A new co-antibody therapy for UC and CD

Bruce E. Sands, MD, from the Icahn School of Medicine at Mount Sinai, and Maria T Abreu, from Cedars Sinai Medical Center, presented data on the efficacy and safety of the co-antibody therapy, JNJ-78934804, in patients with moderately to severely active Crohn’s disease (CD) or ulcerative colitis (UC) refractory to systemic therapies – DUET-CD and DUET-UC.

The phase 2a VEGA trial in UC was the first to explore combination treatment with the anti-IL-23 guselkumab and the anti-TNF golimumab. The study demonstrated a synergistic effect compared to either monotherapy, which prompted the development of a fixed-dose combination as a co-antibody. The DUET-CD trial compared placebo and each monotherapy to three different doses of the co-antibody, administered subcutaneously, with a co-primary endpoint of clinical remission and endoscopic response at week 48. A total of 693 patients were randomized 2:2:2:2:2:1 with corticosteroid tapering by week 12. Secondary endpoints were endoscopic remission, deep remission, and corticosteroid-free clinical remission at week 48. At baseline, patients had a mean duration of disease of 11 years, with high CDAI and SIS-CD scores. A history of inadequate response or intolerance to at least one advanced therapy mechanism of action was seen in 45% of patients and to two or more mechanisms of action in 55% of patients. Discontinuation was very high in the placebo group.

At week 48, the co-antibody achieved significantly higher clinical and endoscopic response compared to golimumab monotherapy and numerically higher efficacy compared to guselkumab monotherapy, with a roughly additive effect. In patients refractory to two or more previous advanced therapy mechanisms of action, co-antibody efficacy was significantly higher than either monotherapy, and the highest dose of the co-antibody achieved a synergistic effect. The same patterns were seen for the key secondary endpoints of endoscopic remission, deep remission, and corticosteroid-free clinical remission at week 48. No increase in adverse events occurred with the co-antibody compared to either monotherapy. The most common adverse events were nasopharyngitis, upper respiratory tract infection, CD exacerbation, and fever. Infection and serious infection rates were low and similar across all groups, and did not lead to discontinuation. DUET-CD results support advancement to phase 3 in the rapidly growing population of patients with CD that is refractory to multiple systemic advanced therapies.

The DUET-UC trial enrolled 572 patients with moderate to severe UC who were refractory to at least one advanced therapy mechanism of action. The design was similar to DUET-CD, with three doses of the co-antibody compared with golimumab, guselkumab, and placebo, and steroid tapering at week 12. The primary endpoint was clinical remission by Mayo score at 48 weeks. Most patients had severe disease at baseline (Mayo score 7-9). The highest dose of the co-antibody was statistically more effective than golimumab and numerically better than guselkumab, with a synergistic effect in patients refractory to two or more advanced therapy mechanisms of action. Similar patterns were seen for endoscopic improvement at 48 weeks, histologic remission, and steroid-free clinical remission. All patients who achieved clinical remission were able to discontinue corticosteroids. The highest number of adverse events were reported in the placebo group and the lowest in the highest dose co-antibody group. Nasopharyngitis and UC were the most common adverse events, with no new safety signals compared with each monotherapy.