IBD Drive Time: Raymond Cross, MD and Millie Long, MD Inaugurate Podcast Series

Welcome to a new podcast series, IBD Drive Time. Our regular moderators Raymond Cross, MD, and Millie Long, MD, will host regular discussions on anything and everything related to managing inflammatory bowel disease. In this first podcast, Dr Long reviews the SERENE study of high-dose adalimumab in ulcerative colitis, and Dr Cross discusses the STARDUST study of ustekinumab in Crohn disease.

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.

TRANSCRIPT:

Raymond Cross:  Welcome, everyone, to the inaugural episode of "IBD Drive Time." I'm Raymond Cross, professor of medicine and director of the IBD Program at the University of Maryland School of Medicine.

I'm very happy to introduce my cohost for this series, Millie Long, who's an associate professor of medicine and director of the Gastroenterology and Hepatology Fellowship Program at the University of North Carolina at Chapel Hill.

The goals of this podcast are to educate gastroenterologists and advanced practice providers on the most up-to-date research in IBD, as well as management dilemmas in our most complex cases. We envision that this would be a 20-minute podcast and that providers could even listen to this on the drive to or drive home from work—therein it's the IBD Drive Time.

For our first podcast, Millie and I are going to go over 2 very important studies that were recently presented at UEG: the SERENE-UC study as well as the STARDUST trial.

Future topics may include COVID-19 vaccination in patients with IBD, the role of dietary therapy and Crohn's disease, and novel surgical approaches in the management of Crohn's disease.

I'd like to introduce Millie Long. We're going to discuss the SERENE-UC study. Welcome, Millie.

Millie Long:  Thanks, Ray. This is going to be fun. We're going to have a good bit of time here on our so-called drive to talk about 2 important studies that could actually change my practice. Let's see if you agree.

Let me first do a brief overview of the SERENE-UC study. Then we can run through what our thoughts are on it. I thought that this study might turn out in a different direction. In my clinical practice in UC, I felt using higher dose was maybe improving some of my outcomes. This study sought to prove that.

What they did is they did a randomized controlled trial, where they randomized patients with ulcerative colitis to either high dose, and by high dose I mean very high dose, even starting with 360 mg, induction as compared to standard induction.

Then individuals were rerandomized in terms of maintenance, and maintenance, they could be in either a weekly arm, or a therapeutic drug monitoring-guided arm, or a standard dosing arm.

What were the results? For the induction there was no difference. Clinical remission at the end of induction was 13% in the high-dose arm and 11% in the standard arm. It didn't improve either clinical remission or the endoscopic outcomes in their postinduction.

For the maintenance in this study, individuals that were randomized to the therapeutic drug monitoring arm were increased on dosing if they had a level less than 10 of adalimumab, or if they had rectal bleeding subscore greater than or equal to 1. In other words, they had some relapse symptoms or their level was less than 10.

Then the other 2 arms, of course, were standard dosing or weekly dosing. Essentially, what the outcomes showed is that overall for those who are on weekly adalimumab, approximately 40% ended up in clinical remission as compared to 29% in the every other week. This didn't meet statistical significance, but it was close.

Then in the therapeutic drug monitoring arm, about 37 % ended up in clinical remission. Overall, these arms were very similar for maintenance. In essence, we have a study that high-dose induction didn't change immediate outcomes. Then in the long term, particularly the weekly adalimumab was not any different than the therapeutic drug monitoring-guided adalimumab.

I mentioned that this changed my practice. I want to throw it back to Ray. Did this change your practice, or what are your thoughts of how this impacted your management of ulcerative colitis?

Dr Cross:  Millie, we all thought that adalimumab was a fine drug until you see that it was underdosed and being responsive to the key account leader's opinions on this, this study was designed to test that. As you said, despite giving very high doses of induction, doses of adalimumab, it didn't have a meaningful difference on short-term response rates.

I practice proactive therapeutic drug monitoring anyway, and certainly use reactive testing as well. Pragmatically for me, it doesn't change what I do for maintenance. What would have changed for me would have been the dosing for induction. That's not going to be possible with these results, and pragmatically giving that much drug isn't going to happen.

Dr Long:  Right. For me again, high dose isn't necessary for induction. For maintenance, an easy button if someone isn't perfect going into weekly adalimumab is comparable to doing therapeutic drug monitoring. There are a couple of different ways to handle the maintenance data.

Remember, this was a pick-the-winners design in that only responders were randomized into maintenance. Remember that it was relatively low numbers that reached clinical remission after induction.

Then those that responded, of those about anywhere from 35% to as high as 40%, were in remission at a year. Keeping those numbers in mind is also helpful. It helps you to understand where this drug may fall in terms of positioning and efficacy for our patients.

Dr Cross:  Millie, I want to follow up on your summary. There's some confusion about the overall results and then the integrated results which included a substudy of Japan. Can you clarify that for the listeners?

Dr Long:  Absolutely. I mentioned that the main results for maintenance did not reach statistical significance for a weekly adalimumab maintenance as compared to every other week. However, there was also a separate study performed in Japan, and once those results were integrated, there was a significant difference between weekly and every other week.

That's where those data come in. Granted that was a separate study that was integrated, but overall, it demonstrated the same theme of about a 10% delta between the weekly and the every-other-week.

Dr Cross:  Millie, to follow up on that, now that the integrator analysis show that there is a significant difference for maintenance, you are not a proactive drug monitoring advocate. In your practice, are you going to automatically place your patients on adalimumab weekly for maintenance if they respond to induction?

Dr Long:  I'm going to have a very low threshold to do that based on these data. In my clinical practice, frankly, I do use adalimumab in ulcerative colitis. There are many instances where this could be a good drug. Many of my patients have a preference for an injectable agent as compared to an IV agent. If they have more moderate disease, then adalimumab is a reasonable option.

Most of them end up on weekly, anyway. This is what I found in my practice, and again having that low threshold to get there. I will say, and I don't know if this is true for you, Ray, but more recently I've been having a lot of insurance difficulties with getting weekly adalimumab. There's always a fight there as well, but I try to be prepared and have data such as these at hand.

Dr Cross:  This is a common problem around the country, and maybe in one of our future podcasts, we'll have Dave Rubin come in, teach us how to use Twitter to try to shame payers into paying for things, be it any dose escalation we're struggling with.

One plug for proactive monitoring may be that in this study you can avoid dose escalation in approximately 1 in 5 patients. That may be one reason to want to implement this for adalimumab in your clinical practice, but I don't think Millie and I are ever going to agree on that.

Millie, you've already told us how you position adalimumab in practice; my sense is, other than lower threshold to escalate, probably not going to change what you do very much.

Dr Long:  You and I practice similarly, Ray, and likely similarly to many of the folks out there listening. If I have a severe UC patient who is biologic naive, I am going to use infliximab in that patient. Obviously, it has our best level of data in acute severe ulcerative colitis.

When you're in a realm in the outpatient world and you have various options for treatment, I have a shared decision-making discussion with my patients. One of the data we didn't talk about is, we also have the VARSITY Trial that showed that vedolizumab was about 9% greater in terms of efficacy as compared to adalimumab. I think that that's something to consider.

When you're talking to a patient about efficacy and safety, vedolizumab has become much more a first-line agent for me for a moderate patient out there. However, you've got to also give the patient a drug that they're going to be able to take and be able to continue to use consistently.

For patients who travel a lot, for patients who aren't able to come in for infusions, we’ve got to think about other options, and that could be adalimumab. It certainly could also be ustekinumab, which also, obviously, has quite efficacious data in ulcerative colitis as well.

As a reminder is that one-time IV infusion followed by acute 8-week maintenance injection. That's how you think about it too, Ray?

Dr Cross:  Yeah, I agree. In your less sick outpatient, we should try to pick the safest drug first, and that is ustekinumab and vedolizumab. I don't think that's debatable. Depending on where you live, these drugs may not be positioned within the formulary of the payer in such a way that you can use them first-line, and frankly, adalimumab is often positioned in that area.

I think, in a patient who doesn't have a compelling reason to be on one of these agents, if they say adalimumab is approved, and they're not that ill as an outpatient, I'll absolutely give it.

I tend to use combination therapy and that situation to try to enhance the PK, but given the SERENE-UC results, I'm not sure that that's even the right strategy, although the guidelines are to use combination therapy in general.

Dr Long:  I was going to bring that up myself. You and I differ on proactive therapeutic drug monitoring routinely. I think we practice very similar from that perspective that the data are fairly clear that a TNF combination therapy with an immunomodulator can improve outcomes, particularly for induction and frankly maintenance permission early in the course of disease.

I often will use combination therapy upfront, get the patient into a deep clinical remission. Then I'll think about backing off or potentially dropping the immunomodulator. I think that many of the risks that we all know about associated with immunomodulators are more with long-term use. The idea of using it in the right place up front is very important.

I want to emphasize that to me, thiopurine is not dead, I still use thiopurines. I know you use more methotrexate, but I know you use thiopurines too.

Dr Cross:  Yeah, of course. Millie, 2 more questions. One, any critiques of this study, any major flaws that you can really point out to the listeners?

Dr Long:  It wasn't powered for the TDM arm. I want to emphasize that that was more of an exploratory arm from that perspective. We can't make firm conclusions surrounding therapeutic drug monitoring.

But overall, this was a robust randomized control trial. It doesn't have the combo therapy piece that may improve efficacy associated with this therapy. That's one aspect that is missing.

We may see better numbers if we're using thiopurine associated with adalimumab in terms of this first year, but it is important data. These are data that you can also argue with insurance companies, particularly the integrated analysis for your weekly adalimumab.

Dr Cross:  One thing I forgot to mention in the introduction, this podcast is also going to give us a chance to learn about our faculty. The last question for Millie before we talk about STARDUST is, tell the audience something about you that they may not know, Millie?

Dr Long:  By the way, Ray just surprised me with that question. I've got to figure out what is going to come to me at the top of my head. I'm fairly an open book, I will say I am a big swimmer in the real world, and do enjoy swimming and with some of our other IBD colleagues, I've done a few triathlons.

People may not know that Maria Abreu is an avid triathlete as well. There's a nice little community of IBD people who enjoy those types of things.

Dr Cross:  Millie's being a little too humble. She was a Division I collegiate swimmer, more than just an avid swimmer, I would say.

Dr Long:  Ray, Watch out, that question may be coming back to you after STARDUST.

Dr Cross:  OK, before we talk about STARDUST, I want to thank Advances in IBD and the Gastroenterology Learning Network, who are supporting this podcast. Speaking of advances in IBD, there is an upcoming virtual regional program in Houston on June 19th.

In 2 weeks, we plan to have our next podcast, which is going to focus on pregnancy and IBD. I'm going to turn it over to Millie to ask me about STARDUST.

Dr Long:  We had fun selecting these two studies from UEG that we thought might make the biggest difference. Ray, give us an overview of STARDUST. What happened in this study? What was it? Our drive-time participants may not be aware.

Dr Cross:  Thanks, Millie. STARDUST is a complex trial design. It's a phase 3b, randomized controlled trial of patients with moderate to severe Crohn's that failed either conventional therapy or one biologic. They’re defined moderate to severe, not only based on symptoms.

All of these patients had a baseline endoscopy and using the SCS CD, which is one of the standardized endoscopy scoring systems. They had to have a score of greater or equal to 3 to be included in the study. The study was designed for 48 weeks, and the primary endpoint was an endoscopic endpoint of a 50% or more reduction in the STS CT score from baseline.

Five hundred patients were included, and they received standard intravenous weight-based induction dosing of ustekinumab followed by 90mgs at week eight.

At week 16, the responders were 88% of the patients responded which is striking, but at 6 weeks, patients were randomized to either a treated target arm or a standard of care arm. In the standard of care arm, patients that responded received 90mgs of ustekinumab every 12 weeks for maintenance.

That is different than the maintenance dosing we use in the US. During the follow-up from week 12 to 48, clinicians could adjust the dose of ustekinumab based on their clinical intuition, whether it be symptoms, biomarkers, etc., they can escalate the dose.

The treat-to-target group underwent a week 16 colonoscopy. If they had a 25% or more decline in the SCS CD from baseline, they received ustekinumab every 12 weeks. If they had less than the 25% improvement, they then went to 90mgs every eight weeks.

At the follow-up visit, if they had a CDAI score of 220 or higher, or a CRP that was above 10, or a CALPRO above 250, they could then escalate. So, if they were on 12 weeks, they went to 8 weeks, 8 weeks went to 4 weeks, if they were already on 4 weeks they exited the study.

Dr Long:  It's complicated, but so important because this is one of the first treat-to-target studies outside the TNF class. It's among the first to use endoscopy to help us with stratifying into those groups.

Dr Cross:  Yeah, to my knowledge this is the first one that used endoscopy to stratify the treat-to-target. Most of our listeners will be familiar with the CALM study, John Frederick Colin Bell is the lead author in that.

They used a combination of symptoms and biomarkers to escalate at adalimumab in Crohn's disease, starting with immunotherapy, escalating to weekly if needed, and then adding an immune suppressant. That study did show superior endoscopic outcomes compared to the standard of care treatment. This is different in that they're using the endoscopy at week 16 to start to dose escalation if needed.

Dr Long:  That might be something we do in practice. We often are using a treat-to-target approach, and I want to see how my patient is after they've been induced, and use that to help to determine what to do next. This is probably about right, wouldn't you say, for when you might relook in practice?

Dr Cross:  Yes and no. Often what we do in clinical practice is at 60 or 90 days we reassess based on symptoms and biomarkers. If they're not doing great, we're already adjusting. This is using the endoscopy first and then adjusting based on symptoms and biomarkers after.

In real life, it's more of a hybrid approach, where you're adjusting even before that 16-week or 26-week colonoscopy. It's a bit of a mix, but this is what we do in real life.

Dr Long:  You've baited us with that complicated design. What were the results? What happened?

Dr Cross:  The primary outcome was endoscopic improvement. In the treat-to-target arm about 38% hit that benchmark, and it was about 30% in the standard of care arm, which was not significant using nonrandomized imputation.

When they looked at it using last observation carried forward, the results were better for the treat-to-the-target arm, it was 40% and about 31% in the standard of care, which was statistically significant. There was about a 10% delta for endoscopic response in a dose-escalation arm.

If you look at clinical parameters, they're again quite striking. Clinical response rates at 48 weeks were in favor of the standard of care, 78% to 68% remission, and 70% in standard of care versus 61% in the treat-to-target.

This is another interesting facet of this. At 48 weeks of responders which is in the majority, about 60% of patients were able to do well on the every 12-week dosing of ustekinumab. In and of itself, that's an important take-home message in this.

Dr Long:  Absolutely. Overall, results were similar, but I don't think that this is, nor do I think you think, that this means treat-to-target doesn't work. Treat-to-target is effective and does work, but this drug's different. This isn't a TNF. What do you think it is about ustekinumab that makes it so that this treat-to-target may not be as necessary with ustekinumab?

Dr Cross:  With this drug, this confirms what we're starting to learn, is the PK of this drug is good. It was manufactured in such a way that most patients have drug in their system before their maintenance dosing, and there is very little immunogenicity.

We're applying dose-escalation approaches for ustekinumab based on what we've done with anti-TNF, which may not be an appropriate strategy. I'm not saying that you shouldn't dose escalate, but when I look at studies like these, it makes me pause before I dose escalate because dose-escalation is expensive, and wonder, am I doing the right thing by going to 6 weeks and 4 weeks now?

They could have used drug levels here, and if we'd agree that the drugs should at least be there. Some would say it should be above 4 1/2. You could argue if you had a robust drug level, are you going to get any benefit from going to 6 weeks or 4 weeks?

That is one wrinkle here that could have been added, and maybe some of this dose escalation wasn't necessary. Pragmatically, in real life, if this is your third biologic, you're going to optimize people to the very end because you're running out of options.

You don't have a lot of other choices for management, whereas if this is the first biologic and the patient's not doing well, I'm not sure we should be waiting 3 to 6 months to try to optimize them, particularly if the drug level seems to be good. What do you think?

Dr Long:  No, I agree. In a patient where this might be my first treatment, who seems to be a primary nonresponder to this therapy, based on these data, I am no longer trying to jump through hoops and dose optimize them. I'm really not.

Each scenario is different, but these data show us that the pharmacokinetics of this drug are good. That's helpful to know particularly in a patient who still has other options. The final bit to talk on ustekinumab before we do our summary and wrap up, because drive time is getting to an end. By the way, I still have to ask you your question.

Before we go there, combination therapy. Do you use much combination therapy with ustekinumab? In this study, it was not a part of it. Is that a problem? Is this something that we should be doing?

Dr Cross:  Most post hoc analyses show that continuing an immune suppressant isn't really associated with better outcomes. We saw that with the anti-TNFs as well. When ustekinumab first launched, patients were all treatment refractory. Many of us were trying to maximize mechanisms of action because we didn't have anywhere to go.

Many patients in the beginning of our practices with this drug, wrong combination. Now, knowing what I know and with the emerging data, if I have a patient on immunosuppressant, I won't continue it. I'll stop it unless I'm trying to be aggressive with treat-to-target, and I want to leave it on just in case I'm going to go back to anti-TNF to prevent immunogenicity.

I'm certainly not using low-dose for enhanced PK, because I don't know how you can enhance the PK. In short, I don't think it's essential unless you're worried that you might need to go back to an anti-TNF and want to prevent immunogenicity.

Dr Long:  I agree. I think that's a great take home point. Ray, now before we wrap up, tell us something interesting about yourself that our audience may not know. You could stick with the athletics theme. I know you're an athlete yourself or go in a totally different direction.

Dr Cross:  I'm going to go in a totally different direction because I bet you don't even know this about me, Millie. I'm actually a decent gardener. I, 2 years ago, had a massive yield of cucumbers. One of my friends gave me a pickling recipe. Apparently, I make very good pickles as I've been told, and I bet you didn't even know that.

Dr Long:  I did not know that. That's good to know. You got to plant some zucchini next time. I make a good zucchini bread. That's great to hear. Let's wrap up. I'm going to do 1 minute SERENE-UC, your take-home points.

Ray's going to do 1 minute on STARDUST, and then you'll hopefully leave having gained that knowledge for your clinical practice and come back to see us on your next drive time.

Jest remember that high-dose adalimumab does not improve short-term outcomes for induction of ulcerative colitis, but that weekly adalimumab in integrated results does show some benefit over every 2-week adalimumab for maintenance of remission in UC. Ray, what about STARDUST?

Dr Cross:  In summary, STARDUST showed that clinical outcomes in patients with Crohn's treated with ustekinumab are not superior using a treat-to-target approach compared to a standard-of-care approach. However, there is about a 10% endoscopic improvement in patients undergoing a treat-to-target approach without any decline in safety.

Dr. Long:  Great. With that, we will wrap up. We look forward to having you back on the next IBD Drive Time.