Introduction

Ulcerative colitis (UC) is characterized by inflammation of the colon, with neutrophils playing a key role in disease activity, prognosis, and response to therapies. Though several therapeutics are available for the treatment of UC, they have limited efficacy and potential for significant side effects, including infections and malignancy. Substantial unmet need remains for effective and safe therapies. ADS051 is a novel, oral, gut-restricted, small molecule derived from a cyclosporine A scaffold. It is specifically designed to inhibit both MRP2-driven neutrophil migration into the colon and FPR1-mediated neutrophil activation, without blocking T-cell activation, which limits off-target immunosuppression. Study NCT05084261 evaluated the safety, efficacy, and pharmacokinetics (PK) of ADS051 in patients with moderately to severely active UC.

Aims & Methods

Phase 1B, multiple ascending dose, randomized, placebo-controlled, double-blind, multicenter study enrolled patients with a complete Mayo score ≥6 and on stable treatment with aminosalicylates, thiopurines, and/or corticosteroids (≤20mg prednisone). Patients received oral ADS051 or placebo (3:1) once daily for 28 days (dose cohorts: 200mg, 800mg, and 3200mg) followed by 30 days off study drug. Primary outcome was safety and tolerability of ADS051 with secondary efficacy endpoints at Day 28 of clinical remission (modified Mayo score ≤2, endoscopic subscore ≤1 point, stool frequency subscore ≤1 point, rectal bleeding subscore=0), endoscopic response (decrease in baseline UC endoscopic index of severity [UCEIS] ≥2 points), and histologic remission (Geboes score ≤2B.0 or Nancy index=0 OR Robarts histopathological index [RHI] ≤3). Weekly assessments of PK, disease activity, and fecal calprotectin were performed during the treatment period. Safety was evaluated throughout the study. Endoscopy was performed at screening and Day 28.

Results

All 24 patients enrolled completed the study (8/cohort). 16.7% of patients on ADS051 vs 66.7% on placebo had at least 1 treatment-emergent adverse event (TEAE). No serious adverse events were reported. No TEAE resulted in dose modification or drug discontinuation. Concentrations of ADS051 achieved in stool were greater than IC₅₀ for MRP2 and FPR1 targets at all dose levels. There was low systemic exposure, with <1% of daily dose of ADS051 excreted in urine. For pooled ADS051 and pooled placebo, clinical remission was achieved in 22% ADS051 vs 0% placebo at Day 28, and endoscopic response was achieved in 50% ADS051 vs 17% placebo at Day 28. Of the 4 patients on ADS051 with clinical remission, 3 achieved histologic remission.

Conclusion

Phase 1B study of ADS051, a novel, oral, gut-restricted neutrophil modulator, demonstrates favorable safety and tolerability with signals of pharmacologic activity, warranting additional investigation in larger studies.

Disclosure

J. Allegretti is a consultant for Janssen, Pfizer, Abbvie, Iterative Scopes, Finch Therapeutics, Seres Therapeutics, Ferring, Merck, Bristol Myer Squibb, Adiso; speaker for BMS, Abbvie, Janssen; research support from Pfizer and Merck.
A.S. Cheifetz is a consultant for Janssen, Abbvie, Protagonist, Spherix, Artizan, Food is Good, Clario, Pfizer, Fresenius Kabi, Takeda, Fzata, BMS, Procise, Prometheus, Samsung, Artugen, and Equillium.
P.S. Dulai is a consultant for Abbvie, Abivax, Adiso, Bristol Myers Squibb, GSK, Janssen, Lilly, Pfizer, Takeda, Roivant, Adiso; grant support from Bristol Myers Squibb, Janssen, Pfizer, Takeda; Licensing royalties from PreciDiag.
A. Stevens is a consultant to ClearB therapeutics and Surrozen. Previous clients include Artugen, Bacain, and Astria Therapeutics.
J. Chapas-Reed is an employee of Adiso Therapeutics, Inc. and has no disclosures to declare.
L. Chesnel is an employee of Adiso Therapeutics, Inc. and has no disclosures to declare.
B. Dixit is an employee of Adiso Therapeutics, Inc. and has no disclosures to declare.
R. Farquhar has ownership of shares in Adiso Therapeutics, Inc., paid employment by Bacainn, board membership of Bacainn and co-inventorship of Bacainn’s Patent applications.
P. Ghahramani is a consultant to Adiso Therapeutics, Inc.
B. Miller is a former employee of Adiso Therapeutics, Inc. and a current employee of Ipsen.
C. Murphy is an employee of Adiso Therapeutics, Inc. with stock options. CKM is an inventor of patents owned by Adiso Therapeutics, Inc.
M. Quintas is an employee of Adiso Therapeutics, Inc. and has no disclosures to declare.
R. Tanase has no disclosures to declare.
T. Telia has no disclosures to declare.
B. Wozniak-Stolarska has no disclosures to declare.
R. Gupta is an employee of Adiso Therapeutics, Inc. and has no disclosures to declare.

Introduction

Etrasimod is an investigational, once-daily (QD), oral, selective sphingosine 1-phosphate (S1P)_1,4,5 receptor modulator in development to treat immune-mediated inflammatory disorders. CULTIVATE (NCT04173273) is a seamless phase 2/3 trial comprising 5 substudies designed to evaluate the efficacy, safety and tolerability of etrasimod in patients with moderately to severely active Crohn’s disease (CD).

Aims & Methods

Here, we report the induction data from the first substudy (Substudy A). Substudy A was a phase 2, randomised, double-blind study using a 14‑week induction period followed by a 52-week extension period. Adults (18–80 years) with moderately to severely active CD and an inadequate response, loss of response or intolerance to ≥1 conventional or advanced treatments for CD were randomised 1:1 to etrasimod 2 or 3 mg QD. Patients were stratified by baseline biologic failure status and oral corticosteroid use. The primary efficacy endpoint was achievement of endoscopic response (defined as endoscopic remission [SES-CD ≤4 and ≥2-point reduction from baseline with no subscore >1] or ≥50% decrease in SES-CD score) at Week 14. Secondary/exploratory endpoints included achievement of endoscopic remission, clinical remission (CDAI <150) and IBDQ remission (IBDQ ≥170), at Week 14. Outcomes were analysed in the full analysis set (all randomised patients treated with ≥1 dose of etrasimod) using non-responder imputation or observed data.

Results

Of 83 patients randomised to either etrasimod 2 or 3 mg QD, 32/42 (76.2%) and 36/41 (87.8%) completed Week 14, respectively. Overall, 21.4% and 9.8% of patients receiving etrasimod 2 and 3 mg QD, respectively, achieved the primary endpoint of endoscopic response, 14.3% and 7.3% achieved endoscopic remission, 31.0% and 43.9% achieved clinical remission, and 33.3% and 40.0% achieved IBDQ remission at Week 14. Most TEAEs were mild or moderate. The incidence of serious TEAEs (4.8% and 2.4%) and TEAEs leading to discontinuation (4.8% and 7.3%) was low with etrasimod 2 and 3 mg QD, respectively (Table). Two patients randomized to etrasimod 3 mg QD experienced second-degree atrioventricular block type I TEAEs (one patient during 2-mg titration).

Conclusion

Data from this substudy of patients with moderately to severely active CD suggest endoscopic and clinical improvement with both etrasimod 2 and 3 mg QD. However, the small sample size and lack of a placebo arm limit the ability to draw conclusions about efficacy, including comparison between the etrasimod 2 and 3 mg groups. Both doses were well tolerated, and safety was consistent with other etrasimod clinical programmes. Data from the extension phase of Substudy A and the placebo-controlled, dose-ranging phase 2b Substudy 1 are forthcoming.

Disclosure

GD’H: advisor: AbbVie, AstraZeneca, Alimentiv, Bristol-Myers Squibb, Boehringer Ingelheim, Celltrion, Cosmo, Eli Lilly, Galapagos, GSK, Johnson & Johnson, Takeda, Pfizer, Polpharma, Prometheus, Tillotts, Ventyx; speaker: AbbVie, Boehringer Ingelheim, Celltrion, Johnson & Johnson, Takeda, Pfizer, Tillotts.
MCD: grant/research: Janssen; consultancy: AbbVie, Arena, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Genentech, Gilead, Janssen, Pfizer, Prometheus, Takeda, Trellus Health, UCB; shares/royalties: Trellus; directorship/ownership interests: Trellus.
LPB: grant/research: Takeda, Fresenius Kabi, Celltrion; consultancy: AbbVie, Alimentiv, Alma, Amgen, Applied Molecular Transport, Arena, Biogen, Bristol-Myers Squibb, Celltrion, CONNECT Biopharm, Cytoki, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer, GSK, HAC, IAG Image Analysis, Index, Inotrem, Janssen, Eli Lilly, Medac, Mopac, Morphic, MSD, Norgine, Novartis, OM, ONO, OSE, Pandion, Par'Immune, Pfizer, Prometheus, Protagonist, Roche, Sandoz, Takeda, Theravance, Thermo Fisher, TiGenix, Tillotts, Viatris, Vifor, Ysopia, Abivax; speaker: Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillotts, Celltrion, Takeda, Pfizer, Sandoz, Biogen, MSD, Amgen, Vifor, Arena, Eli Lilly, Gilead, Viatris, Medac, Sanofi; stock: CTMA.
SD: consultancy/advisory: AbbVie, Allergan, Amgen, AstraZeneca, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Gilead, Hospira, Janssen, Johnson & Johnson, MSD, Mundipharma, Pfizer, Roche, Sandoz, Takeda, TiGenix, UCB, Vifor; speaker: AbbVie, Amgen, Ferring, Gilead, Janssen, Mylan, Pfizer, Takeda; directorship/ownership interests: Gastroenterology and Endoscopy.
BES: grant/research: Arena, Janssen. Lecture fees/Speakers Bureau: BMS, Janssen, Lilly, Pfizer, Takeda; consultancy/advisory: AbbVie, Alimentiv, Amgen, Arena, AstraZeneca, Boehringer-Ingelheim, BMS, Celltrion, Fresenius Kabi, Genentech, GSK, Janssen, Lilly, Merck, Pfizer, Prometheus Biosciences, Sun Pharma Global, Takeda Pharmaceuticals International, Teva Branded Pharmaceutical Products R&D; stock: Ventyx Biosciences; non-financial support: Janssen, Lilly, Pfizer, Takeda.
DCW: grant/research: AbbVie, Arena, Bristol Myers Squibb, Janssen, Pfizer, Takeda, Ventyx; speaker: AbbVie, Bristol Myers, Squibb, Janssen, Pfizer, Takeda; consultancy: AbbVie, Arena, Bristol Myers Squibb, Janssen, Pfizer, Takeda.
AJY: consultancy: Pfizer, Arena, Takeda, Bristol-Myers Squibb; speaker: Bristol-Myers Squibb.
MVC: grant support: Pfizer, Janssen, Novartis, Bristol-Myers Squibb; consultancy fees: AbbVie, Arena, Bristol-Myers Squibb, Medtronic, Pfizer, Prometheus, Eli Lilly, Janssen, Takeda; speaker fees: AbbVie, Janssen, Medtronic, Pfizer, Bristol-Myers Squibb, Takeda.
DD: employee of Pfizer Inc at the time of the abstract.
IM, HT, GG, CS: employees & shareholders of Pfizer Inc.
CL, FC: employees of Pfizer Inc at the time of this analysis.
JZ: employee & shareholder of Arena Pharmaceuticals.
AMcD: employee & shareholder of Pfizer Ltd.
SS: speaker: AbbVie, Arena, Biogen, Bristol-Myers Squibb, Celgene, Celltrion, Dr. Falk, Fresenius, Janssen, MSD, Pfizer, Takeda; consultancy/advisory: AbbVie, Arena, Biogen, Bristol-Myers Squibb, Celgene, Celltrion, Dr. Falk, Fresenius, Gilead, IMAB, Janssen, MSD, Mylan, Pfizer, Protagonist, Provention, Takeda, Theravance.
BGF: consultant/advisory board: AbbVie, AbolerIS, AgomAB, AllianThera, Amgen, AnaptysBio, Applied Molecular Transport, Arena, Avoro Capital, Atomwise, BIOJAMP, Biora, Boehringer Ingelheim, Boxer, Celsius, Celgene/Bristol-Myers Squibb, Connect, Cytoki, Disc Medicine, Duality, EcoR1, Eli Lilly, Equillium, Ermium, First Wave, FirstWord, Galapagos, Galen Atlantica, Genentech/Roche, Gilead, Gossamer, GSK, Hinge, HotSpot, InDex, Imhotex, Immunic, JAK, Janssen, Japan Tobacco, Kaleido, Landos, Leadiant, L.E.K., Lenczner Slaght, LifeSci, Lument AB, Millennium, MiroBio, Morgan Lewis, Morphic, Mylan, OM, Origo, Orphagen, Pandion, Pendopharm, Pfizer, Prometheus, Diagnostics, Play to Know AG, Progenity, Protagonist, PTM, Q32, Rebiotix, REDX, Roche, Sandoz, Sanofi, Seres, Silverback, Surrozen, Takeda, Teva, Thelium, TiGenix, Tillotts, Ventyx, VHSquared, Viatris, Ysios, YSOPIA, Zealand; speaker: AbbVie, Janssen, Takeda; Alimentiv Senior Scientific Director, provides central reading services; not a company employee, no equity stake; shareholder: Gossamer.
SV: grant/research: AbbVie, MSD, Pfizer, Galapagos, Takeda; consultancy/advisory: AbbVie, AbolerIS, Alimentiv, Arena, AstraZeneca, Avaxia, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Dr. Falk, Eli Lilly, Ferring, Galapagos, Genentech/Roche, Gilead, Hospira, Imidomics, Janssen, Johnson & Johnson, Materia Prima, MiroBio, Morphic, MrMHealth, MSD, Mundipharma, Pfizer, Prodigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts, Zealand; speaker: AbbVie, Dr. Falk, Ferring, Hospira, MSD, Takeda, Tillotts.

Introduction

Endoscopic submucosal dissection (ESD) has evolved to become a viable treatment option for oesophageal squamous dysplasia (SD) and early squamous cell carcinoma (ESCC). Although enbloc, R0, excision has the potential to yield an endoscopic cure, surgery remains the standard of care in the West. Furthermore, Western data pertaining to endoscopic outcomes is limited. We aimed to assess the efficacy and safety of ESD for SD and ESCC in a single tertiary referral centre.

Aims & Methods

We conducted a prospective observational cohort study over 87 months until November 2023 in consecutive patients undergoing ESD for SD or ESCC. The primary outcomes were enbloc, R0 and curative resection rates. Secondary outcomes included procedure duration, tumor recurrence and adverse events.

Results

112 consecutive patients were referred for treatment and underwent ESD (median age 73 [IQR 68-78]; 50% male; Table 1). Median lesion size was 30 mm (IQR 20-50mm) and Paris IIa was the most common morphology (58.9%). Enbloc resection was achieved in 109 (97.3%) and R0 excision in 87 (77.7%). Curative resection in cases of LGD and HGD, where margins were clear of dysplasia, was 7/11 (63.6%) and 31/34 (91.2%) respectively. In those with T1a/T1b SCC, the curative resection rate was 20/61 (32.8%). In T1a SCC lesions, 11/20 (55.0%) had a curative ESD. Of the remainder, 6/9 were poorly differentiated, 1/9 had LVI, and 2/9 had positive margins (1 deep, 1 peripheral). In T1b SCC lesions, 9/41 were curative (22.0%). The remainder were either poorly differentiated, >T1b-SM1, LVI positive or a combination. In those with T1a/T1b disease, without adverse tumor biology, ESD achieved curative resection in 20/22 (90.9%).
In the 41/61 (67.2%) T1a/T1b patients that did not meet criteria for cure, subsequent treatment included surgery (n=5), radiotherapy (n=5) and chemoradiotherapy (n=1). After MDT discussion, the remaining 30 were managed conservatively, due to advanced age or comorbidities. In these, recurrence occurred in 6/30 patients (1 local, 3 nodal, 2 metastatic) at a median follow up of 12 months (6-18 months). The median hospital length of stay was 1 day (IQR 1-3). Oesophageal strictures occurred in 46 patients (41.1%), requiring a median of 3 dilations (IQR 1-8). There were 2 cases of delayed bleeding. There were no perforations.

Table 1

Conclusion

ESD is curative for low and high-grade dysplasia. In a Western setting, ESD offers definitive T-staging and has the potential to yield a cure in almost 33% of T1a and T1b SCC cases. Due to a high risk of disease recurrence, adjuvant therapy should be considered in cases of a non-curative resection.

Introduction

Post-ERCP pancreatitis (PEP) is the most important adverse event of ERCP. In order to make a decision to take adequate preventive measures, it is necessary to estimate the risk of PEP in individual cases. Several models have been reported to predict PEP, but these models do not have high generalizability.

Aims & Methods

The aim of this study is to develop a reliable prediction rule for PEP in biliary ERCP for patients with intact papilla.
We had conducted a multicenter prospective cohort study which investigated the incidence of adverse events of biliary ERCP in patients with intact papilla (1). This study is a sub-analysis of the cohort study. A total of 3739 patients were prospectively enrolled at 36 hospitals of the Biliopancreatic Study Group of West Japan between April 2017 and March 2018. Exclusion criteria were acute pancreatitis, altered gastrointestinal anatomy, and an ASA physical status greater than 3.
The primary outcomes were the incidence of PEP. The diagnosis and severity of PEP were defined by the lexicon for endoscopic adverse events (2). Patient-related factors, operator-related factors, procedure-related factors and preventative measures were accumulated.
Multivariable logistic regression analysis with stepwise methods were used to identify predictors for PEP and a scoring model was developed based on their β coefficients.
The performance of the model was evaluated based on area under the receiver-operating characteristic curve (AUC), calibration and clinical adequacy. In addition, internal validity was assessed using the bootstrap method by sampling with replacements for 2000 iterations.

Results

PEP developed in 258 cases (6.9%), 201 mild, 39 moderate, 17 severe and 1 fatal. Significant factors with adjusted odds ratios (OR) in multivariate analysis were under 50 years old (OR: 1.78 [95% confidence interval (CI), 1.10-2.79]), female (OR: 1.33 [95% CI, 1.02-1.73]), ASA 3 (OR: 0.62 [95% CI, 0.39-0.95]), cholangitis (OR: 0.72 [95% CI, 0.52-0.98]), hypoamylasemia (OR: 0.62 [95% CI, 0.37-0.97]), obstruction of the main pancreatic duct (MPD) at the pancreatic head (OR: 0.41 [95% CI, 0.22-0.71]), cannulation time > 20 min (OR: 1.43 [95% CI, 1.03-1.97]), guidewire insertion into pancreatic duct (OR: 2.88 [95% CI, 2.17-3.82]), intraductal ultrasonography (IDUS) (OR: 1.49 [95% CI, 1.00-2.17]), biopsy (OR: 1.51 [95% CI, 1.00-2.23]) and total procedure time > 60 min (OR:1.64 [95% CI, 1.17-2.28]).
A scoring system was constructed from the eleven clinical variables as below. Under 50 years old: 2 points, female: 1 point, ASA 3: -2 points, cholangitis: -1 point, hypoamylasemia: -1 point, obstruction of the MPD at the pancreatic head: -2 points, cannulation time > 20 min: 1 point, guidewire insertion into pancreatic duct: 3 points, IDUS: 1 point, biopsy: 1 point and total procedure time > 60 min: 2 points. The points were added up to a total score that predicts the risk of pancreatitis.
AUC of this scoring model was 0.721. A bootstrap analysis revealed a corrected AUC of 0.728 (95%CI: 0.697 - 0.759).
When all cases were divided into three groups; a low-risk group (scoring -1 points or fewer), an intermediate-risk group (between 0 and 3 points) and a high-risk group (more than 4 points), the incidence of PEP were 1.6% (17/1048), 6.0% (121/2012) and 17.7% (120/679), respectively.

Conclusion

This scoring model is useful for predicting and stratifying the risk of PEP in individual cases. Aggressive preventive measures are recommended for patients in the high-risk group with a score of 4 or higher.

References

1. Fujita K, Yazumi S, Matsumoto H, Asada M, Nebiki H, Matsumoto K, et al. Multicenter prospective cohort study of adverse events associated with biliary endoscopic retrograde cholangiopancreatography: Incidence of adverse events and preventive measures for post-endoscopic retrograde cholangiopancreatography pancreatitis. Dig Endosc. 2022;34(6):1198-204.
2. Cotton PB, Eisen GM, Aabakken L, Baron TH, Hutter MM, Jacobson BC, et al. A lexicon for endoscopic adverse events: report of an ASGE workshop. Gastrointest Endosc. 2010;71(3):446-54.

Introduction

Pancreatic duct (PD) stones frequently occur in chronic calcifying pancreatitis (CCP) and are a main factor contributing to pain onset and exacerbation as well as impaired quality of life (QOL). In these patients endoscopic intervention with removal of obstructing pancreatic duct (PD) calculi and regaining pancreatic duct drainage should be performed. In this regard, digital single operator video pancreatoscopy (d-SOVP) is still under investigation for the treatment of PD stones but seems to be an emerging alternative to standard endoscopic procedures with reported success rates between 43%-100%, based on small retrospective studies. However, while reported short term success rates seem very promising, there is still poor evidence for long-term clinical success and benefit for patients` quality of life.

Aims & Methods

Aims: To investigate the role of d-SOVP guided PD-stone lithotripsy in patients with CCP on clinical success and QOL in a long-term follow-up (FU).
Methods: Patients with CCP undergoing d-SOVP (SpyGlass DS) guided lithotripsy of PD stones with initial technical and clinical success were recruited in this retrospective analysis. Persistence of technical success (ductal clearance) and clinical success (defined as pain reduction >50 % in numerical rating scale (NRS)) as well as postinterventional QOL were evaluated by database analysis and a systematic questionnaire (based on SF-12) regarding pain intensity and incidence, painkiller intake and impact on QOL every 6 months obtained in the respective outpatient clinic. Data are presented as mean±SD.

Results

A total of 32 patients was evaluated during long-term FU of 40.8±8.3 months (range 32 – 57 months). 81% of patients (26/32) reported a significant and lasting decrease in pain and symptom burden with mean decrease of NRS from 6.1±0.55 (preinterventionally) to 1.6±0.35 at last reported visit of FU, p<0.01. In 4 patients (12.5%) subsequent pancreatic duct stenting was required due to persistent PD strictures, no recurrent intraductal stones were observed. 3 patients (9.4%) reported persistent pain, with 2 of these being eligible for partial pancreatectomy. QOL criteria significantly improved in 81% of patients defined by major improvements of their general health status and everyday life performance. Two patients were lost to follow-up, 3 patients (9.4%) died during follow up.

Conclusion

D-SOVP guided lithotripsy is safe and effective, achieving high rates of initial technical and clinical success rates as defined by complete ductal clearance and QOL. Beneficial effects on symptom control and QOL persist in the majority of CCP patients after approximately 41 months of FU. Therefore, we suggest d-SOVP to become the intervention of choice in these complex patients. Nevertheless, further prospective trials are warranted to prove these results.

Disclosure

Mark Ellrichmann, Horst Neuhaus, Torsten Beyna and Christian Gerges received lecture from Boston Scientific.