IBD Drive Time: Sara Horst, MD, on Risankizumab for Crohn Disease

In this episode of IBD Drive Time, hosts Raymond Cross, MD, and Millie Long, MD, talk to Dr Sara Horst about the newly approved IL-23 inhibitor, risankizumab, and its benefit in treating inflammatory bowel 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. Sara Horst, MD, is an associate professor of medicine Vanderbilt University and a specialist in the treatment of IBD.

TRANSCRIPT:

Dr Ray Cross: Welcome, everyone, to IBD Drive Time. I'm Ray Cross from the University of Maryland School of Medicine. And my cohost today as always is Millie Long from University of North Carolina. And I'm delighted to have my friend and colleague, Sara Horst from Vanderbilt University join us to talk about the most newly approved drug for Crohn's, risankizumab. Sara, welcome to IBD Drive Time.

Dr Sara Horst: Awesome. Thank you. I'm so excited to be here.

Dr Cross: All right, let's jump right in. Sara, can you explain to the listeners that maybe aren't familiar with this mechanism of action, can you describe the MOA of risankizumab?

Dr Horst: Risankizumab is a monoclonal antibody, so we're pretty familiar with those. What this does is it binds the p19 subunit that is on an interleukin called IL-23. And IL-23 is a cytokine that we’ve learned is likely a driver of an immune response down the Th17 pathway. So it promotes proinflammatory cytokines downstream like TNF-α, IL-17, and interferon-gamma. It is somewhat familiar to us because we are also using a drug called ustekinumab and that one also affects the IL-23 cytokine pathway in a little bit of a different mechanism.

Dr Cross:  Great. And the 2induction studies for this drug were named ADVANCE and MOTIVATE. Can you just give the listeners a high-level summary of the results of those trials?

Dr Horst: There were 2 induction studies for risankizumab. So there's ADVANCE and that was a mix of bionaive and bioexperienced patients. And then there was MOTIVATE, and they all were bioexperienced. They had two coprimary endpoints. They looked at CDAI remission, and they also had a subset of that looking at stool frequency and abdominal pain. And then they also looked at endoscopic response, which was a newer endpoint that we haven't seen as much in induction studies. So when you look at these, there was impressive data. So when you look at the clinical remission numbers, I like to kind of look at the delta between the placebo and those who got the medication. There was about a 20% delta difference in both ADVANCE and MOTIVATE, which was really great. And this was really in the bioexperienced patients as well, which is exciting for us to see, because I think we see a lot of patients who've been exposed to biologics.

And then when you looked at the endoscopic response, about 30% of patients had endoscopic response. So they met that endpoint versus 10% of the placebo patients. And really this is a pretty refractory group. Like in the MOTIVATE group where they were all bioexperienced, over half of those patients had actually failed 2 biologics at least, and 20% of those had failed ustekinumab. So to see this response, I think was really good and impressive.

Dr Cross: Yeah. And I think that just following up on that a little bit, I think unfortunately for most of the drugs that are coming to market now they're about as effective as what we have. I think what was unique and you pointed this out, was that in the bioexposed population, the absolute numbers, as far as clinical remission and the delta were really, I think, unlike what we've seen previously.

Dr Horst: Yeah, absolutely. And I really think focusing in on those bioexperienced patients, seeing that improvement was really good to see. So I'm excited about this. I think it's hopefully going to really give us some new strategies to help patients, not only bionaive, but those who've failed biologics before.

Dr Cross: So the 2 induction studies gave intravenous doses at baseline week 4, week 8, and then typical to our other studies that we've seen the responders get randomized. In this case, they got randomized to maintenance therapy first dose at week 12, then every 8 weeks. That was the FORTIFY study. So Sara, do you want to summarize that again for the audience?

Dr Horst: Again, I think we're seeing, when I look at this week 52 data, you see good delta, you've got really good clinical remission rates and endoscopic response is sort of maintained in the group that have already responded. What I think is really interesting is the placebo. So when you look at the placebo rates in the risankizumab maintenance study, so at week 52, the placebo response is really high, like 40% in clinical remission. When you look at that, you're like, what the heck? What is going on? Well, a lot of these patients had actually gotten induction of risankizumab.

So, to me, what's really interesting about the maintenance data is the effect of this drug may be lasting at least for clinical remission a long time. When you really dig into the data, you can see that people who stay on risankizumab there is a statistically significant improvement in maintenance over time. So you really do need to stay on it. And when you look at the endoscopic response, those who were in endoscopic response and maintenance is definitely higher in those who stayed on drug versus placebo. So I think you're starting to see what happens when you stay on it, but if you get a response and then go to placebo, it's just really interesting to see this mechanism of action could be lasting a long time for our patients.

Dr Cross: And it's great that you explained it that way, because we don't want our listeners to think that it's not a great drug for maintenance, that it just works for induction.

Dr Horst: Exactly.

Dr Cross: But it's the long tail of the treatment effect postinduction that really does it. So I'm going to turn it over to Millie. But before I do, I just want to remind everyone that IBD Drive Time is sponsored by the Gastroenterology Learning Network and Advances in IBD. And you still have time to sign up for the AIBD Regional in Chicago on July 23rd, which is in person. So by the time this airs you'll still have maybe a week or 2 to sign up. So I'm going to turn it over to Millie now for the second half of Drive Time.

Dr Millie Long: Of course. Yes. And those AIBD Regionals are great. In fact, Sara participated in one with us earlier at the North Carolina regional and she actually taught us about this very topic. When we think about how we're going to use these drugs clinically, Sara, one of the populations I think of is, I have a lot of patients who've already been on ustekinumab, they've been on this IL-12/23. When you think mechanistically, is there a rationale as to why these may be more efficacious or even potentially safer than ustekinumab or where does that fall out in your mind?

Dr Horst: I think we need some more data. I think how this will play out over time, whether it's IL-12/23 or just IL-23 alone for Crohn's disease, I think we need to learn a little bit more about that. Really, to me, it was pretty fascinating about what the difference is between these two. So when we started to learn about these classes of cytokines, we were really looking at the IL-12 family. And so when ustekinumab and some of these other drugs were being started, they were actually binding p40, which is a subunit that's on IL-12. And that's what we were targeting. Then in the early 2000s, really elegant research found that actually p40 is also on IL-23. And IL-23 is probably the big driver of inflammation in Th17 pathways in inflammatory bowel disease in Crohn's. So I think that's really crazy. We weren't really necessarily targeting this IL-23 and now we found it.

So the question is, if you just target IL-23, are you going to get some advantage over if you target IL-12 and -23? If we stop IL-12, are we decreasing efficacy somehow? In other immune diseases, in psoriasis, there's phase 3 data that actually shows that IL-12/23 versus IL-23, that IL-23 actually has significant efficacy over IL-12/23. So in psoriasis it matters.

Dr Long: Right. And it's really impressive data in psoriasis, too, and it makes you think that this could be true in other autoimmune disease states, but obviously the studies are ongoing. Right now there are several studies that are doing comparative effectiveness, looking at ustekinumab as compared to one of the p19-targeted IL-23 agents.

Dr Horst: And will that matter, will it matter to safety? To me, I don't know. This class is so safe, I think that's one of the things that I love about both of these pathways is that the safety of both of these medications is so great. I mean, basically no increased risk of serious infections. We're not worrying about malignancy. We're not worrying about immunogenicity anywhere near as much as we were with anti-TNFs. So whether that enhanced safety plays out with an IL-23 only, I don't know. IL-12/23 is so safe to begin with. With risankizumab, there is a little caveat to this one over ustekinumab. It is requesting and requiring because there was a patient who had significant liver test abnormalities and induction that with this one, you should check liver tests prior to starting the dose, and then at some point in induction. So for me, that's probably that third induction dose when they're at week 8, because they're at the infusion center, typically we're drawing labs. That's when I'm probably going to draw liver tests.

Dr Long: Well, and you made a great point, obviously the monitoring that's needed, but also, I don't know that we've touched on this. Can you talk about the dosing schedule for risankizumab and how that will be operationalized in your practice?

Dr Horst: Exactly. So it's also a little bit different than ustekinumab, which is a 1-time IV induction dose, and then you go right to subcu. This is 3 induction doses. So your patient is going to have to come in for 3 IV infusions at week 0, 4, and 8. So, that is something that's a little bit different. I think a lot of us are pretty used at this point, giving infusions, but the patient's going to have to understand this isn't just a 1-time infusion and you and your patient are going to have to figure this out and make sure it's going to be feasible for them.

The dosing after that is actually interesting because it's going to be an on-body cartridge because this is a little bit of a higher dosing strategy than the currently available syringes for risankizumab. Because of that, it's going to be a little bit different and we'll just have to learn that a little bit for our patients. But from what I've seen, it looks pretty reasonable. There's some adhesive on the back, the patient will put it on either their belly or their thigh, and then they'll push a button. They'll kind of load a cartridge in there. They'll push a button, a very tiny needle will come out, like a 28-gauge needle will come out, and then the drug will infuse over a period of, I think, about five minutes and then they'll be done.

Dr Long: That's very intriguing. We haven't used one of these before, right? But obviously, this is something that will advise our patients about and it's a very small needle it sounds like. And so we actually think that this will not be a major issue from a site perspective. But we'll have to follow it, right?

Dr Horst: Yeah. And I definitely have patients where sort of the act of having to do a syringe or a pen might be a big deal. So maybe this will offer some advantage to that. I think we'll have to see how that goes.

Dr Long: Let me ask you this. In your clinical practice, where do you think you're going to position this? That's the first question in terms of where you might use it. And the second question is, would you ever consider using this in someone who didn't respond to STELARA or ustekinumab or lost effectiveness? So part 1, where would you position it ideally, and part 1 post-ustekinumab?

Dr Horst: This mechanism, the p19 pathway, has so much advantage. I think for a lot of patients with Crohn's disease using this early, as early as possible is really great. Especially a new diagnosis, inflammatory-only Crohn's disease patient, the safety of this, the efficacy and the low immunogenicity, you can use it as monotherapy. For me, this is a place to go first-line for a lot of patients, personally. I think I will for sure use it for patients who've failed ustekinumab. I think in my practice, I tend to have a refractory group of patients, so I'm always trying to dose escalate and I've just seen enough of patients who I'm having to do that for. And so, if there's some enhanced efficacy with IL-23 only, and I can get that with this sort of dosing strategy and being IL-23 only, I will use it. And I think their data backs this up. There's a few patients, I mean, you're looking into subgroup analysis in the clinical trial, but there were patients who had failed ustekinumab who gained response, clinical response and endoscopic response, with risankizumab.

Dr Long: Great. It's a great tool in our arsenal. And I agree with you that this is hopefully one that could be used earlier, just based on the safety and efficacy data that we have, and the fact that you can use it in monotherapy. I think that, for me, there's still a few areas where TNF and/or combination therapy are really still going to be first line, very aggressive disease, perianal disease, upper tract involvement. I'm probably still going to go with the TNF, but I think this is an intriguing class and hopefully will be quite effective when used in that position. So I'm going to turn it over to Ray because we always ask someone a fun question at the end, and I like to give him the opportunity to ask it.

Dr Cross: Yeah. I agree with everything you said, Millie, just obviously I think patients with skin stuff, so psoriasis and hidradenitis, that maybe this is even more ideal first-line, and then maybe less so for the extra intestinal manifestations, particularly those that we think might not be driven by gut. And my sense here is that for bioexposed patients, this drug is a no-brainer to go to. Maybe the bionaives, it's going to be a battle between the 2 manufacturers to see what rebates and prices that they can capture that are best, but that's okay because they're both really good drugs. So I think that's good for patients. All right, Sara, tell us something about yourself that the audience may not know.

Dr Horst: All right. Well, I was thinking about this, about what's something people might not know about me is I love to play cards. I love to play euchre, rummy, poker, you name it. I'm teaching my kids. My 6-year-old is actually amazingly good at bluffing, which makes me worried about my parenting future to be honest.

Dr Long: That's great. A card game is in Sara's future at the next IBD meeting.

Dr Cross: I did not know that. So Sara and I’ve got to teach you how to play spades at the next meeting.

Dr Long: Yeah. They adore hearts. The tournament is starting.

Dr Horst:  I'm totally in.

Dr Cross: All right, Sara, this has been wonderful. I've learned a lot. I know our listeners have too. Thank you very much. We hope to have you back on Drive Time soon.

Dr Horst: Awesome. Thank you so much.