DUET-UC Data Highlight Potential of Dual-Pathway Targeting in Refractory Ulcerative Colitis

For patients with ulcerative colitis (UC) who have failed multiple lines of therapy, treatment options are limited and outcomes are often poor. A novel investigational approach simultaneously targeting 2 distinct inflammatory pathways with a single fixed-dose co-antibody may offer hope for changing that reality.

Phase 2b data from the DUET-UC trial presented at Digestive Disease Week (DDW) 2026 in Chicago, IL, by Maria Abreu, MD, Executive Director of the F. Widjaja Inflammatory Bowel Disease Institute at Cedars-Sinai, position JNJ-78934804 (JNJ-4804) as a potentially transformational therapy for one of the most difficult-to-treat populations in inflammatory bowel disease (IBD).

"Most of the advanced therapies in ulcerative colitis and Crohn's disease target one very specific thing." Abreu told HCPLive. "I tell my patients an anti-TNF can only do one thing, it can only find TNF and block TNF. In the case of an anti IL-23, it could only do this one thing, so we view that these are 2 different aspects of the immune response, and so targeting these 2 orthogonal pathways makes intellectual sense.”

Study Design and Patient Population

DUET-UC was a phase 2b, randomized, double-blind, dose-ranging study in which 572 patients with moderately to severely active UC were randomized to placebo, guselkumab, golimumab, or JNJ-4804 at low, mid, or high doses. The primary endpoint was clinical remission at Week 48.

Of note, the trial enrolled an unusually refractory population: all patients had inadequate response or intolerance to ≥ 1 systemic therapy class, 45% had failed ≥ 2, and some had cycled through 6 or more prior biologics across multiple mechanisms of action. At baseline, 72% had severe endoscopic disease.

"They enrolled a group of patients that no one wants in their study," Abreu said. "For the most part, studies want people who've never been on any therapy, or maybe they'll let one or two previous therapies. In this study, they said anyone who's been on more than one mechanism of action, not just one drug, but one mechanism of action, is allowed to enroll.”

Efficacy Results

In the overall population, high-dose JNJ-4804 was significantly superior to golimumab for clinical remission at Week 48 and performed similarly to guselkumab. Abreu noted that the most compelling findings, however, came from the highly refractory subgroup who had failed ≥ 2 systemic therapy classes.

In this population, high-dose JNJ-4804 demonstrated clinically meaningful improvements across all endpoints compared with both monotherapies and placebo, including a 28-point advantage over golimumab and a 12-point advantage over guselkumab in clinical remission rates. Benefits were similarly pronounced for corticosteroid-free remission, endoscopic improvement, and histologic remission with endoscopic improvement.

Abreu highlighted the molecular underpinning of these results, noting that earlier biopsy data from the VEGA study showed that combining anti-IL-23 and anti-TNF therapies produced far greater reductions in inflammatory gene expression and greater increases in epithelial repair pathways than either agent alone.

Safety Profile

Safety events per 100 patient-years in the JNJ-4804 groups were comparable to or lower than those observed with the monotherapies. Serious infection rates were low across all arms, and no new safety signals emerged over the 48-week study period.

"There is no increase in adverse events," Abreu said. "And this was a 48-week study — it wasn't like a 12-week study. These people did fine, so I think that there's every reason to believe that in the larger studies, we're not going to unmask yet another side effect of the two together.”

Abreu expressed hope that the results would accelerate phase 3 development and encourage broader collaboration across companies to test additional combination permutations, a shift she described as long overdue for the field.

Editors’ note: Abreu reports relevant disclosures with AbbVie, Bristol Myers Squibb, Eli Lilly and Company, Gilead Sciences, Janssen Pharmaceuticals, Pfizer, and others.

References:

1. Abreu M, Sands BE, Vermeire S, et al. EFFICACY AND SAFETY OF THE FIRST CO-ANTIBODY THERAPY, JNJ-78934804, IN PATIENTS WITH MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS REFRACTORY TO SYSTEMIC THERAPIES. Presented at Digestive Disease Week (DDW) 2026; Chicago, IL; May 2–5, 2026.

2. Johnson & Johnson. Johnson & Johnson investigational co-antibody therapy JNJ-4804 shows potential to raise the bar for clinical efficacy in treating refractory inflammatory bowel disease. PR Newswire. Published May 05, 2026. Accessed May 05, 2026. https://www.prnewswire.com/news-releases/johnson--johnson-investigational-co-antibody-therapy-jnj-4804-shows-potential-to-raise-the-bar-for-clinical-efficacy-in-treating-refractory-inflammatory-bowel-disease-302761831.html

3. Feagan BG, Sands BE, Sandborn WJ, et al. Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trial. Lancet Gastroenterol Hepatol. 2023;8(4):307-320. doi:10.1016/S2468-1253(22)00427-7