CALY-002, AN ANTI-IL-15 ANTIBODY, RESULTS IN HISTOLOGICAL AND CLINICAL IMPROVEMENT IN PATIENTS WITH EOSINOPHILIC ESOPHAGITIS IN A PHASE 1A/B STUDY

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 eosinophilic esophagitis (EoE). Preclinical translational studies in animal models and humans have suggested therapeutic potential of blocking IL-15 for EoE. CALY-002 is an investigational monoclonal antibody that neutralizes with equally high potency free and IL-15Rα-complexed IL-15.
Methodology
A Phase 1a/b study (NCT04593251) evaluated CALY-002 administered intravenously (IV) in single ascending doses (SAD) in healthy volunteers, multiple ascending doses (MAD) in patients with Celiac Disease, and multiple dose cohorts (MDC) in patients with symptomatic EoE (≥5 Straumann Dysphagia Instrument (SDI) score at baseline) who had prior inadequate response or intolerance to corticosteroids. Two dose cohorts (210mg; 700mg) were planned of 4 EoE patients each, to be dosed with active CALY-002 (open-label) for 12 weeks, i.e., 6 IV doses, each 2 weeks apart. Objectives of the study were evaluation of safety, pharmacokinetics (PK), immunogenicity, pharmacodynamics, and exploratory efficacy of multiple doses of IV CALY-002. Esophageal mucosal inflammation was assessed in 6 biopsies obtained from 3 esophageal regions (proximal, mid, distal) during screening and at end of treatment using the EoE Histologic Scoring System (HSS). The SDI was used to assess symptoms.
Results
Interim evaluation of the available safety results shows good tolerability with no safety signals. Serum concentration of CALY-002 reveals a half-life of around 3 weeks and accumulation ratio of around 2.5 reaching steady state at the 6^th dose. Anti-drug antibody testing has not detected anti-CALY-002 antibodies. Histologically evaluable patients include those who had ≥15 peak eosinophil count (PEC) at screening: 3 in the 210mg dose cohort and 2 in the 700mg cohort.
A histologically improvement of mean -53% change from baseline (CFB) in EoEHSS grade total score is observed in these 5 patients, 2 of whom reach deep histological remission and 1 a marked response (Figure 1A). Figure 1B shows the percentage of individual biopsies with ≤6 or 0 eosinophils/hpf pre-treatment versus end of treatment, demonstrating a direct impact of CALY-002 on esophageal eosinophilia. A mean CFB in SDI score of -3 points is observed at week 12 (Figure 2). End of study data from four patients of the 700mg cohort are still pending.
Conclusion
Preliminary data reveal that CALY-002 can reverse esophageal inflammation – eosinophilia and morphological tissue damage, as well as ameliorate symptoms in EoE patients who previously failed on corticosteroids, while showing a good safety profile. This first demonstration of preliminary efficacy in patients with EoE by blocking IL-15 warrants further studies.