IBD Drive Time: Erin Forster, MD, on Risankizumab for Ulcerative Colitis

Dr Erin Forster of the Medical University of South Carolina joins IBD Drive Time hosts Dr Millie Long and Dr Raymond Cross to review results of the trials for risankizumab in ulcerative colitis and discuss its positioning in treatment. 

Raymond Cross, MD, is director of the IBD Center at Mercy Medical Center in Baltimore, Maryland, and professor of medicine at the University of Maryland. 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. Erin Forster, MD, MPH, is an associate professor of gastroenterology and IBD specialist at the Medical University of South Carolina in Charleston, South Carolina.

Hello and welcome to IBD Drive Time. I'm Millie Long, and I'm here with my cohost, Ray Cross. I'm at University of North Carolina and our IBD Center.  And Ray is now at Mercy Medical Center in Baltimore, Maryland.

We’re thrilled to have a guest today who will be speaking to us on our newest drug approval, which is risankizumab for ulcerative colitis. So I’d like to welcome Erin Forster, who is currently associate professor of medicine at Medical University of South Carolina. She also has other leadership roles there, including director of the IBD Center and director of their IBD Fellowship. She also has other leadership roles there, including director of the IBD Center and director of their IBD fellowship. So Erin, welcome to IBD Drive Time.

Dr Forster: Thanks so much, Millie and Ray. I'm really excited to be here and talk about RISA.

Dr Long:  Oh, yeah, we're thrilled to have you. Just as a reminder for our listeners, we are sponsored by the AIBD Network. And also our podcast is available on Apple and Spotify. So please find us in a convenient location.

So Erin, let's get started. My first question is going to be an obvious one which is, risankizumab was just approved for the treatment of ulcerative colitis. Can you talk us through the pivotal trial design that led to this approval?

Dr Forster: Absolutely. So fortunately on July 22 in JAMA the results from the phase 3 study design for INSPIRE and COMMAND were published. Leave it up to the IBD folks to come up with such motivational names for their trials. In INSPIRE, there were 2 kind of groups of patients. You have the patients who are receiving 1200 milligrams IV of risankizumab. If I call it RISA later in the talk, that's because that's how I've come to name it. And they were randomized in a 2-to-1 fashion, drug to placebo, which has favorable odds for a  patient you might be talking about in terms of clinical trials. And this was unique in that 50% of the patients were what we would consider bioexperienced. And so you have to take that into consideration in shared decision-making conversations— is this data applicable to my patient?

In this trial design, there were 3 doses, 3 IV loading doses at weeks 0, 4, and 8, so somewhat familiarish doses. And the primary endpoint, which was clinical remission, was defined at week 12. The secondary outcomes will go over a little bit later.

In the maintenance trial, which was called COMMAND, which was using patients who had received at least one dose of the 1200 milligram IV dose of RISA were rerandomized in1-to-1-to-1 into 360 milligrams, 180 milligrams, and placebo. So keep in mind that placebo is kind of a withdrawal arm. So patients could have received RISA in the beginning, and later were not receiving RISA. But if you imagine the dose, if you compare the UC dose to the Crohn's dose, 1200 to 600, you might have some treatment persistence. And so that will be important when we talk about results coming up next.

Dr Long: Oh, great. No, I think it's really helpful to try to think through the design as we then talk about a number of the results. And certainly it's a similar design to the Crohn's disease trial. I think, interestingly, as we talk through the results, there's going to be a different outcome in terms of the induction dosing in the very least. So talk to us about what were the main results of the induction study?

Dr Forster: Absolutely. So it's really important to distinguish between primary outcomes and secondary outcomes. So the primary outcome for this trial was clinical remission. And so that's different than the secondary outcomes of clinical response and all of that. So the prize, the Holy Grail is clinical remission. And so you would expect patients to be doing really well at that week 12-time frame. So the primary endpoint for this trial would be clinical remission.

And what does clinical remission mean when you're talking about it in a formal sense? That would be a stool frequency score of less than equal to 1 and not more than baseline, a rectal bleeding score of 0, and an endoscopic subscore of less than or equal to 1 without friability. So that's a pretty stringent endpoint that includes both patient-reported outcomes that make up the adapted Mayo score, the stool frequency and rectal bleeding, as well as the endoscopic subscores. So patients were getting scoped at time 0, week 12, and week 52.

Dr Long: I agree, that’s a very robust outcome. I mean, that’s what our goals for our patients are. So tell us, what happened at the end of 12 weeks?

Dr Forster: Well, at the end of 12 weeks, they had very robust responses that were clinically significant. So in those patients who were defined as having clinical remission, there were 20.3% of patients in the RISA arm that achieved that. And single digits, only 6.2% of the patients receiving placebo hit that outcome. So that's pretty serious because sometimes you see like heavy double-digit placebo response rates.

Dr Long: Right. So I think it shows it's a pretty robust outcome. Certainly a delta as compared to placebo.

When I've always kind of asked—we'll do this for both the induction and the maintenance—what happened when they were stratified by prior TNF exposure? You mentioned that about half the population had been previously exposed to other biologics, so I think this helps us a lot with positioning. How were the induction data different for those who had prior exposure versus those who had not?

Dr Forster:  Actually, the induction results for patients who had prior exposure still showed a difference—11.4% of patients with bioexposure versus 4.3% who were on placebo showed achievement of that response, which still, you know, shows a good response, but certainly muted, which we would come to expect because you know the general thinking around first drug is the best drug, or making sure that your first selection is a very thoughtful one, matters. Perhaps the immune system is primed in that first drug and you can have diminishing returns on later agents.

Dr Long: I totally agree, but that’s a different thing. I mean 11% vs 4%, that’s not a very robust response in exposed individuals. And so I think that I think I may incorporate that into my clinical decision making.

And it's interesting because when we look at some prior network meta-analysis data, it looked like maybe the IL-12/23s, and you would think the 23s would be pretty good in that group—but we didn't see that differential in effect. So I think more study is needed, of course, and this is a subgroup analysis, but it does speak to the fact that the IL-23s may be different in UC as compared to Crohn's, would you agree?

Dr Forster: I would, and I'm glad you brought up network meta -analysis, and, you know, as we enter phases where there may be head-to-head trials that are for Crohn's, but not ulcerative colitis, we have to be careful just extrapolating black and white from one disease course to the other, even though potentially we're getting enough gas in the tank with a higher dose, you know, the 1200 versus the 600, but, you know, it's, it's important that we take those things into consideration.

Dr Long: Well, teach us a little bit about the maintenance results. What happened in maintenance for RISA?

Dr Forster: Well, in contrast to the secondary outcomes, which were very much hit across the board, including some new outcomes that were brought up in this trial as a result of the STRIDE II publication, in the maintenance phase, there were some differences, but it seemed perhaps less strong. And actually, you might get some questions about why the 180 versus 360, because you'd think more is better, but that actually, like, didn't exactly play out.

In fact, in some scenarios, the 180 outperformed of 360. In fact, in many of the categories. So if we talk about the primary endpoint, again, clinical remission, in the 180 dose, they were 40.2 responsive compared to 37.6, which is still not that far away from 25.1, which was the placebo response rate.

And so this is sometimes hard to interpret because there's 3 groups we're looking at here. And so you can look at the between-group differences and look at clinical significance and things like that. But again, though they hit their primary outcome in maintenance, the secondary outcomes weren't uniformly positive as they were in the induction. So there was a lot of bang up front and then, you know, perhaps somewhat less. But again, like we talked about, there were patients who were randomized from the 1200 dose in induction and then got nothing in, so maybe some treatment persistence there, like a hangover effect of the medication.

Dr Long:  Right.  Absolutely. I think that could be playing a role. So one last question for me before I turn it over to Ray for some additional questions, which is, what about in maintenance when you stratified by prior biologic exposure versus not? Was there a difference there? We saw something of a difference with the induction data.

Dr Forster: Yeah, so the differences became even more muted in the maintenance phase between the doses. So there were significant differences in the primary outcome between the 180 and the placebo dose, but not so with the 360 and the placebo dose. And as we continue to move down the outcomes, that difference remained less robust.

Dr Long: Okay. So yet again, kind of helpful secondary analyses subsets that help us with positioning. But I know Ray was going to ask a little bit about as well. So Ray, let me turn it over to you for more questions for Erin.

Dr Cross: Yeah, thanks, Milly and Erin. And just before I ask Erin a few more questions, just a reminder to the listeners that the national in-person Advances in IBD meeting in Orlando will be December 9th to December 11th. So we hope to see you all there. Bring your kids before Christmas to Disney.

Erin, so we talked about efficacy, and I'm going to come back to efficacy again in a second. But before I do that, we generally think the IL-12/23s and IL-23 inhibitors are really safe mechanisms of action. Any relevant safety issues that came up in the trial with RISA?

Dr Forster:  I think we can still live in the world where the 23s are considered a safe agent. If we consider the time frame of this study, which had enrollment from August 2018 to March of 2022, there was kind of a big thing that happened across the world called COVID-19. And so that was actually the most prominent reported adverse event. So 5% of patients were diagnosed with COVID-19. Anemia was a second there, with 3.4% of the patients in the RISA group experiencing that. They also reported some worsening of ulcerative colitis, but you might imagine that could be the case, especially in the placebo arm.

There were very low rates of serious adverse effects comparing RISA to placebo, 2.3% to 10.2%. The scarier outcomes, like death—fortunately there was only treatment-emergent death in the RISA group and that was due to respiratory failure due to COVID 19 pneumonia. So that’s something we can understand in that context. There were two malignancies. One was a colon adenocarcinoma that ultimately proved fatal.

They did note that that diagnosis kind of existed prior to administration of the first dose of drug, which would be more than the context of this talk, but if it was already there, then, you know, should they have been in the trial? And the second malignancy was an invasive ductal breast carcinoma in a person who had a history of a breast lump. So I think we can feel very safe in the utilization of this medication. I feel that way in the Crohn's population.

And as we continue to get more information, especially in things like pregnancy, as patient are deciding between ustekinumab or what a next agent might be after ustekinumab, we can feel pretty good about it.

Dr Cross: And in the Crohn’s study, there was one episode of presumed drug-induced hepatitis. And so obviously you were getting labs around the time of that third infusion, which is pretty standard anyway, but I don’t remember in this trial that they saw any events that were possible drug-induced hepatitis. I’m sure there were some abnormal LFTs here and there but I can’t remember them having any severe cases, if I remember right.

Dr Forster: You’re absolutely right. They do report some liver enzyme changes, but no DILI or anything like that. But you bring up a good point that it is a plug for regular lab monitoring for patients that are on biologics. It's not just something we do at the start.

Dr Cross: So for some of the newer therapies like mirikizumab, novel endpoints were assessed like fecal urgency, and we're now focusing on things like we're thinking more about abdominal pain in ulcerative colitis and fatigue, of course. So did they evaluate any novel endpoints in this study or is there anything of interest you'd like to point out? Maybe some of the secondary outcomes.

Dr Forster: Yes, so I'm glad you brought that up because another kind of silver lining of COVID was the publication of the STRIDE II guidelines. And there was some emphasis on some of the quality of life and disability features that patients can have related to IBD. And so this trial predefined secondary outcomes including the absence of bowel urgency, absence of bowel pain, absence of nocturnal bowel movement, absence of tenesmus, and they also asked questions about fecal incontinence, sleep interruption and fatigue scores.

My division director is actually very interested in chronotherapy and sleep disruption. And so it's really kind of exciting to see clinical trials now identifying these types of outcomes, especially because they matter for patients. They're the ones that are experiencing things on a day-to-day basis.

Dr Cross: And, you know, I think when RISA came out for Crohn's, you know, we were so excited because for all these years, second-, third-line therapies, they just don't work as well. And with RISA there was finally an example where that wasn’t the case and it didn’t seem to lose its efficacy. And when MIRI came out and with RISA we were really hoping to see the same thing in UC and it’s doesn’t appear that that is the case. And we don’t really know why, as Millie pointed out, that is. So how are you now going to distinguish? You’ve got MIRI, you’ve got risankizumab, you’ve got ustekinumab, guselkumab’s on the way. How are you going to position these drugs? We’re not supposed to compare across trials but we do it all the time. And so, what are you going to give them?

Dr Forster: Well I’m glad you saved the hardest question for last. So we've mentioned shared decision-making in this podcast already, and I say that that's probably the guiding light of how we all practice IBD. And so I'm going to take a little bit of a straightforward approach and first identify the route and frequency of administration between those medications, because sometimes that's the deciding factor for patients— if they have to think about it every 8 weeks or if it's going to be an every-4-week type of issue. So with ustekinumab, you have an IV load and then subcutaneously administered medication every 8 weeks as standard of care starting at week 8. With RISA, you have the 3 IV loading doses, and then you have that novel on-body injector that's given every 8 weeks starting at week 12.

Now, taking into consideration that sometimes people are really excited about that potential, and sometimes people are terrified about the thought of using this plastic contraption and, you know, thank goodness there's not a needle that's visible, but sometimes patients with less health experience or perhaps more mature patients might be apprehensive about that. And then with MIRI, though it also has an IV load of 3 doses, then it's 2 pens every 4 weeks starting at week 12. So there's some patients who might have feelings about using 2 pens. They might have feelings about the every 4 weeks.

And then we get to kind of the meat and potatoes of things. Millie mentioned network meta-analyses. I mentioned head-to-heads earlier. We don't yet have that data prepared. I'm sure, hopefully, Dr. Singh is already hard at work with his next NMA. But I think right now we can speak to their relative efficacy. But I don't think we're in a place like if we were to extrapolate sequence data to say that the same is exactly true.  You might kind of think that the specificity of a 23 is going to be superior to a 12-23, and I would say that my personal practice leans that direction at the moment, but I don’t think between 23s we’re really seeing that kind of hard outcome. And as you mentioned, guselkumab is about to come market, too, so we’re going to be in an even tighter spot and so we can figure out how that’s going to go, but we’ve already sort of weather the storm and now we’re getting additional indications so sometimes access is what’s going to dictate which medication a patient gets.

Dr Cross: I agree, and I break it down exactly the same way, Erin. And I think honestly a lot of people like just the one IV induction and move on, and I really am looking at the data and I don’t see a big difference between ustekinumab and the p-19 inhibitors. Now I think you brought up guselkumab; now I don’t know if the sub-q induction is going to be approved immediately or if it's going to be intravenous and sub-q. But I think that potentially is the game changer there is to have a sub-q induction, one authorization process, if efficacy and safety is the same. And we'll have to see how that all plays out.

And of course, the payers, right? The payers are going to decide and you're going to learn in your area what, which of these drugs is preferred. And I guess the last point is some patients are sort of just teetering along with their colitis and they're sick, but not sick, sick, sick. And they want to try another drug and another drug and another drug. And it's not unreasonable in someone who is not that ill to keep trying things. And, you know, sometimes you'll find something specific for them that works. So having  more options in those cases is good, I guess.

All right. The fun question, Erin, so tell the listeners, tell me and Millie something about yourself that they may not know. This is the best part of the podcast.

Dr Forster: It really is. Though I really do take after Maria Abreu in terms of liking to dress up for clinic, I also enjoy off-shore fishing. I will absolutely voluntarily wake up at 4 a.m. to drive like 2 hours offshore to slay some wahoo or chase the mahi. My husband and I actually eloped to the Bahamas because we love fishing so much. So we drove our boat down from South Carolina to Florida and then over to Green Turtle Cay, where we fished for a few days, happened to get married on the beach, and then came back to Charleston. So if anybody's in Charleston and wants to go fishing, let me know.

Dr Cross: Well, we’ve got to connect you with Frank Farraye and Ed Barnes, for sure.

Dr Long: Absolutely.

Dr Cross: You're now our third fisher person on the podcast.

Dr Forster: I know Millie loves the runs at AIBD, but maybe we should have like a little fishing tournament.

Dr Cross: It's funny you say that. I am going to be fishing with Frank Farraye and Dr Loftus after the Mayo Jacksonville course in September before I fly home on Sunday. So we're going to do a morning of fishing, which is better than my last excursion, which was in was 30-degree weather near Erie, Pennsylvania, trying to fly fish for steelhead, which is very, very difficult with leaves on the water, very, very challenging. But fortunately, I did not hook Frank Farraye, which was my goal, to not get anyone with my fly reel. And I achieved that goal so that was good.

Dr Forster: Excellent. I know your endoscopy skills shine brighter than perhaps your fishing skills.

Dr Cross: They do, they do. Alright Erin, this has been great, on behalf of Millie and I thank you for doing this and we hope to have you back on IBD Drive Time soon.

Dr Forster: I’d be delighted. Thanks so much for the invitation and the opportunity and I’ll see you in Orlando in December.