Introduction

Tumor necrosis factor–like cytokine 1A (TL1A), a membrane costimulatory protein and serum cytokine, drives multiple pro-inflammatory and fibrotic pathways relevant to the immunopathogenesis of inflammatory bowel disease (IBD). In APOLLO-CD, a phase 2a multicenter open-label study, the anti-TL1A monoclonal blocking antibody PRA023 showed efficacy in adults with moderately to severely active Crohn’s disease (CD). The primary endpoint of endoscopic response and the key secondary endpoint of clinical remission were met. This study analyzed serum and intestinal mucosal biopsies from APOLLO-CD for cellular and molecular biomarkers before and after treatment with PRA023.

Aims & Methods

Serum proteomics and intestinal mucosal biopsy tissue gene expression data were analyzed to evaluate the effects of TL1A blockade in 55 CD patients treated with PRA023 for 12 weeks. Serum cytokine concentrations were measured at baseline and week 2, 6, and 12 using Meso Scale Discovery multiplex assays. RNAseq data from mucosal intestinal biopsies at baseline and week 12 were analyzed using differential gene expression, pathway analysis (gene set variation analysis), and single-cell deconvolution (MUSIC algorithm) approaches. Pathways were curated from public data sets, and the TL1A regulon (TL1A co-expressed gene set) was derived from CD gene regulatory network analysis. Pharmacodynamic (PD) changes were correlated to clinical endpoints.

Results

PRA023 reduced serum levels of inflammatory cytokines derived from T cells (interleukin [IL]-5, IL-17A, IL-9, IL-22) and monocytes/macrophages (IL-1b, IL-6) (p<0.05), but not IL-10. In intestinal biopsies, PRA023 significantly reduced the expression of several inflammatory cytokine genes and pathways, including those associated with inflammatory monocytes, Th1, Th17, as well as a TL1A-induced CD4+ T cell gene signature and an in silico–derived TL1A CD regulon (p<0.05). These serum biomarkers and gene expression changes were observed in the overall cohort and were more pronounced in patients with clinical remission, a ≥25% reduction in endoscopic score, or both. PRA023 also reduced expression of fibrosis-associated gene signatures in the overall cohort, with more pronounced changes in patients who achieved clinical remission or clinical remission and a ≥25% reduction in endoscopic score. Cell-type deconvolution of bulk RNAseq using IBD single-cell reference datasets showed reduced frequencies of activated fibroblasts and inflammatory monocytes in the overall cohort. However, these changes were more pronounced in patients who achieved clinical remission, a ≥25% or 50% reduction in endoscopic score, or clinical remission with a ≥25% reduction in endoscopic score. Immunohistochemistry of intestinal biopsies from a subset of endoscopic responders confirmed the reduction in T cell (CD3+ or CD3+/CD4+) numbers at week 12 vs baseline.

Conclusion

Consistent with the role of TL1A in inflammation and fibrosis in IBD, biomarker analysis of PRA023-treated CD patients showed a reduction in expression of Th1, Th17, and fibrosis pathways as well as in the relative numbers of activated fibroblasts. These data represent the first molecular characterization of TL1A blockade in CD patients and provide insights into the mechanism of action of PRA023.

Disclosure

RL is a consultant to Prometheus Biosciences, Pfizer, and Roivant Sciences.
FR is consultant to or on the advisory board of Adiso, Adnovate, Agomab, Allergan, AbbVie, Arena, AstraZeneca, Boehringer Ingelheim, Celgene/BMS, CDISC, Celsius, Cowen, Ferring, Galapagos, Galmed, Genentech, Gilead, Gossamer, Granite, Guidepoint, Helmsley, Horizon Therapeutics, Image Analysis Limited, Index Pharma, Landos, Janssen, Koutif, Mestag, Metacrine, Mopac, Morphic, Organovo, Origo, Palisade, Pfizer, Pliant, Prometheus Biosciences, Receptos, RedX, Roche, Samsung, Sanofi, Surmodics, Surrozen, Takeda, Techlab, Teva, Theravance, Thetis, UCB, Ysios, and 89bio.
HL, IJ, YW, RM, FT, DDN, and EM are employees and shareholders of Prometheus Biosciences.
DPBM has received consulting fees from Prometheus Biosciences, Prometheus Laboratories, Gilead Sciences, Boehringer-Ingelheim, Pfizer, Prometheus Laboratories, Takeda, Palatin Technologies, and owns stock in Prometheus Biosciences.
BGF has served as a consultant for AbbVie, AbolerIS Pharma, AgomAb, AllianThera, Amgen, AnaptysBio, Applied Molecular Transport, Arena, Avoro Capital Advisors, Atomwise, BIOJAMP, Biora Therapeutics, Boehringer Ingelheim, Boxer, Celsius Therapeutics, Bristol Myers Squibb/Celgene, Connect Biopharma, Cytoki, Disc Medicine, Duality, EcoR1 Capital, Eli Lilly and Company, Equillium, Ermium, First Wave, First Word Group, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer Bio, GSK, Hinge Bio, HotSpot Therapeutics, Index Pharma, Imhotex, Immunic Therapeutics, JAK Academy, Janssen, Japan Tobacco, Kaleido, Landos Biopharma, Leadiant, L.E.K. Consulting, Lenczner Slaght, LifeSci Capital, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic Therapeutics, Mylan, OM Pharma, Origo Biopharma, Orphagen, Pandion Pharma, Pendopharm, Pfizer, Prometheus Therapeutics, PlayToKnow AG, Progenity, Protagonist Therapeutics, PTM Therapeutics, Q32 Bio, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Surrozen, Takeda, Teva, Thelium, TiGenix, Tillotts Pharma, Ventyx Biosciences, VHsquared, Viatris, Ysios, Ysopia, Zealand Pharma; on the speaker’s bureau for AbbVie, Janssen, and Takeda; and on advisory boards for AbbVie, Amgen, AMT, AnaptysBio, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Eli Lilly and Company, Genentech/Roche, Janssen, MiroBio, Origo BioPharma, Pfizer, Prometheus, REDX, Sanofi, Takeda, Tillotts Pharma, Teva, Progenity, Index, EcoR1 Capital, Morphic, GSK, and Axio Research.
ST has received consulting fees from Robarts Clinical Trials and Prometheus Biosciences and owns stock in Prometheus Biosciences; is a member of steering committees of Janssen, AbbVie, Boehringer Ingelheim, Gilead, Celgene, and Bristol Meyers Squibb; has received speaker honoraria from AbbVie, Takeda, Janssen, Ferring, Pfizer, and Celltrion; and has served on advisory committees of Janssen, Takeda, AbbVie, Eli Lilly, Pfizer, Gilead, Galapagos, and Roche.

Introduction

The phase 2b GALAXI 1 and phase 3 GALAXI 2&3 studies evaluated guselkumab (GUS), a dual-acting IL-23p19 subunit inhibitor, in participants (pts) with moderately to severely active CD.¹ Pts treated with ustekinumab (UST) who met inadequate response criteria during the long-term extension (LTE) could cross over to GUS 200 mg SC q4w. Here, we present efficacy and safety results in pts who received GUS after experiencing an inadequate response to UST in the pooled GALAXI LTE.

Aims & Methods

Individuals with prior inadequate response or intolerance to UST were excluded from GALAXI; however, during the LTE, pts treated with UST 90 mg SC q8w who met inadequate treatment response criteria (not in clinical response [≥100-point reduction in CDAI score from baseline or CDAI<150] and CDAI ≥220) between Wks 52-80 of LTE were eligible for a treatment switch to GUS 200 mg SC q4w, without IV induction. Clinical response and clinical remission (CDAI<150) were both assessed 16 weeks after treatment switch. Endoscopic response (≥50% improvement from baseline SES-CD or SES-CD≤2) and endoscopic remission (SES-CD≤4 and ≥2-point reduction from baseline and no subscore >1 in any individual component) were assessed at Wk 96. Safety was assessed through Wk 96.

Results

In total, 80 pts treated with UST underwent treatment switch to GUS 200 mg SC q4w maintenance therapy due to meeting inadequate treatment response criteria between Wks 52-80 of the LTE. Of these 80 pts, 75 were included in the efficacy analyses (baseline mean age, 35.2yrs; male, 64.0%; mean CD disease duration, 8.21yrs; mean CDAI, 291.5; mean SES-CD, 12.8; history of inadequate response/intolerance to biologics [BIO-IR], 60.0%).
The proportions of pts achieving clinical response and clinical remission 16 weeks after treatment switch from UST to GUS 200 mg SC q4w were 61.3% and 52.0%, respectively. These results were comparable to the proportions of pts treated with GUS 200 mg IV q4w induction in the BIO-IR subgroup of the total LTE population who achieved clinical response and clinical remission at Wk 12 (61.7% and 46.7%, respectively).
The proportions of pts achieving endoscopic response and endoscopic remission at Wk 96 (ie, ~1 year after treatment switch from UST to GUS 200 mg SC q4w) were 49.3% and 30.7%, respectively. These results were similar to the proportions of pts in the BIO-IR subgroup receiving GUS 200 mg SC q4w maintenance who achieved endoscopic response and endoscopic remission at Wk 48 (57.2% and 35.5%, respectively).
Safety results are summarized in the Table.

Table. Safety Summary From Treatment Switch Through Week 96

Conclusion

Among pts who experienced inadequate response to UST in the LTE, more than half achieved clinical remission 16 weeks after treatment switch to GUS 200 mg SC q4w, and approximately 50% were in endoscopic response ~1 year after treatment switch. These data suggest pts with an inadequate treatment response to UST may benefit from GUS treatment. Results should be interpreted considering that pts received GUS SC maintenance therapy directly without IV induction. Key safety event rates were consistent with the known safety profile of GUS in approved indications.

References

1) Sachen K, Hammaker D, Sarabia I, et al. Frontiers in Immunology. 2025; doi:10.3389/fimmu.2025.1532852.

Disclosure

AA reports potential conflicts of interest with AbbVie, Bristol Myers Squibb/Celgene, DiaSorin, Eli Lilly, Gilead, IBD Horizons, Janssen, Pfizer, Takeda, and TLL Pharmaceuticals
DW reports consulting fees from AbbVie, Bristol Myers Squibb, Janssen, Lilly, Pfizer, Takeda
RL reports having received advisory board fees from AbbVie, Aspen, BMS, Celgene, Celltrion, Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSD, Novartis, Pfizer, Prometheus Biosciences, and Takeda; received research grants from Celltrion, Shire, Janssen, Takeda, Joanna Tiddy grant from University of Sydney, McCusker Charitable Trust, Gastroenterological Society of Australia, NHMRC, Gutsy Group, and Pfizer
RVR, WvD, and CB are employees of Johnson & Johnson and own company stock/stock options.
TH received grant support from Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Mochida Pharmaceutical Co. Ltd., Boston Scientific Corporation, Kissei Pharmaceutical Co. Ltd., consulting fees from Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, Janssen Pharmaceutical K.K., Pfizer Inc., Nichi-Iko Pharmaceutical Co. Ltd., Eli Lilly, Gilead Sciences, Bristol Myers Squibb, and lecture fee from Mitsubishi Tanabe Pharma Corporation, AbbVie GK, EA pharma Co. Ltd., Kyorin Pharmaceutical Co. Ltd., JIMRO Co., Janssen Pharmaceutical K.K., Mochida Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc. Kissei Pharmaceutical Co. Ltd.
JP reports consultancy fees/honorarium from AbbVie, Alimentiv, Athos, Atomwise, Boehringer Ingelheim, Celsius, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Janssen, Mirum, Nimbus, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Sanofi, Sorriso, Surrozen, Takeda, and Wasserman, and has served on a data safety monitoring board for Alimentiv, Mirum, Sorriso, Sanofi, and Surrozen.

Introduction

Complex perianal fistulas represent one of the most challenging manifestations of Crohn’s disease. Combined surgical and medical therapy with biologic drugs represents today the first-line treatment option, but its efficacy does not exceed 60% in terms of healing. Recently, new therapeutic approaches, such as autologous microfragmented adipose tissue (M-Fat) injection, have shown promising results. Indeed, a recent non-profit prospective pilot study on 15 patients has demonstrated that the local injection of M-Fat is a safe and promising “rescue therapy” for patients with multiresistant complex fistulizing Crohn’s disease (PCD), with a 66.7% rate of combined remission in such difficult patients. It has to be highlighted that the M-Fat injection is minimally invasive, with less risk of sphincteric damage and can be carried out in day-surgery setting.

Aims & Methods

The primary aim of this multicentre double-blind randomized controlled trial (ATTIC) is to evaluate the efficacy of the infiltration of M-Fat in the healing of perianal complex fistulas not-responding to treatment with biologics. Consecutive patients referring to the 6 investigation Centers for surgical treatment of persistent complex fistulizing PCD refractory to biosurgical approach were assessed for eligibility. After baseline pelvic magnetic resonance imaging, those included were submitted to surgical drainage with “cone-like” fistulectomy, and then randomized to receive a 15 to 20 cc local injection, at the internal orifice level and along fistula tracts, of M-Fat obtained by a lipoaspiration and processed with an enzyme-free technology (treatment group), or a suture placement and injection of 15 cc of saline solution at the internal orifice (control group). Clinical follow-up were conducted at 2, 4, 8, 12, and 24 weeks; at 24 weeks after surgery, pelvic magnetic resonance was obtained. Success was defined as “combined remission”, combination of clinical (absence of drainage upon gentle finger compression) and radiological healing (absence of residual collections > 3 mm). Clinical remission was defined as clinical healing of all external openings not confirmed at radiological assessment.

Results

An overall 92 patients were screened, and 66 (33 per group) completed the 24-week follow-up. A statistically significant difference in favour of the treatment group in terms of combined remission emerged at the primary endpoint at 24-week follow-up (control group, 18.18%; treatment group: 57.58%; p = 0.0020). No significant differences in clinical outcome measures were encountered at any of the other follow-up points. No significant differences emerged between the groups in terms of recurrence rate, complication rate, and number of adverse events. Clinical remission was 63.64% in the treatment group compared to 51.52% in the control group with no statistically significant difference (p > 0.05).

Conclusion

This multicentre double-blind randomized controlled trial demonstrates that the intraoperative injection of M-Fat, associated with surgical complete drainage of perianal sepsis, is safe, effective, and reproducible in healing complex multirefractory perianal Crohn's disease, while improving the quality of life and significantly reducing the risk of definitive oostomy.

Introduction

Fistulizing perianal Crohn’s disease (CD) remains a significant therapeutic challenge, with limited randomized controlled trials to date, restricted so far to infliximab and, more recently, filgotinib. The USTAP (NCT04496063) trial aimed to evaluate the efficacy and safety of UST in patients with actively draining perianal fistulas through a multicenter randomized controlled design.

Aims & Methods

This double-blind, placebo-controlled, multicenter trial enrolled adult patients with active draining fistulizing perianal CD. Between April 2020 and June 2024, eligible patients with persistent fistula drainage were randomized 1:1, after seton placement when necessary, to receive either UST (6 mg/kg IV at baseline followed by 90 mg SC at week 8, then every 8 weeks) or placebo. Steroids were allowed at baseline with a standardized steroid taper. Seton removal was planned at week 6. The primary endpoint was combined clinical remission (absence of drainage from all external fistula openings) and radiological remission (defined as the absence of abscesses >2 cm confirmed by blinded central pelvic MRI) at week 12. Secondary endpoints included clinical remission, radiological remission, changes in disease activity (CDAI, PDAI), IBD-DI, and safety. Endpoints were independently reviewed by a blinded adjudication committee. Randomization was stratified by prior anti-TNF exposure and study center. The intended sample size was 73 patients per group to detect a 20% difference in remission rates (power 80%, alpha 5%). Due to slow recruitment, the study was discontinued in June 2024 after randomizing 32 patients, without unblinding the study data. Patients were subsequently followed until week 48.

Results

Thirty-three patients consented to participate with 32 patients (women: 41%; median age: 42) ultimately randomized (UST: 16; placebo: 16) across 10 French centers. Seventy percent had prior anti-TNF exposure (50% in UST arm, 50% in placebo arm), and 23% had previously failed two or more anti-TNF therapies. At baseline, 84% had one draining fistula, 16% had two, and 25% had associated abscesses. At week 12, combined remission was achieved in 62% in the UST group versus 25% in the placebo group (Table). Clinical remission was observed in 69% in the UST group vs. 31% in the placebo group, while radiological remission rates were 87.5% in the UST group and 75% in the placebo group. In the UST arm, mean change in CDAI, PDAI and IBD-DI from baseline to week 12 was -56.3, -2.2 and -4.9, (vs. -9.8, -1.6 and +4.9, in the placebo arm, respectively). Adverse events (AE) and serious adverse events (SAE) were similar in both treatment groups: 23 AE (62%) occurred in the placebo group, and 14 AE (38%) in the UST group. Six SAEs were reported overall, including two gastrointestinal events, one renal disorder, and one anal abscess. Two patients in the placebo group discontinued study by week 6 due to SAEs (an anal abscess and a peri-ileal abscess).

Conclusion

In this trial, where the majority of patients had prior anti-TNF exposure, the observed short-term clinical benefit of UST supports its use in fistulizing perianal CD.

Disclosure

This work was supported by a grant from Johnson & Johnson
Pauline Wils : Johnson & johnson, Takeda, Amgen, Abbvie, Celltrion, Ferring
S Nancey: Abbvie, Johnson and Johnson, Fresenius Kabi, Biogen, Takeda, Medac, Celltrion, MSD, Pfizer, Sandoz, Lilly,Ferring, Amgen
E. Messmer: No conflict of interest for this study
A Bourreille: Johnson and Johnson
A Buisson: Consulting fees from: Abbvie, Amgen, Arena, Biocon, Biogen, Celltrion Healthcare, CTMA, Ferring, Galapagos/AlfaSigma, GutyCare/Resilience Janssen, Lilly, MSD, Nexbiome, Pileje, Pfizer, Roche, Sandoz, Takeda et Tillotts. Lecture fees from: Abbvie, Amgen, Biogen, Celltrion Healthcare Galapagos/AlfaSigma, Ferring, Janssen, Lilly, Mayoli-Spindler, MSD, Nordic Pharma, Norgine, Pfizer, Roche, Takeda, Tillotts and Vifor Pharma. Research grants/fundings from: Abbvie, Celltrion Healthcare, Janssen, Lessaffre, Lilly, Pfizer, Sandoz and Takeda
L Caillo: No conflict of interest for this study
L Vuitton: abbvie amgen J&J Pfizer Takeda Lilly MSD Mayoli Ferring Dr Falk Alpha Sigma
R Altwegg: Abbvie, Johnson ans Johnson, Takeda, Pfizer, Lilly, Alphasigma, Celltrion, Amgen, Biogen, Sandoz, Ferring
X Hébuterne reports clinical research funding from Abbvie, Abivax, Amgen, Celltrion, Lilly, Fresenius-Kabi, J&J, InDex Pharmaceuticals, Pfizer, Prometheus, MSD, Roche, Takeda, serving on advisory boards for Abbvie, Biogen, Celltrion, Lilly, J&J, and participating in lectures and educational activities for Abbvie, Amgen, Celltrion, Lilly, Fresenius-Kabi, Galapagos, J&J, MSD, Nestlé Health Sciences, Nutricia, Pfizer, Tillots, Takeda.
O Ernst: No conflict of interest for this study
P Meunier: No conflict of interest for this study
V Laurent: No conflict of interest for this study
D Laharie: received board and lecture fees from: Abbvie, Alfasigma, Amgen, Biogen, Celltrion, Ferring, Fresenius-Kabi, Janssen, Lilly, MSD, Pfizer, Roche, Sandoz, Takeda
E Vicaut: No conflict of interest for this study
L Peyrin-Biroulet: Consulting : Abbvie, Abivax, Adacyte, Alimentiv, Amgen, Applied Molecular Transport, Arena, Banook, Biogen, BMS, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeuthics, Pandion Therapeuthics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Samsung, Sandoz, Sanofi, Satisfay, Takeda, Telavant, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vectivbio, Ventyx, Ysopia ; lecture : Abbvie, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genentech, Gilead, Janssen, Lilly, Medac, MSD, Nordic Pharma, Pfizer, Sandoz, Takeda, Tillots, Viatris

Introduction

The POWER study evaluated efficacy and safety of a single intravenous (IV) re-induction ustekinumab (UST) dose vs placebo on a background of continued UST subcutaneous (SC) treatment in Crohn’s disease (CD) patients (pts) with secondary loss of response (LoR) to standard q8w UST maintenance therapy. This subgroup analysis reports primary and major secondary endpoints up to week (W)16 in pts with/without a history of inadequate response or intolerance to prior biologics.

Aims & Methods

Adults with moderately–severely active CD who initially responded to UST IV induction therapy per label and later experienced LoR were included. LoR was defined as CD Activity Index (CDAI) score of ≥220 and ≤450, plus either elevated C-reactive protein (CRP; >3mg/L), faecal calprotectin (fCal; >250mg/kg), or endoscopy performed ≤3 months before W0 with evidence of active CD. At W0 randomised pts received ~6mg/kg IV UST/SC placebo (IV arm) or IV placebo/SC UST 90mg (SC arm) followed by 90mg SC UST at W8/16. Clinical/biomarker assessments occurred at W0/8/16. Primary endpoint: W16 clinical response (CRes; decrease of ≥100 points from W0 or CDAI <150). Secondary endpoints: CRes; clinical remission (CRem); normalisation of CRP and/or fCal at W8/16.

Results

The full analysis set comprised 215 pts at W0 (SC, n=107; IV, n=108). At W16, 86.0% (SC) and 92.6% (IV) of pts completed treatment. Most pts (SC, 92.5%; IV, 88.9%) had a history of inadequate response/intolerance to prior biologics. At W16, while CRes did not statistically differentiate between arms, secondary outcomes indicated a difference in the IV vs SC arm. In this analysis, differences were seen in bionaïve pts and those with inadequate response/intolerance to <3 biologics. A numerically greater proportion of pts achieved CRes in the IV vs SC arms in all groups except pts with ≥3 prior biologics, with a nominal difference in pts with 1 prior biologic (p=0.043; Table). A similar trend was observed for pts achieving W16 CRem, albeit the nominal threshold was not reached. A numerically greater proportion of pts in the IV vs SC arm achieved normalisation of CRP and/or fCal at W16, except those with ≥3 prior biologics, and with a nominal difference in pts with 1 prior biologic (p<0.001).

Conclusion

POWER is the first trial to assess the efficacy and safety of UST IV re-induction in pts with secondary LoR. This analysis suggests that both naïve pts and those with prior inadequate response or intolerance to biologics may benefit from UST re-induction therapy.

Disclosure

S. Schreiber has received personal fees from AbbVie, Amgen, Arena, Biogen, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr. Falk Pharma, Fresenius, Galapagos/Gilead, Hikma, I-Mab, Janssen, MSD, Mylan, Pfizer, Protagonist, ProventionBio, Takeda and Theravance Biopharma. S. Lee served as a consultant for Applied Molecular Transport, Arena, Boehringer Ingelheim, Bridge Biotherapeutics, Bristol-Myers Squibb, Celgene, Celltrion Healthcare, Cornerstones Health, Eli Lilly and Company, Janssen, KCRN Research, Samsung Bioepis and UCB; and received research grants from AbbVie, AbGenomics, Arena, Celgene, Janssen, Salix, Takeda and UCB. C.J. van der Woude received grant support from Falk Ben-elux, Ferring and Pfizer; received speaker fees from AbbVie, Takeda, Ferring, Dr Falk Pharma and Pfizer; and served as a consultant for Janssen. I Marín-Jiménez has served as a consultant, advisory member, speaker or has received research funding from Abbvie, Chiesi, Faes Farma, FalkPharma, Ferring, Gebro Pharma, Hospira, Janssen, MSD, Otsuka Pharmaceutical, Pfizer, Shire, Takeda, Tillots and UCB Pharma. D. Wolf has received honoraria as a speaker, consultant and/or advisory board member from AbbVie, Arena, Celgene/Bristol Myers Squibb, Janssen, Pfizer and Takeda. E. Schnoy has received personal fees from AbbVie, Bristol Myers Squibb, Celltrion Healthcare, Dr. Falk Pharma, Galapagos/Gilead, I-Mab, Janssen, Lilly, Pfizer, Pharmacosmos, Takeda and Tillotts Pharma. B. Salzberg served as a consultant for Johnson and Johnson and has received honoraria as a speaker from AbbVie, Bristol-Myers Squibb and Johnson and Johnson. M. Nazar is an employee of Janssen-Cilag Polska Sp. z o.o. and has restricted stocks. C. Busse, W. Langholff, C. Gasink, T. Baker and B. Godwin report employment with/funding by Janssen Research & Development, LLC, a wholly owned subsidiary of Johnson & Johnson, and stock ownership in Johnson & Johnson. B. Feagan received grant/research support from AbbVie Inc., Amgen Inc., AstraZeneca/MedImmune Ltd., Atlantic Pharmaceuticals Ltd., Boehringer-Ingelheim, Celgene Corporation, Celltech, Genentech Inc/Hoffmann-La Roche Ltd., Gilead Sciences Inc., GlaxoSmithKline (GSK), Janssen Research & Development LLC., Pfizer Inc., Receptos Inc./Celgene International, Sanofi, Santarus Inc., Takeda Development Center Americas Inc., Tillotts Pharma AG and UCB; was a consultant for Abbott/AbbVie, AdMIRx Inc., Akebia Therapeutics, Allergan, Amgen, Applied Molecular Transport Inc., Aptevo Therapeutics, Asta Pharma, Astra Zeneca, Atlantic Pharma, Avir Pharma, Biogen Idec, BioMx Israel, Boehringer-Ingelheim, Boston Pharmaceuticals, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Galapagos, Galen/Atlantica, GiCare Pharma, Gilead, Gossamer Pharma, GSK, Inception IBD Inc, Intact Therapeutics, JnJ/Janssen, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck, Mesoblast Pharma, Millennium, Nestles, Nextbiotix, Novonordisk, ParImmune, Parvus Therapeutics Inc., Pfizer, Prometheus Therapeutics and Diagnostics, Progenity, Protagonist, Qu Biologics, Rebiotix, Receptos, Roche/Genentech, Salix Pharma, Shire, Sienna Biologics, Sigmoid Pharma, Sterna Biologicals, Synergy Pharma Inc., Takeda, Teva Pharma, TiGenix, Tillotts, UCB Pharma, Vertex Pharma, Vivelix Pharma, VHsquared Ltd. and Zyngenia; was a member of the speakers bureau for Abbott/AbbVie, JnJ/Janssen, Lilly, Takeda, Tillotts and UCB Pharma; a member of the scientific advisory board for Abbott/AbbVie, Allergan, Amgen, Astra Zeneca, Atlantic Pharma, Avaxia Biologics Inc., Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Galapagos, Genentech/Roche, JnJ/Janssen, Merck, Nestles, Novartis, Novonordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Sterna Biologicals, Takeda, Teva, TiGenix, Tillotts Pharma AG and UCB Pharma; and was a Senior Scientific Officer for Robarts Clinical Trials Inc.

Introduction

​​​​​Guselkumab (GUS) is a selective dual-acting IL-23p19 subunit inhibitor that potently blocks interleukin 23 (IL-23) and binds to CD64, a receptor on cells that produce IL-23¹. In patients with moderately to severely active Crohn’s disease (CD), the GALAXI-2 and GALAXI-3 Phase 3 studies established short- and long-term efficacy of GUS compared to placebo, and statistical superiority to ustekinumab (UST) in prespecified analyses of pooled data at Week (WK)48². We subsequently developed an endoscopic clustering method using Simple Endoscopic Score for Crohn's Disease (SES-CD) segmental scores in patients from GALAXI 2/3 which revealed higher endoscopic remission rates with GUS compared with UST at WK12 and WK48 in pts characterized by ileal disease and strictured right colon³. Here we report molecular differentiation of GUS compared with UST in isolated ileal disease based on serum pharmacodynamic (PD) markers and tissue transcriptomics in CD using pooled samples from the GALAXI studies.

Aims & Methods

Patients (pts) in GALAXI-2 (n=508) and GALAXI-3 (n=513) were randomized 2:2:2:1 to receive GUS 200mg IV q4w x3 → GUS 200mg SC q4w, GUS 200mg IV q4w x3→ GUS 100mg SC q8w, UST ⁓6mg/kg IV x1 → UST 90mg SC q8w or placebo IV q4w x3 (PBO). Serum biomarkers were measured in a subset of (n=50) pts per group at WK0, WK4 and WK12 using a proinflammatory panel and a high sensitivity IL-22 assay. Matched ileal and rectal biopsies were evaluated at WK0, WK12 and WK48 in a subset of 344 pts representative of the full study population. Transcriptional profiling was performed with bulk RNA sequencing (RNAseq) using transcriptional modules. Analysis of treatment effects was performed using molecularly inflamed samples (biopsy molecular inflammation score [bMIS]⁴ >0) from segments with SES-CD >0 at baseline. Serum proteins and transcriptional modules were evaluated for differential expression stratified by isolated ileal, isolated colonic and ileocolonic disease defined during screening.

Results

In pts with isolated ileal disease, GUS decreased serum protein levels of IL-22, IL-17A and IFNγ at WK12 while UST only reduced IFNγ. In ileal tissue, GUS significantly altered inflammatory modules at WK12 and WK48 including reductions in neutrophil, inflamed epithelium, IL-23/Th17 and inflammatory fibroblast biology compared with minimal changes observed with UST, which only significantly reduced neutrophil, plasma cell and macrophage modules at WK48. In contrast, in pts with isolated colonic or ileocolonic disease, both GUS and UST decreased IL-23-dependent serum proteins towards normal levels compared with an independent cohort of healthy control sera. In rectal tissue, both GUS and UST significantly altered key inflammatory transcriptional modules in rectal biopsies at WK12 and WK48. Overall, greater effects of GUS vs UST were observed in ileal tissue at WK12 and at WK48 in transcriptional modules associated with decreasing disease-related features and restoring epithelial health than UST.

Conclusion

GUS decreased IL-23-dependent serum proteins and improved tissue transcriptional profiles in pts with isolated ileal disease while UST only reduced serum IFNγ and had a minimal impact on IL-23-dependent transcriptional modules. These data suggest potential differences in IL-23 and IL-12 pathway enrichment in isolated ileal disease where inhibition of IL-23p19 subunit with GUS achieved greater molecular treatment effects early which were maintained through WK48 and associated with differential clinical outcomes in patients with isolated ileal disease.

References

1. Sachen K, Hammaker D, Sarabia I, et al. Guselkumab binding to CD64+ IL-23–producing myeloid cells enhances potency for neutralizing IL-23 signaling. Frontiers in Immunology. 2025; doi:10.3389/fimmu.2025.1532852
2. Panaccione R, Danese S, Feagan BE, et al. Efficacy and safety of guselkumab therapy in patients with moderately to severely active Crohn’s disease: results of the GALAXI 2 & 3 phase 3 studies. Gastroenterology. 2024; 5 (Supplement): p1057b
3. Richards D, Seridi L, Sohn, K, et al. Guselkumab shows higher endoscopic remission rates than ustekinumab in patients characterized by isolated ileal and srtictured right colon Crohn’s disease: Post-hos analysis of GALAXI 2/3 Ph3 trials. DDW 2025 Abs #4253526; poster.
4. Argmann C, Hou R, Ungaro, R, et al. A biopsy and blood-based molecular biomarker of inflammation in inflammatory bowel disease. Gut. 2022; 0:1-17.

Disclosure

DR, KS, MZ, RP, BM, NAT, MV, DC and PB are current or former employees of Janssen and may hold stock in Johnson & Johnson.
WR has served as a speaker for AbbVie, Celltrion, Ferring, Janssen, 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, Janssen, Medahead, Microbiotica, Pfizer, Takeda; as an advisory board member for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion, Galapagos, Janssen, Pfizer, and has received research funding from AbbVie, Janssen, Sandoz, Sanofi, Takeda.