Introduction

Tumour necrosis factor-like ligand 1A (TL1A) is a novel therapeutic target for inflammatory bowel disease. Patients (pts) with moderately to severely active ulcerative colitis (UC) treated with the anti-TL1A antibody, RO7790121 (formerly PF-06480605 and RVT-3101), showed significant endoscopic improvement and adequate safety in the phase 2a TUSCANY trial.¹ Here, we report data from the global, randomised, double-blind, placebo-controlled, dose-ranging phase 2b TUSCANY-2 (NCT04090411) trial evaluating the efficacy and safety of subcutaneous (SQ) doses of RO7790121 in adult pts with moderately to severely active UC (total Mayo Score [tMS] ≥6, endoscopic subscore ≥2) who had previously failed conventional/advanced therapy.

Aims & Methods

Pts were randomised to receive RO7790121 SQ 50mg, 150mg, 450mg or placebo (PBO) monthly during the 12-week induction period and RO7790121 SQ 50mg, 150mg or 450mg monthly during the treat-through 40-week maintenance period. Efficacy endpoints were assessed at weeks 14 and 56 in the induction and maintenance intent-to-treat analysis sets, respectively. The primary efficacy endpoint was clinical remission at week 14 by tMS. Safety was assessed throughout the induction and maintenance periods. The secondary endpoint of clinical remission using modified Mayo Score (mMS) is aligned to updated FDA guidance. Other secondary endpoints included clinical remission (by tMS and mMS) at week 56 and endoscopic improvement at weeks 14 and 56. Efficacy analysis by pre-defined biomarker subgroups was also performed.

Results

Overall, 245 pts were randomised and treated; 228 completed the induction and 224 entered the maintenance period of the study. At week 14, 25.5%, 23.3% and 23.9% of pts in the RO7790121 50mg, 150mg, 450mg arms, respectively vs 11.6% in PBO experienced clinical remission by tMS (p>0.05 [Table]). The proportion of pts achieving clinical remission using mMS at week 14 was 29.8%, 35.0% and 31.8% in the RO7790121 50mg, 150mg, 450mg arms, respectively vs 11.6% in PBO (nominal p<0.05). Improvements in clinical remission were sustained throughout the maintenance period (Table). A greater proportion of pts demonstrated endoscopic improvement across all doses of RO7790121 vs PBO at week 14 and week 56. Numerically greater treatment effects were observed in biomarker-positive pts relative to all-comer pts. During the induction period, 47.8% (117/245) of pts reported ≥1 treatment-emergent adverse event (TEAE). The most common TEAEs (occurring in ≥5% pts overall) were anaemia (5.3%) and headache (5.3%). In the induction period, 10 pts experienced serious TEAEs (PBO=4; 50mg=3; 450mg=3); 2 treatment-related (PBO=1; 450mg=1). No pts discontinued the study due to TEAEs. A generally similar safety profile was observed during the maintenance period.

Conclusion

Data from the phase 2b TUSCANY-2 dose-ranging study suggests that RO7790121 has a favourable benefit/risk profile with clinically meaningful improvements in pts with moderately to severely active UC. A phase 3 study will be conducted to confirm these results.

Table. Summary of efficacy outcomes at week 14 and week 56

References

1. Danese S, et al. Clin Gastroenterol Hepatol 2021;19:2324–32.e6.

Disclosure

This study was sponsored by Pfizer Inc and Roivant Sciences Ltd. Medical writing support, under the direction of the authors, was provided by Margarita Gkrava, MSc, of Ashfield MedComms, an Inizio company, and was funded by F. Hoffmann-La Roche Ltd.
SD, consultancy/advisory role/board: AbbVie, Alimentiv, Allergan, Amgen, AMT, AstraZeneca, Athos Therapeutics, Biogen, Boehringer, BMS, Celgene, Celltrion, Dr Falk Pharma, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, J&J, Lilly, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc, TiGenix, UCB, Vial, Vifor. Lecture fees: Abbvie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, Takeda.
JRA, consulting/advisory role/board: Abbvie, Adiso, BMS, Ferring, Finch Therapeutics, GSK, Janssen, Merck, Pfizer, Roivant, Seres Therapeutics. Speakers’ bureau: Abbvie, BMS, Janssen. Research funding: Janssen, Merck, Pfizer.
SS, consulting/advisory role/board: AbbVie, Amgen, Arena Pharmaceuticals, Biogen, BMS, Celgene, Celltrion, Dr Falk Pharma, Ferring, Fresenius Kabi, Galapagos/Gilead Sciences, Hikma Pharmaceuticals, I-Mab, Janssen, Lilly, Morphic Therapeutic, MSD, Mylan, Pfizer, Protagonist Therapeutics, Provention Bio, Sandoz/Hexal, Takeda, Theravance Biopharma, and Ventyx Biosciences.
LP-B, consulting/advisory role/board : Abbvie, Abivax, Alimentiv, Alma Bio Therapeutics, Amgen, AMT, Arena, Biogen, BMS, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer, GSK, Hac Pharma, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeuthics, Pandion Therapeuthics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Roivant, Samsung, Sandoz, Sanofi, Takeda, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vifor, Vectivbio, Ventyx, Ysopia. Speakers’ Bureau: Abbvie, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genentech, Gilead, Janssen, Lilly, Medac, MSD, Pfizer, Sandoz, Takeda, Tillots, Viatris, Vifor. Research funding: Celltrion, Fresenius Kabi, Takeda. Support travel: Abbvie, Amgen, Celltrion, Connect Biopharm, Ferring, Galapagos, Genentech, Gilead, Gossamer, Janssen, Lilly, Medac, Morphic, MSD, Pfizer, Sandoz, Takeda, Thermo Fischer, Tillots.
VJ, employment: Western University, London Health Sciences Centre, Alimentiv. Consulting or advisory role/board : AbbVie, Alimentiv, Arena pharmaceuticals, Asahi Kasei, Asieris, AstraZeneca, Avoro Capital, BMS, Celltrion, Endpoint Health, Enthera, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, Gilde Healthcare, GSK, Genentech, Gilead, Innomar, JAMP, Janssen, Lilly, Merck, Metacrine, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Prometheus, Reistone Biopharma, Roche, Roivant, Sandoz, Second Genome, Sorriso, Synedgen, Takeda, TD Securities, Teva, Topivert, Ventyx, Vividion. Speakers’ bureau: AbbVie, Ferring, BMS, Galapagos, Janssen, Pfizer, Shire, Takeda, Fresenius Kabi.
GRD, consulting/advisory role/board: Alimentiv, Abbvie, BMS, Boehringer, Celltrion, GSK, Immunic, Index, J&J, Lilly, Polpharm, Takeda, Tillotts, Ventyx, Pfizer. Speakers’ bureau: Lilly, Pfizer, Takeda. Research funding: Cellitron, Lilly, Pfizer, Takeda.
JK, no COI.
RWL, consulting/advisory role/board: AbbVie, Aspen, BMS, Celgene, Celltrion, Chiesi, Ferring, Glutagen, Hospira, Janssen, Lilly, MSD, Novartis, Pfizer, Prometheus, Takeda. Research funding: Celltrion, Shire, Janssen, Takeda, Gastroenterological Society of Australia, NHMRC, Gutsy Group, Pfizer, Joanna Tiddy grant, McKusker Charitable Foundation.
AJY, consulting/advisory role/board: Abbvie, Takeda, Celltrion, BMS, J&J, Abivax.
JMM, employment/stock/other ownership interests: Roche/Genentech.
DB, employment: F. Hoffmann-La Roche.
KL, employment: Roche/Genentech.
CS, employment/stock/other ownership interests: Roche/Genentech.
KEH, employment/stock/other ownership: Pfizer.
BGF, stock/other ownership interests: Connect Biopharm, EnGene. Honoraria/consulting/advisory role/board: AbbVie, Abivax, Adiso, Agomab, Allianthera, Amgen, AnaptysBio, Arena Pharma, Avoro Capital, Atomwise, BioJamp, Biora Therapeutics, Blackbird Laboratories, Boehringer, Boxer Capital, Celsius Therapeutics, Celgene/BMS, Connect BioPharma, Cytoki, Disc Medicine, Duality, EcoR1, Equillium, Ermium, First Wave, Forbion, Galapagos, Galen Atlantica, Roche/Genentech, Gilead, Gossamer, GSK, Hinge Bio, Index Pharma, Imhotex, Immunic Therapeutics, Intercept, JAKAcademy, Janssen, Japan Tobacco, Kaleido, Klick Health, Landos Biopharma, Lenczner Slaght, LifeSci Capital, Lilly, Lument, Mage Biologics, Mestag, Millennium, MiroBio, Monte Rosa, Morgan Lewis, Morphic Therapeutics, Mylan, Nexys Therapeutics, Nimbus Therapeutics, OM Pharma, OrbiMed, Orphagen, Pandion Therapeutics, Pendopharm, Pfizer, Prometheus, Progenity, Protagonist, PTM Therapeutics, Q32 Bio, Rebiotix, REDX, Roche, Roivant/Televant, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Sobi, Spyre Therapeutics, Surrozen, Synedgen, Takeda, Teva, Thelium, Tigenix, Tillotts, Triastek, Ventyx Biosciences, Zagbio, Zealand Pharma. Speakers’ Bureau: Takeda, Janssen, Abbvie.

Introduction

^​Intestinal ultrasound (IUS) is gaining increasing acceptance as a reliable tool for tight monitoring of ulcerative colitis (UC). Although several IUS scores have been proposed, none has been formally implemented into official recommendations of international scientific societies.

Aims & Methods

We aimed to compare an IUS score validated for Crohn’s disease (CD), the International Bowel Ultrasound Segmental Activity Score (IBUS-SAS)¹, with other IUS scores specifically developed for UC, in terms of correlation with endoscopic activity.
Patients with UC ≥ 18 years old undergoing partial or full colonoscopy between April 2023 and January 2024 were prospectively included. Endoscopic evaluation of at least the sigmoid colon was mandatory for inclusion, and patients with proctitis (Montreal E1) were excluded. Endoscopic activity was scored with both the Mayo Endoscopic Subscore (MES) and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), and defined by MES ≥ 1 and UCEIS ≥ 2. Moderate endoscopic activity was determined by a MES = 2 or an UCEIS = 5-6, while severe activity was defined by a MES = 3 or an UCEIS ≥ 7. IUS was performed within 4 weeks of endoscopy. The IBUS-SAS, the Milan Ultrasound Criteria (MUC)², the UC-IUS score³, the US Score from Parente et al.⁴, and the Hata index⁵ were included in the analysis. Applicability of the Civitelli index⁶, an IUS score developed for pediatric patients, was also evaluated. The Spearman’s rank coefficient [rho = ρ] was used to perform correlations, while receiver operating characteristic (ROC) curves were compared with the Hanley & McNeil method.

Results

Collectively, 104 patients were included in the study. The majority of patients (61.5%) had extensive colitis (Montreal E3), with half of them having an active disease at endoscopy (54.8% using MES and 48.1% using UCEIS). IUS examination was performed at a median time of 8 days (IQR 2-15) after endoscopy. All the investigated scores were significantly able to distinguish between the 3 grades of severity of colonic inflammation, using both MES and UCEIS as a reference, with the exception of the Parente’s US Score for the severe endoscopic activity assessed with UCEIS [0 (IQR 0-1) for UCEIS < 7 vs 1 (IQR 0-1) for UCEIS ≥ 7, p=0.09]. The IBUS-SAS showed a strong correlation with endoscopic activity, both with MES (ρ = 0.71, p < 0.01) and UCEIS (ρ = 0.73, p < 0.01) assessments. The Area Under the Curve (AUC) of IBUS-SAS to detect an endoscopic activity of at least moderate severity (MES ≥ 2 and UCEIS ≥ 5) was 0.85 and 0.90, respectively. The optimal cutoff to detect a MES ≥ 2 and UCEIS ≥ 5 was > 11 (sensitivity 75% and specificity 82%) and > 22 (sensitivity 92% and specificity 80%), respectively. Both cut-offs showed progressive increase from mild to severe activity, with IBUS-SAS maintaining a consistently high AUC at different thresholds. Consistent with IBUS-SAS results, all the investigated UC-developed IUS scores correlated with both the MES and the UCEIS (p < 0.01). AUC values and relative comparisons between the AUC are detailed in Table 1.

Table 1. Relative comparisons between the AUC of each score to detect a MES ≥ 2 (A, top-right) and an UCEIS ≥ 5 (B, bottom-left) are reported.
Grey rows and columns: AUC values (with 95%CI).
White cells: p-values obtained via the Hanley and McNeil method (significant p-values are shown in bold).

Conclusion

In this study we provide a successful validation of 6 IUS scores for UC. The IBUS-SAS has an optimal performance in predicting endoscopic activity also in patients with UC, despite having been developed initially for CD.

References

1. Novak KL, Nylund K, Maaser C, et al. Expert Consensus on Optimal Acquisition and Development of the International Bowel Ultrasound Segmental Activity Score [IBUS-SAS]: A Reliability and Inter-rater Variability Study on Intestinal Ultrasonography in Crohn's Disease. J Crohns Colitis 2021;15:609-616
2. Allocca M, Fiorino G, Bonovas S, et al. Accuracy of Humanitas Ultrasound Criteria in Assessing Disease Activity and Severity in Ulcerative Colitis: A Prospective Study. J Crohns Colitis 2018;12:1385-1391
3. Bots S, Nylund K, Löwenberg M, et al. Intestinal Ultrasound to Assess Disease Activity in Ulcerative Colitis: Development of a novel UC-Ultrasound Index. J Crohns Colitis 2021;15:1264-1271
4. Parente F, Molteni M, Marino B, et al. Are colonoscopy and bowel ultrasound useful for assessing response to short-term therapy and predicting disease outcome of moderate-to-severe forms of ulcerative colitis?: a prospective study. Am J Gastroenterol 2010;105:1150-7
5. Kinoshita K, Katsurada T, Nishida M, et al. Usefulness of transabdominal ultrasonography for assessing ulcerative colitis: a prospective, multicenter study. J Gastroenterol 2019;54:521-529
6. Civitelli F, Di Nardo G, Oliva S, et al. Ultrasonography of the colon in pediatric ulcerative colitis: a prospective, blind, comparative study with colonoscopy. J Pediatr 2014;165:78-84.e2

Disclosure

GD reports speaker fees from Alfasigma, Johnson & Johnson, Novartis, Pfizer, Takeda, and has served in advisory board for Celltrion Healthcare and Pfizer. The other authors have no conflict of interests to declare.

Introduction

Colorectal cancer (CRC) screening programmes have been shown effective in reducing CRC incidence and mortality. Risk stratification offers opportunities for further optimisation of screening programmes by better balancing the harms and benefits of screening. To this day, nearly all population screening programmes only differentiate their screening approach by age, resulting in a fixed upper age limit of screening. While further risk stratification based on prior faecal haemoglobin (f-Hb) concentration seems promising, studies are mainly limited to the target population of screening. Risk-stratified screening beyond the upper age limit might however be beneficial as well considering the increasing life expectancy and the benefit-risk ratio of screening widely varying amongst elderly.

Aims & Methods

This study assessed interval colorectal cancer (IC) risk in individuals that have reached the upper age limit of screening (75 years), and whether this risk differs by the f-Hb concentration of the last faecal immunochemical test (FIT). Individuals with a negative FIT (<47 µg Hb/g faeces) in their final CRC screening round were selected in the national screening database and linked to the Dutch cancer registry to check for a CRC diagnosis within 24 months of the negative FIT. IC risk was compared between different risk groups (sex, prior f-Hb concentration and screening round) and tested with a Chi-squared test. Associations between IC and explanatory factors were assessed using survival and Cox proportional hazards analyses. Factors associated with CRC stage were identified using a multivariable logistic regression analysis.

Results

A total of 311,655 individuals with a complete follow-up (24 months) after a negative FIT were included. Within this population, the overall IC risk was 21.6 per 10,000 individuals with a negative FIT. Individuals with detectable f-Hb (>0µg Hb/g faeces) in the final screening round developed IC more often than those without (HR 4.85, 95%CI: 4.18-5.63) (Table 1). Besides, they were also more likely to be diagnosed at an advanced rather than early stage of the disease (OR 1.45, 95%CI: 1.05-2.00). Individuals who had participated in three or four screening rounds had a lower IC risk than those who had participated once (HR 0.75, 95%CI: 0.56-0.99). Screening round was not associated with stage distribution and sex was not associated with IC nor stage distribution.

Table 1; Overview of IC risk, including results of a Cox regression analysis with IC as a dependent variable and sex, screening round and prior f-Hb concentration as independent variables

Conclusion

Our results indicate that a risk-stratified upper age limit in CRC screening based on prior f-Hb concentration may prevent CRC cases and CRC-related morbidity by early detection. While individuals with detectable f-Hb in their final FIT may benefit from additional screening, screening of the elderly is not without risks. Follow-up studies should therefore assess the benefit-risk ratio of a risk-stratified upper age limit and identify the optimal screening scenario.

Introduction

Acute pancreatitis (AP) is an inflammatory disorder that causes a considerable economic health burden. While the majority of AP shows a mild clinical course, about 10% of patients have moderate or severe disease with major local and systemic complications and a prolonged hospital stay. Still there is a lack of early biomarkers of severity while multiple complicated scoring systems fail to predict the course of disease. Here, we aim to investigate the role of the microbiome to predict the course of AP at admission.

Aims & Methods

In 16 European centers buccal and rectal swabs were collected from 450 AP patients within the first 72h of hospital admission. All samples were sequenced with Oxford Nanopore Technologies. Primary endpoints are the association of orointestinal microbiome with revised Atlanta classification and severity. Secondary endpoints are the association with mortality and length of hospital stay.

Results

In total, 832 samples from 424 patients were sequenced, 26 patients met exclusion criteria. After normalization of microbial data 409 buccal samples and 391 rectal samples remained for subsequent analysis. Significant differences were observed in beta diversities for rev. Atlanta classification (Bray Curtis, p-value 0.009**), severity (Bray Curtis, p-value 0.008**), mortality (Bray Curtis, p-value 0.006**) and length of hospital stay (Bray Curtis, p-value 0.043*) in rectal but not buccal swabs. Notably, these results remain significant after factoring in 74 potential confounding variables such as alcohol consumption, smoking status, and antibiotics. No differences were observed in alpha-diversity. Classifier for severity was built with different abundant taxa achieving an AUROC of 80%.

Conclusion

The rectal but not oral microbiome has the ability to predict the course of acute pancreatitis at admission of the patient.