A first-in-class co-antibody therapy targeting two inflammatory pathways simultaneously demonstrated clinically meaningful efficacy in patients with highly refractory inflammatory bowel disease (IBD), according to results from two phase 2b trials presented at Digestive Disease Week® (DDW) 2026.
The paired DUET-Crohn’s and DUET-UC studies evaluated JNJ-78934804 (JNJ-4804), a fixed-dose combination of guselkumab, an anti–IL-23p19 antibody, and golimumab, an anti–TNF-α agent, in patients with moderate-to-severe Crohn’s disease (CD) and ulcerative colitis (UC) who had failed prior systemic therapies. Across both trials, the therapy produced improvements in clinical remission and endoscopic outcomes, with the most pronounced effects observed in patients who had previously failed multiple advanced therapies.
Investigators emphasized that the rationale for dual-pathway targeting stems from limitations of current treatment paradigms. “Each successive therapy produces diminishing returns,” said Bruce E. Sands, MD, MS, who led the Crohn’s disease study, noting that patients with multiple prior treatment failures have few remaining options. By combining complementary mechanisms, the co-antibody approach aims to overcome immune escape pathways that may limit monotherapy effectiveness.
In the DUET-Crohn’s trial, which enrolled 693 patients, approximately half had failed two or more systemic therapy classes. At week 48, high-dose JNJ-4804 achieved significantly higher rates of clinical remission and endoscopic response compared with golimumab alone, with treatment differences of 25.7 and 18.5 percentage points, respectively (nominal P<.001 for both). While comparisons with guselkumab monotherapy did not reach statistical significance in the overall population, the combination demonstrated numerically higher efficacy across endpoints.
Notably, treatment effects were amplified in the most refractory subgroup. Among patients who had failed at least two prior systemic therapies, high-dose JNJ-4804 produced clinically meaningful gains in clinical remission and endoscopic response versus both monotherapies and placebo, with differences exceeding 20 percentage points versus guselkumab and nearly 40 percentage points versus placebo.
Parallel findings were reported in the DUET-UC study, which included 572 patients with moderate-to-severe ulcerative colitis. Baseline disease severity was high, with approximately 70% of participants demonstrating severe endoscopic disease and modified Mayo scores of 7 to 9. At week 48, high-dose JNJ-4804 was significantly superior to golimumab for the primary endpoint of clinical remission (Δ28.4 percentage points; P<.001) and showed numerically greater efficacy than guselkumab.
As in the Crohn’s cohort, outcomes were strongest among patients with prior exposure to multiple therapies. In this subgroup, the combination therapy demonstrated clinically meaningful improvements across clinical remission, corticosteroid-free remission, endoscopic improvement, and histologic-endoscopic endpoints compared with both monotherapies and placebo.
Maria T. Abreu, MD, who led the UC study, highlighted the mechanistic rationale during her DDW presentation, pointing to earlier work demonstrating synergistic effects at the molecular level when anti-TNF and anti–IL-23 therapies are combined. Dual inhibition not only suppressed inflammatory pathways more effectively but also enhanced epithelial repair processes beyond what was observed with either agent alone.
“In some patients, the immune system essentially finds a way around single therapies,” Dr. Abreu said. “By targeting two pathways at once, we may be able to ‘outsmart’ the immune system and achieve better outcomes.”
The safety profile of JNJ-4804 was consistent across both trials and comparable to monotherapy with either component. Serious adverse events were uncommon and primarily gastrointestinal in nature, with low rates of serious infection reported. In the UC study, adverse event rates were numerically lower in the combination therapy groups than in placebo or monotherapy arms, and no new safety signals emerged.
Investigators noted that the trials were designed to reflect real-world refractory populations, with many participants having prior exposure to anti-TNF agents, anti-integrins, and other advanced therapies. The magnitude of response in these patients — historically among the most difficult to treat — was therefore particularly notable.
“These are the patients we see in clinic who have exhausted multiple options,” Dr. Abreu said, adding that achieving remission in this population represents a meaningful advance.
Taken together, the DUET trials suggest that dual-pathway inhibition with a co-antibody approach may offer a new therapeutic strategy for patients with refractory IBD. Based on the phase 2b findings, investigators indicated that JNJ-4804 is poised to advance to phase 3 development.
Dr. Abreu has served as a consultant for approximately 10 pharmaceutical companies, including AbbVie, Amgen, Bristol Myers Squibb, Eli Lilly, Genentech, Gilead, Janssen, Pfizer, Takeda, and UCB.
Dr. Sands has served as a consultant for numerous pharmaceutical and biotechnology companies (over 60 in total, including AbbVie, Amgen, Pfizer, Takeda, Eli Lilly, Bristol Myers Squibb, Genentech, Merck, and many others). He has also participated in speakers bureaus for several companies (including Abivax, Takeda, Pfizer, Merck, and AbbVie) and holds public stock in J&J Innovative Medicine, Ventyx Biosciences, and Doximity.
DDW is AGA’s annual meeting, jointly sponsored by AGA, AASLD, ASGE, and SSAT. Learn more at ddw.org.