IBD Drive Time: Asher Kornbluth, MD, on New Biologic Therapies for IBD

In this episode of IBD Drive Time, host Raymond Cross, MD, talks with Asher Kornbluth, MD, about choosing and monitoring therapies for inflammatory bowel disease from among the growing number of options.

Asher Kornbluth, MD, is a clinical professor of medicine at the Icahn School of Medicine at Mount Sinai in New York, New York. Raymond Cross, MD, is professor of medicine and director of the IBD Program at the University of Maryland School of Medicine in Baltimore. 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.

Dr. Raymond Cross:

Welcome, everyone, to IBD Drive Time. I'm Raymond Cross from the University of Maryland School of Medicine, and I'm delighted to have my friend and colleague, Asher Kornbluth, from Mount Sinai joining us today to talk about the new biologic therapies in IBD. Asher, welcome to IBD Drive Time.

Dr. Asher Kornbluth:

Thanks very much, Ray. Thanks, Millie. It's a treat to be here, guys.

Dr. Raymond Cross:

So, Asher is one of the best IBD doctors in the country, and I wanted to get his insights into how he positions our newer biologic therapy. So, it's nice that we have more treatments. When I was a resident, all we had was 6-MP and infliximab, steroids and 5-ASAs. But now that we have more of these treatments, it can be really confusing for patients and providers as to how you position these. So, how do you decide which treatment to use? And let's just keep it to biologics. How do you decide which biologic to use for your patient in the office?

Dr. Asher Kornbluth:

Oh. First of all, Ray, you're dating me as an old man... Well, you're not dating with me, but chronologically, you're a kid. Because when I was doing my fellowship, infliximab was still 8 years away. And Dr. Janowitz, my mentor who I love dearly, my late mentor who took over for Dr. Crohn and put Mount Sinai on the map, he actually wrote a paper in the Lancet in 1989, an editorial called “Old Wine in New Bottles”, and he was about 80 then and he was still the most forward-thinking guy I know. He basically said, "Where are we now? We're in 1990. We have the breakthrough Pentasa and Asacol." I know those are brand names, but those are the new 5-ASAs. "We have azathioprine and 6-MP, and we have prednisone. This is what we've been using since the '50s and we haven't made any progress." So you came along as a kid in 1998 and infliximab was approved.

And frankly, we now have, as I say, an embarrassment of riches almost. Until about 2015, we still only have the anti-TNFs and vedo, vedolizumab, ustekinumab as our biologics, and golimumab, et cetera, certolizumab. But we were stuck in the anti-TNFs, until vedo came along, then ustekinumab. And as you know, now, we have small molecules as well, which I think we'll get to, but I think about biologics. So we got the anti-TNFs. We have the anti-integrin, right now, vedolizumab, and we have ustekinumab and risankizumab, anti-IL-12 and 23, for ustekinumab and risankizumab being anti-IL-23. And just because not everyone has these names roll off their tongue, just familiarity, when we say RISA, we're talking about Skyrizi, when talking about UST, we're talking about Stelara, just so we go back to their formulary names and not use their proprietary names.

So, to summarize, if I have a patient with hot disease, whether it's Crohn's or UC, my go-to... And, Ray, I really welcome what you think and if Millie will chime in…I think everyone agrees infliximab is the go-to drug, especially in patients with bad perianal fistulizing disease. Now, I say that based on our experience and I think there's almost a unanimity among us practitioners. So I think we know about our feelings about infliximab, about our own personal use, as well as the network meta-analysis. And unless I miss something, all of the meta-analysis basically put infliximab as top rung, and I think especially when we look at the severe Crohn's and the severe UC.

But here's my editorial remark about network meta-analysis; it really can be spun, in many cases, to what you wanted to show. And frankly, and again from a very cynical view, I look at the acknowledgements often first and I see, has this been funded by one of our pharma companies? Now, that is not to knock our pharma companies. Our breakthrough drugs are because of our pharma companies. But often, you'll see a network meta-analysis and you could tell by the title, by the conclusion in the abstract, who might have funded this study. I don't rely on network meta-analysis. I like to look at the randomized controlled trials and think, "How does that apply to my patient?" Every patient sitting in front of you is essentially an N of 1 and may never have fit into that study to begin with. So, getting back to your question in terms of the hot Crohn's or colitis, I think it's infliximab.

I think in the patient who's failed a biologic—and these days, it's not always infliximab— there, we got lots of options and therein lies the reason all of our IBD meetings, one of the most important meetings or presentations, is positioning. And I think to hit the area that has the most morass of data and spin is first in Crohn's disease. So, these days, if you failed an anti-TNF, let's call it infliximab or adalimumab—and to skip to one of your other questions, before I leave a drug, I want to make sure it's optimized in terms of drug level. I'm sure you've had sessions on therapeutic drug monitoring, but I think in this day and age, all of us would agree we want to make sure the patient is in a "therapeutic drug level" before we switch them to another class.

Now, we know that data best for the anti-TNFs, probably less well, but I think we have enough information, foundational information, for both ustekinumab and vedolizumab. I don't know of it yet for our newest risankizumab. Also, to make the point for our small molecules, which we'll get to in a minute, and I think the easy way to think of that is the pills, we have 2 JAK kinase inhibitors now. We have one S1P now, that's ozanimod, and we're soon to have others. In terms of therapeutic drug monitoring, we abide by it. I think everyone would in terms of reactive therapeutic drug monitoring, meaning you react to a loss of response, whether it's complete loss of response or partial loss of response. I do that before I switch out of ustekinumab to an alternative drug. I make sure I optimize the dose, and I do it as well with vedolizumab where there too we can measure drug levels. For risankizumab, I don't know of that data yet and I'm fairly certain we'll probably be seeing it soon.

A big question that's starting to arise is, can you use it in patients who have failed ustekinumab? As you know, ustekinumab inhibits IL-12 and IL-23, as risankizumab inhibits just IL-23. All of the upcoming drugs that work in that space are going to be anti-IL-23 inhibitors only. I'm not aware of any anti-12/23 inhibitors down the road. We had 1 already approved, that's RISA. And I think within the next 2 to 3 years, we'll probably have at least 2, maybe 3 more, in rapid fire succession. All of them tend to be IL-23 inhibitors, and frankly, the results do look somewhat better.

Now, I phrase it to the patient, "Maybe it is a ‘new and improved’ ustekinumab that it inherently might be a better drug. Maybe inhibiting IL-12 is not such a good thing. Maybe you are mitigating the benefit of inhibiting IL-23. So if you inhibit IL-23, you might in fact be better off," or another potential explanation is, "All the anti-IL-23s that I'm familiar with, their study designs had 3 IV infusions, as opposed to ustekinumab, which is only 1 IV infusion. So it might be that it is a better molecule, or it might be that, for we know, ustekinumab might have done better had it had three monthly IV loading doses." So, that is risankizumab versus ustekinumab.

And in the risankizumab study, 18% of those patients that came in had already failed ustekinumab. And very importantly, those patients had results resembling what other bio-failure patients had, and I really have been applying this all the time now. If a patient did well with ustekinumab and they lost their response, even with therapeutic levels, because I wouldn't move out of it anyway, I have had success and they were success in the studies for both clinical response, clinical remission, and even endoscopic response in patients who had failed or lost response to ustekinumab and then went to risankizumab, so I like that drug. What's going to limit it? And this limits all our decisions, as you know, is what the payers want.

Dr. Raymond Cross:

But, Asher, I just want to follow-up on a couple of questions real quick. So, you moved right into the risankizumab/ustekinumab discussion. So, in your practice, assuming that the payer allows it, that there's no preference, when do you use ustekinumab, when do you use risankizumab, or are you just using risankizumab now? I'm putting you on the spot.

Dr. Asher Kornbluth:

It's a fair question. I think based on the data we have, if I could get them approved, I think risankizumab has stronger data. Patients don't mind if your telling them, “we have better data,” that they're going to get 3 infusions rather than 1, I think that's a small point. I don't see that as a problem, and I'd like-

Dr. Raymond Cross:

I think it's a slam dunk, don't you? In the bio-exposed patient, I think it's a slam dunk.

Dr. Asher Kornbluth:

Yeah. And also, they have the opportunity because ustekinumab didn't enroll these patients. They had patients that failed 2, or even 3, biologics and was pretty striking how well those patients did, even having failed multiple biologics, so I like it a lot. As you know, it's approved now for Crohn's. There's very impressive data for it in UC as well.

Dr. Raymond Cross:

And let's come back to TDM, too, because I don't want to forget that. So, I'm a big TDM person. I think there's no question, as you said, with anti-TNFs. We could argue proactive, but clearly reactive you should be doing. What level are you shooting for before you abandon ustekinumab? And what level are you shooting for vedolizumab? I abandon levels for vedo and just go to 4-week, but what are you shooting for?

Dr. Asher Kornbluth:

Yeah, that's interesting. The short answer is we have a lot less data, as you know, for that rather than the anti-TNFs. So, there's different papers that have looked at ustekinumab, if they'll cite papers, and say, "Patients who had a level greater than 1.1 of ustekinumab did better," but there are other papers that break it down into quartiles and basically 0 to 2, 2 to 4, 4 to 6, and 6 to 8. And the 1 paper that I saw on endoscopic response, you continue to have benefit with each quartile up to 6 to 8. And I'm not sure and I'm very interested to hear how you do it, Ray, but if I'm a patient that's not in that 6 to 8-ish range, I'll push them. If there are 2 or 3, and they had an initial response and now they're losing it, I'll push the dose.

How do I do that? You can't get more than a 90-milligram syringe. I'll push them to either Q6 or Q4, and I've basically stopped going to Q6. Because if I'm going to get an appeal and a denial and I'm going to win it, I'd rather just go straight to Q4 because there's no evidence, to my knowledge, that higher drug levels have ever been associated with greater toxicity. So, I have been-

Dr. Raymond Cross:

That's a great idea because, in 6months, you're coming back fighting then to go through 6 weeks to 4 weeks, and that's just why not just get it approved all at once.

Dr. Asher Kornbluth:

I just started doing that because you're not going to go from a level of 4 to 20 with ustekinumab at Q4 instead of Q6, so I have been doing that. Now, with vedo, I have to say, and again the literature is fuzzy, but for maintenance, I want them at least at 15 and I go up to 30. If someone's in the high 20s and they're not responding, I say it's not working. If they're in the low-teens, 15 or so, I'll still push the dose. Vedo, I'll do the same thing, either Q6 or Q4.

And here's a little pitch, and maybe the thing that your listeners will appreciate the most over the next months to years when they want to kill themselves when they're writing that last appeal letter is to tell them the following: You go to ccfa.org, go to the tab at the top that says professionals, you go to that. It has a page that has every imaginable appeal letter you want already written in template with references. They are bulletproof to a therapeutic drug monitoring payment, fecal calpro payment, and probably most important for us is dose escalation. For each of the drugs, they wrote the letter for us and also have included the references. And I can't think of a single time I've had a denial not overturned with that, and I throw in a couple of very nasty threats, but that will basically do it.

Dr. Raymond Cross:

And the IBD community is strong and supporting one another. And certainly if, in your community, you want to reach out to one of the busier IBD providers, we share letters all the time that are the influential letters, and I practice very similarly. I want to get the ustekinumab level above 4 ½  before I abandon it. I still check it. And if I do check it with vedo, certainly if they're below 13, 14, something like that, I think it's more likely that they're going to respond to dose optimization. And I've actually been doing a little bit more IV reinduction with ustekinumab, and it's actually a little easier, I think, to get that approved sometimes than the dose escalation of the subQ, and I've had some decent results. And it's intriguing that you brought up could risankizumab... Maybe it's not a better molecule, but could it be better just because you're getting a 3-IV dose induction? I didn't really think about that.

Now, you said the hot patient who's super inflamed or maybe has a bunch of extraintestinal manifestations, but what about your more moderate patient who comes in and isn't really missing work, but is suffering in silence? Do you ever use the novel advanced therapies earlier in them and skip the anti-TNF? Are you still pretty much anti-TNF first for most people?

Dr. Asher Kornbluth:

No. No, I'm definitely not relegating anti-TNF to first-line for everyone, mainly because we now have... At least for UC, we have ozanimod, and I like ozanimod a lot, but I'm careful who I use it in, in terms of I don't like it for the very severe patient, I like it for the moderate patient. And if you think about it, moderate is not so bad in UC. If you have, according to Mayo score, and you should never have to do this in real life, but just as an illustration, you have 4 or 5 extra loose pounds a day, half or less than half, have some blood, and the sig looks moderate, means you got a couple of erosions that makes them moderate, that's a patient who you could go to ozanimod after failing 4.8 grams of 5-ASA and/or topical therapy. I like budesonide in the form of Uceris a lot for those patients, but there's no maintenance strategy for those patients.

So, here now, you got a drug. It's PO. I like it for the moderate patient. I'm not putting it first, or even second-line, in the hot patient. We have a lot of good agents for that. It's beautiful in terms of it's oral, it's not immunogenic, it's a small molecule, you don't need to do drug levels, and there are no such thing ever, and it avoids, since it's not immunogenic, that whole discussion about combination therapy, so that's the beauty of S1Ps. And may I add, the same thing goes true for the other orals, the JAKs. Right now, we have tofacitinib, Xeljanz, and upadacitinib, Rinvoq. But also to extend that combo nightmare discussion, since vedolizumab and ustekinumab have such infrequent antibody formation, under 5%, I almost never will use concomitant thiopurine or methotrexate. If the patient comes into either vedo or ustekinumab on it, generally, I'll leave them on it for a few months rather than the pull the rug out from under them. Maybe it's doing something on its own. But by and large after the first few months, I have the benefit of not having to deal with a thiopurine.

When patients first came to me and were freaked out about getting started on ustekinumab or vedolizumab because they thought they were biologics, for a while, it struck me how freaked out they were about biologics. Then I realized it was because, in IBD, the only biologics we had for 18 years were the anti-TNFs. And to their mind, anti-TNFs "cause cancer", they increase the risk of lymphoma. So, I finally recognized that and I see that look on their face when I say, "Yes, this is a biologic." And I say, "All a biologic drug means is that the drug was prepared in part in a living cell. Ancient porcine insulin, in part, pig, that's a biologic in that sense. Humulin, humanized insulin, that's a biologic." So I try and put that concern to bed, especially with those drugs, like vedo or ustekinumab, and now presumably risa, that don't need concomitant thiopurines, which are really the bad actors.

Dr. Raymond Cross:

I completely agree, and I really like ozanimod. Also, for the listeners that want to learn more about ozanimod, David Rubin did an IBD Drive Time with us and really, I think, allayed some of those safety concerns that came out when the drug was first approved, which are really, in my mind, overinflated. And I find patients really like it because it's an oral therapy. And thus far, I've been really delighted with the safety.

Before I move on to a couple more questions for Asher, I just want to remind the listeners that IBD Drive Time is sponsored by AIBD and the Gastroenterology Learning Network, and we have an in-person regional Advances in IBD in Baltimore, March 31st to April 1st. It's a half-day Friday afternoon and all day Saturday, and, Asher, you too are invited to attend.

All right, so I want you to look into your crystal ball. What's going to happen when we have adalimumab biosimilars? So, how's the landscape going to change, if at all?

Dr. Asher Kornbluth:

To my knowledge, I think there are 10, count them, 10 biosimilars to adalimumab. Why? Because it was before, about 10 years now, the largest grossing drug on the Planet Earth, period, the end, so a lot of people want into this game. The one that might be out first is going to change how we practice in terms of we're going to have less options, obviously, to give the proprietary, or reference compounds is the way we refer to the originator. And I think a lot of us have struggled with the "step through therapy", another appeal letter written on the CCFA page, that you need to use adalimumab before anything else, which is okay for Crohn's in my mind, not okay for ulcerative colitis, which we felt all along. And finally, as you know, we have the VARSITY trial, which you folks have covered on a prior Drive Time, where vedolizumab definitely looks better than adalimumab in UC.

What's even more perhaps problematic in our choice is when ustekinumab will, I believe sometime in 2023, have a biosimilar, and then we will perhaps be forced to use the biosimilar for ustekinumab, Stelara, whatever that biosimilar might be. Now that is going to be a problem, presumably, for the drugs out there that are proprietary and newly approved as anti-IL-23 drugs, not anti-IL-12/23, but anti-IL-23. One of them is already on the market, risankizumab. We're probably going to have two more anti IL-23s proprietary newly approved, probably within the next 12 to 18 month. One is guselkumab, and one is mirikizumab.

So you will now have 3 presumably, anti IL-23s versus, possibly, the biosimilar for anti-IL-12 and 23. Now, in that regard it might be a problem. We might be forced to use a biosimilar for anti-IL-12 and 23, which is a very effective drug, but competing against probably far, far more expensive anti IL-23 drugs.

This is such a problem, perhaps, that Janssen—and this is public knowledge, this is on clinical trials.gov—wants to replace their use of Stelara because they're presumably going to lose it to a biosimilar, and prove that their anti-IL-23 is better than their own drug, ustekinumab. Because if ustekinumab's a biosimilar, ain't nobody going to get the originator.

And that's a bold bet because if the biosimilar of ustekinumab is as good as proprietary anti-IL-23 of Janssen, known as Tremfya, I think we'll have a real problem getting an anti-IL-23 brand new drug approved by the payers. So we will eagerly await the results of that trial.

Dr. Raymond Cross:

So yeah, I think for the listeners, unfortunately, our lives aren't going to become simpler with those biosimilars, but hopefully cost will come down. Coming back to your mentor, Henry Janowitz, for the listeners that have not read his book, if you can still find it on Amazon. I read it as a fellow, and it is amazing how good the practitioners were back in that era and managing these patients with very little in their armamentarium, so it's a good read and I should probably read it again. All right, Asher, tell the audience something about yourself that they may not know or that I may not know even.

Dr. Asher Kornbluth:

Well, there's really very, very little of interest. I was a D1 in college, a D1 defensive end... No, actually, that was you, Ray. I forgot, sorry.

Dr. Raymond Cross:

Division 3. Don't give me credit for Division 1.

Dr. Asher Kornbluth:

All right, I'm sorry.

Dr. Raymond Cross:

I would be the smallest D-end in the history of Division 1.

Dr. Asher Kornbluth:

And I was also a D1 swimmer... Oh no, that was Millie, actually.

Dr. Raymond Cross:

Right. She truly was a D1 swimmer.

Dr. Asher Kornbluth:

I know, I know. I could barely play softball with a bunch of Jewish kids in Brooklyn College, so I got nothing to brag about. I stand among giants.

Dr. Raymond Cross:

All right, Asher, this has been wonderful. I learned a lot. As always, thank you for joining us, and hopefully we'll have you on again in the future.