GBR 830, an anti-OX40, improves skin gene-signatures and clinical scores in atopic dermatitis

Publication date: Available online 6 February 2019

Source: Journal of Allergy and Clinical Immunology

Author(s): Emma Guttman-Yassky, Ana B. Pavel, Lisa Zhou, Yeriel D. Estrada, Ning Zhang, Hui Xu, Xiangyu Peng, Huei-Chi Wen, Panayiota Govas, Girish Gudi, C.A. Vinu, Hui Fang, Yacine Salhi, Jonathan Back, Venkateshwar Reddy, Robert Bissonnette, Catherine Maari, Fred Grossman, Gerhard Wolff

Abstract

Background

GBR 830 is a humanized, monoclonal antibody against OX40, a co-stimulatory receptor on activated T-cells. OX40 inhibition may have a therapeutic role in T-cell-mediated diseases, including atopic dermatitis (AD).

Objective

This exploratory phase 2a study investigated safety, efficacy, and tissue effects of GBR 830 in AD.

Methods

Moderate-to-severe AD subjects (affected body-surface area ≥10%, Eczema Area and Severity Index [EASI] ≥12, inadequate response to topical treatments) were randomized 3:1 to intravenous GBR 830 10 mg/kg or placebo on Day 1/baseline and Day 29. Biopsies were collected (n=40) at Days 1, 29, and 71. Primary endpoints included treatment-emergent adverse events (TEAEs) and changes from baseline in biomarkers (epidermal hyperplasia/cytokines) at Days 29 and 71.

Results

GBR 830 was well-tolerated, with equal TEAE distribution (GBR 830, 63.0% [29/46]; placebo, 63.0% [10/16]). One serious TEAE in the GBR 830 group was deemed unrelated to study drug. At Day 71, the proportion of intent-to-treat subjects achieving ≥50% improvement in EASI was higher with GBR 830 (76.9% [20/26]) versus placebo (37.5% [3/8]). GBR 830 induced significant, progressive reductions in Th1 (IFNγ/CXCL10), Th2 (IL-31/CCL11/CCL17), and Th17/Th22 (IL-23p19/IL-8/S100A12) mRNA in lesional skin. Significant, progressive reductions until Day 71 in the drug-group were seen in OX40+ T-cells and OX40L+ dendritic cells (p<0.001). Hyperplasia measures (thickness/K16/Ki67) showed higher reductions with GBR 830 (p<0.001).

Conclusions

Two doses of GBR 830, 4-weeks apart, were well-tolerated and induced significant, progressive tissue and clinical changes until Day 71 (42 days after last dose), highlighting the potential of OX40-targeting in AD.

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