2. Academic Validation
  3. GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis

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

  • J Allergy Clin Immunol. 2019 Aug;144(2):482-493.e7. doi: 10.1016/j.jaci.2018.11.053.
Emma Guttman-Yassky 1,  Ana B Pavel 2,  Lisa Zhou 2,  Yeriel D Estrada 2,  Ning Zhang 2,  Hui Xu 2,  Xiangyu Peng 2,  Huei-Chi Wen 2,  Panayiota Govas 2,  Girish Gudi 3,  Vinu Ca 4,  Hui Fang 3,  Yacine Salhi 3,  Jonathan Back 5,  Venkateshwar Reddy 3,  Robert Bissonnette 6,  Catherine Maari 6,  Fred Grossman 3,  Gerhard Wolff 3
Affiliations

Affiliations

  • 1 Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address: [email protected].
  • 2 Icahn School of Medicine at Mount Sinai, New York, NY.
  • 3 Glenmark Pharmaceuticals, Inc, Paramus, NJ.
  • 4 Glenmark Pharmaceuticals, Ltd, Mumbai, India.
  • 5 Glenmark Pharmaceuticals, SA, La Chaux-de-Fonds, Switzerland.
  • 6 Inovaderm Research, Montreal, Quebec, Canada.
PMID: 30738171 DOI: 10.1016/j.jaci.2018.11.053
Abstract

Background: GBR 830 is a humanized mAb against OX40, a costimulatory receptor on activated T cells. OX40 inhibition might have a therapeutic role in T cell-mediated diseases, including atopic dermatitis (AD).

Objective: This exploratory phase 2a study investigated the safety, efficacy, and tissue effects of GBR 830 in patients with AD.

Methods: Patients with moderate-to-severe AD (affected body surface area, ≥10%; Eczema Area and Severity Index score, ≥12; and inadequate response to topical treatments) were randomized 3:1 to 10 mg/kg intravenous GBR 830 or placebo on day 1 (baseline) and day 29. Biopsy specimens were collected (n = 40) at days 1, 29, and 71. Primary end points 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% or greater improvement in Eczema Area and Severity Index score was greater with GBR 830 (76.9% [20/26]) versus placebo (37.5% [3/8]). GBR 830 induced significant progressive reductions in TH1 (IFN-γ/CXCL10), TH2 (IL-31/CCL11/CCL17), and TH17/TH22 (IL-23p19/IL-8/S100A12) mRNA expression in lesional skin. Significant progressive reductions until day 71 in the drug group were seen in OX40+ T cells and OX40L+ dendritic cells (P < .001). Hyperplasia measures (thickness/keratin 16/Ki67) showed greater reductions with GBR 830 (P < .001).

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

Keywords

Atopic dermatitis; OX40; T(H)1; T(H)17/T(H)22; T(H)2; biomarkers; costimulation; hyperplasia; inflammation; trial.

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