Dual-antibody strategy shows promise in refractory ulcerative colitis in the DUET-UC phase 2b trial

touchIMMUNOLOGY coverage of DDW 2026

What unmet needs persist in the treatment of ulcerative colitis?

Some patients are fortunate in that first-line therapies that are oral, generally very safe and have been used for decades are sufficient to control their disease. However, more than half of patients require stronger treatments to prevent flares and avoid prolonged use of prednisone. Despite therapeutic advances, many patients with ulcerative colitis still end up needing prednisone for extended periods, either between flares or due to recurrent disease activity. Some also become so unwell that they require hospitalization.

In addition, a particularly underserved group includes patients who have already been treated with multiple medications, known as ‘systemic therapies’ by the FDA or previously ‘advanced therapies’. In these patients, especially those who have failed multiple therapies with different mechanisms of action, there is a clear diminishing return with each additional treatment. The likelihood of response decreases as more therapies are tried. For example, if a patient has not responded to an anti-TNF agent, switching to another drug in the same class is unlikely to be effective. As a result, this group of patients remains a major unmet need in ulcerative colitis care.

What is the proposed mechanism of action of the co-antibody therapy, JNJ-78934804?

The therapy combines two medications in a single vial: golimumab, an anti-TNF agent already known to be effective in ulcerative colitis, and guselkumab, an anti-IL-23 agent, which is also effective in this disease. The manufacturer has shown that each agent has a distinct immunologic profile at a molecular level in the tissue. When used together, they appear to produce a a bigger shift toward an anti-inflammatory profile.

There is experimental evidence suggesting that the combination may be more effective than either agent alone. Strictly speaking, we cannot yet claim that they are synergistic, meaning more than an additive effect, but even an additive benefit would be an advancement.

The rationale is that inflammatory bowel disease, including ulcerative colitis, is immunologically complex. Targeting a single pathway may not be sufficient, since the immune system uses various approaches to fight off pathogens. Even though we don’t believe there is a pathogen driving the disease, the immune system responds as though one is present. For that reason, simultaneously targeting different immune pathways is a logical therapeutic strategy.

What were the aims and design of the DUET-UC trial?

This was a phase 2b study. Earlier evidence had already suggested that the combination therapy was more effective than either agent alone in treatment-naïve patients. However, that population is already well served by existing treatments, so the focus shifted to a more difficult-to-treat group. The DUET-UC trial specifically enrolled patients who had previously received at least one mechanism of advanced therapy. For example, patients may have been treated with infliximab or infliximab and adalimumab; even multiple drugs within the same class were still considered one mechanism of action. Importantly, the study also enrolled patients who had failed multiple different mechanisms of action. This is notable because most clinical trials exclude heavily pre-treated patients, as their reduced responsiveness can make new therapies appear less effective due to a “law of diminishing returns.”

The trial compared golimumab and guselkumab as monotherapies versus the combination of both agents, versus placebo. Outcomes were assessed using standard endpoints, including symptom improvement and endoscopic findings. Disease activity was measured using validated tools such as the Mayo score, which incorporates stool frequency, rectal bleeding, and endoscopic assessment. For endoscopic remission, the criteria were strict: complete absence of inflammation, including no friability, as confirmed by expert review of endoscopic recordings.

Patients were followed for 48 weeks, and the results presented reflect that timepoint.

What were the primary and secondary endpoints?

The endpoints were standard but rigorously defined. The primary endpoint was clinical remission, assessed using the Mayo score. Importantly, this included endoscopic assessment, with a strict requirement of a score of zero and no friability.

Secondary endpoints included endoscopic improvement (requiring a score of 0 or 1); histologic remission with endoscopic improvement; and steroid-free clinical remission. Steroid-free remission was a particularly high bar, requiring patients not only to be in clinical remission but also completely off corticosteroids. A substantial proportion of patients, over 40% at baseline, were on steroids when entering the study, making this outcome especially important.

All of these endpoints were met, which is notable given the refractory nature of the enrolled population.

What were the key findings from the study?

Overall, the combination at a high dose showed numerically greater efficacy than either monotherapy. In terms of clinical remission, this really became statistically significant in the subgroup of patients who had failed two or more mechanisms of action—a particularly refractory population. In this group, which represented just under half of study participants, combination therapy clearly outperformed monotherapy.

In future studies, they can focus on enrolling highly treatment-refractory patients with limited remaining options. In this group, existing therapies are unlikely to be effective, creating a clear unmet need and making clinical trial enrolment both more feasible and more appropriate.

What was the safety profile of the combination?

Over approximately 1 year of follow-up, there was no increase in infections compared with either agent alone. This is particularly important because combining two biologic therapies could theoretically increase the risk of immunosuppression-related complications. The absence of a synergistic safety burden is therefore reassuring.

An additional question going forward is whether both agents need to be continued long term. One possibility is that combination therapy could be used to induce remission, followed by de-escalation to a single agent for maintenance once disease control is achieved.