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

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

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