Introduction

Tumor necrosis factor-like ligand 1A (TL1A) has been implicated in numerous immune-mediated and fibrotic diseases, such as inflammatory bowel disease (IBD) and asthma, making it an ideal target for therapeutic intervention. TEV-48574 is a human IgG1 monoclonal antibody with a novel mechanism of action that preferentially inhibits binding of TL1A to the Death Receptor 3 (DR3), involved in proinflammatory signaling, with a greater potency compared to the Decoy Receptor (DcR3), which could preserve the natural homeostatic mechanism. TEV-48574 has been shown to reduce fibrosis, inflammation, and mortality in animal models of IBD and asthma.¹ A phase 1 first-in-human (FIH) study, comprised of a single ascending dose (SAD) and a multiple ascending dose (MAD) phase, assessed safety, tolerability, immunogenicity, pharmacodynamic and pharmacokinetics of TEV-48574 amongst healthy participants and those with asthma. It has also been assessed in a phase 2A uncontrolled T2 low/non T2 asthma proof-of-concept (POC) study, where results from an interim analysis met predefined futility criteria leading to early termination. TEV-48574 is in clinical development as a potential treatment for ulcerative colitis and Crohn’s disease. This analysis aims to evaluate target engagement; free TL1A levels were measured in phase 1 and phase 2A TEV-48574 studies.

Aims & Methods

Free TL1A levels were measured using a ligand binding assay in the FIH and POC studies. In the FIH SAD phase, healthy participants were administered TEV-48574 as a single dose (1-1000 mg) or placebo by subcutaneous (SC) route. In the FIH MAD phase, mild asthmatic patients were randomized to active (up to 2300 mg) or placebo SC treatment. The phase 2A POC study was a 16-week randomized, double-blind, parallel-group trial to evaluate the efficacy, tolerability, and safety of a single dose regimen of TEV-48574 compared to placebo.

Results

In the FIH study, following SAD and MAD administration, while unchanged in the placebo group, free TL1A levels showed a rapid reduction at the first analyzed time point (1 hour after dose) in the active treatment groups. The free TL1A levels in the MAD phase of the FIH study remained suppressed up to day 92 (63 days after last dose, pooled result for doses), despite extremely low remaining TEV-48574 concentrations. In the POC study, TEV-48574 resulted in reduction of free TL1A levels, sustained up to ~10 weeks after the last dose. An analysis of patients who received all doses showed a persistent pharmacodynamic effect, demonstrated by continued suppression of free TL1A despite decreasing concentrations of TEV-48574 after the last dose on day 98.

Conclusion

Target engagement was shown by a rapid and sustained TEV-48574-mediated suppression of free TL1A that persisted longer than the drug exposure. Given that TL1A has been implicated in the pathogenesis of immune-mediated and fibrotic diseases, such as IBD¹, the data herein support further development of TEV-48574 in patients with ulcerative colitis and Crohn’s disease.

References

1. Clarke AW, et al. mAbs. 2018;10:4664-77.

Disclosure

All other authors are employees of Teva Pharmaceuticals. TEV-48574 is being developed in a partnership between Teva and Sanofi.

Introduction

The biomarker fecal calprotectin (FC) is an efficacious tool for evaluating the level of disease activity in Crohn's and Ulcerative colitis, as well as for discriminating between inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Fecal Alpha-1 Antitrypsin (A1AT) is an excellent marker for intestinal protein loss and for an increased mucosal permeability.

Aims & Methods

The aim of this investigation was to determine the relationship between these two inflammatory fecal markers.
The study was performed retrospectively. We've collected test results for both markers between 2018 and 2022 from 459 patients who performed both tests (67.4% females; mean age 35.1±22.7). Linear correlation evaluation between FC and A1At was performed using the Pearson Correlation Coefficient (PCC).

Results

Out of the 459 patients, 274 were diagnosed with IBD, 61 with IBS and the rest with other, non-GI disorders. Out of these, 37.7% were positive for both markers, 45.3% were negative for both markers, 7.6% were positive for A1AT and not FC and 9.4% were positive for FC and not A1AT. Linear correlation between the two markers using six categories for data scoring, was found to be significant by PCC test (R=0.83, P values < 0.001) and sensitivity and sensitivity, specificity and accuracy were 80.1%, 85.6% and 83.0% respectively. Out of the 274 patients in the IBD group, 39.2% were positive for both markers, 45.8% were negative for both markers, 5.4% were positive for A1AT and not FC and 7.6% were positive for FC and not A1AT. Linear correlation between the two markers was found to be significant by PCC test (R=0.87, P values < 0.0001) and sensitivity, specificity and accuracy were 83.7%, 89.8% and 86.9% respectively.

Conclusion

Our study demonstrates that FC had a significant relationship with A1AT in patients with IBD and IBS. Furthermore, A1AT might be used as a surrogate marker for FC in the diagnosis of IBD, IBS-IBD discrimination and disease severity and treatment follow up. In addition to that, both markers used together may be used as a new clinical score for the assessment of IBD and IBS severity.

Introduction

Patients with decompensated cirrhosis have high mortality rates. Several prognostic scores have been developed, based on clinical and laboratory parameters, to assess the prognosis of patients with cirrhosis. However, to date, there is no consensus on the best prognostic model. The MELD 3.0 score was recently published with the aim of refining the MELD score to contemporary data.

Aims & Methods

The objective of this study was to evaluate and compare models based on the hepatic severity index to investigate their predictive performance in mortality.
A retrospective cohort study was conducted, including consecutively admitted patients to a Gastroenterology Department for first admission due to decompensated cirrhosis. MELD, MELD-Na, MELD 3.0, and Child-Pugh scores were calculated upon admission. Mortality at 6 weeks and 180 days was the main outcome studied.

Results

109 patients admitted for the first episode of decompensated cirrhosis were included, 82.6% with alcoholic aetiology. Mean age was 61.8 ±10.8 years, 73.4% were men and 26.6% were women. Of the included patients, 11% died within the first 6 weeks and 25.7% died within the first 180 days after admission.
All models showed good accuracy in predicting mortality at 6 weeks and 180 days, with slight superiority of the MELD 3.0 score (AUC 0.693, 95% CI 0.598-0.778 at 6 weeks; AUC 0.712, 95% CI 0.617-0.795 at 180 days), although statistically significant differences between the different prognostic models were not observed.

Conclusion

The use of models based on hepatic severity indices accurately predicts the risk of mortality at 6 weeks and 180 days in patients with decompensated cirrhosis. The new MELD 3.0 score showed superior predictive performance in mortality, although without statistically significant differences.

Introduction

The interleukin 36 (IL-36) family includes the agonists IL-36α, IL-36β, IL-36γ, which activate the NF-κB pathway and the natural antagonist IL-36RA, which inhibits IL-36 signaling. While missense mutations in the gene encoding IL-36RA (IL36RN) are associated with severe skin inflammation, their role in Crohn’s disease (CD) is currently unknown. Therefore, we here investigated if IL36RN mutations contribute to inflammation in CD and whether IL-36 signaling might represent a potential drug target for personalized therapy.

Aims & Methods

Mutations in IL36RN were identified by whole exome sequencing (WES) followed by targeted Sanger sequencing. Peripheral blood mononuclear cells (PBMCs) of affected patients were analyzed by mass cytometry and serum cytokines were measured by ELISA. Identified IL36RN mutations were characterized by overexpression experiments and functional assays. Clinical and molecular responses of one IL-36RN mutant patient to combined treatment with spesolimab and certolizumab pegol was assessed by fecal calprotectin, endoscopy and mass cytometry at week 0 and 12 of treatment.

Results

In a cohort of 86 ulcerative colitis patients, 244 CD patients and 45 healthy controls, we identified 4 CD patients with heterozygous missense mutations in IL36RN (IL-36RA S113L, IL-36RA P76L and IL-36RA L133I). In the patient carrying the IL-36RA S113L variant, we detected elevated serum levels of IL-18 and IL-23, as well as an increased frequency of TH17 cells in PBMCs, suggesting an overactivation of the IL-36 pathway. Overexpression experiments showed that IL-36RA S113L causes decreased expression of IL-36RA, resulting in increased IL-36 signaling. The patient was therefore treated with 1200 mg of the IL-36R blocking antibody spesolimab every 4 weeks and 200 mg of certolizumab pegol biweekly on the basis of an Out Of Scope request. This approach resulted in reduced intestinal inflammation and a reduction in the frequency of pro-inflammatory myeloid cells in PBMCs.

Conclusion

In this study, we show that pathogenic IL36RN mutations are present in a subset of CD patients and that blocking IL-36 signaling may represent a personalized therapeutic approach for this rare subset of patients in whom conventional biologic therapies have failed.
Disclaimer: Boehringer Ingelheim was given the opportunity to review the abstract for medical and scientific accuracy as well as intellectual property considerations in relation to the potential mention of BI substances.
Boehringer Ingelheim had no role in the design, analysis or interpretation of the results in this study.
Spesolimab was made available on the basis of an out of scope request. Boehringer Ingelheim was given the opportunity to review this abstract as a courtesy.

Disclosure

Britta Siegmund has served as consultant for Abbvie, Abivax, Arena, BMS, Boehringer, CED Service GmbH, Celgene, CT Scout, Endpoint Health, Falk, Forga Software, Galapagos, Janssen, Lilly, Materia Prima, Pfizer, Takeda, Pharma Insight, Predictimmune, PsiCro; Speaker fees: AbbVie, BMS, CED Service GmbH, Chiesi, Falk, Ferring, Gilead, Janssen, Lilly, Materia Prima, Takeda, Pfizer and grant support by Arena/Pfizer (served as representative of the Charité).