PracticeUpdate Conference Series: IID 2018

TheOX40 Inhibitor GBR830 Induces Progressive and SustainedChanges inBiomarkers of Eczema The first-in-class, humanized, monoclonal immunoglobulin G1 antibody specific for inhibiting OX40, a costimulatory receptor on activated T-cells, has been shown to induce significant, progressive, and long-lasting changes in lesional biopsies up to day 71 in patients with eczema, a proof-of-concept, placebo-controlled trial shows.

E mma Guttman-Yassky, MD, PhD, of the Mount Sinai Health System in New York, investigated the effects of GBR 830 on biomarkers of eczema, and generated the first clinical evidence of biological activity. OX40 is a costimulatory tumor necrosis factor R-superfamily immune checkpoint receptor. OX40 is expressed almost exclusively on activated T lym- phocytes, and not on naïve or resting memory cells. Costimulatory signals are essential for T cell activity, and binding between OX40 and OX40L is a biomarker of autoimmune disease severity. Activation of this pathway leads to conversion of activated T cells into memory T cells, which pro- mote inflammation. Regulatory T cells also contribute to inflammation, and OX40 signaling by these cells downregulates immune-suppressing functions. It is believed that GBR 830 may inhibit the dual activities of OX40 and OX40L binding in both activated T cells and regula- tory T cells, thus potentially reducing inflammation associated with symptoms of atopic dermatitis. OX40 signaling can enhance proliferation, sur- vival, and effector functions of T cells with a more pronounced effect on late, chronic, and memory responses. Results of numerous studies have indicated that OX40 may play a central role in various T cell- mediated pathological immune responses, implying therapeutic potential of antagonistic antibodies targeting OX40. Adults with affected body surface area ≥10%, Eczema Area and Severity Index score ≥12, SCORing Atopic Dermatitis ≥20, immunoglobulin A ≥3, and history of inadequate response to topical treatments were randomized 3:1 to GBR 830 (10 mg per kilogram of body weight intravenously at baseline and day 29 or placebo). In all, 63% (39/62) of patients with eczema expe- rienced at least 1 treatment-emergent adverse effect; these were distributed similarly between the GBR 830 and placebo groups. Evaluable skin biopsies were available for 40 patients at baseline, for 39 patients at day 29 (n=28, GBR 830; n=11 placebo). Evaluable skin biopsies were available for 29 patients at day 71 (n=22, GBR 830; n=7 placebo). Significant reductions from baseline (P < .001) were found with GBR 830, but not placebo, in

treatment-specific biomarkers (OX40-positive T-cells, OX40L-positive dendritic cells). Patients who received GBR 830 also exhibited significant reductions from baseline (P < .001) in measures of hyperplasia (epidermal thickness, keratin 16 mRNA and protein expression, and Ki67 cell counts). GBR 830 was associated with significant reduc- tions from baseline (P < .01) in eczema biomarkers, including Th2 chemokines (CCL17, CCL11, TSLPR), Th1/interferon markers (interferon γ, CXCL10), and Th17/Th22-associated products (interleukin 23p19, S100A9/S100A12). Clinically, a greater proportion of GBR830-treated patients achieved Eczema Area and Severity Index score 50 (≥50% reduction in score from baseline) vs placebo at day 29 (43.6% vs 20.0%, P = .11) and day 71 (76.9% vs 37.5%, P = .04). Dr. Guttman-Yassky concluded that GBR 830 induced significant, progressive, and long-lasting changes in lesional biopsies up to day 71 and was well tolerated in this cohort of patients with eczema. A phase IIb clinical trial of GBR 830 for mod- erate-to-severe atopic dermatitis will begin enrollment in June 2018. In this double-blind, placebo-controlled trial, approximately 392 patients will be randomized across four dosing arms to receive GBR 830 or placebo. The trial’s primary objective will be to compare the effectiveness of GBR 830 on reducing the severity of atopic dermatitis vs placebo, as measured by Investigator’s Global Assessment. Secondary efficacy measures will include patients with >75% improvement in disease severity, as measured by the Eczema Area and Severity Index. Other measures will include disease activity using validated assessment tools such as Eczema Area and Severity Index response and Scoring Atopic Dermatitis. The trial will also assess safety, as well as biomark- ers relevant to the disease and unique mechanism of GBR 830. GBR 830 is also being explored to treat other inflammatory autoimmune conditions where dys- regulation of OX40 overexpression is implicated in disease activity.

Dr. Emma Guttman-Yassky

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PRACTICEUPDATE CONFERENCE SERIES • IID 2018