Efficacy in Biologic Failure and Nonbiologic-Failure Populations in a Phase 3 Study of Ustekinumab in Moderate-Severe Ulcerative Colitis: UNIFI

Background:

Ustekinumab (UST) was effective in Ph3 induction & maintenance of moderate-severe UC. Efficacy in biologic-failure (BF) and nonbiologic-failure (NBF) populations was evaluated.

Methods:

Pts were randomized to baseline IV induction UST (130 mg or ˜6 mg/kg) or PBO. Responders to IV UST induction entered maintenance and were randomized to SC UST90 mg (q12wks or q8wks) or PBO. Primary endpoint for wk8 induction and wk44 maintenance was clinical remission. Major secondary endpoints: wk8 induction = endoscopic healing, clinical response, &change from baseline in total IBDQ score; wk44 maintenance = maintenance of clinical response, endoscopic healing, corticosteroid-free clinical remission, &maintenance of clinical remission in baseline remitters.

Results:

Among documented BF patients (51.1% of randomized pts), 98.8% failed ≥1 anti-TNF, 32.6% failed both anti-TNF &vedolizumab. NBF pts were predominantly bio-naïve (94.3%). In induction, for BF&NBF pts, proportions of pts who achieved clinical remission was significantly greater for UST˜6 mg/kg and 130 mg vs. PBO. For BF&NBF pts, major secondary endpoints of clinical response, endoscopic healing &change from baseline in IBDQ were significantly greater for UST˜6 mg/kg and 130 mg vs. PBO (Table1). Though treatment differences were generally similar between BF&NBF pts, rates were consistently lower for BF pts in each treatment group. In maintenance, for BF&NBF pts, proportions of pts who achieved clinical remission was significantly greater for USTq8w and q12w vs. PBO; proportions of pts who achieved each major secondary endpoint were generally greater for USTq8wk and q12wk vs. PBO (Table2).

Tab. 1:

UNIFI Induction key endpoints at Week 8 by biologic failure vs. nonbiologic failure

Primary efficacy analysis N	PBO N = 319	130 mg UST N = 320	6 mg/kga UST N = 322
Pts who are biologic failures N	161	164	166
Pts in clinical remissionb	2 (1.2%)	19 (11.6%) p < 0.001	21 (12.7%) p < 0.001
Clinical responsec	44 (27.3%)	74 (45.1%) p < 0.001	95 (57.2%) p < 0.001
Endoscopic healingd	11 (6.8%)	30 (18.3%) p = 0.002	35 (21.1%) p < 0.001
IBDQ median change from BL N Median (IQ range) Range P-value	159 9.0 (-4.0, 28.0) (-58, 78)	162 26.5 (7.0, 49.0) (-45, 134) p < 0.001	165 27.0 (7.0, 52.0) (-36, 130) p < 0.001
Pts who are not biologic failures N	158	156	156
Pts in clinical remissionb	15 (9.5%)	31 (19.9%) P = 0.009	29 (18.6%) P = 0.022
Clinical responsec	56 (35.4%)	90 (57.7%) p < 0.001	104 (66.7%) p < 0.001
Endoscopic healingd	33 (20.9%)	54 (34.6%) p = 0.006	52 (33.3%) p = 0.014
IBDQ median change from BL N Median (IQ range) Range P-value	158 14.0 (-2.0, 44.0) (-58, 126)	154 37.0 (9.0, 59.0) (-28, 118) p < 0.001	156 33.5 (13.5, 61.0) (-30, 126) p < 0.001
aWeight-range based ustekinumab doses approximating 6 mg/kg: 260 mg (weight ≤55 kg), 390 mg (weight > 55 kg and ≤85 kg), 520 mg (weight > 85 kg), bClinical remission defined as Mayo score ≤2 points, with no individual subscore > 1; primary endpoint, cClinical response defined as a decrease from induction baseline in the Mayo score ≥30% & ≥3 points with either a decrease in rectal bleeding subscore (RBS) ≥1 or a RBS of 0 or 1, dEndoscopic healing (also described as endoscopic improvement in the appearance of the mucosa) was defined as a Mayo endoscopy subscore of 0 or 1 point. IBDQ = Inflammatory Bowel Disease Questionnaire

Tab. 2:

UNIFI Maintenance key endpoints at Week 44 by biologic failure vs. nonbiologic failure

	Placebo SC a N = 175	90 mg UST SC Q12 Wk N = 172	90 mg UST SC Q8 Wk N = 176
Pts who are biologic failures N	88	70	91
Clinical remission at Week 44b	15 (17%)	16 (22.9%) P = 0.044	36 (39.6%) P < 0.001
Maintained clinical responsethrough Week 44c	34 (38.6%)	39 (55.7%) P = 0.008	59 (64.8%) P < 0.001
Endoscopic healing at Week 44d	20 (22.7%)	18 (25.7%) P = 0.163	41 (45.1%) P < 0.001
Corticosteroid-free clinical remission at Week 44e	14 (15.9%)	16 (22.9%) P = 0.026	34 (37.4%) P < 0.001
Maintenance of clinical remission through Week 44 among remitters at baselinef	8/20 (40.0%)	3/8 (37.5%) P = 1.00	10/20 (50.0%) P = 0.751
Pts who are not biologic failures N	87	102	85
Clinical remission at Week 44b	27 (31.0%)	50 (49.0%) P = 0.020	41 (48.2%) P = 0.024
Maintained clinical response at Week 44c	44 (50.6%)	78 (76.5%) P < 0.001	66 (77.6%) P < 0.001
Endoscopic healing at Week 44d	30 (34.5%)	57 (55.9%) P = 0.007	49 (57.6%) P = 0.002
Corticosteroid-free clinical remission at Week 44e	27 (31.0%)	49 (48.0%) P = 0.028	40 (47.1%) P = 0.034
Maintenance of clinical remission through Week 44 among remitters at baselinef	9/25 (36.0%)	23/32 (71.9%) P = 0.008	12/18 (66.7%) P = 0.067
aPatients who responded to ustekinumab IV induction dosing and were randomly assigned to placebo SC upon entry into the maintenance study. b Clinical remission is defined as a Mayo score of ≤2 points, with no individual subscore > 1 c Clinical response defined as a decrease from induction baseline in the Mayo score ≥30% & ≥3 points with either a decrease in rectal bleeding subscore (RBS) ≥1 or a RBS of 0 or 1 dEndoscopic healing (also described as endoscopic improvement in the appearance of the mucosa) was defined as a Mayo endoscopy subscore of 0 or 1 point. eCorticosteroid-free clinical remission is defined as a Mayo score of ≤2 points, with no individual subscore > 1 and not receiving corticosteroids at Week 44 f Pts who were in remission at the start of maintenance therapy and maintained remission through Week 44

Conclusion:

UST was effective for induction &maintenance treatment of moderate-severe UC pts with history of biologic failure (ie, TNF-antagonists and/or vedolizumab) as well as pts without history of biologic failure.