Effects of Ustekinumab Induction Therapy on Endoscopic and Histologic Healing in the UNIFI Phase 3 Study in Ulcerative Colitis

Background: Ustekinumab (UST) is an effective therapy for moderate-to-severe ulcerative colitis (UC), however data regarding histologic healing and the combination of histologic and endoscopic healing are unknown. Methods: We evaluated the effects of UST on histologic and endoscopic activity in the UNIFI Phase 3 induction study of UST in moderate-to-severe UC (n = 961). Two colonic biopsies were collected from the distal colon at Week 8. Subjects not in response to PBO at Week 8 received UST6 mg/kg IV, and those not in response to UST IV received UST90 mg SC; biopsies were obtained from these groups at Week 16. Endoscopic healing (EH) was defined as a Mayo endoscopy score ≤1; histologic healing (HH) comprised the Geboes score-based criteria. Histo-endoscopic mucosal healing (HEMH) was defined as achieving both EH and HH. Results: At Week 8, 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. HH was achieved in 36.8% and 21.9% of UST and PBO-treated subjects, respectively. HEMH was achieved in 19.3% and 8.9% of UST and PBO-treated subjects, respectively. Similar rates of EH, HH, and HEMH were achieved following induction treatment with UST130 mg or 6 mg/kg IV. Subjects not in response at Week 8 were treated with UST re-evaluated at Week 16; of these, 12.1% and 16.5% of subjects who initially received UST or PBO IV, respectively, achieved HEMH. HH at Week 8 or Week 16 was significantly associated with EH and HEMH (Tab. 1). Table 1: Clinical Outcomes for Subjects with or without Histologic Healing at Week 8 and Week 16 in the UNIFI Phase 3 Induction Study Clinical Outcomes Histologic Healing a Without Histologic Healing a p-value b Week 8 N = 283 N = 533 Mayo Score 3.95 ± 2.57 6.89 ± 2.53 < 0.0001 Partial Mayo Score 2.45 ± 1.84 4.39 ± 2.21 < 0.0001 Stool Frequency 1.09 ± 0.95 1.81 ± 1.03 < 0.0001 Rectal Bleeding 0.30 ± 0.56 0.86 ± 0.89 < 0.0001 Change in Mayo Score -4.53 ± 2.65 -2.15 ± 2.39 < 0.0001 Change in Partial Mayo Score -3.46 ± 2.14 -1.89 ± 2.12 < 0.0001 Change in Stool Frequency -1.08 ± 1.01 -0.63 ± 0.90 < 0.0001 Change in Rectal Bleeding -1.18 ± 0.91 -0.69 ± 0.96 < 0.0001 Week 16 N = 140 N = 209 Mayo Score 3.71 ± 1.94 6.01 ± 2.43 < 0.0001 Partial Mayo Score 1.98 ± 1.27 3.44 ± 2.08 < 0.0001 Stool Frequency 0.96 ± 0.83 1.56 ± 1.02 < 0.0001 Rectal Bleeding 0.13 ± 0.38 0.51 ± 0.69 < 0.0001 Change in Mayo Score -4.95 ± 2.02 -3.08 ± 2.32 < 0.0001 Change in Partial Mayo Score -4.04 ± 1.63 -2.83 ± 2.07 < 0.0001 Change in Stool Frequency -1.31 ± 0.90 -0.92 ± 0.99 0.0003 Change in Rectal Bleeding -1.30 ± 0.89 -0.99 ± 0.85 0.0012 a: Values are reported as mean ± SD. b: P-values based on t-test. Conclusions: Among subjects with moderately-to-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 dose.

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