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 Healinga	Without Histologic Healinga	p-valueb
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.