Introduction
Guselkumab (GUS), a selective dual-acting IL-23p19 subunit inhibitor, is approved for the treatment of moderately to severely active CD.1 Intestinal stenosis in CD can lead to obstructive symptoms and interventions; evidence for biologic impacts on stenosis remains limited.2 We present descriptive post hoc results for pts in the GALAXI 2 & 3 and GRAVITI studies through Wk96 who had non-passable intestinal stenosis (NPS) at baseline.
Aims & Methods
Pts with moderately to severely active CD (CDAI 220-450 and SES-CD≥6; or ≥4 for ileal-only disease) and a history of inadequate response/intolerance to oral corticosteroids, AZA/6-MP/MTX, or biologics received GUS induction with 200 mg IV in GALAXI 2 & 3 or 400 mg SC in GRAVITI at Wks0/4/8, followed by either 100 mg SC q8w or 200 mg SC q4w maintenance. Pts who entered the long-term extensions at Wk48 continued their assigned maintenance dose. In GALAXI, pts were also randomized to ustekinumab (UST); GUS 100mg and UST nonresponders were eligible to switch to GUS 200 mg SC q4w without induction between Wks52-80. Centrally read endoscopy was conducted at baseline and Wks48/96. Pts with missing SES-CD data at Wks48/96 were excluded at each timepoint. Transcriptomic profiling of ileum biopsies in a subset of pts collected at Wks0/48 were analyzed for changes in fibroblast-associated biology using co-expressed single-cell fibroblast transcriptional modules.3,4
Results
Across pooled GALAXI 2 & 3 and GRAVITI, 315/1,103 pts (28.6%) randomized to active treatment had NPS at baseline. Baseline characteristics were generally similar across treatment arms. Among pts with NPS at baseline, improvement to passable/no stenosis was observed at Wk48 and increased at Wk96 (Table). Reductions in fibrosis-associated and inflammatory fibroblast biology in ileum samples from pts with ileal stenosis were associated with improvements in ileal stenosis at Wk48. GUS significantly reduced these inflammatory and fibrosis-associated gene modules at Wk48, in addition to increased epithelial- and tissue-supporting fibroblast biology; UST showed no significant changes in fibroblast biology within the ileum.
| Table. Summary of findings through Week 96 in participants with non-passable stenoses at baseline |
| GALAXI 2 & 3
| GRAVITI
|
| GUS 100a
| GUS 200b
| USTc
| UST → GUS 200d
| GUS 100e
| GUS 200f
|
Week 48g
Participants with non-passable stenosis at baseline, N
Participants with SES-CD data at Week 48,h N
No stenosis at Week 48, n (%)
Passable or no stenosis at Week 48, n (%)
Non-passable stenosis at Week 48, n (%)
|
76
66
19 (28.8%)
29 (43.9%)
36 (54.5%)
|
82
74
23 (31.1%)
31 (41.9%)
39 (52.7%)
|
82
69
16 (23.2%)
21 (30.4%)
44 (63.8%)
|
-
-
-
-
-
|
40
38
13 (34.2%)
14 (36.8%)
23 (60.5%)
|
35
32
11 (34.4%)
15 (46.9%)
17 (53.1%)
|
Week 96g
Participants with non-passable stenosis at baseline, N
Participants with SES-CD data at Week 96,h N
No stenosis at Week 96, n (%)
Passable or no stenosis at Week 96, n (%)
Non-passable stenosis at Week 96, n (%)
|
76
63
24 (38.1%)
30 (47.6%)
29 (46.0%)
|
82
68
30 (44.1%)
35 (51.5%)
29 (42.6%)
|
71
54
18 (33.3%)
21 (38.9%)
28 (51.9%)
|
11
9
3 (33.3%)
5 (55.6%)
4 (44.4%)
|
40
30
15 (50.0%)
15 (50.0%)
12 (40.0%)
|
35
29
12 (41.4%)
14 (48.3%)
15 (51.7%)
|
GUS= guselkumab; IV= intravenous; SC= subcutaneous; SES-CD=simple endoscopic score for Crohn’s disease; UST= ustekinumab.
a Participants randomized to guselkumab 200 mg IV q4w → 100 mg SC q8w. Includes participants who dose escalated to guselkumab 200 mg SC q4w. b Participants randomized to guselkumab 200 mg IV q4w → 200 mg SC q4w. Includes participants who received “sham” dose adjustment to guselkumab 200 mg SC q4w. c Participants randomized to ustekinumab ~6 mg/kg IV → 90 mg SC q8w who did not dose adjust. d Participants randomized to ustekinumab ~6 mg/kg IV → 90 mg SC q8w and dose adjusted to guselkumab 200 mg SC q4w. e Participants randomized to guselkumab 400 mg SC q4w → 100 mg SC q8w. f Participants randomized to guselkumab 400 mg SC q4w → 200 mg SC q4w. g Denominators are defined as participants with non-passable stenosis at baseline minus the missing SES-CD data at the respective time point. h Missing SES-CD data is defined as participants who had a non-passable stenosis at baseline and did not have a dilation procedure or an intestinal resection surgery prior to the respective timepoint, and did not have any SES-CD data at the respective timepoint, so it was unknown whether they improved. |
Conclusion
In pts with moderately to severely active CD and NPS at baseline, improvement to passable/no stenosis was observed in GUS-treated pts at 1yr and increased at 2yrs. In GUS-treated—but not UST-treated—ileal samples, stenosis-associated biomarker changes were observed, highlighting the influence of GUS treatment on regulating fibroblast biology.
References
- Sachen K, Hammaker D, Sarabia I, et al. Front Immunol. 2025: doi:10.3389/fimmu.2025.1532852.
- Narula N, Wong ECL, Dulai PS, et al. J Crohns Colitis. 2021; 15(10):1649-57.
- Richards D, Sohn K, Zeeman M, et al. Oral presentation presented at: UEGW; October 5, 2025; Berlin, Germany.
- Hart A, Sridhar S, Venkat S, et al. BMJ Open Gastroenterol. 2026: doi:10.1136/bmjgast-2025-002153
Disclosure
WR has served as a speaker for AbbVie, Celltrion, Ferring, Johnson & Johnson, Galapagos Medice, MSD, Roche, Pfizer, Sobi, Takeda, as a consultant for AbbVie, Amgen, AOP Orphan, Boehringer Ingelheim, Bristol Myers Squibb, Calyx, Celltrion, Eli Lilly, Galapagos, Gilead, Index Pharma, Johnson & Johnson, Medahead, Microbiotica, Pfizer, Takeda; as an advisory board member for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Galapagos, Johnson & Johnson, Pfizer, and has received research funding from AbbVie, Johnson & Johnson, Sandoz, Sanofi, Takeda.
AA reports having received consulting fees from AbbVie, Bristol Myers Squibb, Celgene, Criscot, Eli Lilly, Janssen, Johnson & Johnson, Pfizer, Sanofi, and Takeda; Speaker fees from AbbVie, Johnson & Johnson, Pfizer, and Takeda; and served on Advisory Boards for: AbbVie, Criscot, Eli Lilly, Janssen, Johnson & Johnson, Pfizer, Sanofi, and Takeda. Board of Directors: Scrubs & Heels Foundation (non-profit).
HB, RVR, WvD, SA, DR, and NAT are employees of Johnson & Johnson and may own company stock/stock options.
DTR has received grant support from Takeda; and has served as a consultant for Abbvie, Abivax SA, Altrubio, Athos Therapeutics, Inc, Bristol-Myers Squibb, Celltrion, Connect BioPharma, Eli Lilly & Co., Genentech (Roche) Inc., Iterative Health, Janssen Pharmaceuticals, Johnson & Johnson, Merck & Co., Mirador, Odyssey Therapeutics, Pfizer, Sanofi, Spyre, Takeda Pharmaceuticals, Vedanta Biosciences, and Ventyx. Board of Directors: Cornerstones Health (non-profit), iUSCAN (non-profit).