Introduction

Specific antagonism of α4β7 by the monoclonal antibody vedolizumab is a proven mechanism for IBD treatment¹. MORF-057 is an orally dosed small molecule designed to selectively inhibit the α4β7 integrin, avoiding the need for parenteral administration. This Phase 2a open label study aimed to assess the safety, tolerability, pharmacokinetics, and efficacy of MORF-057 dosed 100 mg twice daily (BID) for induction treatment in adults with moderately to severely active ulcerative colitis (UC).

Aims & Methods

Key eligibility criteria included a modified Mayo Score of 5-9, a centrally read endoscopy sub-score of ≥2, a Robarts Histology Index (RHI) score of ≥ 10 and a history of insufficient response, loss of response, and/or intolerance to conventional and/or advanced therapies (approved biologics, JAK inhibitors, and S1P modulators). Patients received 100 mg orally BID of MORF-057 during the induction period of 12 weeks. Saturation of α₄β₇ in peripheral blood was evaluated using a validated FACS analysis. The primary efficacy endpoint was mean change from baseline to Week 12 in the RHI Score.

Results

Of the 35 patients in the Full Analysis Set (FAS), 31/35 (89%) completed the 12-week induction Period. The mean baseline modified Mayo score was 6.7 (SD=1.07) and the mean RHI score was 22.7 (SD=7.32) (Table 1).
At Week 12, the primary endpoint of the study was met with a mean reduction in the RHI score of - 6.4 (SD=11.2) (p = 0.0019). For the secondary endpoint of change from baseline in the modified Mayo Clinic score (mMCS), a change of ‑2.3 (SD=2.14) points was observed. 25.7% of patients achieved mMCS clinical remission. The proportion of patients achieving a mMCS clinical response was 45.7% and endoscopic improvement was achieved in 25.7% of patients.
Pharmacokinetic (PK)/pharmacodynamic (PD) evaluations confirmed results seen in the healthy volunteer studies^2,3, with trough drug concentrations sufficient to lead to a median α₄β₇ receptor occupancy (RO) of >99%. The RO saturation was achieved early and sustained at week 12 that was accompanied by selective increases in circulating ITGb7⁺ lymphocyte subsets without a corresponding rise in the total lymphocyte counts.
.The rates of treatment-emergent adverse events (TEAEs) were low. Common (>5%) TEAEs were exacerbation of UC in 4 patients (11.4%) and anemia in 3 (8.6%) patients. Overall, there were no safety signals identified.

Table 1. Demographic and Disease Characteristics at Baseline

Conclusion

MORF-057 demonstrated desired PK and PD profile. Consistent changes in key efficacy outcomes including statistically significant outcome in the primary endpoint observed. MORF-057 was well tolerated. An ongoing Phase 2b randomized, double blind, placebo-controlled trial is being conducted to further confirm these findings and find optimal dosages for further development.

References

1. Entyvio® (vedolizumab) prescribing information. (https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/125476Orig1s046lbl.pdf)
2. Ray A et al. MORF-057, An oral selective α4β7 integrin inhibitor for inflammatory bowel disease, leads to specific target engagement in a single and multiple ascending dose study in healthy subjects. ECCO. 2021; ePoster 306
3. Hussain, A., et al. Increase in Circulating T and B Lymphocyte Subsets After Treatment with the Potent, Selective, Oral Small Molecule α4β7 Inhibitor MORF-057 In Healthy Subjects. UEG Week, 2022; Poster number P0417

Disclosure

Current employee and stockholder

Clinical Case Summary

An 18-year-old female was diagnosed with very early-onset Crohn’s disease (CD) in 2008. Due to steroid dependence, adalimumab 40 mg biweekly was initiated in 2019, with escalation to 40 mg weekly in February 2023 following secondary loss of response. In November 2023, despite clinical and biochemical remission (CRP <0.5 mg/L, fecal calprotectin <50 µg/g), the patient developed painful purpuric and ulcerated lesions on both lower limbs. Histological examination of a skin biopsy confirmed leukocytoclastic vasculitis (LCV), revealing perivascular neutrophilic infiltrates, nuclear debris, and fibrinoid necrosis in post-capillary venules. Infectious and autoimmune screening, including ANA, antiphospholipid antibodies, p-ANCA, and c-ANCA, were negative. Following consultation with an immunologist, adalimumab was discontinued, and oral prednisone 25 mg/day was initiated. However, the clinical course was complicated by a skin abscess, which was treated with oral amoxicillin/clavulanate (1 g three times daily for 3 days). As vasculitic lesions worsened, the patient was hospitalized, and prednisone was increased to 50 mg/day. Intravenous cefazolin (2 g every 8 hours for 5 days) was also administered, resulting in stabilization and partial clinical improvement. A multidisciplinary team, including a gastroenterologist, immunologist, and dermatologist, opted to initiate off-label treatment with upadacitinib 30 mg/day, a selective Janus kinase 1 (JAK1) inhibitor. After four weeks, the patient showed improvement in the vasculitic lesions, and corticosteroid therapy was tapered. At the six-month follow-up, the patient remained on upadacitinib monotherapy, with sustained clinical and biochemical remission of both CD and LCV, without any adverse events. This case highlights the potential of JAK1 inhibition as an effective and safe therapeutic option for leukocytoclastic vasculitis in patients with Crohn’s disease.

References

Photographic documentation of the clinical case:
1. Images showing the initial presentation of petechial and purpuric lesions on the lower limbs.
2. Images of severe vasculitis characterized by confluent and ulcerated lesions.
3. Images documenting cutaneous healing following upadacitinib treatment.

Introduction

Mirikizumab is a monoclonal antibody directed against the p19 subunit of interleukin (IL)-23 approved for the management of patients with moderate-to-severe ulcerative colitis (UC). Currently, there is no large study supporting the effectiveness of mirikizumab in UC in a real-life setting.

Aims & Methods

This study aims to evaluate the effectiveness and safety of mirikizumab in real-life setting. This was a retrospective multicenter cohort study of a prospectively collected database including adult patients with confirmed diagnosis of UC treated with mirikizumab according to clinical practice. Patients were enrolled in three third-level italian centers (San Raffaele Hospital, Humanitas Research Hospital, and Federico II Hospital) from June 2024 to February 2025. All patients with at least 3 months of follow-up after therapy initiation were eligible. The primary outcome was the clinical remission rate (defined as partial Mayo Score (pMS) < 2 with a rectal bleeding subscore of 0) at week 12. Secondary outcomes included changes in bowel urgency (measured by the Numeric Rating Scale (NRS) urgency score), changes in serum C-reactive protein (CRP) and fecal calprotectin (FC) levels from week 0 to 12, safety profile of mirikizumab during induction therapy.

Results

In total 100 patients (60% male, with median age 48.53 ± 15.36) with UC were included. Most patients had a left-sided colitis (55, 55%) or a pancolitis (41, 41%). Most patients (81, 81%) were already treated with at least one advanced therapy before starting mirikizumab (including 28 patients treated with ustekinumab, 28%). A fifth of patients (19, 19%) were exposed to ≥ 4 advanced therapies. A significant reduction in pMS was observed from baseline to week 12 (median [IQR]: 4.0 [1.75–6.0] vs. 2.0 [0.0–4.0]; Wilcoxon signed-rank test: W = 312, Z = -5.35, p < 0.00001, n = 69) with 48 (48%) patients reaching clinical remission at week 12. Moreover, a significant improvement in bowel urgency was observed from baseline to week 12 (t(98) = 6.58, p = 2.28×10⁻⁹), with a moderate-to-large effect size (g = 0.66). From baseline to week 12, both FC and CRP levels showed significant reductions following treatment (FC: V = 1153.00, p = 2.4×10⁻⁵, r = 0.67; CRP: V = 680.00, p = 0.03, r = 0.37). Effect sizes were large for FC and moderate for CRP with paired data from 53 and 47 patients being analyzed, respectively. In total, 39 patients (39%) underwent extended induction while 3 patients (3%) discontinued the drug at week 12. There were no adverse events leading to discontinuation or death. Two mild adverse events were reported (upper respiratory tract infection in 1 patient and pyrexia in 1 patients). No significant changes were observed in liver aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels over time (AST: χ²(2) = 0.21, p = 0.90, W = 0.005; ALT: χ²(2) = 3.73, p = 0.16, W = 0.08).

Conclusion

This is the largest study demonstrating the effectiveness and safety of mirikizumab in inducing clinical remission in patients with UC in a real-life setting. Patients treated with mirikizumab achieved a significant reduction in bowel urgency, FC and CRP levels. No statistically significant increase in liver toxicity was detected during the induction treatment.

Disclosure

F. D'Amico. OM Nardone, A. Zilli, M. Allocca, S. Danese, L. Peyrin-Biroulet and A. Armuzzi have served as speaker and advisory board member for Lilly

Introduction

Surgical management of hemorrhoidal disease (HD) in patients with inflammatory bowel disease (IBD) remains controversial due to concerns about impaired wound healing and disease flare, especially in Crohn’s disease (CD). In Europe, current evidence is mainly based on small historical single-center case series.¹

Aims & Methods

We sought to evaluate the safety and effectiveness of surgical treatments for HD in IBD patients and identify potential risk factors for complications. HEAD-IBD is a retrospective cohort study promoted by the Italian Group for the study of Inflammatory Bowel Disease (IG-IBD) and the Italian Society of Colorectal Surgery (SICCR). Patients with established IBD who underwent surgery for HD between December 2004 and March 2024 were included. Data were collected across multiple centres using the REDCap system. IBD activity was measured by the Harvey-Bradshaw Index for CD and the partial Mayo score for ulcerative colitis (UC). Surgical techniques, short- and long-term complications, disease flare, and continence status were analyzed. Only patients with ≥1 year follow-up were considered.

Results

A total of 38 patients were initially identified from 8 centres. Two patients with unclassified IBD were excluded from stratified analysis, leaving 36 patients (Table 1): 21 (58%) with UC and 15 (42%) with CD. Overall, 53% were male. The median age at surgery was 49 years (IQR 13) in UC and 37 years (IQR 22) in CD. At the time of surgery, biologic therapy was ongoing in 10% of UC and 40% of CD patients. Clinically active disease at the last gastroenterology visit was reported in 6 CD patients (40%) and 5 UC patients (24%). The time interval between the last IBD evaluation (clinical or endoscopic) and surgery was significantly longer in UC compared to CD patients (table 1). Distribution of Goligher grade suggested a higher proportion of grade III–IV disease in UC (72%) than in CD (53%). Open hemorrhoidectomy was the most frequent procedure in both groups (66% UC, 73% CD). Non-excisional techniques (DG-HAL +/- mucopexy) were used in 29% of UC and 27% of CD patients. Stapled hemorrhoidopexy was performed only in UC (10%). Median hospital stay was 1 day (IQR 1) in both groups. No 30-day or 6-month postoperative complications were reported in CD, while 14% of UC patients experienced early or mid-term complications. One UC patient experienced IBD flare at 6 months. At 12-month follow-up, one UC patient reported new-onset soiling; continence was otherwise preserved in all cases.

Conclusion

This multicenter study represents the largest European series on surgical treatment of HD in patients with IBD, confirming its safety, with low complication rates and no new perianal disease. Short- and mid-term complications occurred only in UC patients, possibly reflecting both more advanced HD (Goligher grade III–IV) and less intensive preoperative monitoring. These findings highlight the need for close gastroenterological pre-operative assessment and shared decision-making. The ongoing HEAD-IBD II prospective study will provide further insight into optimal management strategies.

References

1. Grossi U, Gallo G, Di Tanna G, et al. Surgical Management of Hemorrhoidal Disease in Inflammatory Bowel Disease: A Systematic Review with Proportional Meta-Analysis. J Clin Med. 2022 Jan 28;11(3):709. doi: 10.3390/jcm11030709

Disclosure

None

Introduction

Digestive neuroendocrine tumors (DNETs) are rare and ubiquitous neoplasm of the digestive tract, with an incidence that is increasing significantly in recent years. Special AT-rich sequence-binding protein 2 (SATB2) and the homeotic transcription factor (CDX2) are markers of intestinal differentiation that may be involved in the in the topographic diagnosis of DNET and thus orientate towards the site of the primary NET.

Aims & Methods

The aim of our work was to evaluate the immunohistochemical expression of CDX2 and SATB2 in DNET according to the topography and the histoprognostic factors. We conducted a longitudinal and retrospective study including 39 DNETs. Epidemiological and anatomopathological data according to the 2019 WHO classification were studied. The study of CDX2 and SATB2 was performed by immunohistochemical method. Positivity was considered in the presence of a nuclear immunoreactivity greater than 10%.

Results

The mean age of patients diagnosed with DNETs was 51.4 years with a sex ratio M/F of 0.77. The predilection sites were the small intestine and the appendix, in 33.3% of cases each. CDX2 was expressed in 64% of DNETs. It was positive in 90-100% of small intestine, appendix and colon neuroendocrine neoplasms. SATB2 was expressed in 60% of DNETs. It was found in 100% of appendicular and colorectal neuroendocrine tumors. A weak staining was observed in 69% of small intestine neuroendocrine tumors. Gastric and pancreatic tumors pancreatic tumors did not express CDX2 nor SATB2. This variation in expression was statistically significant (p<0.001). Grade G1 tumors (67%) were in 70% CDX2+/SATB2+. Grade G2/G3 tumors (33%) were in 68% of cases SATB2- without significant difference. The pT1/pT2 DNET (n=19) were CDX2+/SATB2+ in 68%. The pT3/pT4 tumors (n=17) were CDX2- in 35% and SATB2- in 47% without significant difference. Lymph node and distant metastases were found in 28% and 14% of cases respectively. No statistically significant correlation was noted between CDX2 or SATB2 and the presence of lymph node metastases. However, the loss of SATB2 was significantly associated with the metastatic potential (p<0.001).

Conclusion

CDX2 and SATB2 are highly sensitive and relatively specific markers of the digestive tract. They would be useful in the topographic approach of neuroendocrine tumors of unknown origin.