Introduction
Interleukin-15 (IL-15) is a 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 celiac disease (CeD). Preclinical translational studies in humans and animal models have suggested therapeutic potential for blocking IL-15 in CeD. CALY-002 is an investigational therapeutic monoclonal antibody that neutralizes with equally high potency free and IL-15Ra-complexed IL-15.
Methodology
A Phase 1a/b study (NCT04593251) evaluated double blind, placebo-controlled intravenous administration (IV) of CALY-002 in single ascending doses (SAD) in healthy volunteers and multiple ascending doses (MAD) in patients with well-controlled CeD challenged with 3g/day gluten during the 8-week treatment period, while maintaining their gluten-free diet (GFD). Each of the three MAD cohorts (70 mg, 210 mg, 700 mg) was planned for 6 patients receiving CALY-002 and 3 receiving placebo for 8 weeks, i.e. 4 IV doses, each 2 weeks apart.
Objectives of the study were evaluation of safety, pharmacokinetics (PK), immunogenicity, and exploratory efficacy. Safety of CALY-002 was assessed by recording adverse events (AE), hematology and biochemistry lab testing, ECG, and vital signs. Exploratory efficacy endpoints included villous height-crypt depth ratio (VH:CD) and intra-epithelial lymphocyte density per 100 villous enterocytes (IEL) assessed in endoscopic duodenal biopsies during screening and at the end of the 8-week treatment and concomitant gluten challenge. Inclusion was restricted to those patients who had initially a histologically largely unaffected mucosa under GFD as reflected in a VH:CD >1.5 and IEL <40.
Results
Evaluation of the safety results of the 34 randomized and dosed patients shows good tolerability and no safety signals. Histologically evaluable patients included those who had received all 4 doses, undergone both endoscopies and been compliant with the gluten challenge for the 8-week treatment period. The change from baseline (CFB) VH:CD results of the pooled placebo-treated patients and of the CALY-002-treated cohort patients is shown in Figure 1A, while Figure 1B shows CFB for IEL. Patients who had received placebo show the expected decrease from baseline in VH:CD (mean CFB -0.69) and increase in IEL (mean CFB +15) validating the study design and conduct. Patients who had received CALY-002 demonstrate a marked numerically reduced deterioration of VH:CD and IEL, especially at the 700mg dose (mean CFB VH:CD -0.28 and mean CFB IEL +2).
Conclusion
This Phase 1a/b trial is the first to demonstrate that blocking IL-15 using a potent antibody can attenuate mucosal injury induced by gluten challenge in well-controlled CeD patients. These encouraging results warrant further investigations of CALY-002 in CeD.

Peter Hasselblatt

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