Introduction

MORF-057 is an oral α₄β₇ integrin inhibitor that prevents immune cell entry into the gut to alleviate inflammation.

Aims & Methods

EMERALD-2 is a phase 2b, randomized, double-blind, placebo-controlled study evaluating MORF-057 efficacy and safety in adults with moderately to severely active ulcerative colitis (UC). Participants with Modified Mayo Score (MMS) 5–9, inadequate/loss of response or intolerance to conventional or advanced therapy (AT), and who were integrin inhibitor-naïve received 1 of 3 MORF-057 doses or placebo (1:1:1:1). The primary efficacy endpoint was clinical remission at Week 12; secondary and exploratory efficacy endpoints were rates of clinical response and endoscopic improvement, respectively. Pharmacokinetic and pharmacodynamic endpoints and safety were evaluated. The study is registered with ClinicalTrials.gov (NCT05611671).

Results

The study enrolled 280 participants (mean [SD] age, 40.2 [14.6] years; 55.4% male; mean [SD] time since UC diagnosis, 6.7 [7.2] years). At baseline, mean (SD) MMS was 6.7 (1.0); 39.3% of participants were on a stable corticosteroid dose, 20.4% were on an immunomodulator, and 31.1% were AT-experienced.
Clinical remission rate with MORF-057 at Week 12 was dose dependent, ranging from 17.1% (100 mg QD) to 31.9% (200 mg BID) vs. 24.3% with placebo (Table 1), with the same trend in the AT-experienced subgroup (N=87; 100 mg QD, 4.3%; 100 mg BID, 13.6%; 200 mg BID, 21.1%; placebo, 13.0%). Compared with placebo, 200 mg BID MORF-057 had numerically higher clinical response and endoscopic and histo-endoscopic mucosal improvement (HEMI) rates, with the latter 2 endpoints showing an increasing trend with higher doses.

Table 1. Efficacy endpoints in EMERALD-2 at Week 12

Rate (proportion of patients, %)	MORF-057			Placebo (n=70)
	100 mg QD (n=70)	100 mg BID (n=71)	200 mg BID (n=69)
Clinical Remissiona	17.1	23.9	31.9	24.3
Clinical Responseb	57.1	53.5	62.3	54.3
Endoscopic Improvementc	31.4	32.4	43.5	31.4
Histo-Endoscopic Mucosal Improvementd	27.1	31.0	42.0	25.7

^aBased on MMS (stool frequency=0/1, RB=0, MES=0/1 [excluding friability]). Non-significant vs. placebo.
^b≥2-point reduction in MMS and ≥30% change from baseline, and ≥1-point reduction in RB score from baseline or RB=0/1.
^cMES≤1.
^dMES=0/1 (excluding friability) and neutrophil infiltration in <5% of crypts; no crypt destruction; and no erosions, ulcerations, or granulation tissue (Geboes scoring).
MES, Mayo Endoscopic Subscore; MMS, Modified Mayo Score; RB, rectal bleeding.

There was a dose-dependent increasing trend in α4β7 receptor occupancy. Treatment-emergent adverse events (TEAEs) in the MORF-057 groups were mostly of mild (42/76, 55.3%) or moderate (25/76, 32.9%) severity; TEAE frequency was similar to the placebo group (36.0% [pooled rate for 3 dose regimens] vs. 34.8%). Among all participants, there were 5 serious AEs not considered treatment-related (UC exacerbation [n=2], AST increase, pneumothorax, vertebral disc herniation). There were no cases of progressive multifocal leukoencephalopathy or meaningfully increased absolute lymphocyte count and no deaths.

Conclusion

Dose-dependent responses to MORF-057 were observed for clinical remission and hard-to-achieve endpoints such as HEMI at Week 12. The clinical remission rate with MORF-057 was numerically higher but did not achieve statistical significance vs. placebo, which showed higher-than-expected responses. MORF-057 had a favorable safety profile with no meaningful safety findings. The study is ongoing to evaluate maintenance safety and efficacy, with further clinical development of MORF-057 planned.

Disclosure

BES: Honoraria for consulting--AbbVie, Adiso Therapeutics, Agomab, Alimentiv, Amgen, AnaptysBio, Arena Pharmaceuticals, Artugen Therapeutics, Astra Zeneca, Biolojic Design, Biora Therapeutics, Boehringer Ingelheim, Boston Pharmaceuticals, Calibr, Celgene, Celltrion, ClostraBio, Equillium, Enthera, Enveda Biosciences, Evommune, Ferring, Fresenius Kabi, Fzata, Galapagos, Genentech (Roche), Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Imhotex, Index Pharmaceuticals, Innovation Pharmaceuticals, Inotrem, Kaleido, Kallyope, Merck & Co., Microbiotica, Mitsubishi Tanabe, Mobius Care, Morphic Therapeutics, MRM Health, Nexus Therapeutics, Nimbus Discovery, Odyssey Therapeutics, OSE Immunotherapeutics, Palisade Bio, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Q32 Bio, Rasayana Therapeutics, Recludix Therapeutics, Reistone Biopharma, Sanofi, Sorriso Therapeutics, Spyre Therapeutics, Surrozen, Target RWE, Teva, TLL Pharmaceutical, Tr1X, Union Therapeutics, Ventyx Biosciences. Consulting and speaking fees--Abivax. Consulting and speaking fees and other support--Eli Lilly and Company. Research grants, consulting and speaking fees, and other support--Bristol Myers Squibb, Eli Lilly and Company, Janssen, Pfizer, Takeda. Research grants and consulting fees--Janssen. Stock/stock options--Ventyx Biopharma.
BGF: Senior Scientific Director at Alimentiv Inc. Consulting--AbbVie, Abivax, Adiso, AgomAB Therapeutics, Akros, Alira Health, Ally Bridge Group, AnaptysBio, Apini Therapeutics, Argenx, Attovia Tx, Avoro Capital Advisors, Belmore Law, BioFactura, BioJamp, Biora Therapeutics, Blackbird Laboratories, Boehringer-Ingelheim, Boxer Capital, Celsius Therapeutics, Celgene/Bristol Myers Squibb, Celltrion, Clarivate, Connect BioPharma, Disc Medicine, Duality, EcoR1, Eli Lilly and Company, Ensho Therapeutics, Equillium, Evida, Enveda, Faes Farma, First Wave, Forbion, Galapagos, Galen Atlantica, Genentech/Roche, General Atlantic, Genesis Therapeutics, Gilead, Gossamer Pharma, GSK, Imhotex, ImmiDomics, Immunic Therapeutics, Intercept, Janssen, Japan Tobacco Inc., Klick Health, LifeMine Therapeutics, Mage Biologics, Merck, Mestag, Mirador Therapeutics, Mobius Care, Monte Rosa Tx, Morphic Therapeutics, Nexys Therapeutics, Nighthawk Therapeutics, Nimbus Therapeutics, Novartis, OncoC4, OrbiMed, Orphagen, Palisade Bio, Pendopharm, Pfizer, Protagonist,32 Bio, REDX, Roche, Roivant/Televant, Sanofi, Sobi, Sorriso, Spyre Therapeutics, SRT Therapeutics, Sun Pharma, Surrozen Inc., Synedgen, Takeda, Teva, Triastek, Trex Bio, TR1X Inc. TVM Lifesciences, Ventyx Biosciences, Versant Ventures, Vida Ventures, Zagbio. Speaker's Bureau--AbbVie, Janssen, Takeda. Scientific Advisory Board (DSMB)--AbbVie, AnaptysBio, Boehringer-Ingelheim, Celgene/Bristol Myers Squibb, Eli Lilly and Company, Genentech/Roche, Janssen, Merck, MiroBio, Origo BioPharma, Pfizer, REDX Pharma, Sanofi, Takeda, Teva, Ecor1Capital, Morphic, GSK. Stock shareholder--Connect BioPharma, EnGene. Provided expert testimony--Belmore Law.
SS: Received fees--AbbVie, Amgen, Arena, Biogen, Bristol Meyers Squibb, Celgene, Celltrion, Falk, Ferring, Fresenius Kabi, Galapagos, Gilead, IMAB, Janssen, Eli Lilly and Company, MSD, Mylan, Novartis, Pfizer, Protagonist, Provention Bio, Roche, Sandoz/Hexal, Shire, Takeda, Ventyx.
LP-B: Consulting--AbbVie, Abivax, Adacyte, Alimentiv, Amgen, Applied Molecular Transport, Arena, Banook, Biogen, Bristol Myers Squibb, Celltrion, Connect Biopharm, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, Gossamer Bio, GSK, IAC Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Nordic Pharma, Novartis, Oncodesign Precision Medicine, ONO Pharma, OSE Immunotherapeuthics, Pandion Therapeuthics, Par' Immune, Pfizer, Prometheus, Protagonist, Roche, Samsung, Sandoz, Sanofi, Satisfay, Takeda, Telavant, Theravance, Thermo Fischer, Tigenix, Tillots, Viatris, Vectivbio, Ventyx, Ysopia. Grants--Celltrion, Fresenius Kabi, Medac, MSD, Takeda. Lectures--AbbVie, Alfasigma, Amgen, Arena, Biogen, Celltrion, Ferring, Galapagos, Genentech, Gilead, Janssen, Kern Pharma, Eli Lilly and Company, Medac, MSD, Nordic Pharma, Pfizer, Sandoz, Takeda, Tillots, Viatris. Travel support--AbbVie, Alfasigma, Amgen, Celltrion, Connect Biopharm, Ferring, Galapagos, Genentech, Gilead, Gossamer Bio, Janssen, Eli Lilly and Company, Medac, Morphic, MSD, Pfizer, Sandoz, Takeda, Thermo Fischer, Tillots.
SD: Consultancy fees--AbbVie, Alimentiv, Allergan, Amgen, Applied Molecular Transport, AstraZeneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly and Company, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial, Vifor. Lecture fees--AbbVie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer, Takeda.
BA, MC, YW, SKL, MM, AW, XZ, NME: Employees and stockholders of Eli Lilly and Company.

Introduction

Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are characterized by dysregulated T-cell responses, causing chronic intestinal inflammation.¹ While anti-TNF therapy is established in IBD, targeting additional pathways may improve outcomes for patients who do not respond adequately to current treatments.² OX40L, an immune co-stimulator, has been implicated in the pathogenesis of several inflammatory conditions.³ Our study provides a comprehensive analysis of the effects of combined TNF and OX40L blockade in a murine adoptive T cell transfer (ATC) model of colitis, examining body weight, detailed histopathological parameters, and a broad range of inflammatory cytokines in colon tissue.

Aims & Methods

Colitis was induced in severe combined immunodeficiency (SCID) mice by intraperitoneal transfer of CD4⁺CD45RB^high T cells isolated from healthy BALB/c donor mice. We established five treatment groups (n=8-10): 1) CD45RB^low transfer “healthy control”, 2) CD45RB^high transfer with isotype antibodies “disease control group”, 3) CD45RB^high transfer with anti-TNF antibody (XT3.11, 250 μg/mouse), 4) CD45RB^high transfer with anti-OX40L antibody (RM134L, 250 μg/mouse), and 5) CD45RB^high transfer with both antibodies at 250 µg/mouse, each. Body weight was monitored for 46 days as a measure of disease progression and normalized to baseline weight at day 1. At study termination, we collected colon tissue for analysis of inflammatory cytokines using multiplex immunoassays and conducted histopathological examination. Histopathological scoring was performed blinded using a validated scoring system for colonic inflammation.⁴

Results

Overall, combined anti-TNF/anti-OX40L therapy was most effective in preventing body weight loss compared to the isotype disease control group, followed by anti-TNF monotherapy and anti-OX40L monotherapy (p<0.0001, p=0.0009, and p=0.03, respectively). Mean normalized body weight (MNBW) of the CD45RB^low healthy control group at termination on day 46 was 115.2 %, while CD45RB^high cell transfer in the disease control group triggered disease induction and body weight loss, with a MNBW of 93.8 % at day 46. The CD45RB^high groups treated with anti-TNF or anti OX40L monotherapy reached a MNBW of 107.6 % and 102.9%, respectively. The CD45RB^high group treated with combination therapy reached 112.6%, closest to the CD45RB^low healthy control group. Notably, only combination therapy led to a significant improvement in histopathological scoring (p=0.0176) compared to the isotype disease control. Similarly, combination treatment consistently resulted in the strongest downregulation of several inflammatory cytokines including IFNg, IL-4, or TNFa, which are increased in colon tissue in the CD45RB^high disease group compared to the CD45RB^low healthy control group.

Conclusion

Combined blockade of TNF and OX40L demonstrated significantly greater efficacy in the ATC preclinical model of IBD in prevention of weight loss, downregulation of key inflammatory cytokines, and reduction of histological damage compared to either monotherapy. These data suggest potential additive efficacy for TNF and OX40L inhibition in controlling intestinal inflammation, and warrant further exploration of dual TNF/OX40L inhibition in clinical trials, particularly among those with inadequate response to anti-TNF monotherapy.

References

1. Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol. 2010;28:573-621.
2. Vermeire S. Combination biologic therapy for ulcerative colitis. Lancet Gastroenterol Hepatol. 2023;8:288-90.
3. Fu Y, Lin Q, Zhang Z, Zhang L. Therapeutic strategies for the costimulatory molecule OX40 in T-cell-mediated immunity. Acta Pharm Sin B. 2020;10:414-33.
4. Erben U, Loddenkemper C, Doerfel K, Spieckermann S, Haller D, Heimesaat MM, Zeitz M, Siegmund B, Kühl AA. A guide to histomorphological evaluation of intestinal inflammation in mouse models. Int J Clin Exp Pathol. 2014;7:4557-76.

Disclosure

Thomas Leeuw, Rolf Keiffer, Danping Ding-Pfennigdorff, Christian Asbrand, Raaj Mehta, Matthias Herrmann are employees of Sanofi and may hold stock or equity options in Sanofi

Introduction

Immune checkpoint inhibitor (ICI) mediated enterocolitis (IMC) may lead to treatment discontinuation. Corticosteroids for IMC is associated with serious side effects and might affect cancer progression in addition to preclude continued ICI treatment. We hypothesized that vedolizumab, a gut selective α4β7 integrin inhibitor, is effective as a first-line treatment and investigated whether vedolizumab reduces corticosteroid exposure and facilitate ICI resumption.

Aims & Methods

We conducted a single center, open-label, explorative phase 2 trial including patients treated with ICI who developed IMC. Patients were randomized 1:1 ratio to receive vedolizumab (300 mg) or standard treatment with corticosteroids, with infliximab used as recue therapy for corticosteroid failure. The primary outcome was cumulative corticosteroid dose at week 30. Key secondary outcomes included cumulative corticosteroid dose at week 10, corticosteroid free remission at week 10 and ICI resumption rates.

Results

Twenty-two patients received vedolizumab, and 19 patients received standard treatment. At week 10, the mean cumulative corticosteroid use was significantly lower in the vedolizumab arm (1157 mg vs. 2207 mg). By week 30, the mean corticosteroid use remained lower but not statistically significant (1378 mg vs. 2390 mg, estimated difference 1012 mg, 95% CI -229 to 2253, p=0.107), Among patients with less severe IMC, who did not need corticosteroids during screening, vedolizumab-treated patients used in average 1729 mg less corticosteroid (95% CI 631 to 2827). Corticosteroid-free remission at weeks 2 and 10 was more common with vedolizumab. Seven patients (33.3%) in the vedolizumab group resumed with ICI compared to three (16.7%) in the standard arm. In patients with severe colitis, who required upfront corticosteroid treatment, a trend towards longer hospitalization in the vedolizumab arm was observed.

Conclusion

For patients with less severe colitis, not needing corticosteroids during screening, vedolizumab may be a viable corticosteroid-sparing option, enabling faster remission and ICI resumption.

Disclosure

The study was funded by Aage og Johanne Louis-Hansens Fond, National Research grants. Takeda Pharma provided the study drug vedolizumab.

Introduction

Side effects, patient preference, and high costs may prompt cessation of anti-TNF therapy in ulcerative colitis (UC) patients in sustained remission. Given the risk of relapse, careful patient selection is essential. This study aimed to assess relapse rates and identify predictors of relapse following anti-TNF cessation in UC patients in remission.

Aims & Methods

A systematic search on cohort studies reporting relapse rates after cessation of anti-TNF therapy in ≥30 UC patients in clinical remission was performed 6 September 2024. Individual patient data was requested. We excluded patients with steroid use, ≤6 months anti-TNF therapy, ≤16 years, previous colectomy (n=4), golimumab as anti-TNF therapy (n=3) or without follow-up. Continuation of treatment with immunomodulators or mesalamine at cessation of anti-TNF was allowed. Relapse was defined as the need to (re)start treatment with steroids, anti-TNF or other advanced therapies, or the need for surgical treatment, as applied by the original author. Pooled relapse rates were computed using a random-effects model. A prediction model was built with a Cox proportional hazards model, performance assessed by iteratively leaving one study out (internal-external cross-validation, IECV). Missing covariate data were multiply imputed 100 times using the MICE algorithm. Variable selection was guided by three criteria: ≤20% missing data, a univariate p-value ≤ 0.2, and input from clinical experts.

Results

In total, 654 patients from 8 studies were included in the individual participant data meta-analysis. At anti-TNF cessation, median age was 40 years (IQR 31-51) with a median anti-TNF treatment of 18 months (IQR 18-36). The majority of patients were treated with infliximab (n = 610, 93%). Only 42 patients (9%) received a second-line anti-TNF therapy. The pooled relapse rate were 24% [95% CI 19-29%, I² = 44%] and 34% [95% CI 29-40%, I² = 39] at 1 and 2 years after cessation, respectively. Upon cessation, 211 patients (33%) continued mesalamine, 239 (39%) thiopurines, and 136 (22%) a combination of both. In our model, thiopurine therapy and older age at cessation were associated with a reduced risk of relapse, whereas immunomodulator refractoriness as an indication for starting anti-TNF therapy was associated with an increased risk. Other factors included in the prediction model were disease extent, type of anti-TNF therapy, history of anti-TNF therapy, fecal calprotectin level and endoscopic activity, leading to a c statistic of 0.55 [95% CI 0.51-0.59] (Table 1).

Table 1: Predictors of relapse in a pooled Cox regression analysis

Variable	Hazard Rate	95% Confidence interval
Age at discontinuation, per 10 years	0.80	0.72 – 0.88
Ulcerative colitis disease extent, Proctitis vs. extensive Left-sided vs. extensive	1.4 1.1	0.92 – 2.1 0.87 – 1.5
Type of anti-TNF therapy, adalimumab vs. infliximab	0.91	0.55 – 1.5
≥1 previous anti-TNF, yes vs. no	1.5	0.95 – 2.3
Indication anti-TNF therapy Immunomodulator refractoriness, yes vs no/unknown	1.5	1.1 – 2.2
Concomitant treatment after anti-TNF therapy, None vs thiopurine Mesalamine vs. thiopurine Combination of mesalamine and thiopurines vs thiopurine	1.8 1.2 1.2	1.1 – 3.0 0.86 – 1.6 0.81 – 1.7
Fecal Calprotectin (µg/g), per 100	1.1	0.95 – 1.3
Endoscopic activity, yes (mild, moderate or severe) vs. no	1.3	0.91 – 2.0

Conclusion

Approximately 1 in 4 patients experience a relapse of UC within 1 year after anti-TNF cessation, increasing to 1 in 3 within 2 years. Continuation of thiopurines is associated with a reduced risk. A prediction model for relapse was developed in this large IPD meta-analysis cohort and may aid in shared decision-making on anti-TNF cessation. However, its limited discriminative ability underscores the need for further refinement, incorporating data on microscopic remission and molecular and immunological markers to better capture deeper disease control.

Introduction

Very early onset inflammatory bowel disease (VEO-IBD) is often associated with a severe disease course and unique characteristics including an underlying monogenic defect. In this study, we identified new pathogenic mutations in CGNL1 associated with VEO-IBD and other inflammatory GI disease. CGNL1 (Cingulin Like 1) encodes an epithelial junctional protein whose function was previously unknown in the gastrointestinal tract.

Aims & Methods

Whole exome sequencing (WES) was performed on the affected patient with VEO-IBD and all first-degree relatives with IBD and other inflammatory disease. Intestinal epithelial organoids (IEOs) were generated from the affected patient and were characterized by transepithelial electrical resistance (TEER), FITC-dextran permeability assay on epithelial cell monolayer, immunostaining, RNA sequencing, and transmission electron microscopy (TEM). In addition, we generated a new Cgnl1^-/- mouse model, which was characterized using FITC-dextran permeability assay, TEM, dextran-sodium sulfate (DSS)-induced colitis, and infections by Citrobacter rodentium and Clostridioides difficile. Single-cell datasets were analyzed to determine CGNL1 expression in IBD, primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH).

Results

In the affected patient with VEO-IBD who required early total colectomy and pouch formation with coexistent PSC and celiac disease, WES identified two rare, new, pathogenic variants in the CGNL1 gene. Both pathogenic variants were also present in the patient’s younger sister, who has a similar history including early-onset, fulminant ulcerative colitis requiring total colectomy with ileostomy and PSC-AIH overlap syndrome. Furthermore, multiple relatives of the patient suffer from IBD and other inflammatory conditions including celiac disease, eosinophilic esophagitis, and type-1 diabetes. The RNA and protein levels of CGNL1 were significantly diminished in the patient’s intestinal epithelial cells compared to that of healthy individuals and other IBD patients by RNA-seq, immunoblotting, and immunostaining. The patient’s IEOs from pouch body and pre-pouch ileum formed smaller 3D spheroids with altered cell composition and significantly impaired barrier function compared to those from healthy controls and other IBD patients. Immunofluorescence and TEM demonstrated that CGNL1 is required for the assembly of junctional complexes in human IEOs and an epithelial cell line. Similarly to findings from the patient, impaired junctional complexes in intestinal epithelial cells and elevated intestinal permeability were present in Cgnl1^-/- mice at steady state. Cgnl1^-/- mice showed substantial vulnerability to DSS-induced colitis and bacterial infections that directly compromise the epithelial barrier. In addition, 6-month-old Cgnl1^-/- mice exhibited spontaneous inflammation in the colon and terminal ileum due to disrupted intestinal barrier, which was microbiome-dependent. Furthermore, single-cell analysis revealed diminished expression of CGNL1 in the intestinal and hepatic epithelial cells from patients with IBD or PSC/AIH, respectively.

Conclusion

The pathogenic CGNL1 variants contribute to VEO-IBD by disrupting gut barrier integrity, as demonstrated by patient’s cells and novel murine models. This study expands our understanding of epithelial barrier impairment in the pathogenesis of VEO-IBD, and highlights intestinal epithelium as a therapeutic target in some IBD patients.