Results from KRYPTOS, a Phase 2/3 Study of Lirentelimab (AK002) in Adults and Adolescents With EoE

Introduction: Eosinophilic esophagitis (EoE) is a chronic disorder characterized by an inflammatory infiltrate of eosinophils (eos) and mast cells and associated esophageal dysfunction, structural tissue damage, and remodeling. Lirentelimab (LIR, AK002) is a humanized IgG1 mAb directed against Siglec-8, which is expressed selectively on the surface of mature eos and mast cells. The aim of this randomized, double-blind, placebo-controlled phase 2/3 clinical trial was to evaluate the safety and efficacy of LIR in adults and adolescents with active EoE (KRYPTOS, NCT04322708). Methods: Patients ≥12 years old with symptoms of dysphagia and ≥15 eos/hpf on esophageal biopsy 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 histologic response (defined as the proportion of patients who achieved a peak eos count of ≤6 eos/hpf) at week 24 (W24) and mean absolute change in the daily Dysphagia Symptom Questionnaire (DSQ) score from baseline to weeks 23-24. EGD with esophageal biopsies was performed at screening and at W24. Results: Of the 276 patients who completed the study, 51 were adolescents (12-17 ys) who had a higher proportion of atopic diseases, peripheral blood eos, serum IgE levels, and prior EoE treatment (Table). In the overall cohort, the histologic co-primary endpoint was met by 88% HD and 92% LD vs. 11% PBO (P < 0.0001; Figure A1). For adolescents, 94% HD and 94% LD met this compared to 6% PBO (Figure A2). The change in DSQ co-primary endpoint for the overall cohort showed a reduction from baseline of -17.4 HD and -11.9 LD vs. -14.6 for PBO (P=0.2372; Figure B1), whereas the change in adolescents was -18.4 HD and -16.4 LD vs. -8.9 PBO (P=0.1316; Figure B2). The most common adverse events (AEs) were infusion related reactions (38.5% HD, 25.8% LD, 12% PBO) and headache (6.6% HD, 8.6% LD, 6.5% PBO); there were 3 serious AEs (2 HD, 1 PBO). Conclusion: This phase 2/3 trial of lirentelimab met the histologic co-primary endpoint but did not meet the DSQ symptom co-primary endpoint, although in adolescents there was a trend in DSQ response over PBO. Lirentelimab was generally well-tolerated. This study included a broad range of patients with EoE, and identification of factors associated with symptoms and histologic response will improve our understanding of disease activity and help identify patients who may respond to biologic therapy.Figure 1.: Co-Primary Endpoints: Topline and Adolescent Subpopulation A. Histology co-primary endpoint is proportion of histologic responders defined as esophageal intraepithelial eosinophil count of ≤6 eosinophils/hpf at week 24; A1. Overall population, A2. Adolescent subpopulation. missing data were treated as non-responders. With observed data, the histology response rate is 100% (80/80), 99% (86/87), and 11% (10/88) for the overall population, and 100% (16/16), 100% (16/16), and 6% (1/6) for the adolescent subpopulation. B. Change in DSQ co-primary endpoint at weeks 23-24; B1. Overall population; B2. Adolescent subpopulation. LS Means and HD lirentelimab from placebo p-values derived from ANCOVA model Table 1. - Baseline Characteristics a. Asthma, allergic rhinitis, atopic dermatitis and/or food allergy b. Adolescent prior treatment data were collected from chart reviews Patient Characteristic OverallN=276 Adults n=225 Adolescents n=51 Age, years, mean±SD 33±15 38±13 15±2 Female sex, n (%) 103 (37) 92 (41) 11 (22) Duration of EoE, years, mean±SD 6.2±6.5 6.3±6.9 6.0±4.2 History of atopya, n (%) 208 (75) 163 (72) 45 (88) History of esophageal dilatations, n (%) 17 (6) 17 (8) 0 (0) Food elimination diet at screening, n (%) 30 (11) 18 (8) 12 (24) Prior Treatmentsb, n (%)PPI useSteroid use 191 (69)71 (26) 143 (64)45 (20) 48 (94)26 (51) Peak esophageal eosinophil counts/hpf, mean±SD 60±34 58±34 68±32 Peripheral blood eos cells/μL, median (IQR)mean±SD 300 (210-460)357±227 290 (200-430)333±205 395 (252.5-635)467±285 Serum IgE, kU/L, median (IQR)mean±SD 96 (39-275)260±462 83 (32-241)203±315 213 (98-535)513±807 Baseline DSQ [0-84], mean±SD 35±12 35±12 35±13