Ozanimod in Ulcerative Colitis

Miguel Regueiro, MD: In this section, we’re going to focus on S1P [sphingosine-1-phosphate] receptor modulators and other emerging treatments for ulcerative colitis [UC]. Ellen, we’re going to focus on ozanimod now, can you review some of the data from the phase 3 True North study with ozanimod? Give us the overview and any other information you want to add about ozanimod, and then Dave I’ll move to you, and then Marla as well. Ellen, why don’t you kick us off?

Ellen J. Scherl, MD: This is a phase 3 study that achieved clinically meaningful improvement in endoscopic mucosal healing as well as steroid-free remission. At week 52, 37% of patients on ozanimod were in clinical remission as opposed to only 18.5% on the placebo. Adverse events were similar and not significant: low incidence of anemia, headaches, and nasopharyngitis, which we tend to see. This is an important study that showed regardless of whether the patient was TNF [tumor necrosis factor agent] experienced or naive, these were the remission rates. They were also comparable in terms of who went into the trial, again, equal for disease severity and gender. I want to come back to ECCO [the European Crohn’s and Colitis Organization meeting] 2022, which recently, with Britta Siegmund, MD, et al,showed the rapidity of onset, with a 2-week response in patients who had a response, and a 5-week response with those who were in clinical remission. There was a slight improvement in those who were anti-TNF naïve, but overall, no difference in the TNF experience versus naive. We’ve made this point so many times, but you want to get this in as a first-line treatment before the patient has experienced a TNF. Whether you try a non-TNF biologic or small molecule first is a topic I will cover later.

Miguel Regueiro, MD: Nice overview on ozanimod, this new mechanism of action, first in its class showing that there is benefit in the moderate to severe UC study. Nice job outlining the overall data related to True North and some of the more recent data on rapidity of onset with ozanimod, and now long-term extension. I’m going to ask all 3 of you this, but I’ll start with Dave and then Marla, can you tell me your experience with ozanimod? And Dave, if you want to add anything to what Ellen said about the trials, but I want to get into your experience in your clinics with ozanimod.

David P. Hudesman, MD: Sure, I’ll start with my experience and then touch on the safety or the screenings; that’s a concern both for providers and patients. When you look at the data, and Ellen outlined it nicely, about 70% of the patients included in the True North were TNF-naive or biologic-naive. This medication is going to play in those moderate patients, biologic-naive. Of the patients I’ve used it for so far in that group, I’ve had good results, response rates, remission, and I’ve had them on long enough now where I’ve seen mucosal healing. Anytime a new therapy comes on, we all have patients who have failed multiple therapies, and you’re giving them another shot. In those situations, I haven’t seen as good of results, just like I didn’t see as good of results with our other therapies when vedolizumab and ustekinumab came out. But as a first-line agent, it plays well. It’s how do you select that.

There were a couple of things that came up from the trial when this therapy came out. First is this idea of getting an EKG [electrocardiogram] and realizing this is a screening EKG. There are 5 S1P receptors, and ozanimod touches on 2 of them, type 1 and 5, whereas fingolimod, which is approved for multiple sclerosis [MS], covers all of them. That’s where you saw this AV [atrioventricular] conduction delay and bradycardia. For ozanimod, they’re looking for a baseline screening EKG, and if there’s no significant bradycardia/AV conduction delays, it’s OK to use. If you look at the True North data, the average drop was less than 2 beats per minute, nothing significant. Another concern is the lymphocyte count and that dropping, is that going to increase risk of infections? We’re going to need more real-world data on that, but in the clinical trials, at least to date, we haven’t seen that, and lymphopenia might be a biomarker of efficacy, almost like when we’re using thiopurines. It looks like the lymphocyte count might drop by about 50%, and that plateaus during induction around week 8 to week 10, and then it stays there. We’re going to have to see analysis, but for patients in that True North data who had low lymphocytes counts, less than 200 per mm3, there were no associated opportunistic infections.

Just one last comment on the safety, there was something else that got brought up about using it with certain types of foods or overlapping SSRIs [selective serotonin reuptake inhibitors] or SNRIs [serotonin-norepinephrine reuptake inhibitors]. The breakdown, the metabolites of ozanimod interact with monoamine oxidase. The concern is, if a patient is on an SSRI or an SNRI with ozanimod, are they more likely to have serotonin syndrome? There was a nice abstract that was just released looking at all of the patients with ulcerative colitis, all of the patients with MS, there were close to 300 patients who were on an SSRI or SNRI with ozanimod, and there were no cases of serotonin syndrome. So I don’t think it’s something we need to be concerned with.

Miguel Regueiro, MD: To add on to that, we’re seeing good safety with ozanimod. To your point, the expected lymphocyte drop doesn’t seem to be clinically significant in an adverse events form. The other thing that I tell my patients who read about ozanimod and may be worried about the cardiac part, is that ozanimod doesn’t cause cardiac abnormalities. It’s just that if they have an underlying preexisting block that they’re not aware of, because of the first dose heart rate reduction, we must be careful, but it doesn’t cause these. The final thing, before I move to Marla, is that I agree David, and I’m wondering as I say this, Marla, what are your thoughts? Could ozanimod possibly be used in that moderately severe patient who’s failed a 5-ASA [5-aminosalicylic acid], for whom we’re looking for that next therapy, and maybe even not steroids? Is this something that we can use in that biologic-naive patient? It’s just an interesting thought as I look at my own practice. We don’t get those patients as often because they’ve usually been on 3 or 4 things. Marla, your experience with or any other comments related to ozanimod?

Marla Dubinsky, MD: Sure. Remember that at week 52, the average heartbeat change per minute was 1 from baseline to week 52. When you included the patients with MS, it was 1.2 beats per minute at 2 years. We must keep everything in context, which you just said, because the idea of us ordering EKGs sets people into a different mindset about, “Oh my God, something bad is going to happen with this drug in my heart.” Thank you for clarifying the screening and what the reason for the screening EKG is. I’ve used it in several different ways. I presented at ACG [American College of Gastroenterology] the matched indirect adjusted comparison, and it looks very similar to vedolizumab. I think about ozanimod as an oral alternative for a patient you would use VEDO [vedolizumab] on, so I want you to think in that concept. It also looks similar to ustekinumab, and superior to adalimumab. This isn’t a head-to-head, so take everything within these network meta-analyses and these matched indirect adjusted comparisons for what they are. They try to match study to study, but Brian Fagan, MD, is in the bubble in my head saying, “never compare across trials.” So I say that with Brian as an asterisk footnote.

What’s interesting is, I think about it as an oral alternative. I don’t have to fail a TNF. Maybe it’s a similar patient population, I think of it like a traffic cop, just like I think about vedolizumab. Instead of it going and binding to the lymphocyte once it’s exited the lymph node, these drugs go to the lymph node, which is why you have lower circulating lymphocytes, because it’s going after those that are carrying this S1P hat. I think of it in that vein, so it made sense to me to think of it in that category. I have definitively used it as an add-on with someone who is partially responding, or I scope them, and they have just a bit of proctitis left. I don’t want to abandon my biologic—I’ve added it by the way to every biologic that we have—it works differently. It’s not increasing the rates of infection; it’s not like me adding a JAK inhibitor to a TNF, that’s not what I’m doing here so. I’m thinking about the mechanism of action, are they complementary to another cytokine-based interaction? That’s where I am using it. I am looking at it in the naïve instead of vedolizumab if they so choose.

The other question that patients want to know is, “Am I going to have a problem eating cheese?” The reason I say that is the tyramine. The amount of tyramine toxicity means they could eat cheese for 24 hours straight; I believe it’s 150 g before you get an effect from it. I tell them that unless there’s some sort of mouse that is eating cheese for 24 hours, I think we’re OK. That’s the biggest question I get asked, “Can I eat cheese and deli meat?” That must be written somewhere about the cheese and deli meat. I like to talk about that because it is important for patients.

Miguel Regueiro, MD: Sometimes beer and wine too, patients ask. And I agree, to put that to rest, the amount of tyramine you would need to have is nearly impossible. I guess nothing’s impossible in eating. To Dave’s point about SSRIs, SNRIs, and showing safety, it’s the same thing with tyramine, it’s essentially a nonissue. Ellen, I’m going to ask you the same question, how are you using ozanimod in your practice?

Ellen J. Scherl, MD: First, I’m starting to use it more in the biologic-naive patient, but we did participate in the trial. We enrolled all the anti-TNF, multiple failures, with a tremendous response, so we use it in the refractory patients as well. The ophthalmologic exam, we get it as routine, having to do with the vasculature trapping of lymphocytes. But these are not problems. When we think about steroids, all of our patients should have ophthalmologic exams, and that’s exactly what I say. There’s no stigma to this. I’m using it in both of those patient populations. It’s relatively easy to get approved, and the results are quite good. Also, the washout period; to Marla’s point, in the real world, if you have a patient who’s on an anti-TNF, we go right onto ozanimod, no washout, whereas with a JAK inhibitor, maybe we want a bit of washout.

Miguel Regueiro, MD: What I’m hearing from all 3 of you is that you’re comfortable with the safety profile of ozanimod. It may be good to use early, prior to biologics, or off-label, just to make that clear to the audience, like Marla said, as an add-on to another biologic. And because of the lymphocyte trafficking, it works differently than most, except vedolizumab. I also want to say, I’m glad Ellen that you brought up the eye because we talked about the heart and the lymphocytes. But the ophthalmologic exam, and I think you alluded to this, is only necessary for those patients who have concerns of macular edema. If they have a diagnosis of macular edema, end-stage diabetes, or uveitis, but that’s a small percentage. Ellen and I agree, if they have 1 of those 3 conditions, they’re probably getting yearly exams by an ophthalmologist already. If our patients ask about the eyes, I’d say over 98% of my patients don’t need the screening exam; it’s really that rare group.

Transcript Edited for Clarity