Society: AGA

Introduction Interleukin-15 (IL-15) is an important cytokine involved in tissue homeostasis and inflammation, and a potent regulator of innate and adaptive immune responses. IL-15 expression has been shown to be dysregulated in several gastro-intestinal inflammatory diseases, including celiac disease (CeD) and eosinophilic esophagitis (EoE). Preclinical studies in animal models with genetic loss or gain of function of IL-15, or using antibodies neutralizing IL-15, have suggested therapeutic potential of blocking IL-15 for CeD and EoE. CALY-002 is an IgG1k monoclonal antibody that neutralizes with equally high potency free and IL-15Ra-complexed IL-15.
Methodology A first-in-human study evaluating intravenously administered (IV) CALY-002 in single ascending doses (SAD) in healthy volunteers and multiple ascending doses (MAD) in subjects with CeD and EOE (NCT04593251) is ongoing. The SAD part of the study has been completed investigating the dose range of 0.01 - 10 mg/kg CALY-002 as 60 minutes infusion. Safety and pharmacokinetics were the primary endpoints. The pharmacodynamic effects of CALY-002 were assessed by analyzing peripheral blood leukocyte subsets using flow cytometry.
Results Adverse events were balanced in incidence and severity between CALY-002 and placebo-dosed subjects. No serious adverse events or adverse events above grade 2 occurred; marked safety observations in blood laboratory results, vital signs, ECGs, or physical examination were absent. Plasma CALY-002 concentration increased dose-proportionally with an average half-life of 22 days (Figure 1). CALY-002 induced, starting from Day 28, a 25-30% decrease in circulating NK cells starting from the anticipated pharmacologically active dose of 0.3 mg/kg confirming non-clinical modeling estimates (Figure 2). There was no observed effect on other lymphocyte subsets including T, B and Treg cells, or monocytes.
Conclusion In single doses up to 10 mg/kg, CALY-002 was well tolerated and demonstrated PK characteristics typical for an IgG monoclonal antibody. In contrast to an earlier report on effects of IL-15 blockade on peripheral blood NK cell numbers in humans, CALY-002 treatment did result in decreased NK cells numbers. The observed pharmacological activity at and above 0.3 mg/kg is consistent with the neutralization of the known homeostatic and anti-apoptotic effects of IL-15 on NK cells as also reported for JAK inhibitors. Multiple dosing for 8 weeks in gluten-challenged subjects with CeD and for 12 weeks in subjects with EoE is ongoing.

<b><u>Mean CALY-002 Plasma Concentration-Time Plots by Dose Cohort</u></b><br /> Figure shows plasma concentration levels of CALY-002 (mean standard deviation, semi-logarithmic scale - Y axis) across time (day - X axis) after single IV administration of CALY-002. Each symbol represents a different dose group, as indicated.

Mean CALY-002 Plasma Concentration-Time Plots by Dose Cohort
Figure shows plasma concentration levels of CALY-002 (mean standard deviation, semi-logarithmic scale - Y axis) across time (day - X axis) after single IV administration of CALY-002. Each symbol represents a different dose group, as indicated.

<b><u>Percent Change from Baseline of Blood NK Cell Counts upon a Single IV Dose of CALY-002</u></b><br /> Figure shows heatmap representation of the mean percent change from baseline (color code on the right side of the figure) of blood NK cells determined as CD3-CD16+CD56+ cells by flow cytometry, after single IV injection of CALY-002. The X axis represents placebo or each CALY-002 dose group. The Y axis represents study days and end of study (EOS) samples.

Percent Change from Baseline of Blood NK Cell Counts upon a Single IV Dose of CALY-002
Figure shows heatmap representation of the mean percent change from baseline (color code on the right side of the figure) of blood NK cells determined as CD3-CD16+CD56+ cells by flow cytometry, after single IV injection of CALY-002. The X axis represents placebo or each CALY-002 dose group. The Y axis represents study days and end of study (EOS) samples.

Background: Celiac disease (CeD) is a common disorder. The global prevalence of CeD is about 1% (0.5-2.5%), with some variations across different countries. However, the total population-based prevalence in most countries is not known. Studies in Western populations point to a high ratio of undiagnosed to diagnosed CeD cases (4:1 to 7:1) - a phenomenon known as “the coeliac iceberg”. The aim of this study was to settle the total prevalence of CeD, including the undiagnosed cases, in an adult general population.

Methods: The study was based on the fourth Trøndelag health study (HUNT4), which took place from August 2017 to February 2019, including 56,042 adult (>20 years of age) inhabitants in Trøndelag country, Norway (54% response rate). Serum samples from 54,566 participants in HUNT4 were analyzed with a newly developed serological assay for simultaneously measurements of IgA and IgG anti transglutaminase 2 (anti-TG2) at Oslo University Hospital from June 2019 to October 2021. To validate the serological results, all seropositive participants were invited to clinical examination with upper endoscopy and small bowel biopsies from the horizontal part and bulb at Levanger Hospital. The diagnosis of CD was confirmed by histopathological findings corresponding to Marsh grade 3. To identify the seronegative participants with a previous CeD diagnosis, the Norwegian Patient Register and the participants medical records were searched and the diagnose verified.

Results: A total of 1049 individuals were seropositive, corresponding to a rate of 1.9% (1049/54,566). By March 2022, 750 seropositive individuals have been invited to the clinical examination and 686 of these have attended endoscopy with biopsies. Among these attendees, a new previously unknown CeD diagnosis was confirmed in 350 individuals. In addition, 51 seropositive individuals had already a CeD diagnosis. From the register and medical record searches, 374 previously known and seronegative CeD cases were identified. In total, 775 individuals with CeD have been identified so far, corresponding to a total populations-based prevalence of CeD of 1.4% (774/56,042). The ratio of previously diagnosed to previously undiagnosed CeD cases was 1.2 (425/350).

Conclusion: The total population-based biopsy confirmed prevalence of CeD in an adult general population in Norway, including both previously unknown and known CeD cases, was higher than the average global figures. The amount of newly diagnosed cases was high and shows that CeD is still an underdiagnosed condition, but the ratio was not as high as reported elsewhere.

David Warren

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