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.
