Anti-OX40: A New Frontier in Atopic Dermatitis Management?
The development of new treatments for atopic dermatitis aim to provide disease control and thus improve the overall burden of disease. Over the past decade, there has been substantial progress with respect to understanding the pathogenesis of atopic dermatitis. These new insights, largely related to the genetic and immunologic impacts, have paved the way for emerging therapeutics specifically focused on the role of cytokines and cytokine receptors, such as OX40.
OX40 is a co-stimulatory T-cell receptor belonging to the TNF family. Alongside its ligand, OX40L, these molecules regulate cytokine production from T cells, antigen-presenting cells, natural killer cells and also modulate cytokine receptor signaling.2 The OX40/OX40L interactions have been found to play a central role in the development of multiple inflammatory and autoimmune diseases. When compared to normal or psoriatic skin, atopic skin has increased expression of both OX40 and OX40L.3 Inhibition of this axis has been the subject of recent research in the field of atopic dermatitis therapeutics, where more novel, durable, safe treatment options are needed.
An exploratory phase 2a study published in The Journal of Allergy and Clinical Immunology investigated the safety, efficacy, and tissue effects of GBR 830, a humanized monoclonal antibody against OX40. The study participants were adults with moderate to severe atopic dermatitis and were randomized to receive either 10mg/kg of intravenous GBR 830 or placebo on day 1 and then again on day 29. The primary endpoints for the study included treatment-emergent adverse events (TEAEs) and changes in baseline biomarkers, including epidermal hyperplasia, OX40/OX40L and cytokines at day 29 and 71. Skin biopsies were collected at baseline, day 29, and day 71 to assess these biomarkers. Secondary endpoints included clinical severity scores such as Eczema Area and Severity Index (EASI) score. It is important to note that this study was not powered to detect clinical efficacy or differences between the treatment groups.
Safety and tolerability were assessed in all subjects who received at least one dose of treatment (n=62). GBR 830 was well tolerated versus placebo, with equal rates of TEAEs observed. The most common TEAE amongst both groups was headache and most TEAEs were mild to moderate. There were 4 patients in the GBR 830 group that had post-procedural infection, the majority of which were biopsy site infection. There were 2 subjects that had severe cardiac TEAEs, one in the GBR 830 group and the other in the placebo. The cardiac event was judged to not be related to the study drug.
Biomarker assessment was performed only in subjects who received 2 treatments and provided a biopsy specimen before and once after treatment (GBR 830, n=29; placebo, n=11). Significant reduction in OX40/OX40L was seen in lesional skin of the GBR 830 group at day 29 (p<.05), with drug versus placebo significance trending in favor of GBR 830 at day 71 (p<.001). There were also statistically significant reductions in epidermal thickness and proliferation in the GBR 830 group at day 29 and day 71. Down regulation of number of key cytokines within the TH1 group (INF- γ), TH2 group (CCL11 and CCL17), and TH17/TH22 group (IL-23p19 and S100A12) were seen in the GBR 830 group compared to placebo. Interestingly, there was no measurable impact on IL-4, IL-13, IL-17, or IL-22 compared with placebo. At day 71, the proportion of intent-to-treat subjects achieving ≥ 50% improvement in EASI score was greater with GBR 830 (76.9%) versus placebo (37.5%).
Limitations of the study include its small sample size, high dropout rate in the placebo arm, and short study duration. In addition, the overall study design functioned as a safety and biomarker study; no clinical efficacy conclusions can be definitively drawn. Additional studies of longer duration with a focus on clinical efficacy are needed. Nonetheless, the safety profile and data trends exhibited in this study suggest targeting T cell receptors like OX40 have the potential to be a new therapeutic strategy in the management of atopic dermatitis.
1. Silverberg JI, Garg NK, Paller AS, Fishbein AB, Zee PC. Sleep disturbances in adults with eczema are associated with impaired overall health: a US population-based study. J Invest Dermatol. 2015;135(1):56-66.
2. Webb GJ, Hirschfield GM, Lane PJ. OX40, OX40L and autoimmunity: a comprehensive review. Clin Rev Allergy Immunol 2016;50:312-32.
3. Guttman-Yassky E, Pavel AB, Zhou L, et al. GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis. J Allergy Clin Immunol. 2019;144(2):482-493.e7.
Eileen Cheever MPAS, PA-C, resides with her husband Aaron in Lunenburg, Massachusetts. She works at Clearview Dermatology in Leominster, Massachusetts. In her spare time, she enjoys cheering on her favorite Boston sports teams and exploring the outdoors with her husband and their dog, Jasta.