Dr Abreu recaps the results of a late breaking abstract from Digestive Disease Week on the DUET-UC study, which tested whether a combination of two advanced therapies showed an additive or synergistic effect in patients refractory ulcerative colitis.

Maria Abreu, MD, is the executive director of the IBD Institute at Cedars-Sinai Medical Center in Los Angeles, California.

DUET-UC Study of Golimumab + Guselkumab Combination Therapy

• In the DUET-UC study, researchers evaluated the anti-TNF golimumab, the anti-IL-23 guselkumab, and their combination in ulcerative colitis patients exposed to other advanced therapies to test whether combining orthogonal immune pathways could improve outcomes versus either mechanism alone.
• Across efficacy measures, the combination arm numerically outperformed either monotherapy during the 48-week trial. In this more refractory cohort of patients, the combination therapy also showed greater reductions in inflammatory biomarkers, including molecular studies and tissue inflammation.
• The benefit was observed across patient subgroups, including those with severe disease and molecular features associated with poor anti-TNF response. Combination therapy produced the highest remission rates overall, with the highest golimumab dose plus guselkumab showing the strongest numerical efficacy signal in this biologic-naive ulcerative colitis population.

My name is Maria Abreu. I am the executive director of the IBD Institute at Cedars-Sinai. And I have the privilege at the DDW of presenting at a late-breaking abstract on the results of DUET, a study that was conducted in ulcerative colitis patients using the combination of golimumab, which is an anti-TNF, with guselkumab, an anti-IL-23.

And so what is the problem we're trying to address? Well, the first thing is, you know we've all been contemplating how can we overcome this idea of the therapeutic ceiling, meaning by and large most studies at best show a 405 of clinical remission in any of these studies of ulcerative colitis when you hold it to the highest possible standard. I'd like to believe in real life eventually we do better than that but at least in the clinical trials that's about as good as we can do.

The audience will know that most of the therapies that we have for ulcerative colitis, all of the advanced therapies, are targeting generally one molecule or one pathway. They're very, very specific, right? They're monoclonal antibodies, generally against cytokines like TNF, like interleukin-23. or maybe against a t-cell population like vedolizumab which is an anti-alpha 4 beta 7. And so the natural question is if you use orthogonal approaches, complementary distinct approaches, can you do better than either one alone? Is there an additive effect? Is there even a synergistic effect, which means that more than the sum of its parts in terms of efficacy in this patient population?

So in an earlier study called VEGA, done in ulcerative colitis patients, but in ulcerative colitis patients that were naive to therapy, the combination of the golimumab plus guselkumab did better than either alone. And it was a 12-week study. So it gave the idea that yes, in fact, the 2 together seemed to be a good combination. In addition to it having this beneficial clinical effect, the company also did molecular studies on the tissue from these patients to show that the combo really at a molecular level, at gene transcriptional level, showed that, wow, the two together had a much bigger effect than either of these therapies alone.

So now in the DUET study they raised the bar. How did they raise the bar? They enrolled patients that had been on previous therapies and we know that that group is more refractory, harder to treat. You don't want them in your study often because they're the most recalcitrant to treat, right? We know that patients that are naive to therapy the world is your oyster and almost anything is going to work in those patients. And so they allowed patients that had been on one or more mechanisms of action, different mechanisms of action type therapies, for ulcerative colitis and so essentially, you can divide the group of patients in the study into two broad categories. Those that had been on only one mechanism of action previously or those that have been on two or more mechanisms of action. I'm picking my words carefully because that means that they could have been on all 3 anti-TNFs or they could have been on all 3 IL-23 inhibitors, right? So that counts, all of those count as one mechanism of action, right?

What was found was that people who were on at least one mechanism of action, the overall patient population, you can see that the combo, especially the highest dose of the combo of golimumab and guselkumab, numerically had the highest rate of clinical remission compared to guselkumab and golimumab. But in terms of statistical significance, guselkumab by itself actually did pretty well. And so the difference did not reach statistical significance. It was numerically better with the combo, but still not statistically significant.

So I think you can learn a few things. One is, you know, could it be that if you did more patients, you could see a bigger separation? Maybe. Or guselkumab by itself is actually a pretty good therapy in patients that have been previously on an anti-TNF. So that's another way to look at it. On the other hand, these patients that have been on more than 2 therapy mechanisms of action of therapies in the past—again a very refractory group of patients—the placebo group you saw nothing, really, they did not respond to golimumab below almost no response, the guselkumab a little bit but of course the 2 together, this combination had a synergistic effect; it was more than the sum of the 2 of the guselkumab and the golimumab in terms of clinical remission. So there's a clear separation. About a third of patients had clinical remission in a very difficult to treat group of patients so that was very important.  

Other secondary endpoints that again showed more or less what I just shared with you; endoscopic response there even in the overall population you can see that the 2 together did better than either alone in histologic remission combined with endoscopic response.

Again we could see that the combination was better; and corticosteroid-free remission for all intents and purposes, the people who went into clinical remission were able to get off of steroids if they had been on steroids so that was all very good.

The study endpoint was at 48 weeks so that we know it wasn't just sort of a fly-by-night thing.  These results that I'm sharing with you lasted for almost a year. So we at least have some certainty that this is a worthy of pursuing strategy going forward for these refractory patients with ulcerative colitis.