IBD Drive Time: Russell Cohen, MD, on New Therapies for IBD

In this episode of IBD Drive Time, Dr Raymond Cross and Dr Russell Cohen review several new therapies and formulations that have been recently approved for treating inflammatory bowel disease and discuss how best to position these medications.

Raymond Cross, MD, is a professor of medicine and director of the IBD Program at the University of Maryland School of Medicine in Baltimore. Russell Cohen, MD, is professor of medicine and director of the Inflammatory Bowel Disease Center at the University of Chicago.

TRANSCRIPT:

Raymond Cross:

Welcome everyone to IBD Drive Time. I'm Raymond Cross from the University of Maryland School of Medicine, and I am delighted to have Russ Cohen from the University of Chicago here today as our, guest. Russ, welcome to IBD Drive Time.

Russell Cohen:

Thanks, Ray, and thanks everybody for making this possible. Looking forward to it.

Raymond Cross:

So, Russ, you're you're a master clinician in IBD, and we've had an explosion of new therapies. But over the last 4 to 6 weeks, there have been a number of new drugs approved or new formulations of existing drugs approved, which has crowded the landscape even more. I wanted to start with subcutaneous vedolizumab because we've been looking forward to that for some time. Can you just summarize for the listeners, the studies that led to the approval of the subcutaneous formulation?

Russell Cohen:

Oh, absolutely. Yeah. We have been waiting, and we're very happy. October was a good month for IBD. We had 4 approvals for ulcerative colitis within relatively—right around October. So, as many of you know, vedolizumab has been given IV 300 milligrams, only. Week 0, 2, 6 was the load and then every 8 weeks afterwards. Subsequently, there were studies done looking at a subcutaneous version of vedolizumab. The way the studies worked is that patients received the first 2 IV doses, and then subsequently at week 6, were switched to the subcutaneous dose. The next subcutaneous dose happens to be 108 milligrams for those taking notes, and it's given every 2 weeks.

So that's how the trials were done, and the patients were either switched to where they were kept on the IV, and the outcomes, that's either staying on the IV or switching to the subcutaneous were comparable. You know, one thing I actually, I was reading up on it. It's interesting is, people will say, well, you know, it's given subcutaneously, but, you know, would it be as effective as IV? Well, Ray, in our world, we often look at trough levels for drugs, and I looked up the trough levels for after the initial first 2 IV doses, trough level's around 26, but staying on IV, the trough level at end of 52 weeks was 11 for vedolizumab. But if you went to the subcutaneous after the initial induction, these trough levels were 35.

So, this is interesting because, certainly the intent is not for the subcutaneous to be better, but it may be better because now we're seeing that you have tripled the trough levels, at least from that trial about, you know, after they switched over, and which actually may help. You and I use that vedolizumab a lot, and you know that there are some patients who can't make it the full 8 weeks. They're chugging, and they can get to week 4 to week 6. Well, maybe we won't have that issue and, and we're able to treat them straight through. So I think that, is very, very exciting.

Raymond Cross:

Yeah. It's a really astute observation, and my understanding is the way they formulated the sub q or the way the PK of the sub q formulation is designed to be 300 milligrams IV q 6. So that explains why the levels are better compared to the infusion every 8 weeks. So I think for transitioning our patients that are already on 6 weeks or 8-week dosing, it's going to be fairly easy. I guess the question for you and I, what are we going do with that patient that's on 300 milligrams every 4 weeks? We either keep them on the 4 weeks or we switch them to the sub q and just cross our fingers and hope that that that's enough. What do you think?

Russell Cohen:

Well, you know, again, if you look at the trough levels, I mean, after, a patient's got Week 0 and Week 2 in the IV studies, their trough was 26. I mean, it wasn't with the maintenance part, but, you know, and then given the subcutaneous ones, over time it's about 35. So it may even be possible that, you know, again, we think that the biologics, the trough is important. But vedolizumab, sometimes we're not quite sure how the drug may work because seems that some of the interesting studies suggest that it may work through perhaps more through dendritic cells or others than what we initially thought was the true cellular trafficking. But I think that just like many things, we'll learn with time.

Initially, the easy ones are going to be the people who are on vedolizumab IV already. So for example, if you have someone who's been on IV vedolizumab, and is interested in switching, the time that you would switch would be at the time for their next IV dose. So patients will be inquiring, and then at the time of the next IV dose, you'd switch them. And, but, you know, sometimes we also wonder, you know, the patient's on 300 every 4 weeks. I mean, are they in remission? I mean, if they have that fecal cal that are higher, scopes that show inflammation, perhaps not. You probably want to change it to a different therapy altogether.

Raymond Cross:

One of the things that's a little puzzling, and I can't quite understand why it's approved for ulcerative colitis and not for both, and it's something with the delivery device. But, I'm going to offer it to both UC and Crohn's. And if they say no because they have Crohn's and not UC, then I'll just wait a little later until it's approved for Crohn's. I presume you're going to take the same approach to that.

Russell Cohen:

Yeah. So as you're pointing out right now in the United States the FDA approval is only for moderate to severe ulcerative colitis, although as you know it’s been available in subcutaneous form for many years for both UC and Crohn’s disease and there hasn’t been much concern about efficacy. I think it's just a matter of the timing. The FDA had the company do whatever studies they did, and the first study results are in for UC. And then I believe the Crohn's ones will be in in a few months.

Raymond Cross:

And, you know, I'm personally going to just go ahead and do the 3-dose intravenous induction. You're not required to go to sub q at week 6, you could wait to week 14. So I think for me, assessing their response and whether they're doing well on the drug before going through the hassle of another approval, that's how I'm going to do it, but you could do it either, as Russ said, the way they did it in a clinical trial, or you could wait to some other time point during maintenance to transition. Either would be appropriate. So let's switch to subcutaneous infliximab. And I don't know if I'm pronouncing this correctly, but Zymfentra is, I think, how you pronounce it. So this is the sub q biosimilar version of infliximab. Russ, what's the evidence for that, and how do you transition to sub q?

Russell Cohen:

Great. Well, you know, it's interesting because, I agree with the vedolizumab, why didn't they just do a full load, 0 to 6, before switching patients to the sub q? Well, that's actually what they did with the infliximab trial. So the patients got the 3-dose of infliximab IV weeks 0, 2, and 6. So the induction was all IV, and then, patients were randomized to switch to the injectable every 2 weeks of the infliximab or to stay on the IV. And patients did just as well with either. The studies also showed a clear benefit over placebo.

What it is is that the dose is 120 milligrams subcutaneously, and it's given every 2 weeks also. So typically, what would happen is that patients who are already on infliximab and doing well, presumably IV, you would start the subcutaneous at the time of their next IV infusion. And, again, looking at trough levels, not surprisingly, the trough levels were very nice with the subcutaneous every 2 weeks. In the studies, steady state with the injection was by week 22, and the troughs were in ulcerative colitis were 14.6, and in Crohn's, it's also 14.6. Well, so that's certainly higher than the 7 to 10 range that we're hoping to achieve with the IV every Q8. And, I think, again, it's something for us to consider, you have patients who might be on the IV not making it the full 8 weeks. Well, maybe if they're getting the dosing every 2 weeks, they would be able to do that. So that's exciting.

You know, it's the one thing that you mentioned, the word biosimilar, well, so the IV version is a biosimilar to the brand named Remicade, and it's a biosimilar, that many of us know either, from Celltrion, either as Inflectra in the United States or Remsima inother places too. But since the injectable, and no one's had injectable infliximab before, this is actually not a biosimilar. This is the originator drug.

Raymond Cross:

That's right. So it's the biosimilar in intravenous form, but in sub q, it's the reference product. The first in our field to further make things more confusing. So the manufacturer actually has both the biosimilar and the reference product for, and they'll they'll have to find they'll have to fend off their own biosimilars. So the beauty of this is that we know what drug levels mean. And so, again, I thought this was the PK was really modeled after the 5 mgs per kg q6. So for those that are on dose on more frequent doses or higher doses than that, we have the ability to check levels and make sure we're hitting the sweet spot. And as Russ said, if you're overshooting, then and you go to sub q, you could potentially drop down and get into the range. So we'll be at least able to know if we're giving the appropriate dose for the sub q.

I had an interesting question that came up in clinic yesterday. I don't know the answer to, and I'm interested to see your thoughts. I have a patient who's been on infliximab for a long time, prior significant infusion reactions, gets premeds, a little bit of postmeds, does some Singulair for a week before the infusion, is getting home infusions doing well. And I mentioned this to her because it takes her obviously a bit longer to get the infusion in. It's a little bit more hassle factor. She's tired for a day or two after. So she asked about, would she have a reaction with the sub q? And I said, I don't think you would have a reaction to the sub q, but I offered to bring her into the office for the first dose and have her sit for a few hours to just see what happened. What do you think about that, Russ. I'm not trying to put you on the spot, but I'm putting you on the spot.

Russell Cohen:

No. It's fine. Well, we certainly know that patients who are on brand name, let's say, Remicade, if they have infusion related reactions or make antidrug antibodies, we typically don't go to the one of the biosimilar infliximabs or vice versa. Kind of IV. It's kind of game over. But for patients who may not have a true immune reaction such as neutralizing antibodies, you know, there is a difference giving an infused protein than an injected protein, and, everything depends on the situation that the patient was in. Certainly, as long as it's not been a severe reaction, would be reasonable. I don't expect that you'd see a change, while they're sitting in your office, but I guess we'll find out.

Raymond Cross:

Yeah. I don't know how to do it, but maybe that'll be a test case, and I'll give you you and the listeners some follow-up as to how it went. So let's transition to one of the newly approved therapies. So we have our second S1P receptor modulator for ulcerative colitis, etrasimod. The trade name is Velsipity. I think that's how you say it. Russ, you want to summarize those studies and then any anything in particular you want to point out about them that was different from others?

Russell Cohen:

Yeah. Sure. So, you know, etrasimod is the second S1P as you mentioned, ozanimod is the first. They're both FDA approved for ulcerative colitis. They are not approved yet for Crohn's disease. Their oral therapies, that’s very attractive. They're once a day dosed. In the newer medicine, the etrasimod studies, they're called the ELEVATE Studies— I guess it's good to be good to be optimistic—the ELEVATE 52 for 52 weeks was basically an induction and maintenance study altogether. And then the ELEVATE 12 was just an induction for 12 weeks also. Once a day, patients are randomized 2 to 1 to the drug, it's a 2 milligram dose, or a placebo, and they actually stratified the randomization based on which they've had previous biologics or JAK inhibitors, steroids and disease activity. And, you know, the results actually from the inductions for both were actually very promising. For the year-long study, the initial or 12-week induction, the remission rates at 12 weeks were about a quarter, 27% of the patients who got the drug, versus 7% without placebo, so that's a 20% difference in remission by 12 weeks. And at week 52, it was 32% versus 7% too. So look at the 7%. Usually, you know, that didn't budge. So you got about a third of the patients, a year out. The second induction trial, had, again, actually, 25%, about a quarter of the patients again by week 12, were in remission.

And I think what's also of interest is, Marla Dubinsky gave a recent oral presentation at American College Gastroenterology, which showed that some patients began to have symptomatic improvement within the first 2 days on this therapy, which many of us thought were a little surprising. Often, we felt that the S1Ps, because of their mechanism of action, might not be an instant gratification, if you will, with decreasing inflammatory mediators, but at least for the ulcerative colitis indications where patients had decrease in bowel movements and bleeding, the difference between placebo and drug was by day 2, which was surprising and encouraging.

Raymond Cross:

Yeah. I agree. And the reason that they were able to do this compared to ozanimod is because, remember, ozanimod has, for the listeners, it has the ramped up dosing, the blister pack, whereas this drug, you're starting with the standard dose from the get go, so you could actually do those early diary cards that reflect the standard dose, so that's a nice advantage. The other thing for the listeners is Russ pointed this out, this is a treat straight through trial design. Almost all of our studies other than ACT 1, ACT 2 for infliximab in UC or what we call pick the winner studies where there's placebo induction, responders are rerandomized to active treatment or placebo. And so the results at maintenance always look better in those studies than they will for a treat straight through design. So when you're looking at the results, you should in interpret it understanding that there's some trial design differences.

So one other cool thing about these studies, Russ, is they included ulcerative proctitis patients, since which no one has had the courage to do. And I would have predicted that those patients would have been a little more difficult to treat because of some nuisance urgency-frequency Symptoms, but the results look pretty good with the UP population.

Russell Cohen:

Yeah. You know, it's interesting, that that was the case. As you mentioned, some of those patients have a lot of symptoms, and some of the outcomes in our clinical trials obviously are symptom based. So, so many of the others haven't been brave enough to do that. You know, I think that it's something that, perhaps the others haven't done, but doesn't telling me they wouldn't work, but, certainly, it helps us expand the patient base.

Raymond Cross:

And so, I'm going to put both of us on the spot here. So we have 2 S1Ps for UC. Where are you positioning these drugs? How are you going to select one over the other. Obviously, if the payer says 1 or the other, then it makes things somewhat easy. But so how are you going to position these, Russ?

Russell Cohen:

Well, you know, I think these are oral ones today, and there's no there's no requirement for prior TNF or anything too. And for ulcerative colitis, I think it's very easy. Your ulcerative colitis patients, most of them are probably already taking a handful of pills anyway. And if they have active disease, then you're just saying, well, you know, we have a therapy. It's 1 pill a day. When I do my scopes, I actually, take a picture of the EKG or the printout. I show that they're not in right bundle branch block or something too. So as long as there's no cardiac issue, we can get started. There is a little bit difference in the labeling, with etrasimod, the newer one, does require, ophthalmologic examination and requires a skin examination either before or shortly after starting; that's not true with ozanimod. So there is a little difference in the regulatory too.

As far as, the other differences, the half-life of ozanimod is longer. So is that a good thing? Maybe. The patients aren't taking their medicine every day. Is it a bad thing? Well, if you want it to wear off quickly, if it's a side effect, perhaps we'll have we'll have to see. But I don't think that there's going to be payers that are going to have 2 S1Ps at equal status on their formulary. I presume that they're going to tier them, and they're probably going to just go with whatever whatever the payer pays for.

Raymond Cross:

Yeah. I agree. And I gave Russ so many topics, we can't touch on efficacy and safety, but there was no new safety signals with the etrasimod study compared to ozanimod. My take on it is they seem pretty similar as far as efficacy depending on the study you look at. For women of childbearing age, I'm going to give them etrasimod because of the short half-life. So if they do become pregnant, we can wash it out quickly. Whether that's sensible or not, I don't know. And then also for the ulcerative proctitis patients who have not responded or responded incompletely to a 5-ASA product. Because they did the study in the UP population, I'm going to use etrasimod in that population. So that's how and the other patients, I'll probably do ozanimod, and maybe everyone will be happy then with that approach.

Alright. Let's shift to Mirikizumab, Russ. I don't know if I'm pronouncing this right. Umvoh, I think, is the trade name for this. So approved for UC. What's the evidence for this, and how does it compare to the other drug in the class, ustekinumab? Of course, it's a p19, not an anti-p40 inhibitor.

Russell Cohen:

Right. So, this is the first in class for ulcerative colitis. In Crohn's disease, many of you know that we already have risankizumab, brand name Skyrizi, on the market, but we do not have that for ulcerative colitis. Mirikizumab is the first, so mirikizumab is the first IL-23 inhibitor, and it's directed towards the p19 subunit. This is a little different than ustekinumab or Stelara, which is IL-12/23.

And I think, as gastroenterologists, we have to stop lumping them together, even though they both have the word IL-23 in their targets, they're different medicines. They're different downstream effects on the receptor stimulation or on the immune system, and I think we really have to consider them as separate classes.

So this is exciting. We were waiting for this drug. It was delayed, not because of efficacy, but just because of some issues with FDA and the factory, it's now out on the market. Just like many of the others, it's initially given as an IV, week 0, 4, and 8. It happens to be 300 milligrams. It takes 30 minutes, and subsequently, the patients are changed then to a subcutaneous injection, of 200 milligrams starting at week 12 and every 4 weeks afterwards.

So I want to make it clear, though, that, it was a little different than risankizumab. There's not an on-body injector. So the 200 milligrams subcutaneous are two 100-milligram injections. So after the first 3 IV doses, it's then starting in week 12, a every 4-week, double injection of the product. You know, there is very good data in with risankizumab for Crohn's disease and now mirikizumab for ulcerative colitis. The safety these therapies have been excellent. Mirikizumab was not on the market previously for psoriasis or psoriatic arthritis. So this is —we're the first ones to get this one, and I think it's a great option for patients with moderate to severe ulcerative colitis.

Raymond Cross:

Yeah. I think the one other thing to point out is that currently, the sub q version of mirikizumab has citrate in it, like the old adalimumab prefilled syringes or pens, so it can be a painful injection. I don't remember significant injection site reactions being a problem in the trial, but you should just make your patients aware of that. And, you know, I was hoping that this would be much better than ustekinumab for bioexposed patients similar to risankizumab in Crohn's. And my interpretation is it's not a whole lot different, but we'll see how that plays out in clinical practice, but definitely effective medication and not sure if it's not approved for psoriasis, whether that mechanism would still be preferred in someone with dermatologic issues, but we'll figure that out.

Before I go to the fun question, just want to remind the listeners that we are sponsored by the Gastroenterology Learning Network and Advances in IBD, and we are available on both Spotify and Apple Podcasts. Go to Gastroenterology Learning Network, and you'll see IBD Drive Time and subscribe, and listen to us for every episode. So, Russ, this has been great. The fun question. Tell me and the listener something about yourself that we may not know. What's the fun fact for Russ Cohen?

Russell Cohen:

So believe it or not, about 40 years ago, I broke the record at for rib eating in Times Square, New York City. And it's the first time in my life I'd eaten ribs. Some of you can probably surmise why. And when I went back to that restaurant it had closed, so perhaps I had put them out of business.

Raymond Cross:

I would never in a million years have guessed that you're a champion rib eater. That is a nugget to keep in my brain. Alright, Russ. This has been great. Thanks for doing this. We hope to have you back soon.

Russell Cohen:

Great. Thanks, Ray. Thanks, everyone.