Introduction

Janus kinase inhibitors (JAKi), including tofacitinib (TOFA, a pan-JAK inhibitor) and filgotinib (FILGO, a selective JAK1 inhibitor), represent an emerging class of orally administered agents for moderate-to-severe ulcerative colitis (UC). Comparative real-world data on their effectiveness and safety are limited.

Aims & Methods

We conducted a multicenter, real-world, propensity score-weighted cohort study using data from the Sicilian Network for Inflammatory Bowel Diseases (SN-IBD). All adult UC patients treated with TOFA or FILGO with ≥16 weeks of follow-up were included. The primary outcomes were steroid-free clinical remission and clinical response at weeks 8 and 24. Treatment persistence and adverse events were also assessed. Inverse Probability of Treatment Weighting (IPTW) was applied to adjust for baseline differences.

Results

A total of 263 patients were included (TOFA: n=171; FILGO: n=92). At week 8, steroid-free clinical remission was achieved in 53.2% of patients treated with TOFA and 43.4% of those treated with FILGO (IPTW-adjusted OR: 1.51; 95% CI: 0.88–2.61; p=0.14). Clinical response at 8 weeks was reported in 75.4% of TOFA-treated patients versus 69.6% in the FILGO group (IPTW-adjusted OR: 1.34; 95% CI: 0.73–2.46; p=0.34). At week 24, steroid-free clinical remission was observed in 58.8% of the TOFA group and 44.9% of the FILGO group (IPTW-adjusted OR: 1.37; 95% CI: 0.76–2.49; p=0.30). Clinical response rates at 24 weeks were 63.6% for TOFA and 59.0% for FILGO (IPTW-adjusted OR: 1.13; 95% CI: 0.62–2.08; p=0.69). IPTW-adjusted Kaplan–Meier and Cox proportional hazards analyses showed no statistically significant difference in the likelihood of treatment discontinuation (log-rank p=0.294; IPTW-adjusted HR for TOFA: 0.78; 95% CI: 0.49–1.25; p=0.30). Adverse event rates were 12.7 and 5.4 per 100 person-years for TOFA and FILGO, respectively, with no significant difference (p=0.152).

Conclusion

In this real-world, IPTW-based study, TOFA and FILGO were well tolerated and demonstrated comparable and high effectiveness and treatment persistence in patients with moderate-to-severe UC, supporting their use as viable oral options in routine clinical practice.

Disclosure

FSM served as an advisory board member and/or received lecture grants from AbbVie, Ferring, Galapagos, Giuliani, Janssen, Lilly, Liohealth s.r.l., Pfizer, Sandoz, Takeda Pharmaceuticals. WF served as an advisory board member and/or received lecture grants from Abbvie, MSD, Takeda, Pfizer, Biogen, Sandoz, Zambon, Ferring, Sofar. AV received lecture grants from Pfizer. MC served as an advisory board member for AbbVie, MSD, Takeda Pharmaceuticals, and received lecture grants from AbbVie, MSD, Chiesi, and Takeda Pharmaceuticals. MC served as an advisory board member for AbbVie, MSD, Takeda Pharmaceuticals, and received lecture grants from AbbVie, MSD, Chiesi, and Takeda Pharmaceuticals. FM served as an advisory board member for Janssen and Galapagos, and received lecture grants from Takeda Pharmaceuticals. SR served as an advisory board member for AbbVie, Janssen, and MSD Pharmaceuticals, and received lecture grants from AbbVie, Galapagos, Janssen, MSD, Pfizer, and Takeda Pharmaceuticals. AO served as an advisory board member for AbbVie, Ferring, Galapagos, Lilly, MSD, Janssen, Pfizer, Samsung Bioepis, and Takeda Pharmaceuticals, and received lecture grants from AbbVie, Fresenius Kabi, Galapagos, Lionheath s.r.l., MSD, Sofar, Chiesi, Janssen, Pfizer, and Takeda Pharmaceuticals. All other authors: nothing to disclose.

Introduction

Ustekinumab has pioneered IBD treatment by targeting the p40 subunit shared by IL- 12 and IL-23, crucial cytokines in gut inflammation. Despite its lower binding affinity compared to more recent anti-IL-23 antibodies targeting the p19 subunit, ustekinumab achieves comparable remission rates in IBD. This unexpected efficacy likely stems from its dual action; IL-12 neutralization suppresses the initiation of new inflammatory gut lesions, while IL-23 inhibition maintains disease control (Eftychi et al., 2019). However, ustekinumab's sub-optimal binding affinity and immunogenicity (3-12% neutralizing ADA per Stelara Prescribing Information), presents clear opportunities to develop MVP-523 as a next-generation, bio-better therapeutic. Discovered 25 years ago, ustekinumab predates our current understanding of IBD pathology and antibody optimization techniques. Its sub-optimal performance characteristics present opportunities for improvement. Moreover, ustekinumab's extensive patient years of data and favorable safety profile make it an ideal template for next-generation drug development.

Aims & Methods

Computational protein design enabled by CCG Molecular Operating Environment and Epimatrix software.
Variants were expressed, purified and tested experimentally biochemically, in vitro cell models and in vivo in mice.

Results

Our optimization efforts have yielded MVP-523, featuring increased binding affinity/potency and reduced immunogenicity, while having the potential to extend halflife and dosing intervals. CDR amino acid substitutions in both heavy and light chains reduced KD from ~300 pM to ~50 pM, significantly improving IC50 in cell-based assays and enhancing in vivo IL-12 neutralization. Concurrently, computational protein design combined with EpiVax's ISPRI (Interactive Screening and Protein Reengineering Interface) was employed for in-silico deimmunization. This process successfully reduced the anti-drug antibody (ADA) score from 10.4% (which correlates with 3-12% observed clinically) to a predicted score of 1.5%. Considering that the majority of ustekinumab-induced ADAs are neutralizing, this substantial improvement could potentially lead to significantly enhanced outcomes in clinical trials and increased treatment durability.

Conclusion

MVP-523 represents a novel, bio-better therapeutic, built on ustekinumab's reliability and offers a de-risked clinical development candidate for IBD and other diseases. Furthermore, it provides an intriguing platform for engineering trispecifics (IL-12, IL-23, other target) while maintaining the preferred bivalent structure of classical IgG.

Disclosure

JHS BLB AFH are shareholders in Multiverse Pharma

Introduction

​Post-ERCP pancreatitis (PEP) is still the most common major complication of ERCP despite technical advancements and meticulous patient selection. The efficacy of the existing techniques is conflicting.

Aims & Methods

We aimed to compare the efficacy of peripapillary epinephrine injection in combination with rectal diclofenac for the prevention of PEP in high-risk patients .
Methods Between January 2023 and August 2023, a total of 378 patients were enrolled. We calculated that 189 patients in each group (rectal diclofenac – Group A and peripapillary epinephrine injection plus rectal indomethacin – Group B) would suffice based on a previous study by our group (α:0.05, 80% power). Patients with a non-naive papillae, ampulla of Vater cancer, biliary pancreatitis, altered anatomy, pregnancy, and pancreatic diseases such as chronic pancreatitis were excluded. Patients were assigned in a 1:1 simple randomized fashion. The primary outcome was the rate of PEP. Secondary outcomes were the rate of hyperamylasemia and rates of other adverse events.

Results

​Demographic characteristics, indications, and procedure-related risk factors were similar between the groups. The overall success rate of selective cannulation was 99.2% in Group A and 99.3% in Group B (p=0.997). PEP occurred in 9 of the 189 (4.8%) patients in Group A and 2 of the 189 (0.5%) patients in Group B. All cases were mild and managed conservatively. The rate of post-procedure 4th-hour hyperamylasemia was significantly higher in Group A (19% vs 5%, p<0.001). Postsphincterotomy-related bleeding developed in 5 patients in Group A (2.64%) but none of the patients had bleeding in Group B. Stapfer type-II perforation occurred in two patients in each group. No major cardiac adverse events-related to epinephrine injection were detected in Group B.

Conclusion

Compared to rectal diclofenac, peripapillary epinephrine injection significantly reduced the incidence of PEP, post-procedure hyperamylasemia, and sphincterotomy-related bleeding.

Clinical Case Summary

Aim: Abdominal Cocoon syndrome is the complete or partial wrapping of the abdominal organs with a membrane structure. Diagnosis can be made by laparoscopy. Patients mostly present with acute abdomen symptoms due to intestinal obstruction.
Case: 27-year-old male patient had recurrent abdominal pain for 12 years and was diagnosed with Behçet's disease and started on treatment. The patient’s abdominal pain increased in the last 6 months. He was followed up 4 months ago with suspected ileus, recovered with symptomatic treatments. A colonoscopy was performed and aphthous ulcers were detected in the terminal ileum and linear ulcers in the sigmoid colon. Tuberculosis,vasculitis and amyloid was excluded in the biopsies .With the preliminary diagnosis of Crohn's disease, 5-ASA and Azathioprine were started, and when no clinical response was obtained, Adalimumab was switched. The patient, who had no history of alcohol, cigarette use or any surgery, stopped all of her medications because she had not had symptomatic improvement for a long time, and was relieved by vomiting voluntarily. Her family history included rheumatoid arthritis in her sister and ulcerative colitis in her cousin. In the physical examination, there was no pathology other than widespread tenderness in the abdomen. In the ultrasonography; the small intestine walls were seem to be slightly edematous and retracted. Enteroscopy was completely normal. In the CT-Enterography, it was thought that it could be an "abdominal cocoon", so a laparotomy was performed and the diagnosis. The small intestines were freed from the fibrotic bands. The patient did not develop any post-operative complications, and her abdominal pain completely resolved after the operation.
Conclusion: Abdominal cocoon syndrome should be kept in mind as a very rare disease that can cause diagnostic confusion, remain undiagnosed for a long time, and cause unnecessary treatments, and can be fixed totally with surgical treatment.

Introduction

Bowel urgency (BU) is a bothersome symptom experienced by patients with ulcerative colitis (UC) and is associated with high clinical and quality-of-life burdens. Mirikizumab (MIRI), an anti-IL-23 antibody approved for the treatment of moderately-to-severely active UC, significantly reduced BU severity compared with placebo (PBO), and these improvements were associated with better clinical outcomes.¹ We evaluated the association between incremental improvement in BU severity at Week (W)12 and W52 with other patient-reported outcomes for MIRI-treated patients.

Aims & Methods

In LUCENT-1 (induction), patients were randomized 3:1 to intravenous MIRI 300 mg or PBO every 4 weeks (Q4W) for 12W. MIRI responders during induction were re-randomized 2:1 to subcutaneous MIRI 200 mg or PBO Q4W for 40W in LUCENT-2 (52W of continuous treatment). BU severity was measured using the Urgency Numeric Rating Scale ([UNRS] 0–10). Incremental improvement of BU severity was assessed as reduction of each single point of UNRS score from baseline (BL). The reduction of >7 points was pooled into one category due to sample size. The accumulative benefit of reducing 1 additional point of UNRS score was evaluated at W12 and W52 and was assessed for its association with mean percent improvement in inflammatory bowel disease questionnaire (IBDQ) total score, fatigue NRS, short-form (SF)-36 mental component score (MCS) and physical component score (PCS), and work productivity activity impairment (WPAI) productivity loss.

Results

Significantly greater proportions of patients receiving MIRI achieved UNRS score reduction at certain points versus PBO at W12 and W52. The reduction of each single point of UNRS score was associated with improvement in patient’s physical and mental health, fatigue, work productivity, and quality of life. At W12, fatigue and IBDQ showed greater percent improvements among all the PRO outcomes studied for each 1-point reduction of UNRS. Similar results were observed at W52 (Table 1).

Week 12 (N=868)	UNRS reduction	Fatigue NRS	IBDQ Total Score	MCS	PCS	WPAIa	Week 52 (N=365)	UNRS reduction	Fatigue NRS	IBDQ Total Score	MCS	PCS	WPAIb
	≤0	-11.9	16.0	6.6	9.4	4.9		≤0	8.9	35.9	18.5	21.2	23.9
	1	15.4	25.9	14.6	11.3	16.9		1	5.8	30.6	13.4	12.7	11.2
	2	28.7	31.1	13.7	14.0	20.1		2	32.4	37.5	18.8	18.6	30.1
	3	43.5	35.8	17.9	16.9	24.1		3	59.5	33.9	10.8	20.4	27.5
	4	49.8	49.1	19.7	23.5	24.2		4	62.4	55.6	17.9	33.7	42.1
	5	54.5	43.3	13.1	22.9	28.8		5	52.2	54.0	21.7	27.7	38.2
	6	59.3	55.2	22.1	24.0	36.4		6	68.9	63.0	26.0	26.5	41.9
	7	81.2	64.6	25.9	30.1	29.8		7	83.8	67.3	30.1	30.1	50.6
	>7	73.6	75.4	29.7	39.1	38.5		>7	88.1	87.6	35.0	45.4	54.8

^a Note: N=532, population was restricted to patients with baseline employment status = Yes.
^b Note: N=224, population was restricted to patients with baseline employment status = Yes.
Abbreviations: IBDQ = inflammatory bowel disease questionnaire; MCS = short-form-36 mental component score; N = number of patients in the analysis population; n = number of patients in the specified category; NRS= numeric rating scale; PBO = placebo; PCS = short-form-36 physical component score; UNRS = urgency numeric rating scale; WPAI= work productivity activity impairment productivity loss.
UNRS score was averaged from daily diary entries for a 7-day period. Data were considered as missing for that week if less than 4 days were available.

Conclusion

Incremental improvement in bowel urgency corresponded to improvements in outcomes important to patients, underscoring the importance of managing BU symptoms in improving the quality of life for patients with UC.

References

1. Dubinsky MC, et al. Crohns Colitis 360 2023;5(1):otac044.

Disclosure

MD reports consultancy fees from AbbVie, Arena Pharmaceuticals, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Gilead Sciences, Janssen, Pfizer, Takeda, and UCB.
ST reports grants and/or research support from AbbVie, Buhlmann Diagnostics, Celgene, Eli Lilly and Company, the International Organization for the Study of Inflammatory Bowel Disease, Janssen, the Norman Collisson Foundation, Takeda, UCB, and Vifor Pharma; consulting fees from Abacus Pharmaceuticals, AbbVie, Actial, ai4gi, Alcimed, Allergan, Amgen, Arena Pharmaceuticals, Asahi Kasei Pharma, Astellas Pharma, AstraZeneca, Atlantic Pharmaceuticals, Barco, Biocare Pharma, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Buhlmann Diagnostics, Calcico, Celgene, Cellerix, Celsius Healthcare, Cerimon Pharmaceuticals, ChemoCentryx, Cisbio, Coronado Biosciences, Cosmo Pharmaceuticals, Ducentis BioTherapeutics, Dynavax, Elan Corporation, Eli Lilly and Company, Enterome, Falk Foundation, Ferring Pharmaceuticals, FPRT Bio, Giuliani, Genentech, Genzyme, GlaxoSmithKline, Glenmark Pharmaceuticals, Grünenthal, GW Pharmaceuticals, Immunocore, Immunometabolism, Indigo Biosciences, Janssen, Lexicon Pharmaceuticals, Medarex, Merck, MSD, Neovacs, Netbiotix, Novartis, Novo Nordisk, NPS Pharma, Ocera Therapeutics, Otsuka, Palau Pharma, Pentax Medical, Pfizer, Philips, Procter & Gamble, Pronota, Proximagen, Ptima Pharma, Receptos, Resolute, Robarts Pharmaceutical, Roche, Sandoz, Santarus, Sensyne Health, Shire, Sigmoid Pharma, SynDermix, Synthon, Takeda, Theravance Biopharma, TiGenix, Tillotts Pharma, TopiVert, TxCell, UCB, Vertex, VHsquared, Vifor Pharma, Warner Chilcott, and Zeria Pharmaceutical; and speaker fees from AbbVie, Amgen, Biogen, Falk Foundation, Ferring Pharmaceuticals, GlaxoSmithKline, Janssen, Shire, Takeda, and Zeria Pharmaceutical.
TK has served as a speaker, a consultant or an advisory board member for AbbVie, Ajinomoto Pharma, Asahi Kasei Medical, Astellas, Alfresa Pharma, Celltrion, Covidien, EA Pharma, Eisai, Eli Lilly, Ferring Pharmaceuticals, Gilead Sciences, Janssen, JIMRO, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda Pharmaceutical, Thermo Scientific, Zeria Pharmaceutical, and received research funding from AbbVie, Alfresa Pharma, Asahi Kasei Medical, EA Pharma, Kyorin Pharmaceutical, Mochida Pharmaceutical, Nippon Kayaku, Otsuka Holdings, Sekisui Medical, Thermo Fisher Scientific, Zeria Pharmaceutical.
BA-B has served on advisory board for Bristol Myers Squibb, Pfizer; and reports speaker fees from AbbVie, Takeda, Bristol Myers Squibb, Janssen Pharmaceuticals.
JW, BZ, HQ, CM, SF are employees and minor shareholders of Eli Lilly and Company.
DR reports grant support from Takeda and has served as a consultant for AbbVie, AltruBio, Arena Pharmaceuticals, Bristol Myers Squibb, Eli Lilly and Company, Genentech, Gilead Sciences, Iterative Scopes, Janssen, Pfizer, Prometheus Biosciences, Roche, Takeda, and Techlab.

Introduction

Endoscopic resection (ER) of duodenal tumors carries a high risk of intraoperative or delayed perforation because of the thin duodenal wall and exposure to bile and pancreatic juice. Delayed perforation can particularly cause serious condition due to the leakage of the digestive fluids. The detailed management and clinical course following duodenal perforation remains unclear. This study aimed to clarify the optimal management of duodenal perforation following ER.

Aims & Methods

This single-center retrospective study included cases of perforation among patients who underwent ER for duodenal tumors at our institution between April 2013 and October 2024. The study endpoint was the clinical course after perforation, including the hospitalization period after ER for duodenal tumors. Perforation was defined as the presence of extraluminal gas on computed tomography (CT) scan. Delayed perforation was defined as a perforation that was not endoscopically recognized during the procedure but was diagnosed postoperatively. In contrast, intraoperative perforation was defined as a case in which a perforation was endoscopically identified during the endoscopic procedure. Long hospitalization was defined as a hospital stay of 20 days or longer.

Results

Of the 1,475 cases with duodenal tumors underwent ER during the study period, intraoperative perforation occurred in 8 cases (0.5%) and delayed perforation in 10 cases (0.7%). The median age of patients with perforation was 62 (range: 47–80) years, and 50% (9 patients) were male. The 18 cases included 6 cases of endoscopic papillectomy (EP), 7 cases of endoscopic mucosal resection (EMR), 2 cases of endoscopic submucosal dissection, and 3 cases of endoscopic submucosal resection with a ligation device. Among the cases of intraoperative perforations, long hospitalization, 61 days of conservative treatment, was required in one case who developed a large perforation during scope insertion of single‑balloon enteroscopy for duodenal adenoma resection. The remaining 7 cases achieved successful endoscopic closure intraoperatively and hospitalization periods were within 17 days. Of the 10 delayed perforation cases, 2 occurred after EP and 8 after EMR for non-ampullary tumors. The median time from the end of endoscopic resection to the diagnosis of perforation was 24 hours (4–46 hours). The median hospitalization period of the cases with delayed perforations was 32 days (9–81 days), and significantly longer than that of intraoperative perforation (13 days) (p<0.05). Long hospitalization was required in 8 cases (80%) of delayed perforation. None of the delayed perforation cases required surgical intervention, and endoscopic nasobiliary and nasopancreatic duct drainage (ENBPD) was performed in 7 cases (70%). Ascites was observed on CT scan at the time of diagnosis of delayed perforation in 7 of the 8 patients who required long hospitalization. One case without ascites at the diagnosis of delayed perforation still required long hospitalization, possibly due to the 10-hour delay from the diagnosis to ENBPD. On the other hand, two cases who did not need long hospitalization showed no ascites at the diagnosis of delayed perforation.

Conclusion

Compared to intraoperative perforation, delayed perforation was associated with significantly prolonged hospitalization, particularly in cases with ascites. Early detection of ascites and prompt initiation of ENBPD may help mitigate the clinical burden. Establishing an emergent backup system for ENBPD is essential for the safe management of delayed perforation after duodenal ER.