Molecular response to ustekinumab in moderate-to-severe ulcerative colitis by serum protein and colon transcriptomic analysis: Results from the UNIFI phase 3 maintenance study

INTRODUCTION:

The cytokines IL-12 and IL-23 are elevated in ulcerative colitis (UC), and genetic association suggests they play causative roles in the disease. Ustekinumab (UST), an anti-IL- 12p40 monoclonal antibody that binds both cytokines, is an effective therapy for moderate-to-severe UC. We previously observed a partial normalization of UC disease signatures in colonic biopsy gene expression and serum protein levels following UST induction therapy. However, the molecular effects of maintenance UST therapy in UC pts are unknown.

METHODS:

We evaluated the molecular effects of UST in the UNIFI Phase 3 maintenance study of moderate-to-severe UC (n = 961). Pts in response to UST 8 wks after intravenous induction were randomized to maintenance treatment with subcutaneous placebo or UST 90 mg q12w or q8w. Colonic biopsy mRNA and serum samples from the first ;60% of pts treated in the UNIFI phase 3 induction study were analyzed, with equal representation of pts with or without a history of biologic therapy failure (Table 1). Biopsy and serum samples from healthy pts were analyzed as controls.

RESULTS:

At Wk44 after the start of maintenance therapy, expression of colonic genes dysregulated in UC was altered towards normal levels in all treatment groups, with the greatest improvements among those receiving UST and those in clinical remission (P < 0.05 for Wk 44 versus start of maintenance). No dose effect was observed between q8w and q12w UST doses, and no significant improvements in disease signature occurred in non-responders to placebo or UST. UST maintenance therapy magnified the normalization of serum proteins following UST induction; among pts receiving q8w UST who were in remission at Wk44, the proteins IFNγ, IL-17A, MMP3, and SAA reached concentrations comparable to those seen in healthy controls. Similar trends occurred in pts in remission following q12w UST and to a lesser degree among UST-treated pts not in remission at Wk44. Among pts receiving placebo maintenance therapy who were in remission at Wk 44, the disease-associated serum proteins that decreased following UST induction were not further reduced during maintenance. As previously observed in the induction studies, UST maintenance did not reduce serum TNF levels.

CONCLUSION:

UST maintenance therapy suppressed IL-12 and IL-23-related serum proteins and promoted normalization of the UC disease transcriptomic profile. These results provide insight into the molecular mechanisms associated with the efficacy of UST maintenance therapy.