Dr Rubin reviews results from the GRAVITI and GALAXI phase 3 trials of guselkumab, an interleukin-23/p19 inhibitor, presented at the ACG Scientific Meeting in Phoenix, Arizona, October 27-29, 2025.

David T. Rubin, MD, is the Joseph B. Kirsner Professor of Medicine, chief of Gastroenterology, Hepatology and Nutrition and director of the Inflammatory Bowel Disease Center at the University of Chicago.

TRANSCRIPT:

Hi, it's Dr. David Rubin from the University of Chicago. I had the pleasure of being at the American College of Gastroenterology meeting in Phoenix, Arizona, for their annual 2025 meeting. And among the many scientific abstracts that were presented and discussed at the meeting, there were a number related to the therapy guselkumab, which is an p19 IL 23 inhibitor for the treatment of moderately to severely active Crohn's disease and moderately to severely active ulcerative colitis in adults. I'm going to discuss now the data that were presented related to the treatment in Crohn's disease, which featured three phase 3 trials and the ongoing follow-up of those trials.

The GALAXI 2 and GALAXI 3 studies were the primary trials that led to the initial approval of guselkumab for moderately to severely active Crohn's disease. But the third study of interest was called GRAVITI. And all of these studies had a similar design in the sense that there was an induction phase and then a maintenance phase, and they obviously used guselkumab, but the distinction was in GALAXI 2 and GALAXI 3 the induction dosing was intravenous. Guselkumab was given as a dose of 200 milligrams IV at weeks 0, 4, and 8, and then the patients continued on therapy into the maintenance phase at 2 different doses, or if they received placebo and responded, they continued on placebo. It was a treat through study design. And interestingly, GALAXI had a comparator arm of ustekinumab, the p40 inhibitor, which is of great interest to us as well.

GRAVITI, in contrast, had induction with subcutaneous dosing, 400 milligrams subq at weeks 0, 4, and 8. And then similarly, the 2 doses in maintenance, the 2 doses studied in maintenance, in GRAVITI and GALAXI 2 and 3 were the same. It was either 200 milligrams every 4 weeks given subq or 100 milligrams every 8 weeks given subq. And the long-term follow-up of these studies is of great interest, what was presented at ACG or a number of different analysis of these trials in comparison of some of their results.

The bottom line for clinicians to know is that whether you induce with the subcutaneous dosing from the GRAVITI study, which was in the label and it's an available option, or the IV dosing, which was the GALAXI studies, the results at week 12, and then the maintenance dosing results, whether you're in either of the two different maintenance arms, were similar. In fact, there was no difference that was easily discernible. Now, while these studies weren't designed to be compared head to head in their designs, there was enough there to understand that the patient populations were relatively the same and the results were very good, which tells us there was no specific reason to think about doing subq induction or IV induction as a matter of the biology of the individual patient, but rather perhaps due to patient preference due to convenience issues. And in the US especially, it may be due to the idea behind having one preauthorization as opposed to getting two when you have to do IV and subq.

What was presented at ACG were ongoing interpretation of these studies, which included 96-week follow-up from the 2 studies both, GRAVITI and GALAXI, looking at how patients did after they finished the primary study and were followed out longer. The good news is that patients who did well in the guselkumab studies, whichever ones they were in, continue to do well in their long-term follow-up. This isn't necessarily a new message. In general, we know that when patients are doing well at the end of one year, they continue to do well as you follow them, as long as they stay on their medicines. But whether you looked at the clinical remission rates out to 2 years, whether you looked at endoscopic response, even endoscopic remission with the GRAVITI study as well, or deep remission, where you combined clinical remission with the endoscopic remission, you were able to see consistent and stable results through week 96. And this is going to go on for longer periods of time.

Another important question that has some new answers from the ACG meeting in the analysis of guselkumab was which maintenance dose should you choose. In the general analysis, looking at primary and secondary endpoints in GRAVITI and GALAXI, there was no difference seen between the 2 different maintenance doses, 200 milligrams every 4 weeks or 100 milligrams every 8 weeks. But when you look more carefully, you can see that there were some predictors in post-hoc analysis that suggested the higher dose in maintenance would be preferred in specific patients. Who are they? Well, for example, people who still have elevated inflammatory markers at week 12, suggesting that they may have responded to the therapy, but they hadn't achieved deep remission yet. Those who have more extensive disease at baseline were also at a greater likelihood to need higher doses and maintenance.

And this is of interest to us, of course, because it suggests that these are just people who hadn't achieved deep remission before they got to the maintenance phase. So the 200 milligram subq every 4 weeks might be the equivalent of an extended induction period. And therefore, assessment of your patient after you've started therapy after 12 weeks, to know if they're still inflamed, can guide your choice of maintenance therapy.

Now, having said all that, what we see across the class of the IL 23 inhibitors is great safety, and there's no distinct safety difference between the doses. So you might argue that the higher dose is a reasonable thing to do in most people because there's not a safety compromise. The one thing you are compromising, however, is the convenience of every 8 weeks versus every 4 weeks. But of course, the therapy that's least convenient and least safe is the one that's not doing its job. So you don't want to compromise on efficacy. S

So to summarize, what we saw at the ACG meeting were ongoing analysis of these phase three trials in moderately to severely active Crohn's disease with guselkumab. And what we've learned is that IV and subcutaneous induction have similar week 12 and week 48 outcomes. We've also learned that when you follow these patients out to week 96, they have stable, ongoing clinical remission and endoscopic response remission, and even deep remission rates, which is a very nice thing to know and to share with your patient. And your patients who have more severe inflammation and certainly those who have not healed completely by week 12 are likely the ones you should stick to the higher dose in maintenance. It's been my pleasure discussing this with you today. I hope you've learned a bit more about this therapy and the evolving information about the entire class of IL 23 inhibitors. Thank you very much.