David Hudesman, MD, on The Promise of Sphingosine-1-Phosphate Receptor Modulators in IBD

Dr Hudesman reviews his talk from the 2022 Interdisciplinary Autoimmune Summit on emerging challenges for the management of patients with IBD and the promise of sphingosine-1-phosphate receptor modulators.
 

David Hudesman, MD, is codirector of the Inflammatory Bowel Disease Center at NYU Langone Health and an associate professor of medicine at the NYU School of Medicine.

For more content from the 2022 Interdisciplinary Autoimmune Summit, visit our Newsroom.

TRANSCRIPT:

Hi, I'm Dr. David Hudesman, Co-director of the Inflammatory Bowel Disease Center, NYU Langone Health, an associate Professor of medicine. I'm happy to give an overview on the talk I just gave at IAS 2022, on emerging challenges in inflammatory bowel disease, the promise of the Sphingosine-1 receptor modulators.

So I first started my talk, just talking about the overall disease burden of both Crohn's and ulcerative colitis, and how over 1.6 million Americans are afflicted with this disease and over two million Europeans. And how the incidence and prevalence rates are increasing across the world and popping up in areas we didn't really typically see such a high incidence and prevalence rate, some areas in South America and Asia. The cost of care and the burden of care has really been going up as well. There's some studies showing the cost of IBD care is three times higher versus non-IBD patients.

As we know many of our IBD patients have significant comorbidities, which increases that cost and the costs are really going up in all aspects in patient care, outpatient care medications, procedural and so forth. Patients with chronic disease do really need a multidisciplinary approach. High needed psychosocial support, nutritional support, working with our surgeons, our mid-level providers, our ostomy care. And when you look at extra-intestinal manifestations and inflammatory bowel disease, up to 50% of our patients will have some type of EIM most commonly joint manifestations or skin manifestations.

So having good relationships with our rheumatologists and dermatologists is critically important. When speaking about our goals of care for our patients, this is really involved over the past 10 years. And I think it really speaks to the nature of both Crohn's and ulcerative colitis, both Crohn's and ulcerative colitis are progressive diseases.

Meaning with Crohn's initially about 80% of our patients will present with an inflammatory phenotype, diarrhea, abdominal pain, and so forth. And 20, 25 years later without appropriate treatment, these patients could progress to developing strictures, fistulas, abscesses and so forth. Maybe 20 years after diagnosis, two thirds of our Crohn's patients will require surgery. And I think it's important to remember that ulcerative colitis is also a progressive disease.

About a third of our patients with ulcerative colitis will require a colectomy long term inflammation. Histologic inflammation has been associated with dysplasia and just having disease for a long term could lead to that lead pipe colon, we described that we see on colonoscopy. Which could lead to urgency, looser stools, and incontinence issues down the road. So our goals of treatment are not only to make sure our patient feels great is in clinical remission, off of steroids, but also to be healed on the inside, right?

And our ultimate goal is if they're feeling great, and healing on the inside. They're an endoscopic remission. We really could change the natural history or change the course of the disease. I touched on this concept of treat to target and trying to achieve those goals. And I reviewed the Crohn's study, which was one major prospective randomized study looking at this concept of treat to target about 250 patients were randomized.

They were both getting started on adalimumab and they were randomized to escalation of the dose of adalimumab based on symptoms alone, or symptoms or biomarkers such as C-reactive protein or faecal calprotectin And when the decisions were made, not only based on symptoms, but based on the target of biomarkers at the end of the year, there was a statistically significant higher rate of endoscopic remission and the patients, again that were treated to a target to get a biomarkers versus ones that were treated to symptoms alone about 46% versus 30%.

And then they were not able to follow all of these patients long term, but the patients that did follow three years out, it seems like those patients that did achieve endoscopic remission did have lower rates of complications, such as fistulas structures need for surgery. Really supporting that concept of treat to target. Now we have many different options for our patients with Crohn's and ulcer colitis. It's a pretty exciting time to manage these patients. We have our anti TNF biologics. We have our anti-integrins, our anti-IL-12/23s.

We have now two Jack inhibitors on the market that are FDA approved for ulcer colitis, and then one S1P modulator. Sphingosine-1-phosphate receptor modulator, or ozanimod that's been improved. And although it's an exciting time, it's very important we have these newer agents. When you look at our biologics, about 70% of our patients respond to drug, which is great, but still a 30% will be primary non-responders.

And then our patients that do respond to biologics upwards of 40 to 50% can lose response over time. Usually within those first one to two years, whether that's due to immunogenicity or antibodies to the drug or change in the mechanism. And if you look in the clinical trials, less than 50% of our patients are achieving mucosal healing or endoscopic remission. So really having some of our newer agents extremely important to give us more options for our patients.

So now to speak specifically about ozanimod, our S1P receptor modulator. So first, just to briefly touch on the mechanism of action, what this medication, this therapy does, is it internalizes the S1P receptor that are on lymph nodes. So it's pretty much keeping the white blood cells in lymph nodes and not allowing them to leave the lymph node, get into the bloodstream and eventually to the intestine to cause inflammation.

So the way I like to explain this to patients, if you're talking about adalimumab or our anti-integrin, if you imagine the cars on the highway are white blood cells going to our bloodstream and each exit off the highways at different part of your body, your brain, your heart, your lungs, your intestine, and so forth, what our anti-intergrins or adalimumab does, is it messes with those cars' GPS.

So it can't get off the exit to the intestine, the white blood cell can't get to the intestine, whereas ozanimod, these cars aren't even leaving the garage. So they're not even getting into the bloodstream. When you look at the registration trials, a True North's trial that helped get this medication, FDA approved. They looked at both week 10 and week 52 outcomes for both induction and maintenance. And during induction about 80% were in clinical remission, about 50% of patients had a clinical response.

And when these patients were re-randomized at week 10. So when responders were re-randomized to drug at the end of one year, you had now remission rates that were higher mucosal endoscopic remission rates of about 30% response rates at 60% endoscopic response rates at about 45%. And it also showed improvement in both patients that were naive to biologics and patients that were previously exposed. And this is important as well when we're talking about sequencing therapies, whether it's first line or second line.

So really show that it's an efficacious drug. The other nice thing about this therapy is that it's an oral therapy compared to our biologics, which are infusion or injections. So very easy for a patient to take. Then I just want to... I touched on some different safety aspects of this therapy. There's a concern about you need an EKG screening before starting, because there's a concern for bradycardia, if you have underlying arrhythmias or AV conduction delays, but if you actually look in the trial, the average heat per minute drop in these small amount of patients were only two beats-per-minute, so not clinically significant.

So really a screening EKG they're titrated up over the first week. And then you know needs EKGs down the road, there was a nice post-hoc analysis looking at the lymphocyte count. So since the white blood cells are not leaving the lymph nodes, they looked at the drop in lymphocyte count in the close to 1,150 patients in all of the ozanimod development program. And what they found is that about 50% did have a drop in their lymphocyte count. And they had a... sorry, an average of about a 50% drop. And that drop though sort of peaked around week eight to week 10. And that drop then stayed stable throughout the year of the trial.

And if you were to stop drug, then your lymphocyte count would come up and go back to normal. About eight weeks later, they didn't do the full analysis yet on whether these drop and lymphocyte count was associated with infections. What I can tell you is that a very low lymphocyte count less than 200 was extremely uncommon about two patients in the induction, four patients in the maintenance. And none of them in those extremely low lymphocyte counts was associated with any serious infection.

There was some post hoc analysis looking at pregnancy as well. There's a concern that the S1P, so ozanimod touches on S1P1 and S1P5 there's five subtypes S1P1, 2 and 3 are involved with embryogenesis. And so there's been 60 patients to date that's been reported. That's been pregnant on ozanimod, whether it's been Crohn's ulcerative colitis or multiple sclerosis, the rates of spontaneous portion and preterm birth was similar to the general population, but it's still too early to say and giving that it is involved with embryogenesis. We are recommending not starting or this medication and somebody that... and a young female that is looking to get pregnant, and if they do get pregnant to not hold that therapy.

And lastly, I just want to say, we now have the combined a safety data from the 1,150 or so patients within the ulcerative colitis program, as well as a close to 2,500 patients in the multiple sclerosis program, looking at serious adverse events, treatment related adverse events, and really there's nothing that stood out, nothing that we haven't seen in other trials compared to the general population. Most commonly, we see lymphopenia, which is expected with the therapy, iron deficiency, anemia, and some nasopharyngitis, which we see with all of our biologic therapies. And then there was just one last safety slide I did discuss there's this theoretical concern since the products of ozanimod is involved with monoamine oxidases, that if patients are on ozanimod plus an SSRI or SNRI for anxiety or depression, there's an increased risk of serotonin syndrome.

So they went back and they looked at all the patients in the UC program. All the patients in that MS program there was about 60 or so in the UC that was on an SSRI or SNRI close to two fifth in the MS group and none of them had serotonin syndrome. So I think it's something that it's important that we know, but we don't need to start adjusting or holding anti-anxiety or anti antidepressant. I also touched on etrasimod is another S1P receptor modulator. Ozanimod, again, works on S1P1 and 5 etrasimod, works on S1P1, 4 and 5. They completed their Phase 2 data, which showed improvement, clinical response, clinical remission, mucosal healing, pretty low placebo rates. So it looked pretty good, and they also had some nice data with histologic healing as well. And they're currently on-going in their Phase 3, so this is not yet FDA approved.

So the last part of my talk, I really talked about positioning therapy. So we have a new patient that comes into the office with moderate-to-severe ulcerative colitis. How should we manage that patient? What therapy should we start them on and what goes through our head? So efficacy is obviously extremely important and we need this therapy to work. And I reviewed the efficacy stats already with ozanimod. Safety, ozanimod seems to be a pretty safe agent. And I touched on that as well. We talked about onset of action, right? How long does it take for this therapy to work? They had some nice post-hoc analysis looking at ozanimod and in patients that were bio-naive, about a third of patients had a good response within two weeks and up to 50% at four weeks. So in your biologic naive patient, I think this therapy, the data does suggest that it does work pretty quickly, and then things like ease of administration.

So oral therapy and so forth, obviously patients are going to prefer something oral to a more frequent infusion or an injection. So now when we're thinking about that moderate, severe ulcerative colitis patient, when we're thinking about first line agents, I think ozanimod should be in the discussion as well as vedolizumab and ustekinumab and so forth.

And the last point I made is another thing, when we're thinking about what therapy we want to choose is again, coming back to those extra intestinal manifestations and joint pains is one of the most common, extra intestinal manifestations. We do see with our patients with ulcer colitis and Crohn's again, I had mentioned 40,50% of our patients will have some complaint. And there's this theory of this gut joint access where patients have with inflammatory bowel disease could have this subclinical inflammation. And these cells, these white cells could go to the joints release cytokines and lead to this joint pain and swelling. And so theoretically, if an S1P receptor modulator prevents those white blood cell else from getting into the bloodstream from leaving the lymph node could possibly be a good option for patients with ulcer colitis and joint pains. We don't have any data on that now. It's an interesting thought, and we're going to need some trials to take a closer look. Thank you for listening and have a great one.