Introduction

Guselkumab (GUS) is a dual-acting IL-23p19 subunit inhibitor that potently neutralizes IL-23 and binds to CD64, a receptor on cells that produce IL-23. In the QUASAR studies, GUS intravenous (IV) induction and subcutaneous (SC) maintenance demonstrated symptomatic, endoscopic, and histologic efficacy through 2 years.^1,2 Here, we describe maintenance of endoscopic and histologic efficacy in the long-term extension (LTE).

Aims & Methods

At maintenance week (W) 0, GUS IV induction responders were randomized 1:1:1 to GUS 100 mg SC every 8 weeks (q8w), GUS 200 mg SC q4w or placebo (GUS withdrawal). Participants (pts) completing the W44 visit could enter the LTE and continue the treatment regimen they were receiving at W44. Placebo pts discontinued after study unblinding. Efficacy data for randomized pts who continued to receive their GUS regimen assigned at W0 in the LTE were analyzed using 2 methods: 1) nonresponder imputation (NRI) accounting for pts with treatment failure or missing data, and 2) “as observed.”

Results

Overall, 303 randomized pts (155 for 100 mg q8w and 148 for 200 mg q4w) continued their GUS treatment assigned at W0 in the LTE. Of pts who achieved endoscopic improvement at W44, 87.2% of GUS 100 mg q8w pts and 80.2% GUS 200 mg q4w pts maintained endoscopic improvement through W92 (NRI analysis; Table). Of pts who achieved histologic improvement at W44, 77.9% and 75.2%, respectively, maintained histologic improvement at W92. Of pts who achieved histo-endoscopic mucosal improvement (HEMI) at W44, 73.5% and 75.5%, respectively, maintained HEMI through W92. Of pts who were in histologic remission at W44, 71.2% maintained histologic remission at W92 in both GUS groups. Results of the as-observed analysis were consistent with the NRI analysis; the dropout rate was low among GUS-treated pts in the LTE. Proportions of pts who maintained endoscopic and histologic outcomes from W0 to W92 are presented in the Table.

Conclusion

High rates of long-term sustained endoscopic and histologic endpoints were observed at W92 of the LTE with both GUS dose regimens.

References

1. Rubin DT, et al. Guselkumab in patients with moderately to severely active ulcerative colitis (QUASAR): phase 3 double-blind, randomised, placebo-controlled induction and maintenance studies. Lancet. 2025;405(10472):33-49.
2. Lichtenstein GR, et al. Efficacy and safety of guselkumab for ulcerative colitis through week 92 of the QUASAR long-term extension study. Presented at: Digestive Disease Week (DDW); May 4–6, 2025; San Diego, CA.

Disclosure

Study support: Johnson & Johnson.
TH: AbbVie, Bristol Myers Squibb, Daiichi-Sankyo, EA Pharma Co, Ltd., JIMRO, Eli Lilly, Gilead Sciences, Johnson & Johnson, Kissei Pharmaceutical Co, Ltd., Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Pfizer Inc, Takeda Pharmaceutical Co., Ltd.
JP: AbbVie, Alimentiv, Athos, Atomwise, Boehringer Ingelheim, Celsius, Ferring, Galapagos, Genentech/Roche, GlaxoSmithKline, Johnson & Johnson, Mirum, Nimbus, Pfizer, Progenity, Prometheus, Protagonist, Revolo, Sanofi, Sorriso, Surrozen, Takeda, Wasserman.
FM: AbbVie, Arena, Celltrion, Eli Lilly and Company, Ferring, Fresenius, Galapagos, GlaxoSmithKline, Johnson & Johnson, Merck, Pfizer, Prometheus Biosciences, Roche, Sandoz, Tillots, Takeda, Teva.
GRL: AbbVie, American College of Gastroenterology, CellCeutrix, Celgene, Clinical Advances in Gastroenterology, Ferring, Gastroenterology and Hepatology [Gastro-Hep Communications], Gilead, Johnson & Johnson, Orthobiotech, Eli Lilly, Luitpold / American Regent, Merck, McMahon Publishing, Pfizer, Prometheus, Romark, Salix/ Valeant, Shire, SLACK, Springer, Takeda, UCB, Up-To-Date, Vindico, Virgo.
JRA: Abbvie, Bristol Myer Squibb, Ferring, Finch, Iterative Scopes, Johnson & Johnson, Merck, Pfizer, Roivant, Seres Therapeutics, Roivant Adiso.
BB: AbbVie, Alimentiv, Allergan, Amgen, AMT, Bausch Health, Bristol Myers Squibb, Business Intelligence, Celgene, Celltrion, Eupraxia Fresenius Kabi, Ferring, Genentech/Roche, Gilead, Iterative Scopes, GlaxoSmithKline, Jamp, Johnson & Johnson, Merck, Microbiome Insights, Mylan, Novartis, Organon, Pendopharm, Pfizer, Protagonist, Qu Biologic, Sandoz, Takeda, Viatris.
WA: AbbVie, Amgen, BMS, Dynacare, Eli-Lilly, Johnson & Johnson, Merck, Novartis, Pfizer, Prometheus, Sandoz, Sanofi, Takeda, Theradiag.
MAS: AbbVie, Bristol-Myers Squibb, Falk, Galapagos, Janssen, Lilly, MSD, Pfizer, Samsung Bioepis, Sandoz, Sanofi, STADA, Takeda, Tillotts.
BDY: AbbVie Korea, BMS Pharmaceutical Korea Ltd., Celltrion, Chong Kun Dang Pharm, CJ Red BIO, Cornerstones Health, Curacle, Daewoong Pharm, Dong-A ST, Eisai Korea, Eli Lilly and Company Korea, Ferring Korea, Imscout, IQVIA, Johnson & Johnson, Johnson & Johnson Korea, JEIL PHARMACEUTICAL CO., Kangstem Biotech, Korea Otsuka Pharm, Korea United Pharm, Medtronic Korea, NanoEntek, ORGANOIDSCIENCES LTD, Pfizer Korea, Samsung Bioepis, Takeda, Takeda Korea, Yuhan.
SY, MG, NS, DP, YM, HZ: Johnson & Johnson.
AD: Abivax, AbbVie, Amgen, Arena Pharmaceuticals, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, CED Service GmbH, Celltrion, Dr Falk Foundation, Ferring Pharmaceuticals, Fresenius Kabi, Galapagos, Gilead, High5MD, Johnson & Johnson, Lilly, Materia Prima, MedToday, MSD, Pfizer, Pharmacosmos, Roche, Sandoz, Stada, Takeda, Thieme, Tillotts, UniMed Verlag, Vifor Pharma.
DTR: Abbvie, Altrubio, Apex, Avalo Therapeutics, Bristol-Myers Squibb, Buhlmann Diagnostics Corp, Celgene, Connect BioPharma, Intouch Group, Iterative Health, Johnson & Johnson, Lilly, Pfizer, Samsung Neurologica, Takeda.
BES: AbbVie, Abivax, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, AstraZeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Celltrion, Equillium, Enthera, Enveda Biosciences, Evommune, Ferring, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Johnson & Johnson, Kaleido, Kallyope, Lilly, Merck, Microba, Mirador Therapeutics, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Sorriso Pharmaceuticals, Spyre Therapeutics, Sun Pharma, Surrozen, Takeda, Target RWE, Teva, TLL Pharmaceutical, Tr1X, Union Therapeutics, Ventyx Biosciences, and Vividion Therapeutics.

Introduction

A marked decrease of Faecalibacterium prausnitzii is a well-established hallmark of Crohn’s disease (CD)-associated dysbiosis and predicts disease relapse (1-2). Several strains of F. prausnitzii exhibit anti-inflammatory effects in vitro and in rodents colitis models, positioning this species as a promising therapeutic candidate (3-4). However, it has never been administered to humans. Here, we present the development and first-in-human evaluation of F. prausnitzii strain EXL01 for CD treatment.

Aims & Methods

F. prausnitzii EXL01, isolated from a healthy donor, was selected based on strict safety and preliminary in vitro efficacy criteria. Its anti-inflammatory effect was tested in trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats and dextran sodium sulfate (DSS)-induced colitis in mice. After favorable toxicological studies, a first-in-human, open-label, single-arm study (Part A) was conducted in patients with mild to moderate ileal CD (CDAI 180–350), following clinical remission (CDAI <150) or response (CDAI decrease ≥70) after corticosteroids (CS). EXL01 (10¹⁰ total cell count/day) was administered orally for 24 weeks, with a 6-week CS taper. Colonoscopies were performed at baseline and week 24. The primary endpoint was safety; secondary endpoints included clinical efficacy, blood/fecal biomarkers, transcriptomic analysis, and gut microbiota profiling. Part B, initially planned as a placebo-controlled phase, was not pursued due to low recruitment.

Results

According to classical evaluation endpoints, EXL01 demonstrated dose-dependent anti-inflammatory effects in both TNBS and DSS models. Between March 2023 and October 2024, 8 patients were enrolled across Belgium and Poland. Baseline characteristics were consistent with the target CD population. After corticosteroid induction, the parameters were as follow: CDAI = 78.1 (42-105); SES-CD= 6.9 (2-17); CRP = 5.7mg/l (3-13). EXL01 was well tolerated; no treatment-related serious adverse events or safety signals were observed. Six participants (75%) completed the 24-week treatment; two discontinued due to disease flare. Compared to patients who remained in remission, those who flared during the study showed higher baseline systemic inflammation markers (CRP, neutrophils, platelets) and innate immunity gene expression, with limited corticosteroid response. While gut microbiota composition remained largely stable, transcriptomic analyses revealed distinct changes in ileal gene expression following EXL01 treatment, notably modulation of immune-related genes and upregulation of energy metabolism pathways, similar to what we saw previously in vitro (bioRxiv 2024.10.06.616495).

Conclusion

EXL01, administered during and after CS tapering, was safe and well tolerated for up to 24 weeks in patients with CD. Though limited by small sample size, the study supports the biological activity of EXL01, notably through its impact on ileal gene expression. A phase 2 randomized controlled trial is ongoing to further assess efficacy.

References

1. Rajca S, Grondin V, Louis E, et al. Alterations in the intestinal microbiome (dysbiosis) as a predictor of relapse after infliximab withdrawal in Crohn's disease. Inflamm Bowel Dis. 2014 Jun;20(6):978-86. doi: 10.1097/MIB.0000000000000036. PMID: 24788220.
2. Pascal V, Pozuelo M, Borruel N, et al. A microbial signature for Crohn's disease. Gut. 2017;66(5):813-22.
3. Sokol H, Pigneur B, Watterlot L, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A. 2008;105(43):16731-6.
4. Martin R, Chain F, Miquel S, et al. The commensal bacterium Faecalibacterium prausnitzii is protective in DNBS-induced chronic moderate and severe colitis models. Inflamm Bowel Dis. 2014;20(3):417-30.

Disclosure

HS, PhL and BH are co-founder of Exeliom. PR, DS, BH are employees of Exeliom Biosciences

Introduction

Esophageal squamous cell carcinoma (ESCC) is associated with poor prognosis despite advances in neoadjuvant immunochemotherapy (NICT). With highly variable treatment responses, identifying reliable predictive biomarkers remains crucial. While gut microbiome influences on immunotherapy efficacy are increasingly recognized, the specific role of the fungal microbiome (mycobiome) in NICT outcomes for ESCC remains unexplored, representing a significant gap in developing personalized treatment strategies.

Aims & Methods

This study aimed to characterize gut mycobiome signatures in ESCC patients and develop fungal biomarker-based predictive models for NICT response. We conducted ITS2 sequencing on 136 fecal samples collected from 68 ESCC patients (pre- and post-NICT) and 19 healthy controls (HC). Patients were stratified as responders (R, n=26) or non-responders (NR, n=42) based on tumor regression grade (TRG) scores. We performed comprehensive analyses of mycobiome diversity, composition, co-occurrence networks, and functional pathways across groups. The Boruta algorithm was employed for feature selection to identify fungal biomarkers, followed by multilayer perceptron (MLP) machine learning with five-fold cross-validation to develop predictive models. Additionally, ESCC xenograft models were established to investigate gut mycobiome-immune interactions through fecal microbiota transplantation (FMT) and targeted fungal manipulation experiments.

Results

ESCC patients demonstrated significant mycobiome dysbiosis compared to healthy controls, characterized by reduced fungal alpha diversity and distinct beta diversity patterns. At baseline, ESCC patients showed enrichment of Rhodotorula minuta, Actinomucor elegans, and several Candida species. Responders exhibited significantly higher baseline fungal diversity than non-responders, with enrichment of Meyerozyma, Candida boidinii, Trichosporon dermatis, and Cryptococcus species, whereas non-responders showed predominance of Saccharomyces, Nakaseomyces, and pathogenic Candida species (C. glabrata, C. parapsilosis, C. albicans). Responders also displayed more complex, stable fungal co-occurrence networks with higher density and clustering coefficients. Post-NICT, both groups showed partial recovery of mycobiome diversity, with significant increases in beneficial fungal taxa. Functional pathway analysis revealed distinct metabolic profiles between responders and non-responders. Using the Boruta algorithm, we identified 23 genus-level and 22 species-level fungal biomarkers that demonstrated high predictive value. The MLP model based on genus-level markers achieved AUCs of 90.2% (training) and 91.9% (test), while the species-level model showed comparable performance. In animal experiments, mice receiving R-FMT exhibited reduced tumor growth and enhanced CD8+ T cell infiltration compared to NR-FMT recipients. Notably, Candida boidinii supplementation synergized with anti-PD-1 therapy, while Saccharomyces depletion enhanced treatment sensitivity.

Conclusion

Our findings establish the gut mycobiome as a powerful predictor of NICT response in ESCC, with machine learning models achieving >90% accuracy using fungal biomarkers. Experimental validation not only confirms mechanistic links between specific fungi and antitumor immunity but also demonstrates that targeted mycobiome modulation can enhance immunotherapy efficacy. This dual approach of prediction and intervention offers a novel framework for precision oncology in ESCC, potentially transforming clinical decision-making and treatment outcomes in this challenging malignancy.

References

1. Li J, Xu J, Zheng Y, et al. Esophageal cancer: Epidemiology, risk factors and screening. Chin J Cancer Res. 2021; 33(5): 535-547.
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3. Schroeder W, Ghadimi M, Schloesser H, et al. Long-Term Outcome After Histopathological Complete Response with and Without Nodal Metastases Following Multimodal Treatment of Esophageal Cancer. Ann Surg Oncol. 2022.
4. Rosner S, Liu C, Forde PM, Hu C. Association of Pathologic Complete Response and Long-Term Survival Outcomes Among Patients Treated With Neoadjuvant Chemotherapy or Chemoradiotherapy for NSCLC: A Meta-Analysis. JTO Clin Res Rep. 2022; 3(9): 100384.
5. Coker OO, Nakatsu G, Dai RZ, et al. Enteric fungal microbiota dysbiosis and ecological alterations in colorectal cancer. Gut. 2019; 68(4): 654-662.
6. Dohlman AB, Klug J, Mesko M, et al. A pan-cancer mycobiome analysis reveals fungal involvement in gastrointestinal and lung tumors. Cell. 2022; 185(20): 3807-3822.
7. Wurster S, Albert ND, Kontoyiannis DP. Candida auris Bloodstream Infection Induces Upregulation of the PD-1/PD-L1 Immune Checkpoint Pathway in an Immunocompetent Mouse Model. Msphere. 2022; 7(2): e81721.