AIM:There is an unmet need for more effective therapies in inflammatory bowel disease (IBD). A single drug that blocks multiple distinct pathogenic pathways may offer therapeutic benefit superior to current monotherapies. PF-07261271, a bispecific antibody targeting both the p40 subunit of interleukin-12/23 and tumour necrosis factor-like cytokine 1A (TL1A), is being investigated as a potential new IBD therapy. This study evaluates the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of PF-07261271 in healthy participants. METHODS:This phase 1, randomized, double-blind, placebo-controlled study assessed single ascending doses (SAD; intravenous 30-1000 mg) and multiple doses (MD; subcutaneous 300 mg once every 4 weeks) of PF-07261271 in healthy adults. Safety, PK, immunogenicity and exploratory PD serum biomarkers (total soluble TL1A [sTL1A] and p40) were evaluated. RESULTS:Thirty-five participants were enrolled (Part A: SAD, N = 27; Part B: MD, N = 8). PF-07261271 was generally safe and well tolerated; all treatment-emergent adverse events were mild/moderate. Following peak serum concentration, there was a multi-phase decline with a trend towards increased terminal half-life at the higher doses. For the MD cohort, the estimated bioavailability of PF-07261271 administered subcutaneously was 48%. Dose-dependent increases from baseline in serum total sTL1A and p40 levels were observed in participants receiving PF-07261271, demonstrating target engagement. There was no apparent impact of anti-drug antibodies on safety, PK or PD parameters. CONCLUSION:PF-07261271 demonstrated p40 and TL1A target engagement and a favourable safety profile. Further studies are warranted to evaluate its safety and efficacy in patients with IBD. CLINICALTRIALS:gov: NCT05536440.

Inflammatory bowel disease (IBD) increases the risk of colorectal cancer (CRC). Genetic variants in TNFSF15, encoding tumor necrosis factor (TNF)-like cytokine 1A (TL1A), associate with severe IBD and advanced CRC. Here, we investigated how TL1A signaling promotes colitis-associated tumorigenesis. Deletion of the TL1A receptor in tissue-resident type 3 innate lymphoid cells (ILC3s) reduced colitis-associated tumorigenesis. TL1A signaling promoted neutrophil recruitment to the colon, which was required for tumor development. TL1A-stimulated ILC3s activated neutrophils, inducing a tumor-associated neutrophil (TAN)-like gene signature, and transfer of these neutrophils was sufficient to promote tumor growth. A similar TAN-like gene signature was enriched in human colitis-associated dysplasia but reduced following TL1A blockade in ulcerative colitis patients. Mechanistically, TL1A and colitis triggered emergency granulopoiesis, expanding granulocyte-monocyte progenitors and neutrophils in a manner dependent on ILC3-derived granulocyte-macrophage colony-stimulating factor (GM-CSF). Thus, a TL1A-ILC3-GM-CSF axis links colitis with emergency granulopoiesis and may serve as a therapeutic target to reduce colitis-associated CRC.

Background and Aims:The safety of gastrointestinal endoscopy in neutropenic patients remains unestablished. Gastrointestinal and infectious disease society guidelines indicate that infectious adverse events are increased after endoscopy in neutropenic patients. We performed a systematic review and meta-analysis to assess the safety of endoscopy in neutropenic patients. Methods:Cochrane Library, Embase, Google Scholar, MEDLINE, PubMed, Scopus, and Web of Science were searched through September 2025 for studies in neutropenic patients (absolute neutrophil count <1000 cells/μL) undergoing endoscopy with outcome data on infections, mortality, or fever. Conference abstracts from January 2017 to September 2025 were also searched. Two reviewers independently identified studies meeting inclusion criteria, performed data extraction, and assessed risk of bias. Coprimary outcomes were 30-day infection-related mortality and infectious adverse events within 7 days of endoscopy. Secondary outcomes were new bacteremia and new fever within 7 days of endoscopy. Random-effects meta-analyses were performed. Results:Six cohort studies met eligibility criteria (N = 1241 patients). Pooled incidence was 0.0% (95% confidence interval [CI] 0.00%-0.03%; I2 = 0.0%) for infection-related mortality and 7.3% (95% CI 0.00%-25.57%; I2 = 98.6%) for infectious adverse events, which consisted of bacteremia (2.4% [95% CI 0.03%-6.99%; I2 = 87.3%]) and new fever (4.8% [95% CI 0.00%-9.74%; I2 = 99%]). Preprocedural antibiotic use did not reduce infectious adverse events or bacteremia as compared to no antibiotic use: odds ratio = 2.97, 95% CI 0.47-18.67. Conclusion:Infection-related mortality within 30 days was 0% and infectious adverse events within 7 days occurred in 7.3% of neutropenic patients undergoing endoscopy. These findings suggest endoscopy maybe safely performed in appropriately selected neutropenic patients.

PF-06480605, a fully human IgG1 monoclonal antibody targeting tumor necrosis factor α-like ligand 1A (TL1A), has demonstrated acceptable safety and the potential as an effective treatment for inflammatory bowel disease in phase 1/2a studies. To facilitate future clinical development in Japan and China, a Japan local phase 1 study was designed in consultation with the Japan regulatory authority. In addition to fulfilling Japan regulatory requirements, this study will bring operational efficiency and speed to global and China development by evaluating PF-06480605 in Japanese healthy adults prior to a China local phase 1 study as required by the China regulatory authority. This phase 1, randomized, double-blind, placebo-controlled, single-dose escalating study investigated the safety, tolerability, immunogenicity, pharmacokinetics (PK), and pharmacodynamics of PF-06480605 in Japanese healthy adults assigned to receive a single subcutaneous (SC) dose of PF-06480605 150 mg (N = 6), 450 mg (first-in-human dose level, N = 6), or placebo (N = 4). PF-06480605 was well tolerated and absorbed slowly with a median Tmax of 217.5 h for both 150 and 450 mg doses. Mean t1/2 was 18.4 and 19.1 days for 150 and 450 mg, respectively. Exposure parameters showed dose proportionality. No ethnic differences in PF-06480605 PK were observed. Serum TL1A levels increased in a dose-dependent manner. Immunogenicity was high with 100% of anti-PF-06480605 antibody formulation. This study satisfied the Japan regulatory requirements, while the favorable tolerability and PK of 450 mg SC in Japanese contributed to a waiver of the 150 mg SC cohort in the China local phase 1 study. NCT04269538.

BACKGROUND:TNF-like ligand 1A (TL1A) is an emerging therapeutic target for inflammatory bowel disease. We evaluated the safety and efficacy of multiple doses of afimkibart, a TL1A-directed antibody, in patients with moderately-to-severely active ulcerative colitis. METHODS:The multicentre, double-blind, treat-through, multi-dose, randomised, placebo-controlled, phase 2b, TUSCANY-2 trial was conducted at 114 centres in 23 countries across North America, Europe, Asia, Africa, Australia, and South America. Adults (aged 18-75 years) with moderately-to-severely active ulcerative colitis (total Mayo score [tMS] 6-12, endoscopic subscore ≥2) were randomly assigned (2:2:2:2:2:3:1:1:1) to one of nine treatment sequences to receive subcutaneous afimkibart 50 mg, 150 mg, 450 mg, or matched placebo every 4 weeks during the 12-week induction period, and subcutaneous afimkibart 50 mg, 150 mg, or 450 mg during the treat-through 40-week maintenance period. Investigators and patients were masked to treatment. Study drugs were administered by masked site personnel following preparation by an unmasked pharmacist at the investigational site. Efficacy was assessed at weeks 14 and 56 in the intent-to-treat populations. The primary efficacy endpoint of clinical remission at week 14 by tMS (defined as tMS ≤2, with no individual subscore >1) was assessed in those who received at least one dose of drug or placebo during induction, excluding patients who had missing data due to complications resulting from COVID-19. Safety endpoints were also analysed in those who were randomly assigned and received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, NCT04090411. FINDINGS:Between Dec 19, 2019, and Oct 25, 2022, 246 patients were randomly assigned treatment, of whom 245 were treated, 228 completed induction, and 178 completed maintenance. Median age was 39 years (IQR 30·0-51·0), 99 (40%) patients were female and 146 (60%) were male; median disease duration was 4·7 years (IQR 2·5-10·2). At week 14, the primary endpoint of clinical remission by tMS was reported in 12 (26%) of 47 patients in the afimkibart 50 mg group (risk difference vs placebo [RD] 13·9% [90% CI -0·2 to 27·7]; p=0·0545), 14 (23%) of 60 patients in the afimkibart 150 mg group (RD 11·7% [-1·7 to 24·1]; p=0·0823), and 21 (24%) of 88 patients in the in the afimkibart 450 mg group (RD 12·2% [-0·6 to 22·9]; p=0·0642) versus five (12%) of 43 patients in the placebo group. In alignment with updated US Food and Drug Administration guidance, clinical remission using the modified Mayo score at week 14 was reported in 14 (30%) of 47 patients in the afimkibart 50 mg group (RD 18·2% [90% CI 3·3 to 32·2]), 21 (35%) of 60 patients in the in the afimkibart 150 mg group (RD 23·4% [6·2 to 36·3]), and 28 (32%) of 88 patients in the in the afimkibart 450 mg group (RD 20·2% [3·2 to 31·3]) versus five (12%) of 43 patients in the placebo group. Overall, 117 (48%) of 245 patients in the induction phase and 132 (59%) of 224 patients in the maintenance phase reported at least one treatment-emergent adverse event; incidences of treatment-emergent adverse events during induction were similar with placebo and afimkibart. The most common treatment-emergent adverse events (occurring in ≥5% of patients) during induction were nausea, urinary tract infection, ulcerative colitis, anaemia, fatigue, headache, and pyrexia. Six serious adverse events were reported during induction in the active treatment groups and four in the placebo group. Two patients who completed induction and did not receive the study drug during maintenance had serious adverse events during safety follow-up. During the maintenance period, 12 (5%) of 224 patients had 13 serious adverse events. No deaths occurred. INTERPRETATION:Differences in the primary endpoint of clinical remission by tMS were not significantly different for any dose of afimkibart compared with placebo. However, secondary endpoints suggest that afimkibart was associated with a favourable benefit-risk profile, with clinically meaningful improvements in clinical remission with the modified Mayo score for patients with moderately-to-severely active ulcerative colitis. These results support the continued development of afimkibart. FUNDING:Pfizer, Roivant Sciences, and F Hoffmann-La Roche.

The proportion of individuals ≥ 65 years of age in the global population is rapidly increasing. Gastrointestinal (GI) bleeding is one of the common GI conditions affecting older individuals. These individuals have unique comorbid conditions, exposures to anticoagulants or Helicobacter pylori, and physiologic changes that increase their propensity for developing ulcers or angioectasias, raise their bleeding risk, and affect their treatment plans. This review summarizes the epidemiology, pathophysiology, evaluation, and management of GI bleeding in older individuals. Frailty and increased use of anticoagulants and antiplatelet agents have negatively impacted GI bleeding outcomes. Novel risk scores have been developed to predict mortality, rebleeding, and need for endoscopic therapy. Several studies and guidelines have been published on timing of endoscopic interventions, strategies to prevent rebleeding, and peri-procedural anticoagulation management. Older age is a risk factor for mortality in GI bleeding. Timely endoscopic evaluation and management of modifiable risk factors such as anticoagulation and Helicobacter pylori infection may mitigate bleeding risk in this population and reduce mortality.

Background and Aims: Ritlecitinib, an oral JAK3/TEC family kinase inhibitor, was well-tolerated and efficacious in the phase 2b VIBRATO study in participants with moderate-to-severe ulcerative colitis [UC]. The aim of this study was to identify baseline serum and microbiome markers that predict subsequent clinical efficacy and to develop noninvasive serum signatures as potential real-time noninvasive surrogates of clinical efficacy after ritlecitinib.Methods: Tissue and peripheral blood proteomics, transcriptomics, and faecal metagenomics were performed on samples before and after 8 weeks of oral ritlecitinib induction therapy [20 mg, 70 mg, 200 mg, or placebo once daily, N = 39, 41, 33, and 18, respectively]. Linear mixed models were used to identify baseline and longitudinal protein markers associated with efficacy. The combined predictivity of these proteins was evaluated using a logistic model with permuted efficacy data. Differential expression of faecal metagenomics was used to differentiate responders and nonresponders.Results: Peripheral blood serum proteomics identified four baseline serum markers [LTA, CCL21, HLA-E, MEGF10] predictive of modified clinical remission [MR], endoscopic improvement [EI], histological remission [HR], and integrative score of tissue molecular improvement. In responders, 37 serum proteins significantly changed at Week 8 compared with baseline [false discovery rate of <0.05]; of these, changes in four [IL4R, TNFRSF4, SPINK4, and LAIR-1] predicted concurrent EI and HR responses. Faecal metagenomics analysis revealed baseline and treatment response signatures that correlated with EI, MR, and tissue molecular improvement.Conclusions: Blood and microbiome biomarkers stratify endoscopic, histological, and tissue molecular responses to ritlecitinib, which may help guide future precision medicine approaches to UC treatment. ClinicalTrials.gov NCT02958865

Abstract Inflammatory changes play an important role in tumorigenesis, and patients with chronic inflammatory bowel disease (IBD) are at an increased risk of developing colitis-associated cancer (CAC). Variants in TNFSF15, the gene that encodes TL1A, are associated with more aggressive IBD and advanced CRC. Here, we show that TL1A signaling is required for colitis-associated tumorigenesis and sufficient to promote CRC in mouse models. TL1A signaling in group 3 innate lymphoid cells (ILC3) promotes GM-CSF dependent activation of colonic neutrophils and colitis-associated tumors in mouse models. TL1A-mediated ILC3-dependent tumor-associated neutrophil (TAN) signatures were evident in mouse models and reduced in subjects with UC treated with anti-TL1A therapy. Furthermore, TL1A promoted ILC-dependent emergency granulopoiesis, which is similarly evident in IBD subjects with TNFSF15 risk variants. These results reveal a new mechanism by which TL1A signaling in tissue resident ILCs shape TANs and emergency granulopoiesis with the potential to guide emerging anti-TL1A therapies for IBD.

Background and Aims:The gastroenterology (GE) hospitalist staffing model has multiple potential benefits for the inpatient and outpatient care of GE patients. The GE hospitalist model may improve inpatient endoscopy efficiency via better provider familiarity with management of GE emergencies, hospital systems, and workflow, and may also increase outpatient endoscopy capacity by decreasing the need for inpatient coverage by outpatient providers. However, the real-world impact of this model on inpatient and outpatient endoscopic volume remains uncertain. Methods:We conducted a controlled interrupted time-series analysis from September 2018 to March 2020 comparing inpatient endoscopy volume at 2 high-acuity hospitals within the same academic health system, one of which adopted a 2-physician GE hospitalist model in July 2019. We also performed a single interrupted time-series analysis of outpatient endoscopic volume of the practice employing GE hospitalists. Results:After implementation of the GE hospitalist model, weekly volume of inpatient endoscopic procedures increased by 10.9 (95% CI, .6-21.2; P = .024) compared with a hospital using traditional staffing. Outpatient endoscopic procedure volume also increased by 39.8 per week (95% CI, -5.78 to 85.44; P = .09), with no change in the number of physicians performing endoscopy. Conclusions:Our findings demonstrate that introduction of a GE hospitalist model increased inpatient and outpatient endoscopic volume in a large academic center.