University of North Carolina School of Medicine Chapel Hill, North Carolina
Introduction: In the KRYPTOS phase 2/3 randomized, double-blind, placebo controlled clinical trial of lirentelimab (LIR), an IgG1 Ab against siglec-8, in EoE patients (NCT04322708), a significant histologic response was observed but the co-primary symptom endpoint was not met. However, LIR may be more effective among those with greater active inflammation. This supplementary analysis explores the effect of LIR in a subpopulation of patients with EoE and baseline esophageal eos >24/hpf, a threshold previously suggested to differentiate EoE from a cofounding condition like GERD.
Methods: Patients were randomized 1:1:1 to high dose LIR (1 mg/kg x 1 dose then 3 mg/kg x 5 doses [HD]), low dose LIR (1 mg/kg, [LD]) or placebo (PBO) for 6 monthly infusions. Co-primary endpoints were the proportion of patients who achieved an esophageal intraepithelial eos count of ≤6 eos/hpf at week 24 and the mean absolute change in daily Dysphagia Symptom Questionnaire (DSQ) score from baseline to weeks 23-24.
Results: There were 48 patients with baseline peak esophageal eos ≤24/hpf (n=14 HD, n=18 LD, and n=16 PBO) and 228 patients with eos >24/hpf (n=77 HD, n=75 LD, n=76 PBO; Table) which was related to other markers of severity including higher median levels of serum IgE (≤24/hpf: 83kU/L HD, 64kU/L LD, 65 kU/L PBO vs. >24/hpf: 105 kU/L HD, 117 kU/L LD, 98 kU/L PBO) and median levels of peripheral blood eosinophils (≤24/hpf: 310 cells/µL HD, 175 cells/µL LD, 220 cells/µL vs >24/hpf: 300 cells/µL HD and LD, 380 cells/µL PBO). Significantly more patients with eos >24/hpf met the histologic co-primary endpoint vs placebo (91% [HD], 92% [LD], 8% [PBO]; P< 0.0001). Patients with baseline eos >24/hpf also demonstrated a significant mean change and percent change in DSQ co-primary endpoint (mean change DSQ: -17.6 HD, -12.7 LD, -12.5 PBO, P=0.0222, Fig A; Percent change DSQ: -56% HD, -38% LD, -29% PBO, P=0.0019, Fig B). Safety profile was no different among patients with eos >24/hpf compared to patients with eos ≤24/hpf.
Discussion: Supplementary analysis of the KRYPTOS phase 2/3 EoE trial revealed that patients with eos >24/hpf had a significant decrease in symptoms of dysphagia with lirentelimab compared to placebo showing a difference in response when separated from other cofounding conditions like GERD. The safety profile of lirentelimab was consistent with previous reports. Further study is warranted to identify patients with EoE who may be most likely to respond to treatment with lirentelimab.
