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

OZA is a sphingosine 1-phosphate receptor modulator approved for the treatment of moderately to severely active UC. In the phase 3 TN study, OZA was efficacious for up to 52 wk with a favorable safety profile. IL-17A, a proinflammatory cytokine, sustains the release of other inflammatory mediators and is associated with inflammatory bowel disease.

Aims & Methods

This analysis assessed the effect of OZA on IL-17A levels and the association of IL-17A levels with OZA efficacy during TN. During the 10-wk induction period, pts in Cohort 1 were randomized to OZA 0.92 mg or placebo (PBO) and pts in Cohort 2 received open-label OZA 0.92 mg. Pts with clinical response to OZA at Week (W) 10 were rerandomized to OZA or PBO for maintenance through W52. IL-17A levels were assessed at baseline, W10, and W52. Disease activity scores (rectal bleeding and stool frequency subscores, Physician’s Global Assessment subscore, endoscopy subscore, and partial and total Mayo scores) were assessed at baseline and W10. Efficacy endpoints (clinical remission, clinical response, endoscopic improvement, mucosal healing, and histologic remission) were assessed at W10 and W52. Associations of IL-17A levels with disease activity and efficacy endpoints were assessed using Spearman’s correlation and logistic regression, respectively.

Results

In all, 645 pts were randomized to OZA (n=429) or PBO (n=216) and 367 pts received open-label OZA; 230 and 227 OZA-treated pts were rerandomized to OZA and PBO, respectively, for maintenance. Pts on OZA demonstrated reductions from baseline in IL-17A at W10, which was significant vs PBO (P<0.001, both cohorts) (Table). IL-17A reductions were significantly greater in pts with vs without clinical response at W10 in all OZA and PBO treatment groups (P<0.01, all groups) (Table). Significantly greater IL-17A reductions occurred with OZA vs PBO at W10 regardless of prior biologic or anti–tumor necrosis factor exposure (P<0.001, all groups). IL-17A reductions were maintained through W52; pts who continued OZA had significantly greater IL-17A reductions at W52 vs pts who switched to PBO (P<0.001) (Table). IL-17A reductions were significantly greater in pts with vs without clinical response at W52 (P<0.001, OZA and PBO groups) (Table). Baseline IL-17A levels were significantly correlated with all baseline disease activity scores (Spearman’s rho 0.1–0.2, P<0.05, all scores), but were not associated with treatment responses at W10. Change in IL-17A from baseline to W10 was significantly correlated with change in all disease activity scores at W10 with OZA and PBO (Spearman’s rho 0.2–0.4, P<0.05, all scores in both groups). Furthermore, greater reductions from baseline to W10 in IL-17A was significantly associated with higher probability of achieving clinical remission, clinical response, endoscopic improvement, and mucosal healing at W52 (P<0.05, all endpoints) in pts on continuous OZA through W52.

Conclusion

OZA led to IL-17A reductions, indicative of decreases in inflammatory responses. Higher baseline IL-17A was associated with higher baseline disease activity, and greater reductions in IL-17A were associated with better short- and long-term disease outcomes. These data support IL-17A as a good disease marker for UC.

Disclosure

This study was funded by Bristol Myers Squibb, Princeton, NJ, USA
SH, RM, CW, YH, and AP: employees and/or shareholders of Bristol Myers Squibb.
SV: received research funding from AbbVie, Galapagos, Johnson & Johnson, Pfizer, and Takeda; received consulting and/or speaking fees from AbbVie, Abivax, AbolerIS, AgomAb, Alimentiv, Arena, AstraZeneca, Avaxia, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, CVasThera, Cytoki Pharma, Eli Lilly, Falk Pharma, Ferring, Galapagos, Genentech/Roche, Gilead, GlaxoSmithKline, Hospira, IMIDomics, Janssen, Johnson & Johnson, Materia Prima, MiroBio, Morphic Therapeutic, MRM Health, MSD, Mundipharma, Pfizer, ProDigest, Progenity, Prometheus, Robarts Clinical Trials, Second Genome, Shire, Surrozen, Takeda, Theravance, Tillotts Pharma AG, and Zealand.

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

Butyrate has shown anti-inflammatory effects and plays an important role in maintaining gut homeostasis, providing symptomatic relief when orally supplemented in patients suffering from various colonic diseases. In a previous pilot study, we demonstrated an important biologic effect of microencapsulated sodium butyrate (BLM) in patients with IBD(1).

Aims & Methods

In this randomised, double-blind, placebo-controlled study, 140 IBD patients in remission or with mild disease (n=60 Crohn's disease, CD and n=80 Ulcerative Colitis, UC) were randomized to oral administration of BLM/placebo for 3 months, in addition to conventional therapy. As primary aim we investigated the changes in microbiome composition induced by BLM treatment. Fecal microbiota from stool samples was assessed by 16S sequencing. Clinical disease activity assessed by using Harvey Bradshaw Index (HBI) for CD and partial-Mayo Score (pMS) for UC, quality of life assessed by using Inflammatory Bowel Disease Questionnaire 32 (IBDQ-32) and adherence-dietary-raccomandation were evaluated before and after treatment (T0=0 day and T1=90 days).

Results

Demographics and clinical characteristics were similar between the two populations. Moreover, they adhere to the recommendations of World Cancer Research Fund/American Institute for Cancer Research(WCRF-AIRC) regarding good and healthy nutrition(Table.1). After treatment of CD patients, the HBI score, dichotomized into remission and active disease, showed a significant improvement for those treated with BLM as compared to placebo (McNemar’s p=0.013 vs p>0.9). IBDQ-32 significantly improved in CD and UC, more markedly in the treatment group (CD: treat. 170/184 vs Pb. 188/196_95% CI 4.1,21 vs1.1,9.8;; UC: treat.185/195 vs Pb.188/188_95% CI 4.5,19 vs 2.8,7). The microbiota sequencing highlighted two different enterotype in CD population: the first one was characterized by Bacteroidota prevalence (with a genus prevalence of Fecalibacterium, Alistipes, and Roseburia). The second enterotype was characterized by Firmicutes prevalence (with a genus prevalence of Escherichia-Shigella and Lachnoclostridium). BLM had a more pronounced effect on the Bacteroidota enterotype where the taxa associated with intestinal comfort, SCFA production, and anti-obesity increased after treatment, while the taxa associated with CRC and intestinal inflammation, decreased. Finally, a significant separation was observed in samples from patients who have undergone minor surgery (ileo-colon), compared to non-surgery patients. The variable “surgery” seems to be associated with the Bacteroidota enterotype.

Conclusion

Sodium butyrate supplementation significantly improved clinical outcomes and quality of life in patients with CD. The subpopulation of patients undergoing ileo-colonic resection was microbiologically diversified compared to the non-surgery population. These results indicate that butyrate therapy may be more appropriate for the treatment of CD subjects with colonic preservation.

References

1. Facchin S, Vitulo N, Calgaro M, et al.. Microbiota changes induced by microencapsulated sodium butyrate in patients with inflammatory bowel disease. Neurogastroenterol Motil. 2020 Oct;32(10):e13914. doi: 10.1111/nmo.13914. Epub 2020 May 31. PMID: 32476236; PMCID: PMC7583468.

Disclosure

Sonia Facchin has received lecture or consultancy fees from SILA and Unifarco ; Edoardo Savarino has received lecture or consultancy fees from Abbvie, Amgen, Bristol-Myers Squibb, Fresenius Kabi, Grifols, Janssen, Johnson&Johnson, Innovamedica, Merck & Co, Novartis, Sandoz, Shire, SILA, Sofar, Takeda, Unifarco.