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

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

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

The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) published an update of its guideline in 2021, in which vancomycin or fidaxomicin replaced metronidazole as the preferred first-line treatment option for non-severe Clostridioides difficile infection (CDI). This decision was controversially discussed since outcome data in this particular patient group remains limited. The IBIS study aimed to close this evidence gap.

Aims & Methods

The IBIS multicentre cohort enrolled patients with an index episode of CDI between August 2017 and September 2020. The primary endpoint was event-free survival (EFS), defined as response to treatment with metronidazole or vancomycin within ten days of initiation, absence of recurrence and death from any cause up to 90 days post-treatment. A Cox proportional hazards model with inverse probability of treatment weighting was used to investigate the comparative effectiveness of this outcome. Additionally, subgroup analyses were performed based on severe and non-severe infections.

Results

​Of the 489 patients included, 118 (24%) received initial treatment with metronidazole and 371 (76%) with vancomycin. Of these, 78/118 (66.1%) and 247/371 (66.6%), respectively, responded to treatment within ten days, neither developed a recurrence nor died within 90 days and thus achieved the outcome of EFS. In the subgroup of non-severe infections, 74/293 patients (25.3%) received metronidazole, and 219/293 (74.7%) received vancomycin. Of these, 33/74 (44.6%) metronidazole patients and 150/219 (68.5%) vancomycin patients survived event-free. The Cox proportional hazards model revealed differences in EFS for the overall population and both sub-groups (reference metronidazole: all severity levels: hazard ratio [HR] 0.46, [95% Cl 0.33-0.65]; non-severe: HR 0.39; [95% Cl 0.24-0.60]; severe: HR 0.52; [95% Cl 0.28-0.95]).

Conclusion

Our analysis confirms current changes in guidelines, as it supports the superiority of vancomycin compared to metronidazole across all severity levels.

References

1. Khanna S, Pardi DS. The growing incidence and severity of Clostridium difficile infection in inpatient and outpatient settings. Expert Review of Gastroenterology & Hepatology. 2010;4(4):409-16.
2. van Prehn J, Reigadas E, Vogelzang EH, Bouza E, Hristea A, Guery B, et al. European Society of Clinical Microbiology and Infectious Diseases: 2021 update on the treatment guidance document for Clostridioides difficile infection in adults. Clinical Microbiology and Infection. 2021;27:1-21.
3. McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):e1-e48.
4. Manthey CF, Epple H-J, Keller K-M, Lübbert C, Posovszky C, Ramharter M, et al. S2k-Leitlinie Gastrointestinale Infektionen der Deutschen Gesellschaft für
5. Zar FA, Bakkanagari SR, Moorthi KMLST, Davis MB. A Comparison of Vancomycin and Metronidazole for the Treatment of Clostridium difficile–Associated Diarrhea, Stratified by Disease Severity. Clinical Infectious Diseases. 2007;45(3):302-7.
6. Debast SB, Bauer MP, Kuijper EJ. European Society of Clinical Microbiology and Infectious Diseases: Update of the Treatment Guidance Document for Clostridium difficile Infection. Clinical Microbiology and Infection. 2014;20:1-26.

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.

Clinical Case Summary

Clostridium perfringens is a gram-positive spore-forming anaerobic bacillus belonging to the family of Clostridiaceae, which can be found everywhere in nature and is also a component of the human intestinal and genital tract. Its virulence depends on the production of different toxins.
In our clinical case, a 71-year-old Caucasian male was transferred from the emergency department of a hospital in Bavaria to our intensive care unit due to acute liver failure. On arrival at our hospital, we measured elevated heart frequency and elevated breathing-rate with the need for oxygen supplementation via a mask, the general state of the patient was reduced, and the GCS was 5. The laboratory showed elevated kidney markers, elevated liver enzymes (AST 209 U/l, ALT 135 U/l, Bilirubin 22.1 mg/dl), restricted coagulation (INR 1.29, Quick 65 %), elevated infection-markers (CRP 386 mg/l, PCT 19.40 ng/ml, Leukocytes 21.05 /nl) and a highly increased LDH (915 U/l). Most important, a CT scan revealed pneumobilia.
Due to the results of the pneumobilia without a history of a recently performed GI endoscopy, an infection with Clostridium perfringens was suspected, and antibiotic treatment with Meropenem, Metronidazole, Penicillin, and Clindamycin was initiated. The patient recovered within a few days and was transferred to the regular ward after five days. Blood cultures confirmed infection with Clostridium perfringens later on. After recovery, the patient reported that he had worked in his garden one week before admission to the ICU and had suffered a minor injury to his hand while gardening. The patient fully recovered after another ten days and was discharged in excellent condition.
Our case shows that pneumobilia without a history of a recently performed GI endoscopy can be an important hint for infection with Clostridium perfringens in patients presenting with acute liver failure. Rapid diagnosis and treatment are live saving in patients with Clostridium perfringens infections.