, chief of the Division of Gastroenterology, Hepatology, and Nutrition, and codirector of the Digestive Diseases Center at The University of Chicago Medicine.

TRANSCRIPT:

Dr. Raymond Cross:  Welcome, everyone, to "IBD Drive Time." I'm Raymond Cross. I'm a professor of medicine at the University of Maryland School of Medicine. My cohost today is Millie Long, who's an associate professor of medicine at the University of Carolina at Chapel Hill. We're delighted today to have David Rubin as our guest.

David is the Joseph B. Kirsner professor of medicine, chief of the Section of Gastroenterology, Hepatology and Nutrition, and codirector of Digestive Diseases Center at the University of Chicago. David is also current chair of the National Scientific Advisory Committee for the Crohn's and Colitis Foundation.

He's a premier clinician and researcher with particular interest in biomarkers, development of complications due to poorly controlled inflammation, and the role of the microbiome in the etiopathogenesis of IBD. He is, in my opinion, a true quadruple threat —clinician, educator, researcher, administrator —and is one of the best IBD speakers in the world. David, welcome to IBD Drive Time.

Dr. David Rubin:  Thanks, Ray, and thanks, Millie, and thanks for that really nice introduction.

Dr. Cross:  I'm going to start off with something that is fairly obvious to our listeners. What are the unmet needs for therapies in patients with ulcerative colitis?

Dr. Rubin:  First of all, we still don't know the cause of ulcerative colitis, or maybe we should say the ulcerative colitides, since we think there are probably many types of chronic inflammatory colitis-type conditions. When it comes to other parts of this that are certainly unmet, we recognize the burden these diseases have on patients who live with them.

We know that, compared to other chronic conditions like rheumatoid arthritis, or asthma, or migraine headaches, people who have ulcerative colitis express that it has a greater impact on their quality of life, their ability to function. And we know why this is. Some of it is obvious. It has a significant impact on people's ability to socialize for fear of having a relapse or if they're living with active disease. We also know, related to that, that many patients do live with active disease either because they haven't been told that they should expect to be in remission or one of the other major unmet needs is that our therapies don't work in many patients. Or even when they do work, they don't last.

We have a number of challenges here. Among the therapies that we currently use and that are regulated and approved by the FDA, we also have seemingly hit a ceiling or a plateau in our ability to succeed in achieving remission. We're trying to figure out how we can optimize that best, but clearly, there's a lot of room for improvement in the way we treat these conditions. There's other unmet needs, but those are the main ones.

I think that our job as providers to patients living with these conditions is to try to make sure they understand what the expectations are, to choose therapies that are effective and safe and well-tolerated, and also to advocate for our patients individually and as a whole to get the therapies they need and to make sure we have the investments in research and other things that will move the field forward.

Dr. Cross:  In addition to just wanting to talk to you in general, we wanted to have you on today to talk about ozanimod, which is going to hopefully fulfill some of the unmet need. Can you explain the mechanism of action of ozanimod to the audience?

Dr. Rubin:  Ozanimod is a first-in-class therapy available in IBD. First-in-class means that it's a new class, a new mechanism, and it's the first drug approved that we can use in our IBD population. It was approved for moderate-to-severe ulcerative colitis last month.

What makes this unique are a number of things beyond its mechanism. First of all, it is what we call a synthetic targeted small molecule. The term small molecule actually means that the molecule is small enough to be absorbed through the lining of the small intestine. That's important. That means it can be delivered orally. Technically, the reason our biological therapies are parental, either intravenous or injection, is because they're large molecules. The molecules are too big to get into the lining of the small bowel to get into our bloodstream to do their jobs. People often confuse that and think that because it's an injection or an infusion, those other therapies are more dangerous. That's not the reason that they're delivered that way, and that's something that I think we spent a lot of time trying to explain to people.

Ozanimod is not a biological therapy. It's a small molecule, and its target is a receptor that is present on activated lymphocytes. That receptor is how the lymphocytes follow their way through a gradient of signaling proteins to get to an area of injury, infection, or inflammation.

If you ever wondered how our body knows where to activate its immune system and how to send cells there to do their job to protect us, one of the ways they do that is by following a gradient of signaling proteins. In other words, proteins that are made when there's been an injury to the part of the body of the tissue —in this case, the gut —that are in higher concentrations at the site of the problem, and they track their way through the lymphatic system, and then lymphocytes become activated, and then literally follow their way along the gradient to get to where they need to go.

There's other parts of this that we already know about in our field in IBD. The integrins are the proteins that are on the white blood cells that help them travel through the blood vessels into the tissue of interest, so we have anti-integrin therapies in IBD. When we work with the S1P-type therapies like ozanimod, we're targeting a different mechanism that inhibits the cell's ability to actually find their way to get to the tissue.

Now, the way I've tried to explain this to people is to say that the sphingosine-1-phosphate signaling molecules are like breadcrumbs, and the lymphocytes are like Hansel and Gretel trying to find their way home. It follows the breadcrumbs to get to where it needs to go. When you use ozanimod and other drugs in the class —these are receptor modulators — they actually bind to the receptors so that receptors can't detect those signaling proteins. Therefore, it's like putting blindfolds on poor Hansel and Gretel, and they can't find their way.

That's the way I've explained this and tried to help people understand what we're doing with these drugs and why they're called receptor modulators and not inhibitors or some other terminology, because they're modulating those transmembrane receptors on those lymphocytes.

Now, it happens to be that there are different signaling proteins in the body — S1P1 through S1P5—and they're expressed somewhat ubiquitously throughout the body depending on the tissue we're talking about. Ozanimod inhibits S1P1 and S1P5, so it's more selective than inhibiting all of them. Therefore, it does have more of an effect on the activated lymphocytes that would like to get out of lymph nodes and work their way to our gut, but it has an effect in other parts of our body too. That's part of what we come to understand about potential side effects or adverse events related to the therapy.

Hopefully, I've explained the mechanism a little bit for you in a new way, and why we think this is of interest, and why new mechanism like this might work.

The second part of this is we've thought maybe from our experience with vedolizumab, for example, that a cellular-based drug would be slower acting than a cytokine-based drug like one of our anticytokine therapies, whether we talk about anti-TNF or even a JAK inhibitor, but actually, the cell turnover in actively inflamed tissue is quite rapid. So when you inhibit cells from getting through the lymphatics to the tissue that's inflamed, it shuts down inflammation very rapidly. That's part of what we've learned about ozanimod, is that within the first 2 weeks, you can see separation between drug and placebo in stool frequency and rectal bleeding ,which truly, in ulcerative colitis is a very important part of making sure people start to feel better with the therapy.

Dr. Cross:  Perfectly said, David. Let's get into some of the data. You started mentioning onset of action. TRUE NORTH was the pivotal study that led to ozanimod being approved, and the study design was fairly straightforward for our classic IBD trials. Do you want to speak a little bit of some of the newer endpoints that were used in this study or outcome measures?

Dr. Rubin:  The TRUE NORTH study was the pivotal phase 3 trial of ozanimod, and it was designed like other UC trials as you said, Ray. One of the things that was set up here was they wanted to recruit patients with moderate to severe UC. We now expect that when we recruit patients into trials like this that we're going to confirm that they truly have active UC, so there was an endoscopic entry criteria.

The first part of TRUE NORTH was an induction trial in which patients were randomized to the drug or placebo, and the primary endpoint was clinical remission at week 10. Similar to other trials that we've performed, those who responded — they didn't have to be in remission but responders —went into the maintenance phase of the trial, and they looked at a 1-year endpoint of clinical remission.

There are a bunch of other ranked secondary endpoints of interest including, of course, remission but also endoscopic response, endoscopic remission, and even histology which of course, we have some interest in and we want to know about.

Obviously, the drug has been approved. It did meet its primary endpoints in both week 10 and week 52, but it met most of its secondary endpoints as well. We're happy about that, but of course, as always, we look to what might have been better if we could do it differently.

For example, the clinical remission rate at the end of 10 weeks was only 18% compared to placebo of 6%. So it's nice to know it works, but gosh, that's a lot of patients who didn't respond to it, who have moderate-to-severe UC. Even more, if you looked at subset analyses, as we've always done, patients who had already been an anti-TNF and weren't doing well or didn't tolerate their anti-TNF before they got into the trial, they actually did not have a benefit over placebo and induction.

If they responded and went into the maintenance phase, the anti-TNF-intolerant, or loss of response patients, did have a benefit over placebo by the end of the year. But there are some limits to understanding that, and we should keep that in mind.

Just like any therapy, we've now seen that works in ulcerative colitis, it did achieve endoscopic remission in a number of these patients and very nicely histologic remission which we've learned is predictive of stable response over time. That part of it is all quite good.

Dr. Cross:  Correct me if I'm wrong, David, but this is the first trial that used histology as an endpoint for UC? Is that correct?

Dr. Rubin:  It's the first trial that looked at histology as a standalone. We've seen with ustekinumab when it was studied in ulcerative colitis that they combine histology with endoscopy to come up with that unique combined endpoint. But here, they specifically looked at histology. Previously, that was considered an exploratory endpoint in some other trials where people have tried to look at it. It is of interest.

Histology is not a target that we treat to achieve, but like the early days of mucosal healing with endoscopy, we've learned that when you get histologic remission, you know it's a good thing, and it predicts that patients are likely to be stable over time. That seems to be the case here. In subset analyses of our other therapies, some of which was presented at DDW this year, we certainly saw that as well.

Dr. Cross:  I was trying to get at, in the older studies, we would use the term mucosal healing, which now is going to really be endoscopic remission, because as we added the histology, when you say mucosal healing, it tends to be more of that composite endpoint. We talked about efficacy a bit. What were the high-level safety results of the induction and maintenance study?

Dr. Rubin:  There are a couple things to know about this. The first thing is that, as with any study in UC, the most common adverse event is worsening colitis. That happens more in the placebo arm than in the drug arm, but it's reported in both arms and of course, we expect that. There were also headaches and nasal pharyngitis, which we see in all of our trials for UC.

But a couple things that are of interest and we should know about include an elevation of a transaminase, so monitoring liver enzymes is of interest and should be looked at here carefully. Also of interest, given the mechanism and maybe predictive of response, although that analysis hasn't been revealed yet, is that the lymphocyte count drops when people get this therapy. And it drops pretty fast, and it's associated with presumably inhibition of lymphocytes from getting into the circulation from those lymph nodes, so it's directly related to how the drug may be acting. That can last even after you stop the therapy for up to 30 days.

You do need to keep an eye on the lymphocyte count. It doesn't make patients neutropenic or even lymphopenic per se, but it does happen, and it's a marker that number one, that the patient's taking the therapy, and I predict it's going to be directly related to response to therapy.

The other things, of course, that we're interested in is where all S1P may be expressed, and that would include understanding how it might affect the heart or cardiac conduction abnormalities. It is known that this class, especially when you have nonselective receptor modulation of all the S1Ps, can induce a bradycardia. It's thought to be dose-related and also thought to be transient. Therefore, with ozanimod and in the trial, there were a couple patients who had a transient asymptomatic bradycardia when they first started therapy.

In order to overcome that, number 1, the therapy is contraindicated in people who have secondary heart block. That's obviously rare in our patient population with ulcerative colitis, but we should always be aware of that. And 2, it's dosed in the first week as a blister pack that titrates the dose up to the target dose of 0.92 mg daily. Therefore, by titrating that dose, it's thought to mitigate that risk. The third, of course, is before you start, if you don't know about your patient's cardiac history, obtaining an EKG or just a rhythm strip when you do your colonoscopy would be helpful to confirm a normal sinus rhythm.

Then the last part of this is that patients with known uveitis, or diabetes, or glaucoma, those are patients in whom this therapy is relatively contraindicated because inhibition, or blockage, or modulation of the S1P mechanism can increase edema in the eyes, and therefore it can cause a problem.

So we need to know our patient's ocular history. It doesn't mean you need to send them to an ophthalmologist. It doesn't even necessarily mean you need to do your own exam in the office, but you certainly should know about their history and consider whether you want to evaluate further before you start the therapy.

Those were some of the things that we need to keep in mind. They were rare, thankfully, in the clinical trials for ulcerative colitis and certainly something we'll learn more about as we roll this out into the real world.

Dr. Millie Long:  Hello again. This is Millie Long, your cohost. I'm at University of North Carolina, and I am excited to ask a few more questions to Dr. Rubin, but I wanted to take a brief pause and just remind everyone that this podcast is brought to you by the Advances in IBD meeting and the Gastroenterology Learning Network.

We're also excited that there will be upcoming Advances in IBD Regionals. The next one coming up in August is in Chicago, although it's virtual this year. Please tune in for those virtual meetings because you'll get to hear people like Dr. Rubin and other great thought leaders in IBD.

I actually learned a great deal in that first segment about the mechanism of ozanimod. I'm going to fess up to everyone that I have not used this drug yet, and I know Dr. Rubin has. So I'm really interested to learn a little bit more about how he envisions using this in his practice and a little bit more on the safety as well.

One of the things, David, that in my practice, I use a lot of antidepressants. Depression is common in patients with inflammatory bowel disease, and I think it's very important to treat the whole patient. Are their concerns about interactions with other medications like antidepressants with this drug? What are you telling your patients?

Dr. Rubin:  First of all, I want to encourage everyone to join us August 7th.

Dr. Long:  [laughs] Yes.

Dr. Rubin:  This is the AIBD Regional Meeting. It'll be great. The second thing is that we also screen patients for mental health disorders.

As you know, Millie, because we were coauthors on the UC guidelines, both the ACG UC and Crohn's guidelines emphasize the need to screen and treat mental health disorders among our patients, and 50 to 60% of our patients with active disease may be suffering from mild to moderate depression or anxiety.

The issue of whether or not patients who are taking the old class of MAO inhibitors — which practically no one's on — but the newer drugs have SSRIs which are listed in the label as being potentially something to monitor patients if you're starting this therapy is of interest.

I didn't know much about this. So in preparation for our podcast today, I went to read about it. The S1P receptor modulator mechanism's been present in the multiple sclerosis field for years and with different drugs, and now ozanimod had been approved for MS as well. Despite that potential drug interaction, there is not very much that has ever been reported of problems with drugs together. There's a potential for it causing high blood pressure. There's also interesting older literature that SSRIs can result in QT prolongation.

Again, getting back to the cardiac conduction question, maybe there was concern that if you use a drug that can affect your cardiac conduction, it might be another reason to be more cautious with ozanimod. But to be honest with you, I found 1 open-label study in Sweden, looking at fingolimod, a different drug in this class with some SSRIs. They reported absolutely no adverse events when they were monitoring all these people prospectively.

So I think we can be cautious, we should know about it, but it doesn't limit our use of the therapy. In terms of how we're using it, I want to point out that the label for this drug, unlike our other therapies, does not require failure of conventional therapies. It does not require an anti-TNF before you can get to it. The label is clean. In other words, we can position this drug as an oral, once-a-day therapy anywhere we want. In theory, that could mean after the first course of steroids. It certainly could also mean after patients have failed more traditional or existing treatments.

Just remember what I said about the induction results, patients who had failed anti-TNF didn't necessarily do statistically better with this drug compared with placebo. So it may be a better therapy to use earlier or maybe with the more moderate of the moderate-to-severe patients, but that we're going to have to figure out a little bit more.

In the patients in whom I've started this this on, we've gotten a rhythm strip or an EKG. We do the routine baseline labs, like we've done for many of our therapies. Payers want us to check for TB like we do for our other therapies, but that's a remnant of the fact that in the clinical trials, they check for TB. This is not a therapy that's thought to affect the risk of reactivation of latent TB.

Then the other thing to keep in mind is that we're starting to appreciate that patients with IBD may have fatty liver disease more than we realized. If you have patients who are overweight certainly, but remember, patients who are not overweight can have a fatty liver. The question will be whether that puts them at higher risk for having the transaminase elevation that was reported in the trials as well. So there's a few things we have to monitor, keep an eye on, and figure out as we go along.

Dr. Long:  That's great and really helpful. I think that it's so common, we want to make sure that we're not limiting access to the therapy for our patients. Just monitoring patients on SSRIs, monitoring their blood pressure, all of that is very helpful guidance.

The one other thing that I think is a big concern for our patients but is obviously incredibly rare is PML— progressive multifocal leukoencephalopathy, which most of us know as a remnant of back in the natalizumab days, we did see cases of PML. With ozanimod in the MS population, there has been 1 case.

Are you concerned about this in the UC population? Is this something that you counsel patients about? How are you having conversations about this?

Dr. Rubin:  Progressive multifocal leukoencephalopathy is the result of reactivation of a dormant virus called the John Cunningham virus. About 50% of the adult population has been exposed to JC virus and would have it in their bodies. The rate of new infection or primary infection of JC virus varies, but it's about 2% per year. It's likely that patients who we may choose to treat with this therapy have JC virus in their body.

Now, there were no cases of PML in the UC trials within the limits of the follow-up so far, but it's important to know that the 1 case seen in a patient with multiple sclerosis was actually in the long-term follow-up, the open-label extension of ozanimod after 4 years of treatment. It was just that one case, and obviously, it's still very serious and important to know about.

I'll remind the audience that steroids are associated with PML. Anti-TNFs have been associated with PML. Azathioprines have been associated PML. So I don't mean to minimize what this is, but I do want to say that it appears to be a rare. It also appears to be after a long exposure, and it was in 1 patient with MS who'd been on multiple other therapies through their management and had a central nervous system disease.

Personally, I'm not checking JC virus antibodies in patients that I started on this therapy. It's not going to dictate how I do this. I also want to point out to you that in the natalizumab days, when there was a requirement to check for that and then to recheck it over time, we also learned that if you stop therapy, you could actually reset the immune system and then potentially restart.

The problem there, of course, was 2 things. Number 1 is the IBD would come back after a while when you stop therapy, of course. The second was our concern about interrupting a biological therapy and the risk of immunogenicity when you restarted it. With a small molecule, we have the option and the consideration that if we do learn over time that there is something downstream, that we might end up using these therapies as a pulse therapy for some period of time or as a bridge to something else.

I think we're going to need to learn some more. I don't want to pull the fire alarms on this based on what we know because there are many, many thousands of patients in the MS trials that were treated, and there was only that 1 case that's been reported out. It was after long-time exposure and after having been on many other therapies for that MS. I don't want to say more than that right now about that particular adverse event.

Dr. Long:  That's very helpful. Particularly the lack of a need to screen for JC virus antibody, that's very important. We've been through the efficacy. We've been through the safety. We've been through the positioning. We've used it in your practice.

You've given us some clinical pearls for some of the testing we should do ahead of time, what to expect with the therapy, all that's so useful for our clinical practice. Now, I want to turn away from clinical practice. One of the fun things about this podcast is we always get to ask something fun from our participants. We'd love you to tell us something about yourself that the audience may not know.

Dr. Rubin:  Just 1 pearl?

Dr. Long:  Sure, you can go 2, David.

[laughter]

Dr. Rubin:  Probably, the audience doesn't know that I have a couple hobbies, but one of them is home improvement. It is very relaxing to me to do projects around the house. During the pandemic, when we were all stuck at home, I changed out all of our light switches and outlets. I put up some ceiling fans, and I customized a couple closets.

That goes all the way back to my days in college when I was doing that for my friends when we were living in a house together and I got to practice on all of them. I find that to be a very rewarding approach to making our house more livable. It's also a project that has a start and an end.

That's probably the part of me that I also liked GI as a specialty because we get to do things with our hands. That's probably something people don't necessarily know.

Dr. Long:  That's right. [laughs]

Dr. Rubin:  We lived in a house that was built in the 1880s, an old Victorian house here in the neighborhood by the University of Chicago. I didn't do the major renovations, but certainly all the little things over the years, I've really enjoyed doing.

Dr. Long:  That's fantastic. Now, future house guests will have to know to look for the closets. [laughs]

[crosstalk]

Dr. Rubin:  Absolutely. I will announce on this podcast that anyone who wants to come visit Chicago can certainly reach out to me, and I will give them a tour of our beautiful campus and be happy to show them our closets.

[laughter]

Dr. Long:  Fantastic. Thank you so much for your time today, David. This was a great drive-time. Hopefully, again, this 20 or 30 minutes helped you in your drive home to learn something about a new therapy for ulcerative colitis.

We'll definitely have you back as all of us learn more about the use of this therapy in clinical practice and can update you know everyone on what we've learned and how we're using it. Thank you. On behalf of Ray Cross and myself, we look forward to having you on the next IBD Drive Time.

Dr. Rubin:  You guys are naturals. This is so great. Keep up the good work, and I would love to come back another time.