Introduction

Tumor necrosis factor (TNF) inhibitor therapies (anti-TNFs) are routinely used for the management of Crohn’s disease (CD) in patients with moderate to severe disease activity. However, approximately 30% of patients discontinue anti-TNF treatment due to inefficacy or adverse events.

Aims & Methods

This study analyzed the long-term anti-TNFα drug survival in a cohort of patients with CD from central Greece aiming to find potential predictive factors that are associated with increased survival of anti-TNF agents. All adult patients with CD treated with anti-TNF agents including infliximab (IFX) ή adalimumab (ADA) from 2012 to 2022 in the sole tertiary referral center for inflammatory bowel disease in central Greece were screened for eligibility and their electronic medical records were reviewed retrospectively. Data collected included the socio-demographic and clinical characteristics of our population as well as specific information regarding anti-TNF treatment survival, concomitant treatment modalities, treatment compliance, adverse events, and the need for treatment optimization. Parametric and non-parametric statistical tests were used for the description of the study population. To evaluate the survival of anti-TNF agents, a Kaplan-Meier survival curve was performed whereas the influence of population characteristics on the survival of anti-TNF agents was assessed with linear regression. Patients with incomplete data were excluded from the analysis.

Results

193 patients were screened for eligibility and 123 were finally included. Over the study period, 68% and 71% of the population treated with IFX and ADA required treatment optimization. The majority of the population (>60%) received anti-TNF as a 1-st line treatment. At 1 year, the probability of retaining anti-TNFs was>75% with no significant differences being recorded between IFX and ADA whereas the percentage of patients who remained on the same treatment at 5 years gradually reduced to 23% and 35% respectively. Among the population characteristics, the increased disease duration at the onset of treatment was the sole factor that was positively associated with increased survival to both anti-TNFs ([standardized beta: .545, t: 3.690, p: < .001 95,0% Confidence Interval: 1.580-5.511 for ADA], [ standardized beta: .479, t:5.119, p: <.001 95,0% Confidence Interval: 1.738-3.952 for IFX]), whereas the development of antibodies ( standardized beta: .247, t: 2.639, p: < .01 95,0% Confidence Interval: 3.682-26.312) and the early need for treatment optimization (standardized beta: .203, t: 2.128, p: < .037 95,0% Confidence Interval: 1.373-41.358), defined as the need for treatment optimization within the first year, were the sole factors that were associated with reduced survival of IFX.

Conclusion

Treatment survival with anti-TNF agents decreases in CD patients over time. A trend for increased long-term survival was recorded for ADA over IFX. Among CD patients, the increased disease duration at treatment onset was found to be associated with increased treatment survival irrespective of the type of anti-TNF agents that was selected. Immunogenicity and the need for early treatment optimization were the sole factors that were associated with reduced treatment survival among CD patients receiving IFX.

References

Torres J, Bonovas S, Doherty G, Kucharzik T, Gisbert JP, Raine T, Adamina M, Armuzzi A, Bachmann O, Bager P, Biancone L, Bokemeyer B, Bossuyt P, Burisch J, Collins P, El-Hussuna A, Ellul P, Frei-Lanter C, Furfaro F, Gingert C, Gionchetti P, Gomollon F, González-Lorenzo M, Gordon H, Hlavaty T, Juillerat P, Katsanos K, Kopylov U, Krustins E, Lytras T, Maaser C, Magro F, Marshall JK, Myrelid P, Pellino G, Rosa I, Sabino J, Savarino E, Spinelli A, Stassen L, Uzzan M, Vavricka S, Verstockt B, Warusavitarne J, Zmora O, Fiorino G. ECCO Guidelines on Therapeutics in Crohn's Disease: Medical Treatment. J Crohns Colitis. 2020 Jan 1;14(1):4-22. doi: 10.1093/ecco-jcc/jjz180. PMID: 31711158.

Introduction

The cytokine IL-23 is secreted by activated macrophage and dendritic cells (DC) and promotes the expansion and/or activity of Th17 cells, CD8+ T cells, macrophages, and DCs. Its pathogenic role in IBD is suggested by genetic association and has been confirmed in clinical trials demonstrating IL-23 antagonism as an effective and safe treatment for Crohn’s disease (CD) and ulcerative colitis (UC). SPY003 is a novel, extended half-life humanized IgG1 monoclonal antibody (mAb) that binds IL-23 with high affinity and specificity and potently inhibits IL-23-mediated signaling.

Aims & Methods

SPY003 was evaluated in multiple in vitro and ex vivo assays compared to risankizumab (RIS) and guselkumab (GUS). Binding affinity to IL-23 was determined by surface plasmon resonance (SPR) and kinetic exclusion assays (KinExA). Antagonism of IL-23 signaling was measured via a STAT3 reporter cell line and phospho-STAT3 ELISA. SPY003-induced reduction of IL-17 secretion in response to human IL-23 was assessed in mouse splenocytes and human peripheral blood mononuclear cells (PBMC). The binding epitope of SPY003 to IL-23 was determined using cryogenic electron microscopy. Half-life extension was measured via pharmacokinetic analysis in cynomolgus monkeys given a single bolus of SPY003 by intravenous and/or subcutaneous (SC) administration.

Results

SPY003 binds specifically to IL-23 with picomolar affinity. It inhibits STAT3 activity and phosphorylation with IC₅₀ values < 1nM, as well as IL-17 secretion in IL-23-stimulated mouse splenocytes and human PBMC. IL-23 binding potency and IC₅₀ values for IL-23 antagonism are comparable to those of RIS and GUS. Cryo-EM demonstrates the binding epitope of SPY003 within IL-23. The half-life of SPY003 is significantly extended in cynomolgus monkeys compared to both RIS and GUS. Based on allometric scaling of the clearance of SPY003 observed in this study, predictive simulations of SPY003 PK in humans suggest that Q3M-Q6M+ SC dosing will achieve therapeutic exposures in patients across a wide range of body weights and albumin concentrations.

Conclusion

SPY003 exhibits high selectivity and affinity for IL-23 and potently inhibits downstream cellular signaling. With an extended half-life in NHP, SPY003 demonstrates therapeutic potential for effective and safe treatment of CD and UC with the potential advantage of twice a year SC dosing. Further preclinical and clinical studies are warranted to demonstrate this potential.

Disclosure

BK, MA, JM, SO, JO, and HS are employees of Paragon Therapeutics.
JF, DN, and AS are employees of Spyre Therapeutics.

Introduction

Antagonism of the interaction between the cellular adhesion integrin ɑ4β7 and endothelial ligand mucosal addressin cell-adhesion molecule-1 (MAdCAM-1) has proven to be relatively safe and effective in the treatment of Crohn’s disease (CD) and ulcerative colitis (UC). Additional benefit may be gained from an ɑ4β7 antagonist given via the subcutaneous (SC) route at extended intervals (eg, every 8 to 12 weeks) during maintenance therapy.

Aims & Methods

The humanized monoclonal IgG1 antibody SPY001 binds to the same ɑ4β7 epitope as vedolizumab and includes a YTE modification within the Fc region to increase its serum half-life via increased affinity for the neonatal Fc receptor (FcRn), thereby favoring recycling into the circulation over degradation. The binding affinity of SPY001 to ɑ4β7 was determined by kinetic exclusion assay (KinExA), surface plasmon resonance, and flow cytometry. In vitro functional activity was determined by inhibition of MAdCAM-1-mediated cell adhesion. In vivo half-life extension was evaluated via pharmacokinetic analysis in Tg276 transgenic mice (hemizygous for human FcRn) and in non-human primates (NHP). PK simulations in humans were based on allometric scaling of SPY001 clearance observed in NHP. Safety was assessed via a good laboratory practice toxicity (GLP-tox) study in NHP.

Results

SPY001 binds specifically to ɑ4β7 and not to the related integrins ɑ4β1 and ɑEβ7. In cell-based binding assays, SPY001 binds ɑ4β7 expressed on the surface of RPMI-8866 cells with an affinity matching that of vedolizumab, but does not bind to Ramos cells expressing ɑ4β1. It demonstrates high affinity for ɑ4β7, with a K_D of <1 nM. Functionally, SPY001 potently inhibits MAdCAM-1-mediated cell adhesion with an IC₅₀ comparable to that of vedolizumab but has no inhibitory activity for VCAM-1-mediated cell adhesion.

In Tg276 mice, the half-life of SPY001 was approximately 12 days compared to approximately 4 days for vedolizumab. In cynomolgus monkeys, the half-life of SPY001 was approximately 22 days following a single SC infusion, substantially longer than the half-life of vedolizumab (~6 days) in the same study. Based on allometric scaling of SPY001 clearance observed in this study, predictive simulations of SPY001 PK in humans suggest that Q8W-Q12W SC dosing will achieve therapeutic exposure in patients across a wide range of body weights and albumin concentrations. In a repeat-dose GLP toxicity study in NHP no adverse or dose limiting toxicities were observed even at the highest dose tested. Both SC and IV administration were well-tolerated and observations related to the administration procedure were similar across doses including controls.

Conclusion

SPY001 is a novel humanized monoclonal IgG1 with an extended half-life relative to that of vedolizumab in Tg276 mice and cynomolgus monkeys. Repeat-dose toxicity studies at doses up to 160 mg/kg showed no SPY001-related adverse events and a safety profile supportive of progression into clinical development. SPY001 offers the potential for effective and safe treatment of CD and UC with the advantage of infrequent SC dosing. Clinical studies are warranted to demonstrate this potential.

Disclosure

EZ, DR, RV, JO, and HS are employees of Paragon Therapeutics.
JF, DN, AS, MR, and OB are employees of Spyre Therapeutics.

Introduction

Tyrosine kinase 2 (TYK2) mediates cytokine signalling pathways involved in immune-mediated inflammatory diseases, including ulcerative colitis (UC). Zasocitinib (TAK-279) is a highly selective, oral, allosteric TYK2 inhibitor that has shown efficacy and acceptable safety in psoriasis and psoriatic arthritis.^1,2 This phase 2 study (NCT06254950) will assess efficacy and safety of zasocitinib in patients with moderately to severely active UC.

Aims & Methods

This is a multicentre, randomized, placebo-controlled, double-blind induction study in adults (18–75 years) with moderately to severely active UC (modified Mayo score of 5–9 points and endoscopic subscore ≥2) with a documented diagnosis (endoscopic with histology) ≥30 days before screening. Eligible patients must have inadequate/loss of response or intolerance to ≥1 of oral aminosalicylates, corticosteroids, immunosuppressants, biologics, JAK inhibitors (JAKi), α4 integrin antagonists or sphingosine-1-phosphate (S1P) receptor modulators. Patients who have failed <3 classes of advanced therapies will be included. Approximately 207 patients will be randomized 1:1:1 to receive low- or high-dose zasocitinib or placebo orally once daily for 12 weeks. Study doses were selected to provide ≥90% TYK2 inhibition over the 24-hour dosing interval, and were associated with efficacy in preclinical models.³ Randomization will be stratified based on previous biologic, JAKi, α4 integrin antagonist or S1P receptor modulator therapies, and steroid use at baseline. The study comprises a 30-day screening period, a 12-week double-blind induction treatment period, a 40-week open-label treatment period and a 4-week safety follow-up. After Week 12, all patients will be reassigned to receive active zasocitinib treatment in the open-label maintenance period. Enrolment of patients who have received previous biologic, JAKi, α4 integrin antagonist, S1P receptor modulator, anti-interleukin (IL)-23p19 or anti-IL-12/23p40 therapy will be capped.
Primary endpoint analysis will be conducted using a Cochran–Mantel–Haenszel (CMH) test. Binary secondary endpoints will also be analysed similarly to primary endpoints. A mixed-effects model with repeated measures will analyse longitudinal continuous secondary endpoints. Safety data will be presented by treatment group and assessment period.

Results

The study is actively enrolling. An open-label extension is planned for zasocitinib responders. The primary efficacy endpoint is clinical remission at Week 12, assessed as the proportion of patients achieving a modified Mayo score ≤2, with stool frequency and endoscopic subscores ≤1 and a rectal bleeding subscore of 0. Secondary efficacy endpoints at Week 12 include proportion of patients achieving clinical response (reduction from baseline in modified Mayo score ≥2 and ≥30%, and a decrease in rectal bleeding subscore ≥1 or absolute rectal bleeding subscore ≤1), symptomatic remission (rectal bleeding subscore 0 and stool frequency subscore ≤1), endoscopic improvement (modified Mayo endoscopic subscore ≤1), endoscopic remission (modified Mayo endoscopic subscore 0), patient-reported symptoms and disease-specific health-related quality of life (HRQoL). Safety and tolerability will be assessed by monitoring treatment-emergent adverse events (AEs), serious AEs and AEs of special interest throughout the study.

Conclusion

Alongside evaluating the efficacy and safety of zasocitinib in patients with moderately to severely active UC, this study will assess the impact of treatment on HRQoL, a significant unmet need in this population.

References

1. Armstrong A et al. AAD 2023.
2. Kivitz A et al. Arthritis Rheumatol 2023;75(Suppl 9).
3. Kong KF et al. J Crohns Colitis 2024;18(Suppl 18).

Disclosure

LP-B received fees from AbbVie, Abivax, Adacyte, Alimentiv, Alma Bio Therapeutics, Amgen, Applied Molecular Transport, Arena, Biogen, Bristol Myers Squibb, Celltrion, Connect Biopharma, Cytoki Pharma, Enthera, Ferring, Fresenius Kabi, Galapagos, Genentech, Gilead, GlaxoSmithKline, Gossamer Bio, HAC Pharma, IAG Image Analysis, Index Pharmaceuticals, Inotrem, Janssen, Lilly, Medac, Mopac, Morphic, MSD, Nordic Pharma, Norgine, Novartis, OM Pharma, ONO Pharma, OSE Immunotherapeutics, Pandion Therapeutics, Par’Immune, Pfizer, Prometheus, Protagonist, Roche, Roivant, Samsung, Sanofi, Sandoz, Takeda, Theravance, Thermo Fisher, Tigenix, Tillots, Vectivbio, Ventyx, Viatris, Vifor and Ysopia. SGR, LZ, VAN, OA, AND, FN, TF, LS and NS are employees and equity holders of Takeda.

Introduction

The etiology and pathogenesis of inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC) are complex and the mechanisms that lead to the development of these diseases remain unclear. Extracellular vesicles (EVs) are small particles covered with a cell membrane, originating from the emitting cell, excreted into the extracellular medium, and subsequently captured by receptor cells. EVs have a role in multiple diseases and they could also have a function in IBD pathogenesis. Therefore, the analysis of EVs isolated from the serum of newly diagnosed IBD patients (before starting any treatment) may represent an appropriate experimental approach to elucidate their role in IBD pathogenesis.

Aims & Methods

We aimed to evaluate EVs’ composition and potential effects in the pathogenesis of IBD. To assay this, EVs were isolated by size exclusion chromatography from the 500 µl of serum from 100 patients with IBD (50 patients with CD and 50 patients with UC) recently diagnosed and 50 healthy controls (HC). Then, the protein loaded in the EVs was characterized by proteomics and their size and concentration in serum by Nanoparticle tracking analysis (NTA). The biological function of EVs and alterations in signaling pathways related to IBD were determined using Ingenuity Pathways Analysis (IPA) to analyze the OMICs results.

Results

A total of 1,100 proteins have been identified, of which 105 proteins were differentially expressed by patients with CD versus HC, 111 proteins by patients with UC versus HC, and 32 proteins by patients with UC versus CD. IPA analysis revealed that proteins carried in EVs are involved in the dysregulation of immune pathways such as the acute phase response, LXR/RXR activation pathway, and the complement pathway. These pathways were regulated differentially in IBD patients compared with HC, but also when the CU group was compared with the CD group being upregulated nuclear receptors signaling and cytotoxicity pathways.

Conclusion

EVs carry proteins that can be involved in the dysregulation of the immune system in IBD; this effect would be different in UC and CD since their EVs show a differential profile. Consequently, EVs may play role in IBD pathogenesis and source of strong biomarkers candidates for diagnosis in UC and CD. Further studies on their specific function during IBD are warranted.

Introduction

Tumor necrosis factor (TNF)-like ligand 1A (TL1A) mediates a broad spectrum of pro-inflammatory and fibrotic effects and is implicated in the pathogenesis of several immunologic disorders. A pathogenic role for TL1A in IBD is suggested by genetic association. Blockade of the interaction of TL1A with its cognate receptor, DR3, has been shown to ameliorate disease activity in patients with Crohn’s disease (CD) and ulcerative colitis (UC). We have characterized SPY002-091 and SPY002-072, two novel TL1A-specfiic fully human IgG1 monoclonal antibodies (mAbs) with extended pharmacokinetic (PK) half-life. Both antibodies bind soluble and membrane-bound TL1A with high affinity and potently inhibit TL1A-mediated signaling.

Aims & Methods

SPY002-091 and SPY002-072 were evaluated in multiple in vitro and ex vivo assays and compared to other anti-TL1A mAbs in clinical development (MK-7240, RG6631, and TEV-48574). Binding affinity to soluble TL1A was determined by surface plasmon resonance and binding to membrane-bound TL1A was confirmed by flow cytometry (FACS). Competitive blockade of TL1A binding to cell-surface DR3 was determined by FACS, and competition against the decoy receptor, DcR3, was evaluated by ELISA. The binding epitopes of SPY002-091 and SPY002-072 were determined using cryogenic electron microscopy (cryo-EM). TF-1 cell apoptosis and a primary human whole blood-based assay measuring IFNɣ secretion were used to assess functional blockade of TL1A. Half-life extension was measured via pharmacokinetic analysis in cynomolgus monkeys given a single bolus of either SPY002 mAb by intravenous and/or subcutaneous (SC) administration.

Results

SPY002-091 and SPY002-072 each bind to distinct epitopes on TL1A with sub-nanomolar affinity but do not bind the related TNF super family proteins TNF, FasL, TRAIL, or LIGHT. Both antibodies bind soluble TL1A and TL1A expressed on the surface of human embryonic kidney (HEK) cells. Both antibodies potently inhibit TL1A-induced apoptosis in human TF-1 cells and TL1A-induced secretion of IFNɣ in human whole blood, with IC₅₀ values comparable to those of RG6631 and TEV-48574, and a substantially lower IC₅₀ than that of MK-7240.

In cynomolgus monkeys, both SPY002-091 and SPY002-072 exhibit a pharmacokinetic half-life of approximately 25 days compared to an observed half-life of 9-12 days for RG6331 and MK-7240. Structural studies employing cryo-EM show that each SPY002 mAb targets an epitope within a single TL1A subunit enabling binding to both monomeric and trimeric TL1A. Based on allometric scaling of SPY002-091 and SPY002-072 clearance in NHPs, predictive simulations of their human PK properties suggest that Q8W-Q12W SC dosing will achieve therapeutic exposures in patients across a wide range of body weights and albumin concentrations.

Conclusion

We have characterized two anti-TL1A antibodies that exhibit high selectivity and affinity for TL1A, demonstrate effective blockade of the TL1A interaction with DR3, and potently inhibit downstream cellular signaling. With an extended half-life observed in NHP, both SPY002-091 and SPY002-072 demonstrate therapeutic potential for effective and safe treatment of CD and UC with the advantage of infrequent SC dosing. Further preclinical and clinical studies are warranted to demonstrate this potential.

Disclosure

EZ, DR, JM, JM, BK, JO, and HS are employees of Paragon Therapeutics.
JF, DN, AS, and MR are employees of Spyre Therapeutics.

Introduction

Data on the long-term benefit of transmural healing (TH) are scarce in children.

Aims & Methods

We investigated the outcomes of pediatric Crohn's disease (CD) patients with TH comparing them to those with mucosal healing (MH) and with “no healing”.
We conducted a prospective, single-center, observational study conducted at the Pediatric Gastroenterology Unit of Sapienza University of Rome. Children with an established diagnosis of CD and under biological therapy undergoing an MRE and an ileocolonoscopy within a 3-month interval were consecutively enrolled. TH was defined as the complete healing of both the mucosa at endoscopy and of the bowel layers at the MRE. In the presence of a normal colonoscopy but an active MRE children were deemed as MH. The group “no healing” (NH) included children with an active endoscopy, regardless of the MRE classification. At 6, 12, and 24 months number disease flares, CD-related hospitalization, CD-related surgery, need for step-up treatment, and occurrence of complications were collected.

Results

93 children were included (mean age 11,2±3,8). Twenty-three (25%) were classified as TH, 27 (29%) as MH and 43 (46%) as NH. The risk of any unfavorable outcome was lower in both TH and MH patients compared to NH (Log Rank p<0.0001 and p=0.002). Children with TH were at lower risk of hospitalization (p=0.02), and complications (p=0.007) compared to those with NH. No difference was found between MH and NH children for the same outcomes. Both TH and MH children were at lower risk of step-up treatment (p<0.0001 and p=0.0002, respectively) compared to NH. TH and MH patients were comparable for all the outcomes evaluated.

Conclusion

Achieving TH in pediatric CD is associated with better outcomes, although the additional benefit over MH alone does not appear significant. However, the persistence of inflammation is associated with worse outcomes in all patients.