Introduction

Mirikizumab (miri), a p19-directed IL-23 antibody, was efficacious in inducing clinical remission at Week (W)12 (LUCENT-1) and maintaining clinical remission at W52 (LUCENT-2) in patients with moderately to severely active UC in whom conventional or advanced therapy failed. We present results from the ongoing open-label LUCENT-3 extension study evaluating long-term efficacy and safety of miri.

Aims & Methods

In LUCENT-3, patients received 200 mg miri Q4W subcutaneously. Following 104W of continuous miri treatment, we report clinical response and remission, corticosteroid-free (CSF) remission, endoscopic remission, histologic-endoscopic mucosal improvement (HEMI) and histologic-endoscopic mucosal remission (HEMR), symptomatic remission, bowel urgency clinical meaningful improvement (CMI) and remission scores for patients who were W52 responders and remitters, including induction baseline biologic failure status. Symptom scores for abdominal pain, bowel urgency, stool frequency (SF), and rectal bleeding (RB) from induction baseline were recorded for all patients completing W52. Discontinuations or missing data were handled using non-responder imputation. All data were summarized as descriptive. Biologic Failed was defined as prior inadequate response, loss of response, or intolerance to biologic therapy or Janus kinase inhibitors; otherwise, patients were categorized as Not Biologic Failed. Safety data were assessed.

Results

Among W52 miri responders (N=239), 74.5% demonstrated clinical response at W104. Remission rates at W104 for W52 clinical responders were: 54.0% clinical, 52.7% CSF, 65.3% endoscopic, 47.7% HEMR, 67.8% symptomatic and 50.2% bowel urgency. Patients achieving HEMI and bowel urgency CMI at W104 were 53.1% and 67.0%, respectively. For W52 miri remitters, 76.6% demonstrated clinical response at W104. Remission rates at W104 for W52 clinical remitters (N=154) were: 65.6% clinical, 64.3% CSF, 77.3% endoscopic, 59.1% HEMR, 74.0% symptomatic and 51.3% bowel urgency. Patients achieving HEMI and bowel urgency CMI at W104 were 66.2% and 67.3%, respectively.
Biologic Failed/Non-failed subgroup data were generally similar (Table). Symptom score reductions from induction baseline at W52 were sustained through W104; W52 and W104 scores were respectively: SF: -1.68, -1.79; RB: -1.45, -1.45; bowel urgency: -4.03, -4.44; and abdominal pain: -3.74, -3.91. Severe TEAEs were reported in 4.5% of patients, while 5.2% experienced serious AEs,and 2.8% discontinued treatment due to an AE. Most common TEAEs (≥5%) reported were: COVID-19 (12.1), colitis ulcerative (7.6), arthralgia (6.2), headache (6.2), nasopharyngitis (5.9).There were 0 deaths. AEs of interest were: opportunistic infection (1.7%); cerebrocardiovascular event (0.7%); malignancy (0%); hepatic (2.1%); injection site reaction (5.5%).

Conclusion

These data support the long-term benefit of continuous miri treatment through W104 on clinical, endoscopic, histologic, and symptomatic endpoints, including biologic-failed patients, with no new safety signals identified or deaths reported.

Disclosure

BES consulting fees: Abbvie,Alimentiv,Amgen,Arena,Artugen Therapeutics,Astra Zeneca, Boehringer Ingelheim, Boston Pharmaceuticals,Calibr,Celgene, Celltrion,ClostraBio, Equillium,Enthera,Evommune,Fresenius Kabi,Galapagos, Genentech (Roche), Gilead, GlaxoSmithKline,Gossamer Bio, Index, Innovation, Inotrem, Kaleido,Kallyope,Merck,Morphic Therapeutics,MRM Health,Progenity,Prometheus Biosciences/ Laboratories, Protagonist Therapeutics, Q32 Bio,Sun Pharma,Surrozen,Target RWE,Teva,TLL Pharmaceutical, Ventyx Biosciences;research grants, consulting/speaking fees: Abivax,Lilly, Bristol Myers Squibb, Janssen, Pfizer, Takeda, Theravance Biopharma; stock options:Ventyx.
GDH advisor fees: AbbVie, Aliimentiv, AstraZeneca,Boehringer Ingelheim, Bristol-Myers Squibb,Celltrion, Lilly, Galapagos, GlaxoSmithKline, Gossamerbio, Pfizer, Immunic,Johnson and Johnson,Takeda,Prometheus Laboratories,Protagonist, Samsung, Seres,Tillotts,Ventyx.
DBC is an Eli Lilly employee and stockholder.
PMI research grants: Celltrion,Pfizer,Takeda,Galapagos; consulting fees: AbbVie, Arena,Boehringer-Ingelheim, BMS, Celltrion, Elasmogen,Gilead,Janssen,Lilly,Pfizer,Prometheus, Sandoz; Payment for lectures/presentations: AbbVie,BMS, Celgene, Celltrion, Falk Pharma, Galapagos, Gilead, Janssen, Lilly, Pfizer, Takeda,Tillotts;meetings and travel support: Abbvie, Tillotts.
JTJ and THG are Eli Lilly employees and stockholders.
MTA advisory board support: AbbVie,Amgen,Arena,Bristol Myers Squibb,Celsius Therapeutics,Lilly, Gilead,Janssen, Microba Life Sciences,Pfizer, Prometheus Biosciences,UCB Biopharma SRL,WebMD Global LLC; Teaching, lecturing, speaking: Alimentiv, Amgen,Janssen,Takeda.
SDL grant and research support: AbbVie, UCB Pharma, Janssen,Salix, Takeda, Celgene, Pfizer, Atlantic, Gilead Sciences, Tetherex, Arena, Shield Therapeutics PLC; consulted for: UCB Pharma, Mesoblast,Cornerstones, Janssen, Takeda, Lilly,Celgene Pharmaceuticals, Inc, Celltrion Healthcare, Pfizer, Salix.
TH lecture fees: Janssen, EA, AbbVie, Pfizer ,Mitsubishi Tanabe,Takeda,GILEAD,Mochida,Kyorin,JIMRO; Advisory/consultancy fees:Janssen, EA, AbbVie, Pfizer, Mitsubishi Tanabe, Takeda, GILEAD, Lilly; Pharmaceutical/Research grants: EA, AbbVie,Pfizer, Mitsubishi Tanabe, Kyorin, JIMRO, Mochida, Ltd, Nichi-lko, Daiichi-Sankyo,Takeda, Zeria, Nippon Kayaku, Alfresa.
TK speaker, consultant or advisory board support: AbbVie, Alfresa, Bristol Myers Squibb, Celltrion,Covidien, EA, Eiken chemical, Lilly, Ferring, Gilead, Janssen, JIMRO, Kissei, Kyorin, Mitsubishi Tanabe, Mochida, Nippon Kayaku, Pfizer, Sekisui Medical, Takeda, Zeria; research funding: AbbVie, Alfresa, EA, Kyorin, Mochida, Nippon Kayaku, Otsuka Holdings, Pfizer, Sekisui Medical, Zeria.
MCD consulting fees: Abbvie,Arena,Astra Zeneca, Boehringer Ingelheim International GmbH, Bristol-Meyer Squibb, Lilly, F. Hoffmann-La Roche, Genentech, Gilead,Janssen,Pfizer, Prometheus Biosciences, Takeda, UCB SA; Contracted Research: Abbvie, Janssen; Stocks: Trellus Health Inc; Licensing fee:Takeda USA.
SV grants: AbbVie, J&J, Pfizer, Takeda and Galapagos; consulting and/or speaking fees: AbbVie,Abivax, AbolerIS, AgomAb, Alimentiv, Arena, AstraZeneca, Avaxia, BMS, Boehringer Ingelheim,Celgene, CVasThera, Cytoki Pharma,Dr Falk Pharma, Ferring,Galapagos, Genentech-Roche, Gilead, GSK, Hospira,Imidomics, Janssen,J&J, Lilly,Materia Prima, MiroBio,Morphic, MrMHealth,Mundipharma, MSD,Pfizer, Prodigest, Progenity, Prometheus,Robarts Clinical Trials,Second Genome, Shire,Surrozen, Takeda,Theravance,Tillots Pharma AG, Zealand Pharma.
CAS consulting: Abbvie, BMS,Fresnius, Lilly, Janssen, Napo Pharmaceuticals, Pfizer, ProciseDx,Prometheus, Takeda, Trellus Health; speaker for CME activities: Abbvie, Janssen, Pfizer, Takeda; grants: Abbvie, Janssen, Pfizer, Takeda.
LPB consulting and lecture fees: AbbVie, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, BMS, Celltrion, CONNECT Biopharm, Cytoki Pharma,Enthera,Ferring,Fresenius Kabi,Galapagos,Genentech,Gilead,Gossamer Bio, GSK, HAC-Pharma, IAG Image Analysis, Index Pharmaceuticals,Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD,Norgine,Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics,Par’Immune, Pfizer,Prometheus, Protagonist,Roche, Sanofi, Sandoz, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Viatris, Vifor, Ysopia, Abivax
REM, JM, VA are Eli Lilly employees and stockholders.
RP consultant fees: Abbott,AbbVie, Abbivax,Alimentiv, Amgen,Arena, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene,Celltrion,Cosmos Pharmaceuticals, Eisai, lan, Lilly, Ferring,Galapagos, Fresenius Kabi, Genentech, Gilead Sciences,Glaxo-Smith Kline, JAMP Bio,Janssen, Merck,Mylan, Novartis,Oppilan Pharma, Organon,Pandion Pharma,Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz,Satisfai Health, Shire, Sublimity Therapeutics, Takeda Pharmaceuticals, Theravance Biopharma, Trellus, Viatris, Ventyx,UCB; Speaker’s Fees: AbbVie, Amgen, Arena Pharmaceuticals, Bristol-Myers Squibb, Celgene, Lilly, Ferring,Fresenius Kabi, Gilead Sciences,Janssen,Merck, Organon,Pfizer, Roche, Sandoz, Shire, Takeda Pharmaceuticals;Advisory Boards: AbbVie, Alimentiv, Amgen, Arena, AstraZeneca, Biogen,Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Ferring,Fresenius Kabi, Genentech, Gilead, Glaxo-Smith Kline, JAMP Bio, Janssen,Merck,Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma,Pfizer,Progenity,Protagonist Therapeutics, Roche, SandozShire, Sublimity Therapeutics, Takeda, Ventyx.
AD clinical trial participation/review activities: Abivax,AbbVie, Arena,Bristol Myers Squibb/Celgene, Dr Falk Foundation, Galapagos, Gilead, Janssen, Pfizer; consultancy fees: AbbVie, Amgen, Arena,Biogen, Boehringer Ingelheim, Bristol Myers Squibb/Celgene,Celltrion, Dr Falk Foundation, Ferring Pharmaceuticals, Fresenius Kabi,Galapagos,Janssen, Lilly, MSD,Pfizer,Pharmacosmos, Roche/Genentech, Sandoz/Hexal, Takeda, Tillotts,Vifor Pharma; lecture payment: AbbVie,Biogen,CED Service GmbH,Celltrion,Falk Foundation,Ferring,Galapagos, Gilead, High5MD, Janssen,Materia Prima,MedToday,MSD, Pfizer,Takeda, Tillotts,Vifor Pharma; manuscript preparation payment: Falk Foundation,Takeda, Thieme,UniMed Verlag.

Introduction

Guselkumab (GUS), a dual-acting interleukin-23p19 subunit inhibitor, demonstrated efficacy in participants (pts) with ulcerative colitis (UC) treated with intravenous (IV) or subcutaneous (SC) induction. Here, we report the efficacy and safety of SC induction followed by SC maintenance through Week (W) 48 in ASTRO, a phase 3, randomized, double-blind, placebo (PBO)-controlled, treat-through study in pts with moderately to severely active UC.

Aims & Methods

Eligible pts had modified Mayo scores of 5 to 9, rectal bleeding subscore of ≥1, and Mayo endoscopic subscore (MES) ≥2. Pts also had documented inadequate response/intolerance to biologics, Janus kinase (JAK) inhibitors, and/or sphingosine-1-phosphate (S1P) inhibitors (BIO/JAKi/S1Pi-IR) or to corticosteroids, 6-mercaptopurine, or azathioprine. Randomization was stratified by baseline BIO/JAKi/S1Pi-IR status and MES with 418 pts allocated 1:1:1 to GUS 400 mg SC every 4 weeks (q4w) (×3)→GUS 200 mg SC q4w (N=140), GUS 400 mg SC q4w (×3)→GUS 100 mg SC every 8 weeks (q8w) (N=139), or PBO SC (N=139). PBO pts who met rescue criteria were switched to GUS at W16; GUS pts who met rescue criteria stayed on their assigned GUS dose regimen (sham rescue).

Results

At W48, greater proportions of pts in the GUS groups achieved clinical remission compared with PBO (36.7% for GUS 100 mg q8w [Δ 29.5%], 42.9% for GUS 200 mg q4w [Δ 35.6%], 7.2% for PBO) (Table). Endoscopic remission proportions were 25.9% for GUS 100 mg q8w (Δ 20.9%), 26.4% for GUS 200 mg q4w (Δ 21.4%), and 5.0% for PBO. Clinical response, symptomatic remission, endoscopic improvement, histologic improvement, and histologic remission proportions were also greater for GUS vs PBO. Consistent with the results of the overall population, efficacy was also observed for subpopulations of BIO/JAKi/S1Pi-naïve and BIO/JAKi/S1Pi-IR pts. Safety events per 100 pts-years were not greater in the GUS groups compared with the PBO group: adverse events (AE) (GUS 100 mg q8w and 200 mg q4w vs PBO: 308.3 and 310.7 vs 357.1), serious AEs (6.5 and 8.2 vs 38.4), serious infections (0.8 and 2.5 vs 3.7), and AEs leading to treatment discontinuation (4.9 and 4.1 vs 19.8).
Table. Efficacy endpoints at Week 48 in the overall population and by biologic, JAK inhibitor, and/or S1P inhibitor history

Conclusion

GUS SC induction followed by SC maintenance was efficacious through 1 year in pts with moderately to severely active UC, and the safety profile is consistent with GUS in its approved indications including UC.

Disclosure

ML reports research support from Lilly, Pfizer, and Takeda; consulting for AbbVie, Bristol Myers Squibb, Intercept, Janssen (Johnson & Johnson), Lilly, Pfizer, Prometheus, Roivant, Takeda, and Target RWE.
JRA reports grant support from Janssen, Merck, and Pfizer; consultancy fees from AbbVie, Adiso, Bristol Myers Squibb, Ferring, Genentech, GlaxoSmithKline, Janssen, Merck, Pfizer, Roivant, Celltrion, TrexBio, Shattuck Labs and Seres Therapeutics; payments for speaking from AbbVie, Bristol Myers Squibb, and Janssen; and is a steering committee member and investigator for Janssen.
SD reports consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity, Takeda, TiGenix, UCB, and Vifor; and reports lecture fees from AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, and Takeda.
MG, TB, YA, KH, SJ, LJ, and HZ are employees of and may own stock in Johnson & Johnson.
TH reports research grants from AbbVie GK, Boston Scientific Corporation, EA Pharma Co. Ltd., JIMRO Co. Ltd., Kissei Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Pfizer Inc., Takeda Pharmaceutical Co. Ltd., and Zeria Pharmaceutical Co. Ltd.; consulting fees from AbbVie GK, Abivax, Bristol Myers Squibb, EA Pharma Co. Ltd., Gilead Sciences, Janssen Pharmaceutical K.K., Lilly, Mitsubishi Tanabe Pharma Corporation, and Pfizer Inc.; and lecture fees from AbbVie GK, EA Pharma Co. Ltd., Janssen Pharmaceutical K.K., JIMRO Co., Kissei Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Pfizer Inc., and Takeda Pharmaceutical Co. Ltd.
DTR reports consulting and/or speaker fees and/or advisory board participation for AbbVie, Altrubio, Apex, Avalo, Bristol Myers Squibb, Buhlmann Diagnostics, Celgene, Connect BioPharma, Intouch Group, Iterative Health, Janssen (Johnson & Johnson), Lilly, Pfizer, Samsung Neurologica, and Takeda; Altrubio, Datos Health, and Iterative Health stock options; grants from Takeda; and membership on the Board of Directors of Cornerstones Health, Inc. and on the Crohn’s & Colitis Foundation’s Board of Trustees.
LPB reports grants or contracts from Celltrion, Fresenius Kabi, Medac, MSD, and Takeda; consulting and/or payment or honoraria and/or data safety monitoring board or advisory board participation for AbbVie, Abivax, Adacyte, Alfasigma, Alimentiv, Amgen, Applied Molecular Transport, Arena, Banook, Biogen, Bristol Myers Squibb, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GlaxoSmithKline, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Kern Pharma, Lilly, Medac, Mopac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Samsung, Sandoz, Sanofi, Satisfay, Takeda, Telavant, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vectivbio, Ventyx, and Ysopia; and meeting attendance/travel support from AbbVie, Alfasigma, Amgen, Celltrion, Connect Biopharm, Ferring, Galapagos, Genentech, Gilead, Gossamer Bio, Janssen, Lilly, Medac, Morphic, MSD, Pfizer, Sandoz, Takeda, Thermo Fischer, and Tillots.

Introduction

Colorectal cancer (CRC) gradually develops from precancerous lesions - colorectal adenomas or serrated polyps - in the gut. As such, removal of these lesions is an effective prevention of CRC [1]. However, currently currently available non-invasive detection methods – such as the fecal immunochemical test – produce a high number of false positive results, resulting in a high number of unnecessary colonoscopes [1]. CRC has been associated with changes in the gut microbiota, but links between microbiome and pre-cancerous lesions are underexplored and it is unclear if gut microbes can predict the future onset of CRC.

Aims & Methods

We linked the Dutch Microbiome Project - a large-scale prospective population study including 8,208 individuals [3] - with the Dutch nationwide pathology database [4] to identify all recorded cases of colonic biopsies in these individuals from the past five decades. This allowed us to associate gut microbiome to detailed histological information about precancerous lesions and CRC, including when were lesions detected relative to fecal sampling as well as lesion subtype, growth pattern, size, location and the grade of dysplasia. We analyzed the function, composition and metagenome-assembled genome strain profiles of gut microbiota in participants who developed (pre)cancerous colorectal lesions before fecal sampling (n=214, years 2000-2015) and patients developing lesions after fecal sampling (n=305, 2015-2022), using n=202 individuals with normal colonoscopy findings and general population as controls. We associated clinical phenotypes (e.g. type and size of lesion) with microbiome composition and function using multivariate regression and permutational analysis of variance (adonis). Furthermore, we explored strain profiles and functions of associated bacterial species by reconstructing their genomes from metagenomic data using metagenomic assembly and binning approaches.

Results

We found 214 participants with colonoscopy identified precancerous colonic developed before fecal sampling (106 cases of low-grade dysplasia, 24 of high-grade dysplasia, 60 of serrated polyps and 26 cases of CRC), and 305 study participants with lesion developed after the fecal sampling (26 cases of CRC, 149 low grade dysplasias, 78 high-grade dysplasias, 52 serrated polyps and 26 cases of CRC). Microbiome diversity was decreased in participants who developed colonic lesions after sampling (FDR < 0.05) and microbiome composition and function were different in patients with pre-existing or future lesions as well as with types of lesions (CRC, high-grade dysplasia, low-grade dysplasia or serrated polyp; adonis FDR < 0.05). Bacterial species from family of Lachnospiraceae, and the genera Roseburia and Eubacterium were linked with future development of lesions, while associated functions involved methanogenesis, biosynthesis of aerobactin, queuosine and flavine and degradation of lysine. Microbiome composition had a moderate predictive power for future lesions and CRC (AUROC ~0.7).

Conclusion

We found that the gut microbiome of study participants who developed (pre)cancerous colonic lesions in 2015-2022 is significantly different from general population, implying that the gut microbiota might be involved in the development of colorectal lesions and cancer. Our results suggest that the gut bacteria might be used to enhance currently used diagnostics for detection of colorectal polyps and that microbiome-modulating therapies might play a role in prevention of colorectal cancer.

References

[1] Integraal kankercentrum Nederland (IKNL) & National Institute for Public Health and the Environment (RIVM): National monitoring of colorectal cancer screening in the Netherlands (2019)
[2] Yachida, S. et al. Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer. Nature Medicine. 25, 968–976 (2019)
[3] Gacesa, R. et al. Environmental factors shaping the gut microbiome in a Dutch population. Nature. 604, 732–739 (2022)
[4] Casparie, M. et al. Pathology databanking and biobanking in The Netherlands, a central role for PALGA, the nationwide histopathology and cytopathology data network and archive. Anal Cell Pathol. 29 (1), 19-24 (2007)

Disclosure

RKW received unrestricted grants from Takeda, Johnson and Johnson, Tramedico, Ferring, and acted as consultant for Takeda. GAPH acted as consultant for Amgen, Bristol-Myers Squibb, Roche, MSD, Pfizer, Novartis, Sanofi, and Pierre Fabre.

Introduction

Th17 cells are found enriched in inflamed intestinal lesions of Crohn’s disease (CD) patients. Several evidences indicate that Th17 cells may have both a protective role in the gut but also a more pro-inflammatory function. Indeed, in response to specific polarizing cytokines and pathogenic stimuli, Th17 cells can transdifferentiate into IFNγ-producing Th17 cells acquiring a more pathogenic profile. Here, we aimed to identify the specific immunological and transcriptomic profile of intestinal-resident IFNγ-producing Th17 cells, as well as the role in the CD pathogenesis and specific gut microbiota components that induce their activation and selective increase in the gut of CD patients.

Aims & Methods

In order to define the role of IFNγ-producing Th17 cells in chronic intestinal inflammation, CD4⁺T cell subsets from CD patients and controls were phenotypically and functionally analyzed by RNA sequencing and flow cytometry. They were analyzed for responses to CD-relevant antigens with the antigen-specificity assay and monitored in CD patients before and after treatment with antibodies that neutralize TNFα (Infliximab), integrin α4β7 (Vedolizumab), or IL-23p19 (Risankizumab).

Results

Th17 cells expressing CCR5 (“pTh17”) co-produced the highest levels of IFNγ/IL-17 but were distinct from established Th1/17 cells. pTh17 cells were associated with intestinal inflammation in CD, but not with UC. Conversely, Th1/17 cells, which also co-produced IFNγ/IL-17, were not increased in inflamed compared to non-inflamed lamina propria of CD or non-IBD patients. Biological therapies differentially affected intestinal pTh17 cell frequency: whether Infliximab significantly reduced gut-infiltrating pTh17 in CD responder patients, Vedolizumab only impaired migration of cTh17 cells to the gut but did not reduce intestinal-resident pTh17 cells. Notably, pTh17 cells transdifferentiated in-vitro from conventional CCR5^-Th17 cells (“cTh17”) in the presence of IL-23. Consistently, intestinal pTh17 cells were specifically and strongly reduced after Risankizumab therapy in CD patients. Importantly, intestinal pTh17 cells were selectively activated by adherent-invasive Escherichia coli strains, but not by a commensal/probiotic E. coli strain. In contrast, Th1/17 cells were selectively activated by Cytomegalovirus.

Conclusion

We identified a previously uncharacterized subset of human intestinal IFNγ-producing Th17 cells, whose generation was promoted by IL-23 in vitro and in vivo. CCR5⁺Th17 cells (pTh17) produced high levels of pro-inflammatory cytokines, were selectively associated with intestinal inflammation in CD, and responded to CD-associated AIEC strains, suggesting a key pathogenic role in CD. Finally, besides the possibility to use pTh17 cells as a diagnostic or predictive biomarker, they also represent an important novel target for the development of new therapeutic strategies aimed at selectively blocking the harmful signalling pathways driving intestinal chronic inflammation in CD.

Disclosure

• Prof. M. Vecchi served as a consultant to Abbvie, MSD, Takeda, Janssen-Cilag, and Celgene. He received lecturer fees from Abbvie, Ferring, Takeda, MSD, Janssen-Cilag, and Zambon.
• Prof. F. Caprioli has served as consultant to Mundipharma, AbbVie, MSD, Takeda, Janssen, Roche, and Celgene; received lecture fees from AbbVie, Ferring, Takeda, Allergy Therapeutics, and Janssen; and received unrestricted research grants from Giuliani, SOFAR, MS&D, Takeda, Pfizer and AbbVie.
• All other authors have no conflicts of interest to declare.

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.