Introduction

Objective: Tumor necrosis factor–like cytokine 1A (TL1A) regulates pro-inflammatory cytokines and fibrosis. PRA023 is an anti-TL1A monoclonal antibody in development for multiple inflammatory/fibrotic diseases incorporating a precision approach with a predictive genetic-based diagnostic (Dx) tool. This placebo-controlled, double-blind phase 2 study assessed efficacy and safety of PRA023 induction treatment in adults with moderately to severely active ulcerative colitis (UC).

Aims & Methods

Patients with a modified Mayo score (mMS) of 4 to 9, centrally read endoscopy subscore of ≥2, rectal bleeding subscore of ≥1, and history of insufficient response, loss of response, and/or intolerance to conventional and/or advanced therapies (≤4 advanced agents from ≤3 classes allowed) were eligible. Patients were stratified by prior biologic exposure and Dx status and randomized 1:1 to placebo or intravenous PRA023 (1000 mg on day 1, 500 mg at weeks 2, 6, and 10). The primary endpoint was clinical remission per mMS at week 12. Analyses of ranked secondary endpoints were multiplicity-controlled.

Results

Of the 135 patients, 60/67 (89.6%) in the placebo arm and 68/68 (100%) in the PRA023 arm completed the 12-week induction period. Baseline characteristics were similar. A significantly greater proportion of patients who received PRA023 achieved the primary endpoint of clinical remission (26.5% PRA023 vs 1.5% placebo, ∆25.0%, p<0.0001) at week 12 (Table 1). All ranked secondary endpoints for cohort 1 significantly favored drug relative to placebo, including symptomatic remission (19.1% PRA023 vs 6.0% placebo, ∆13.1%, p=0.02), mucosal healing (30.8% PRA023 vs 3.5% placebo, ∆27.3%, p<0.0001), and IBDQ response (82.4% PRA023 vs 49.3% placebo, ∆33.1%, p<0.0001; Table 1). Exposure to prior advanced therapy, antidrug antibody status, and concomitant therapy did not have a major effect on efficacy. Statistically significant reductions in symptom scores (partial Mayo score) were observed in patients receiving PRA023 as early as week 2. C-reactive protein and fecal calprotectin levels were significantly reduced throughout the treatment period with PRA023 compared to placebo. An enhanced treatment effect was observed for the prespecified Dx+ subgroup, with 37.5% for both placebo-adjusted clinical remission and endoscopic improvement. The rates of treatment-emergent adverse events (AEs) were similar between the 2 arms with no serious AEs or AEs leading to study drug discontinuation in the PRA023 arm. There were no safety signals identified from the study.

Table 1: Primary and Secondary Efficacy Endpoints

Conclusion

PRA023 was effective with favorable tolerability for the induction of clinical remission and endoscopic improvement in moderately to severely active UC. A phase 3 study will be conducted to confirm these findings. The enhanced treatment effect in the Dx+ subgroup from cohort 1 is being further evaluated in the Dx+ expansion cohort 2.

Disclosure

BES has served as a consultant for or received speaker’s fees from AbbVie, Abivax, Adiso Therapeutics, Alimentiv, Amgen, Arena Pharmaceuticals, Artizan Biosciences, Artugen Therapeutics, AstraZeneca, Bacainn Therapeutics, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Bristol Myers Squibb, Calibr, Celltrion Healthcare, ClostraBio, Connect Biopharma, Cytoki Pharma, Eli Lilly and Company, Entera, Evommune, Ferring, Fresenius Kabi, Galapagos, Gilead, Genentech, GSK, Gossamer Bio, HMP Acquisition, Imhotex, Immunic, InDex Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Ironwood Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Kallyope, Merck, MiroBio, Morphic Therapeutic, MRM Health, OSE Immunotherapeutics, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, RedHill Biopharma, Sun Pharma Global, Surrozen, Synlogic, Takeda, Target RWE, Theravance Biopharma R&D, TLL Pharmaceutical, USWM Enterprises, Ventyx Biosciences, and Viela Bio and has received stock options from Ventyx Biosciences.
LPB has served as a consultant for or has received fees from AbbVie, Allergan, Alma, Amgen, Applied Molecular Transport, Arena, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Eli Lilly and Company, Enterome, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, Hikma, Index Pharmaceuticals, Inotrem, Janssen, MSD, Mylan, Oppilan Pharma, OSE Immunotherapeutics, Nestlé, Norgine, Roche, Pandion Therapeutics, Pfizer, Pharmacosmos, Samsung Bioepis, Sandoz, sterna biologicals, Sublimity Therapeutics, Takeda, Theravance Biopharma, Tillotts Pharma, and Vifor; has received grants from AbbVie, Fresenius Kabi, MSD, and Takeda; and has stock options from CTMA.
SD has received consultancy fees from AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Dr. Falk Pharma, Eli Lilly and Company, Enthera, Ferring, Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, and Vifor and lecture fees from AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, and Takeda.
DTR has served as a consultant for AbbVie, AltruBio, Aslan Pharmaceuticals, Athos Therapeutics, Bellatrix Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Chronicles, Corp/Syneos, ClostraBio, Connect Biopharma, Eco R1, Eli Lilly and Company, Genentech/Roche, Gilead Sciences, Iterative Health, Janssen Pharmaceuticals, Kaleido, Pfizer, Prometheus Biosciences, Reistone Biopharma, Seres Therapeutics, Takeda, Target RWE, and Trellus Health and has received grant support from Takeda, Helmsley Charitable Trust, and the Gastro-Intestinal Research Foundation.
SV has received grants from AbbVie, Galapagos, Johnson & Johnson, Pfizer, and Takeda and consulting and/or speaking fees from AbbVie, Abivax, AbolerIS Pharma, AgomAb, Alimentiv, Arena, AstraZeneca, Avaxia, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Dr. Falk Pharma, Ferring, Galapagos, Genentech/Roche, Gilead, GSK, Hospira, IMIDomics, Janssen, Johnson & Johnson, Eli Lilly and Company, Materia Prima, MiroBio, Morphic, MrMHealth, Mundipharma, MSD, Pfizer, ProDigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts Pharma, and Zealand Pharma.
OL, AL, DDN, and JDL are employees and shareholders of Prometheus Biosciences.
AWK has nothing to disclose.
JL has received speaker fees from AstraZeneca, MSD, Janssen, and Gilead and research grants from Johnson & Johnson.
RK has received grants from Janssen and Takeda.
JK has received consultation fees, research grants, or honoraria from AbbVie, Egis, Janssen, Nestlé, Nutricia, and Takeda.
CM has received consulting fees from AbbVie, Alimentiv, Amgen, AVIR Pharma, BIOJAMP, Bristol Myers Squibb, Celltrion Healthcare, Ferring, Fresenius Kabi, Janssen, McKesson, Mylan, Takeda, Pendopharm, Pfizer, Prometheus Biosciences, Roche, and Sanofi; speaker's fees from AbbVie, Amgen, AVIR Pharma, Alimentiv, Bristol Myers Squibb, Ferring, Fresenius Kabi, Janssen, Takeda, Pendopharm, and Pfizer; royalties from Springer Publishing; and research support from Ferring and Pfizer.
TER has been a speaker for Takeda Pharmaceuticals, Janssen, Pfizer, Bristol Myers Squibb, and Abbvie; has served on advisory boards for AbbVie, Ardelyx, Arena, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Eli Lilly and Company, Ferring, Genentech/Roche, Gilead, Intercept, Iterative Scopes, Janssen, Pfizer, Prometheus Biosciences, Sanofi, and Takeda; and has been a shareholder for Iterative Scopes.
RP has been a consultant for Abbott, AbbVie, Abivax, Alimentiv (formerly Robarts), Amgen, Arena, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion Healthcare, Cosmos Pharmaceuticals, Eisai, Elan, Eli Lilly and Company, Ferring, Galapagos, Fresenius Kabi, Genentech, Gilead Sciences, GSK, BIOJAMP, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion, Pendopharm, Pfizer, Progenity, Prometheus Biosciences, Protagonist Therapeutics, Roche, Sandoz, Satisfai Health, Shire, Sublimity Therapeutics, Takeda, Theravance Biopharma, Trellus, Viatris, Ventyx, and UCB; has received speakers fees from AbbVie, Amgen, Arena, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Ferring, Fresenius Kabi, Gilead Sciences, Janssen, Merck, Organon, Pfizer, Roche, Sandoz, Shire, and Takeda; and has served on advisory boards for AbbVie, Alimentiv (formerly Robarts), Amgen, Arena, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Ferring, Fresenius Kabi, Genentech, Gilead Sciences, GSK, BIOJAMP, Janssen, Merck, Mylan, Novartis, Oppilan Pharma, Organon, Pandion Pharma, Pfizer, Progenity, Protagonist Therapeutics, Roche, Sandoz, Shire, Sublimity Therapeutics, Takeda, and Ventyx.
BGF has served as a consultant for AbbVie, AbolerIS Pharma, AgomAb, AllianThera, Amgen, AnaptysBio, Applied Molecular Transport, Arena, Avoro Capital Advisors, Atomwise, BIOJAMP, Biora Therapeutics, Boehringer Ingelheim, Boxer, Celsius Therapeutics, Bristol Myers Squibb/Celgene, Connect Biopharma, Cytoki, Disc Medicine, Duality, EcoR1 Capital, Eli Lilly and Company, Equillium, Ermium, First Wave, First Word Group, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer Bio, GSK, Hinge Bio, HotSpot Therapeutics, Index Pharma, Imhotex, Immunic Therapeutics, JAK Academy, Janssen, Japan Tobacco, Kaleido, Landos Biopharma, Leadiant, L.E.K. Consulting, Lenczner Slaght, LifeSci Capital, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic Therapeutics, Mylan, OM Pharma, Origo Biopharma, Orphagen, Pandion Pharma, Pendopharm, Pfizer, Prometheus Therapeutics, PlayToKnow AG, Progenity, Protagonist Therapeutics, PTM Therapeutics, Q32 Bio, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres Therapeutics, Silverback Therapeutics, Surrozen, Takeda, Teva, Thelium, TiGenix, Tillotts Pharma, Ventyx Biosciences, VHsquared, Viatris, Ysios, Ysopia, Zealand Pharma; on the speaker’s bureau for AbbVie, Janssen, and Takeda; and on advisory boards for AbbVie, Amgen, AMT, AnaptysBio, Boehringer Ingelheim, Bristol Myers Squibb/Celgene, Eli Lilly and Company, Genentech/Roche, Janssen, MiroBio, Origo BioPharma, Pfizer, Prometheus, REDX, Sanofi, Takeda, Tillotts Pharma, Teva, Progenity, Index, EcoR1 Capital, Morphic, GSK, and Axio Research.
ST has received consulting fees from Robarts Clinical Trials and Prometheus Biosciences and owns stock in Prometheus Biosciences; is a member of steering committees of Janssen, AbbVie, Boehringer Ingelheim, Gilead, Celgene, and Bristol Meyers Squibb; has received speaker honoraria from AbbVie, Takeda, Janssen, Ferring, Pfizer, and Celltrion; and has served on advisory committees of Janssen, Takeda, AbbVie, Eli Lilly, Pfizer, Gilead, Galapagos, and Roche.
DPBM has received consulting fees from Prometheus Biosciences, Prometheus Laboratories, Gilead Sciences, Boehringer-Ingelheim, Pfizer, Prometheus Laboratories, Takeda, Palatin Technologies, and owns stock in Prometheus Biosciences.

Introduction

Endoscopic ultrasound-guided portal pressure gradient (PPG) measurement (EUS-PPG) is a novel technique demonstrated to be safe and feasible. We aimed (i) to evaluate the utility of preoperative EUS-PPG assessment in patients with cirrhosis or suspected cirrhosis undergoing abdominal surgery, and (ii)to validate the technique against transjugular hepatic venous pressure gradient (HVPG) measurement.

Aims & Methods

This is a single-centre prospective study performed between May 2021 and August 2022. Patients with known chronic liver disease or clinical concern for liver disease planned for abdominal surgery were recruited. All patients underwent both EUS-PPG and transjugular HVPG measurement prior to surgery. EUS-PPG was performed using a linear echoendoscope and a 25G needle attached to a compact manometer. Surrogate markers assessing the severity of liver disease were also performed, including liver elastography, APRI and FIB-4 scores. Assessment of post-operative liver dysfunction and 90-day mortality undertaken were the primary endpoints.

Results

Nine patients (mean age 62; M: 4) with known Child A cirrhosis secondary to non-alcoholic fatty liver disease (NAFLD) (n=6) and deranged liver function test with suspected NAFLD (n=2) and suspected portal hypertension (unknown cause) (n=1) underwent EUS-PPG measurement. These patients were planned to undergo HCC liver resection (n=2), gastrectomy for cancer (n=2), hemicolectomy for cancer (n=2), gastric bypass (n=1), inguinal hernia repair (n=1) and duodenal lesion resection (n=1). EUS-PPG measurement was successful in 8 patients (88.9%) with an unsuccessful case secondary to inability to cannulate a very small hepatic vein (4mm) in a morbidly obesity patient (BMI>60kg/m2). The median pressure gradient was similar between the EUS-PPG measurements (median= 6.65mmHg; IQR: 1.2-15.3) and transjugular measurements (median= 6.5mmHg; IQR: 4.3-12), with a high correlation coefficient between the 2 techniques (R= 0.897; P=0.003). There were no complications from EUS-PPG or transjugular HVPG. EUS-PPG >5mmHg was significantly associated with liver elastography median scores (R=0.815, P=0.014) and FIB-4>3.25 (R= 0.7, P=0.048). Three patients had clinically significant portal hypertension based on EUS-PPG measurement. As a result, one patient was deemed not suitable for surgery. Two patients underwent pre-operative transjugular intrahepatic portosystemic shunt (TIPS) of which one patient underwent surgery, however another had decompensation within a month (hepatic encephalopathy) post TIPS and therefore surgery was cancelled. Despite TIPS, the patient who underwent surgery had mild liver decompensation post-operatively. The remaining five patients all had PPG<10mmHg and four have undergone surgery without any complications. There was no 90-day mortality. Seven patients preferred EUS-PPG over transjugular technique.

Conclusion

PPG measurement by EUS approach is highly feasible, safe and correlates very closely with the gold-standard transjugular approach. EUS-guided PPG is uniformly preferable to transjugular approach. PPG measurement was able to guide decision making and a low PPG predicts a lack of post-operative complication. Findings of clinically significant portal hypertension on PPG measurement allowed for change in management prior to surgery suggesting the utility of EUS-guided PPG measurement in patients with suspected liver disease who require abdominal surgery.

Introduction

The Epi-IBD cohort is a prospective European population-based cohort of 1,390 patients diagnosed in 2010 and 2011 with inflammatory bowel disease (IBD) according to Copenhagen criteria in centres from Eastern and Western European countries.

Aims & Methods

The study aims at describing differences in incidence, treatment strategies, disease course and prognosis of Crohn’s disease (CD) across Eastern and Western Europe. CD patients were followed prospectively from the time of diagnosis until December 31^st, 2020, death, emigration or loss of follow-up. Clinical data on surgery, hospitalizations, and medical treatment, were captured throughout the follow-up period and entered into a validated web-database, www.epi-ibd.org. Associations between surgery and covariates were analysed by multivariate Cox regression analyses.

Results

In total, 482 CD patients aged ≥15 years from 21 centres in 5 Eastern and 11 Western European countries were included. At 10-years follow-up, 101 (21%) patients underwent first intestinal resection and 11 out of these 101 patients (11%) underwent additional resections. Furthermore, 176 (37%) patients had at least one CD related hospitalization. Cancer was diagnosed in 21 (4%) patients, including 4 gastrointestinal cancers. The use of IBD medication was comparable between Eastern and Western European centres apart from 5-aminosalicylic acid agents (Table 1).
During follow-up, 60 out of 360 patients (17%) progressed from non-stricturing-non-penetrating disease (B1) at diagnosis to stricturing or penetrating disease (B2 or B3) while 13 out of 83 patients (16%) with stricturing disease (B2) progressed to penetrating disease (B3). The median time to progression was 28 (IQR: 9-64) months from diagnosis. No patients from Eastern Europe were exposed to biological therapy prior to change in behaviour, compared to 23 out of 66 patients (35%) from Western Europe.
Multivariate Cox regression analysis showed no difference in risk of surgery according to European region (Eastern vs. Western Europe, HR: 0.54, 95%CI: 0.24-1.21). Early intervention with biological therapy (within 6 months) did not influence the risk of surgery (HR:0.75, 95%CI: 0.31-1.83), however early introduction of immunomodulators reduced the risk significantly (HR:0.54, 95%CI: 0.30-0.98). Progression in behaviour from B1 was associated with higher risk of surgery (HR:7.62, 95%CI: 3.91-14.87).

Conclusion

After 10 years of follow-up, 21% underwent intestinal resection and 10% required additional resections. Despite the widespread use of immunomodulators and biological therapy, 16% of the patients had disease behavioural progression, which was associated with higher risk of surgery. Early introduction of immunomodulators was found to be beneficial.