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Two phase III studies presented at the recent Digestive Disease Week (DDW) virtual meeting evaluated the safety and efficacy of risankizumab (Skyrizi), an anti-interleukin (IL)-23 therapy, in adults with moderate to severe Crohn's disease.

In this final of four exclusive roundtable episodes, 口袋女优 has brought together three leaders in the field: moderator , of Baylor College of Medicine in Houston, is joined by , of Michigan Medicine in Ann Arbor, and , of Yale School of Medicine in New Haven, Connecticut, for a discussion on the encouraging findings and the possible implications for clinical practice.

Episode one: Do COVID-19 Vaccines Protect IBD Patients?

Episode two: Biologic Therapies for Crohn's Go Head-to-Head at DDW

Episode three: 'How Long Do I Need to Stay on Crohn's Therapy?'

Following is a transcript of their remarks:

Hou: Hello, everybody. I am Dr. Jason Hou. I am an associate professor of gastroenterology at Baylor College of Medicine. I'd like to welcome you to the DDW Virtual Roundtable on 口袋女优. We're really fortunate to be joined by two panelists here today: Dr. Shirley Cohen-Mekelburg, an assistant professor at the University of Michigan, as well as Dr. Jill Gaidos, associate professor at Yale University.

Okay. We'll be discussing one abstract focusing on things that are hopefully coming in the near future. This is one of what I think is an interesting phase III clinical trial for Crohn's disease for a medication called risankizumab. Risankizumab is an interesting study. We'll be discussing an abstract that was presented for both ADVANCE and MOTIVATE.

Risankizumab is an interesting agent because it's similar to medicines that we currently have available, in that it is an inhibitor, a monoclonal antibody for interleukin-23, IL-23. However, it's a bit more selective. Instead of targeting the p40 subunit, which blocks IL-12 and -23, like ustekinumab [Stelara], this one focuses on the p19 subunit and therefore is selectively blocking IL-23 without interaction, or at least less so, with IL-12.

In other disease states, this mechanism has shown to be potentially beneficial, so this is an agent that's being studied for Crohn's disease ... well, at least this abstract that we'll be discussing ... we'll be discussing specifically in patients with moderate to severe Crohn's disease.

These studies are parallel studies called ADVANCE and MOTIVATE. ADVANCE included both bio-naive and bio-exposed patients. MOTIVATE was entirely patients who've been bio-exposed, and, again, it was a prospective, multicenter, placebo-controlled, randomized controlled trial.

Each study was very sizable, with about 600-700 patients receiving one of the doses of risankizumab in ADVANCE, about 400 patients on active arm in MOTIVATE, and about another 200 patients on placebo in each of those sub-studies. Overall, fairly encouraging results that met its primary input for both ADVANCE and MOTIVATE. Deltas around 20% in the primary endpoint.

This study had a co-primary endpoint for both, with clinical remission defined by the traditional CDAIs [Crohn's Disease Activity Index scores] we have for studies, as well as the PRO2 [two-item patient-reported outcome score] of stool frequency and abdominal pain to define clinical remission, as well as reaching its co-primary endpoint of endoscopic response at week 12 -- again, in both ADVANCE and MOTIVATE.

So encouraging findings and presentations for a new agent -- again, similar, but new. Similar to what we have available, but importantly different.

I'm curious for the panelists. How do you interpret this? What are some contexts that you would get from this study, and what implications do you think this will have in our clinical practice in the near future?

Cohen-Mekelburg: Jason, I agree with what you're saying, which is that the data is very encouraging. We are in need of new drugs for the treatment of Crohn's disease particularly. I think the data shows us that overall this drug seems to have a good safety profile.

I think one of the questions that comes up, in reading about this trial so far and will be interesting to follow when the manuscript comes out is with this similar mechanism of action to ustekinumab, I know that they actually had a decent proportion of patients who had been ustekinumab-experienced in the trial. I think it will be very interesting to see how those patients did as compared to ustekinumab-naive patients.

I think there are questions, obviously, about maintenance, which I think is to be determined, and that data will hopefully come out in the coming year, and I think one of the questions with this drug kind of on the horizon is how would we position this drug and what would be the added benefit of risankizumab to ustekinumab, for example.

Gaidos: No, I agree. It's very encouraging. I think it's always nice to add to our options of treatment, because for those of us, particularly working in academic centers where we see patients who've been through everything, having something new on the horizon that we can potentially treat our patients with is wonderful to have in our back pockets.

I think one of the things that this study shows, similar to other biologic agents, is that patients who've been exposed to a biologic in the past don't respond quite as well, which I think is ... maybe we still don't know if it's related to longer duration of disease, if it's just to changes in the drivers of their inflammation.

But, again, our first drug is usually the one that we can have the best chance with, and then we really try and do the best that we can with the ones that come after that.

Another thing that's really encouraging is I would love to have another agent with a similar mechanism to ustekinumab to potentially drive the cost down of ustekinumab, so that would really help to open up the market for our patients.

Hou: Yeah, I think those are excellent points. I think that one thing you just mentioned, Dr. Gaidos, is the duration of disease. We were comparing ADVANCE and MOTIVATE kind of together. They're both, again, positive studies, in terms of being placebo. The responses numerically were somewhat lower in MOTIVATE, but I would say compared to ... obviously, the obvious caveat, you can compare across trials.

In some other agents we've seen before, we see a much larger decrement in terms of response, of size of response or response rates in patients who were bio-exposed. They were numerically lower, but I would say not as much as we've seen in other studies.

ADVANCE did have a mix of both bio-exposed and bio-naive, but actually, the numbers that we're looking at for clinical remission, ADVANCE was 45.2%, which was a 20% delta over placebo. MOTIVATE was 42.5% compared to the 19% placebo, so not a huge drop.

Again, it will be interesting to see as that gets studied a little further when they split out some analysis of the ADVANCE study, comparing the bio-naive, bio-exposed patients, of how much of a difference that is. But that's what we would ...

Gaidos: Yeah.

Hou: I'm not surprised by that, but it's not quite as much as ... at least, what we've seen in other studies.

Gaidos: Yeah. I think the biggest difference that you see with this one is in the endoscopic response, and I think the question is, with our Crohn's patients, was maybe 12 weeks too early for some of the patients with longer duration of disease? But, yeah, I think with the endoscopic remission, or the response, that they measured is a little bit different between the cohorts.

Hou: To follow up on a comment Dr. Cohen made earlier regarding risankizumab, I'm encouraged that they included this population. In many trials they were seeing they just, for power purposes, they exclude completely patients on prior exposure with a similar MOA [mechanism of action].

Actually, the numbers were fairly sizable -- almost 20% in MOTIVATE; 20% and 22% to 24% of patients in ADVANCE were prior ustekinumab-exposed patients, because I think it's been used out for so many patients, so that's going to be a key question, is if this continues to advance and becomes available for clinical practice for us in Crohn's, how will you position that for those patients.

Does it have an impact? Does it not? I think we're already seeing it with ustekinumab. It's not behaving in the same ways from an immunogenicity standpoint as we've seen with TNF [tumor necrosis factor] inhibitors.

It will be additionally interesting to see kind of as you go to other similar medicines, but different medicines, does that have the same impact as we've seen with TNF inhibitors when we have multiple drugs in the same class, same MOA?

I'm very encouraged they included that population here, although, of course, we'll be looking into the weeds for some analysis as that data starts to roll out.

Gaidos: Absolutely, and it would be really nice to see what the reason for discontinuation of ustekinumab was of the cohort that was included in this study. Because it would be very different if they had responded, but then their insurance didn't cover it, or they lost insurance, as compared to those who had been treated and subsequently lost response.

Cohen-Mekelburg: Yeah, I think that is going to be one of the most interesting points to follow here from DDW.

Hou: I'd like to thank our panelists, Dr. Cohen and Dr. Gaidos, for this great discussion. Thank you, audience, for listening in for our discussion as well. Hopefully we'll see you on one of our other discussion topics.

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