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.

Yolande Chvatchko

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