345 Treatment with amlitelimab—a novel non-depleting, non-cytotoxic anti-OX40Ligand monoclonal antibody—reduces IL-22 serum levels in a phase 2a randomized, placebo-controlled trial in patients with moderate-to-severe atopic dermatitis
Authors: Weidinger Stephan , Cork Michael , Reich Adam , Bieber Thomas , Gilbert Sally , Brennan Nuala , Wilson Rosamund , Lucchesi Davide , Rynkiewicz Natalie , Stebegg Marisa , Porter-Brown Ben 
Published: January 2023

Abstract
OX40Ligand (OX40L) upregulation on antigen-presenting cells (APCs) following antigen presentation contributes to the survival and functional activation of T helper (Th) 2 and Th1/17/22 cells, which are central to the inflammation and pathological outcomes in atopic dermatitis (AD). In a Phase 2a trial (NCT03754309), amlitelimab, a fully human, non-depleting, non-cytotoxic anti-OX40L monoclonal antibody, was effective in treating patients with moderate-to-severe AD. To assess the effects of amlitelimab on interleukin (IL)-22, an important Th22-associated disease mediator of AD. 89 patients with moderate-to-severe AD were enrolled in a Phase 2a randomized, double-blind, placebo-controlled, multicentre trial and randomized 1 : 1 : 1 to intravenous amlitelimab low dose (200 mg loading/100 mg maintenance every 4 weeks [Q4W]; n = 29), high dose (500 mg/250 mg Q4W; n = 30) or placebo (Q4W; n = 29) until week 12. The primary efficacy endpoint was the percentage change in Eczema Area and Severity Index (EASI) from baseline to week 16. Other disease severity measurements included SCORing of Atopic Dermatitis (SCORAD) and validated Investigator Global Assessment (vIGA). Serum was collected at baseline, week 4 and week 16, and further collected at week 24 and week 36 in responders, defined as patients who reached vIGA 0/1 at week 16. IL-22 levels were determined by ultrasensitive single-molecule immunoassay (Simoa). Of 88 subjects who received study treatment, 59 were evaluable at week 16. Amlitelimab was well tolerated with an unremarkable safety profile. The mean percentage change in EASI from baseline at week 16 was −80.12% for amlitelimab low dose and −69.97% for amlitelimab high dose vs. −49.37% for placebo (nominal P-values: 0.009 [amlitelimab low dose vs. placebo] and 0.072 [amlitelimab high dose vs. placebo]). Amlitelimab-treated patients who achieved vIGA 0/1 at week 16 had sustained clinical responses up to week 36. No difference in IL-22 serum levels was found between groups at baseline. IL-22 levels correlated with disease severity at baseline, as measured by EASI and SCORAD (r = 0.53, P &lt; 0.0001; and r = 0.36, P = 0.001; respectively). A significant reduction in IL-22 levels was observed at week 16 in amlitelimab-treated patients (low dose P &lt; 0.0001; high dose P = 0.001), but not in the placebo group (P = 0.381). The amlitelimab-induced decrease in IL-22 levels was maintained until week 36 in those defined as vIGA 0/1 responders at week 16. OX40L blockade on APCs represents a promising novel approach in the treatment of AD by effectively targeting underlying T-cell immune dysregulation. Amlitelimab monotherapy not only provided a sustained and clinically meaningful improvement in disease activity compared with placebo in patients with moderate-to-severe AD, but also significantly decreased serum levels of IL-22, a Th22 cell-associated cytokine involved in the underlying immunopathogenesis of AD.