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DOP71 Effects of ustekinumab induction therapy on endoscopic and histological healing in the UNIFI Phase 3 study in ulcerative colitis

K. Li*1, J. R. Friedman1, C. Marano1, H. Zhang1, F. Yang1, B. G. Feagan2, L. Peyrin-Biroulet3, G. De Hertogh4

1Janssen Research and Development, LLC, Spring House, USA, 2Robarts Research Institute, Robarts Clinical Trials, London, Canada, 3Nancy University Hospital, Université de Lorraine, Nancy, France, 4University Hospitals KU, Leuven, Belgium

Background

Ustekinumab (UST) is an effective therapy for moderate–severe UC; however, data regarding histological healing and the combination of histological and endoscopic healing (also described as endoscopic improvement in the appearance of the mucosa) are unknown.

Methods

We evaluated the effects of UST on histological and endoscopic activity in the UNIFI Ph3 induction study of UST in moderate–severe UC(n = 961). Two colonic biopsies were collected from distal colon at screening and induction Wk8. Subjects not in response to placebo (PBO) at Wk8 received UST 6 mg/kg IV, and those not in response to UST IV received UST 90 mg SC; biopsies were obtained at Wk16. Endoscopic healing (EH; also described a endoscopic improvement in the appearance of mucosa) was defined as a Mayo endoscopy score <1; histological healing (HH) comprised the following Geboes score-based criteria: absence of erosion or ulceration, absence of crypt destruction, and <5% of crypts with epithelial neutrophil infiltration. To encompass both macro- and microscopic scales, histo-endoscopic mucosal healing (HEMH) was defined as achieving both EH and HH.

Results

At Wk8, EH was achieved in 26.6% and 13.8% of subjects treated with UST (combined 130 mg and 6 mg/kg IV doses)and PBO, respectively (adjusted tx difference, 12.8%; 95% CI, 7.9–17.8; p < 0.001). HH was achieved in 36.8% and 21.9% of UST and PBO-treated subjects, respectively (adjusted tx difference, 15.0%; 95% CI, 9.0–21.0; p < 0.001). Histo-endoscopic mucosal (HEMH) was achieved in 19.3% and 8.9% of UST and PBO-treated subjects, respectively (adjusted tx difference, 12.5%; 95% CI, 6.2–14.8; p < 0.001). Similar rates of EH, HH, and HEMH were achieved following induction with UST 130 mg or 6 mg/kg IV. Subjects not in response to PBO or UST at Wk8 were treated with UST at that time and re-evaluated at Wk16; of these, 12.1% and 16.5% of subjects who initially received UST or PBO IV, respectively, achieved HEMH. HH at Wk8 or Wk16 (irrespective of induction tx) was significantly associated with EH and HEMH (p < 0.001) and with both absolute levels and post-tx changes in Mayo score, partial Mayo score, and Mayo symptom sub-scores for stool frequency and rectal bleeding.

Table 1. Clinical outcomes for subjects with or without histological healing at Week 8 and Week 16 in the UNIFI Phase 3 induction study

Conclusion

Among subjects with moderately–severely active UC, those receiving IV UST induction had higher rates of EH, HH, and HEMH than those receiving PBO. Approximately 10% of subjects who did not achieve clinical response 8 weeks after IV UST achieved HEMH following a second (SC) dose. HH is associated with reductions in clinical and endoscopic disease activity as well as patient-reported symptoms.