Introduction

Vedolizumab (VDZ) is efficacious to induce and maintain clinical remission in Crohn’s disease (CD). However, prospective data about its efficacy including endoscopy in early CD are lacking.

Aims & Methods

We conducted a prospective multi-centre international (Belgium, the Netherlands and Hungary) open label trial comparing the efficacy and safety of VDZ therapy in patients with early or late moderate-severe active CD (Crohn’s Disease Activity Index [CDAI] 220-450 and presence of ulcers at endoscopy). Early CD was defined as diagnosis <2 years and treatment naïve or only treated with corticosteroids and/or immunomodulators; late CD was defined as diagnosis >2 years and previously treated with corticosteroids, immunomodulators and anti-tumor necrosis factor agents. Patients received intravenous VDZ (300 mg) at weeks 0-2-6 and q8 weeks thereafter for a total of 52 weeks, with an extra infusion at w10 in the absence of a CDAI drop <70. Ileocolonoscopy was performed at baseline, w26 and w52 and all procedures were centrally read. The sample size was calculated for 1/3 early and 2/3 late CD. An extremely strict primary composite endpoint was used: proportion of patients with clinical and endoscopic remission (CDAI≤150 and Simple Endoscopic Score for CD [SES-CD]<4) at both w26 and w52. Key secondary endpoints included the proportion of patients with absence of ulcers, proportion of patients with endoscopic response (SES-CD reduction ≥50%) at w26 and w52 and safety.

Results

We recruited 86 early and 174 late CD patients, of whom 52 early and 104 late CD patients completed w52 (insufficient clinical response and adverse events were the main reasons for early withdrawal). Baseline characteristics including disease activity parameters were similar across both groups (median total SES-CD 9 [6-17] and 12 [7-17], median CDAI 254.7 [235.7-287.2] and 259 [235.2-314.5] for early and late CD, respectively), apart from disease duration and age (median disease duration 0 [0-1] and 11 [5.5-15.5], median age 29.5 [23.8-45.3] and 36 [28-48] for early and late CD, respectively). The primary endpoint was reached in 31.4% vs. 8.6% (p=0.001; ITT) and 45.0% vs. 16.0% (p<0.001; per protocol [PP]) of patients with early vs. late CD (Table 1). All key secondary endpoints were also met in favour of patients with early CD (Table 1). Serious adverse events (SAEs) occurred in 4.7% of patients with early vs. 27% of patients with late CD (p<0.0001) and included infection (1.2 vs 7.5%) bowel obstruction (0 vs 2.3%), exacerbation of CD (2.3 vs 4%), abdominal pain (0 vs 1.7%) and malignancy (0 vs 1.7%).

Table 1. Primary composite endpoint and key secondary endpoints (ITT and PP analysis)

Conclusion

VDZ treatment is more effective and safer in early than in late CD (IIS Funded by Takeda Nederland B.V. [IISR-2014-100757]; LOVE-CD EudraCT number 2014-005376-29).

Disclosure

GD: served as advisor and/or speaker for Abbvie, Alimentiv, Astrazeneca, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Glaxo Smith Kline, Immunic, Index Pharmaceuticals, Johnson and Johnson, Polpharm, Prometheus biosciences, Prometheus laboratories, Procise diagnostics, Protagonist, Sandoz, Setpoint, Spyre, Takeda, Tillotts and Ventyx.
ML: consultancy/ lecture fees from Abbvie, Bristol Myers Squibb, Eli Lilly, Galapagos, Janssen-Cilag, Johnson & Johnson, Medtronic, Pfizer, Takeda, Tillotts. Central reader for Alimentiv. Grant received from Galapagos and NFU.
FB: reports grants/research supports from AbbVie, Amgen, Takeda, Janssen, honoraria or consultation fees from AbbVie, Amgen, Arena, MSD, Celgene, Kabi-Fresenius, Takeda, Ferring, Pfizer, Norgine, Janssen and participation in a company sponsored speaker's bureau for AbbVie, MSD, Takeda, Ferring, Pfizer, Janssen.
PB: has received research grants from AbbVie, Amgen, Celltrion, Mylan, Pfizer, and Takeda; lecture fees from AbbVie, Celltrion, Janssen, Lilly, and Takeda; and consulting fees from AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb, Celltrion, Dr Falk Pharma, Galapagos, Janssen, Lilly, Pentax, PSI-CRO, Roche, Takeda, and Tetrameros.
FH: has served on advisory boards or as speaker for Abbvie, Janssen, MSD, Takeda, Pfizer, Celltrion, Teva, Sandoz, Amgen and Pendopharm, and has received independent research funding from Janssen, Abbvie, Pfizer and Takeda.
EC: has no conflicts of interest.
LO: has no conflicts of interest.
MH: has no conflicts of interest.
TM: has received speaker’s honoraria from MSD, AbbVie, Egis, Goodwill Pharma, Takeda, Pfizer, Janssen, Sandoz, MundiPharma, Phytotec, Roche, Fresenius and Teva.
SV: financial support for research from: AbbVie, J&J, Pfizer, Takeda and Galapagos and receives speakers’ and/or consultancy fees from: AbbVie, Abivax, AbolerlsPharma, AgomAb, Alimentiv, Arena Pharmaceuticals, Astrazeneca, BioraTherapeutics, BMS, Boehringer Ingelheim, Celgene, Cytoki Pharma, Dr Falk Pharma, Ferring, Galapagos, Genentech Roche, Gilead, GSK, Hospira, lmidomics, Janssen, J&J, Lilly, Materia Prima, Mestag Therapeutics, Microbiotica, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Surrozen, Takeda, Theravance, Tillots Pharma AG, VectivBio, Ventyx, Zealand Pharma.

Introduction

Advanced combination treatment (ACT), defined as the use of two biologics or a biologic and a small molecule drug with distinct mechanisms of action, is increasingly adopted for refractory inflammatory bowel disease (IBD) and overlapping immune-mediated inflammatory diseases (IMIDs). Despite promising clinical results, the immunological consequences of ACT remain poorly characterized. Here, we investigated how two ACT regimens—anti-TNF + anti-integrin and anti-TNF + anti-IL-23—shape the peripheral CD3⁺ T cell landscape at single-cell resolution, with a focus on clonotype architecture, repertoire diversity, and antigen specificity.

Aims & Methods

We aim to characterize the peripheral CD3⁺ T cell transcriptional landscape and clonal architecture in patients with refractory IBD who achieved clinical response following initiation of two different ACT regimens: anti-TNF + anti-integrin α4β7 and anti-TNF + anti-IL-23. Peripheral blood mononuclear cells (PBMCs) were collected from six patients with Crohn’s disease who achieved clinical response to ACT. Four patients received anti-TNF + anti-integrin α4β7, and two received anti-TNF + anti-IL-23. CD3⁺ T cells were isolated and analyzed via single-cell RNA sequencing (scRNA-seq) coupled with paired T cell receptor (TCRα/β) sequencing. Cell state annotations were performed using supervised deconvolution against the scIBD reference atlas, and TCR repertoire metrics (diversity, clonality, evenness) were computed to assess clonal expansion dynamics.

Results

All patients included demonstrated clinical improvement, underscoring the immunological relevance of the findings. Single-cell transcriptomic and TCR repertoire profiling uncovered distinct treatment-specific patterns in peripheral T cell states and clonal architecture. In the anti-TNF + α4β7 group, there was marked enrichment of CD4⁺ tissue central memory T cells (CD4⁺ tissue-Tcm) and CD4⁺ naïve T cells (CD4⁺ Tn), along with greater TCR diversity, reduced clonal dominance, and enhanced repertoire evenness. In contrast, the anti-TNF + IL-23 group exhibited a marked enrichment of CD8⁺ naive T cells (CD8⁺ Tn) and a repertoire characterized by reduced diversity and pronounced oligoclonal expansion.

Conclusion

In difficult-to-treat IBD patients who achieved clinical response to ACT, distinct patterns of immunological remodeling emerged depending on the therapeutic combination. Treatment with anti-TNF + anti-integrin was associated with a diversified, polyclonal T cell repertoire consistent with a systemic rebalancing of the adaptive immune response, whereas anti-TNF + anti-IL-23 drove more focused, oligoclonal expansions indicative of selective immune activation. These divergent signatures underscore mechanistically distinct pathways of immune reprogramming and highlight the potential of T cell–based immuno-profiling to inform the rational selection of biologic combinations. Incorporating single-cell and TCR repertoire analyses into ACT trials may enable a precision medicine framework for optimizing treatment strategies in IBD.

References

Danese S, Solitano V, Jairath V, Peyrin-Biroulet L. The future of drug development for inflammatory bowel disease: the need to ACT (advanced combination treatment). Gut. 2022 Dec;71(12):2380-2387. doi: 10.1136/gutjnl-2022-327025. Epub 2022 Jun 14. PMID: 35701092.

Disclosure

Virginia Solitano has received speaker fees from Pfizer and consultancy fees from Johnson & Johnson. Vipul Jairath has received consultancy/advisory board fees from AbbVie, Alimentiv Inc., Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Reistone Biopharma, Roche, Sandoz, Second Genome, Takeda, Teva, Topivert, Ventyx, and Vividion; and speaker’s fees from, Abbvie, Ferring, Galapagos, Janssen Pfizer Shire, Takeda, and Fresenius Kabi. Silvio Danese has received consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, TiGenixa, UCB Inc, and Vifor; and lecture fees from AbbVie, Amgen, Ferring Pharmaceuticals Inc, Gilead, Janssen, Mylan, Pfizer, and Takeda. The other authors have nothing to disclose.

Introduction

Fistulating peri-anal Crohn’s disease can affect approximately 20% of patients and have a major impact on quality of life. Despite being an important area of unmet clinical need, there is a paucity of evidence for most medical treatments and a lack of dedicated clinical trials for perianal Crohn’s disease. Current studies also report a high level of heterogeneity for outcomes with both treatments and placebo - making interpretation of the available data challenging for both clinical practice and design of clinical trials. Use of Bayesian methodology offers an attractive solution to help address some of these challenges. We sought to conduct a Bayesian prior elicitation exercise to determine the efficacy of licensed medical therapies for fistulating perianal Crohn’s disease.

Aims & Methods

A formal Bayesian prior elicitation meeting was convened. This was composed of a group of 11 gastroenterologists and 5 statisticians. Consensus priors were developed leveraging both published data and expertise of the gastroenterologists, to determine one-year fistula remission rates for seven options of licensed medical treatments based on five different mechanisms of action (anti-TNF, anti-integrin, anti-IL12/23, anti-IL-23, and JAK inhibitor). Consensus priors on the efficacy of each of seven treatment options was determined relative to an elicited consensus prior for placebo control. The log-odds ratio for efficacy for each of the seven therapy options versus placebo control was also established.

Results

Consensus priors were obtained for seven medical treatments for likelihood of fistula remission at one year. The prior mean, together with a 90% prior credible interval, of the one-year fistula remission rate was 0.22 (0.05, 0.46) for placebo, 0.58 (0.09, 0.96) for intravenous infliximab, 0.39 (0.06, 0.82) for adalimumab, 0.53 (0.09, 0.93) for subcutaneous infliximab, 0.24 (0.03, 0.60) for intravenous vedolizumab, 0.44 (0.05, 0.90) for upadacitinib, 0.34 (0.04, 0.77) for ustekinumab, and 0.36 (0.04, 0.82) for risankizumab. When assessing treatment effect on the log-odds ratio scale, oral upadacitinib and subcutaneous infliximab had the strongest “priors”, with the highest probability for likely efficacy, alongside intravenous infliximab.

Conclusion

We have conducted, to the best of our knowledge, the first formal Bayesian prior elicitation exercise for efficacy of medical therapies in perianal Crohn’s disease. These priors developed for the efficacy of licensed medical therapies can be internationally validated and potentially taken forward for planning of dedicated clinical trials. Importantly, these results could be used to enhance the design and analysis of clinical trials for fistulating perianal Crohn’s disease. Notable potential benefits from these findings include: improved estimation of treatment efficacy, reduction in the required sample sizes, and with minimisation or even avoidance of placebo control arms for future dedicated fistulating perianal Crohn’s disease clinical trials.

Disclosure

NMN declares educational/travel grants and/or speaker fees from AbbVie, Bristol Myers Squibb, Celltrion, Dr Falk Pharma, Ferring, Galapagos, J&J, Lilly, Pfizer, Pharmacosmos, Takeda and Tillotts Pharma AG. RC reports personal fees from AbbVie, Galapagos, Lilly outside the submitted work, and grants from Celltrion, Ferring, Tillotts Pharma outside the submitted work; and fees from advisory board membership of AbbVie, Bristol Myers Squibb outside the submitted work. SD reports personal fees from AbbVie, Ferring, Janssen, Takeda outside the submitted work; and grants from AbbVie, Dr Falk, Janssen, outside the submitted work; and fees from advisory board membership of AbbVie outside the submitted work. HG has received speaker fees from: Janssen, Ferring, Takeda, and AbbVie, and consultancy fees from. AbbVie, Galapagos. KBK reports serving as a speaker, a consultant, and/or an advisory board member for Abbvie, Falk, Galapagos, Janssen, and Takeda. JOL reports personal fees from AbbVie, Atlantic Healthcare, Bristol Meyer Squibb, Celgene, Celltrion, Engytix, Eli Lilly, Ferring, Galapagos, Gilead, GSK, Janssen, MSD, Norgine, Pfizer, Shire, and Takeda outside the submitted work; and grants from AbbVie, Ferring, Gilead, Takeda, and Shire outside the submitted work. GWM declares consultancy fees/grant funding from AbbVie, AstraZeneca and Janssen; all outside the submitted work. KVP reports personal fees from AbbVie, DrFalk, Galapagos, Janssen, PredictImmune, Pfizer, Takeda outside the submitted work; and grants from AbbVie, Celltrion, Dr Falk, Ferring, Janssen, Takeda, Tillotts Pharma outside the submitted work; and fees from advisory board membership of AbbVie, Galapagos, Janssen, Pfizer outside the submitted work. SS reports consulting fees from Takeda, AbbVie, Merck, Ferring, Pharmacosmos, Warner Chilcott, J&J Innovative Medicine, Dr Falk Pharma, Biohit, TriGenix, Celgene, and Tillots Pharma outside the submitted work; payment or honoraria from AbbVie, Takeda, Celltrion, Pfizer, Biogen, AbbVie, J&J Innovative Medicine, Merck, Warner Chilcott, Dr Falk Pharma, outside the submitted work; and is co-director of research for the South Asian IBD Alliance. TR has received research/educational grants and/or speaker/consultation fees from Abbvie, Arena, Aslan, AstraZeneca, Boehringer-Ingelheim, BMS, Celgene, Eli Lilly, Ferring, Galapagos, Gilead, GSK, Heptares, LabGenius, Janssen, MonteRosa, Mylan, MSD, Novartis, Numab, Pfizer, Roche, Sandoz, Takeda, UCB, and XAP Therapeutics. SS reports person fees from Abbvie, Celltrion, Dr. Falk, Ipsen, Janssen, Takeda outside the submitted work. ALH has received consultancy fees from AbbVie, Bristol Myers Squibb, Celltrion, Galapagos, Johnson & Johnson, Takeda, Pfizer, and Lilly; has received honoraria from AbbVie, Bristol Myers Squibb, Celltrion, Galapogos, Johnson & Johnson, Takeda, Pfizer, Lilly; and has received support for attending meetings or travel from AbbVie, Bristol Myers Squibb, Celltrion, Galapagos, Johnson & Johnson, Takeda, Pfizer, and Lilly; all outside of the submitted work. MP reports personal fees from Janssen and Takeda outside the submitted work; and grants from AstraZeneca, Galapagos, Gilead, Pfizer outside the submitted work. All other authors declare no conflicts of interest.