ATOPIC DERMATITIS HIDE AND SEEK: THE IMPENDING ROLE OF OX40 INHIBITION

By Warren R. Heymann, MD, FAAD
Sept. 11, 2024
Vol. 6, No. 37

The burden of atopic dermatitis (AD) — for patients, their families, and society — is vast and increasing. AD affects approximately 10% to 30% of children and 2% to 10% of adults in developed countries. (1) Aside from the cutaneous manifestations, AD diminishes the quality of life (QoL), work productivity, and mental health. Zhang et al. state, "Existing research has focused on anxiety and depression, while the results of the current study indicate a significant proportion of patients being affected by other psychiatric disorders in addition to anxiety and depression, including eating disorders and attention deficit hyperactivity disorder. In addition, patients with atopic dermatitis are more likely to experience loneliness compared with healthy persons, in particular those severely affected by atopic dermatitis." (2) Our surgeon general, Vivek Murthy, has highlighted the challenges of loneliness in our society. (3) Loneliness and AD may be hard to bear. 

Treating AD has improved dramatically over the past decade as we have many topical options (corticosteroids, calcineurin inhibitors, PDE4 inhibitors, a topical JAK inhibitor [ruxolitinib], and other agents likely soon to be released [roflumilast, tapinarof]), phototherapy, oral JAK inhibitors (upadacitinib, abrocitinib), and the biologics (dupilumab, tralokinumab). This commentary will focus on the emergence of OX40 inhibitors for AD.

Buhl and Werfel succinctly note that "the pathophysiology of AD is based on a complex interplay of impaired skin barrier function, alterations in the skin microbiome, and type 2 skin inflammation with neuronal involvement." (4) The defective skin barrier in AD is related to filaggrin dysfunction, allowing susceptibility to xerosis and environmental irritants and allergens that lead to inflammation manifested by pruritus and the clinical findings of AD. The inflammation is due to an overactive Th2 response (with increased IL-4 and IL-5 cytokines) in acute lesions and Th1 response (with IFN-gamma and IL-12) in chronic lesions. Other inflammatory cytokines such as TNF-alpha, IL-1, and IL-6 may be at play. Decreased epidermal anti-microbial peptides (human beta-defensins, cathelicidins) contribute to Staphylococcus aureus colonization seen in more than 90% of patients with AD, which may drive its inflammatory process. (1)

Image from JAAD International 2021; 4: 28-31.

According to Sadrolashrafi et al., the OX40-OX40 ligand (OX40L) pathway is a crucial modulator of the adaptive immune response. "The transmembrane glycoprotein OX40 receptor (OX40/CD134/TNFRSF4) and its ligand OX40L (CD252/TNFSF4) influence the production of different T cell populations, including memory T cells, and may be important for AD pathogenesis. OX40 and OX40L are members of the tumor necrosis factor receptor (TNFR)/tumor necrosis factor (TNF) superfamily. TNFR/TNF superfamily members are immune checkpoint molecules that can augment the T cell response through costimulation. The interaction between OX40 and OX40L promotes T cell activation, differentiation, and survival through various mechanisms. The inhibition of this interaction can potentially attenuate T cell-mediated processes that contribute to AD pathogenesis. As such, OX40 and OX40L may serve as viable therapeutic targets for treating AD." (5) 

Four antibodies against OX40 (rocatinlimab, telazorlimab, and IMG 007) or OX40L (amlitelimab) are currently in clinical development for treating moderate-to-severe AD. Early-phase clinical studies of these antibodies have shown auspicious results based on the Investigator Global Assessment (IGA) 5-point scale or the Eczema Area Severity Index (EASI). (6) An example is the phase 2b randomized trial of telazorlimab for patients with moderate-to-severe AD who were not previously controlled with topical agents, systemic immunosuppressants, or biologic agents. Telazorimab induced significant and progressive clinical improvement of AD. The most common adverse effects occurring in > 5% of subjects were nasopharyngitis, upper respiratory infections, and headache. Two patients discontinued the drug because of paresthesias and pernicious anemia/neutropenia/thrombocytosis, respectively. (7)

What are the potential advantages of OX40/OX40L inhibition? According to Guttman-Yassky et al., "Targeting the OX40L/OX40 signalling axis, an upstream regulator of T-cell proliferation and cytokine release that has been specifically implicated in AD, may allow early intervention at the initiation of chronic inflammation. Furthermore, immune homeostasis restoration may be possible through OX40L/OX40 blockade, controlling effector and memory T-cell proliferation while maintaining regulatory T cells. Rebalancing the T-cell-mediated immune response may prevent escalation of inflammation and future disease flares." (8)

The therapeutic advances in AD have been dramatic, but more needs to be done. Patients deserve an improvement in QoL and to come out of hiding due to loneliness. We must continue to seek new treatment. In the children's hide and seek game, players can safely come out of hiding by declaring "Olly olly oxen free!" Perhaps OX40 inhibition can free our long-suffering AD patients. 

Point to Remember: The OX40/OX40 ligand signaling pathway is involved in the pathogenesis of atopic dermatitis. Current trials using OX40/OX40 ligand inhibitors are underway, which are promising. 

Our expert's viewpoint

Emma Guttman-Yassky, MD, PhD, FAAD
Waldman Professor and System-Wide Chair
Department of Dermatology
Icahn School of Medicine at Mount Sinai, New York

While our patients are treated now with effective medications for atopic dermatitis, we as treating dermatologists and our patients aspire for treatments with long lasting responses, that can be given less often and may even entertain the idea of real disease modification. Ideally, this would allow stopping treatment after clearance occurs without recurrence. 

As our recent reviews (6,8) show, it appears that the OX40/OX40L pathway is increased in patients with atopic dermatitis and is part of the pathogenesis of AD. It is involved in T-cell differentiation and creation of memory T-cells that are taking part in the body's memory leading to again populate lesions in the same area once treatment is stopped. This may be the reason why in early studies we saw a hint of long-lasting responses with targeting OX40/OX40L in atopic dermatitis. Both the anti-OX40 and anti-OX40L studies with rocatinlimab and amlitelimab, respectively, showed that upon treatment cessation, in the majority of patients on higher doses, that disease did not come back for a long follow up period. (9) A similar hint was also shown with the OX40L targeting by Weidinger et al. (10)

Nevertheless, these phase 2 studies were small, and in order to prove long-term disease remission and sustainability of responses, we need large studies that will show that when the drug is discontinued, the disease does not recur for several months and perhaps in the entire follow-up period.

The phase 3 studies that are ongoing will be able to prove if indeed long-lasting responses and perhaps disease modification may be attainable with the new OX40/OX40L treatments that are on the horizon.

1. Kolb L, Ferrer-Bruker SJ. Atopic Dermatitis. 2023 Aug 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–. PMID: 28846349.

2. Zhang J, Loman L, Oldhoff JM, Schuttelaar MLA. Beyond Anxiety and Depression: Loneliness and Psychiatric Disorders in Adults with Atopic Dermatitis. Acta Derm Venereol. 2023 Aug 22;103:adv9378. doi: 10.2340/actadv.v103.9378. PMID: 37605893; PMCID: PMC10461544.

3. Murthy VH. Surgeon General: We have become a lonely nation. It's time to fix that. New York Times. April 30, 2023. https://www.nytimes.com/2023/04/30/opinion/loneliness-epidemic-america.html

4. Buhl T, Werfel T. Atopic dermatitis - Perspectives and unmet medical needs. J Dtsch Dermatol Ges. 2023 Apr;21(4):349-353. doi: 10.1111/ddg.15050. Epub 2023 Mar 24. PMID: 36960846.

5. Sadrolashrafi K, Guo L, Kikuchi R, Hao A, Yamamoto RK, Tolson HC, Bilimoria SN, Yee DK, Armstrong AW. An OX-Tra'Ordinary Tale: The Role of OX40 and OX40L in Atopic Dermatitis. Cells. 2024 Mar 28;13(7):587. doi: 10.3390/cells13070587. PMID: 38607026; PMCID: PMC11011471.

6. Croft M, Esfandiari E, Chong C, Hsu H, Kabashima K, Kricorian G, Warren RB, Wollenberg A, Guttman-Yassky E. OX40 in the Pathogenesis of Atopic Dermatitis-A New Therapeutic Target. Am J Clin Dermatol. 2024 May;25(3):447-461. doi: 10.1007/s40257-023-00838-9. Epub 2024 Jan 18. Erratum in: Am J Clin Dermatol. 2024 May;25(3):463. doi: 10.1007/s40257-024-00850-7. PMID: 38236520; PMCID: PMC11070399.

7. Rewerska B, Sher LD, Alpizar S, Pauser S, Pulka G, Mozaffarian N, Salhi Y, Martinet C, Jabert W, Gudi G, Ca V, Gn S, Macoin J, Anstett V, Turrini R, Doucey MA, Blein S, Konto C, Machkova M. Phase 2b randomized trial of OX40 inhibitor telazorlimab for moderate-to-severe atopic dermatitis. J Allergy Clin Immunol Glob. 2023 Nov 22;3(1):100195. doi: 10.1016/j.jacig.2023.100195. PMID: 38187863; PMCID: PMC10770725.

8. Guttman-Yassky E, Croft M, Geng B, Rynkiewicz N, Lucchesi D, Peakman M, van Krinks C, Valdecantos W, Xing H, Weidinger S. The role of OX40L/OX40 axis signalling in atopic dermatitis. Br J Dermatol. 2024 Jun 5:ljae230. doi: 10.1093/bjd/ljae230. Epub ahead of print. PMID: 38836560.

9. Guttman-Yassky E, Simpson EL, Reich K, Kabashima K, Igawa K, Suzuki T, Mano H, Matsui T, Esfandiari E, Furue M. An anti-OX40 antibody to treat moderate-to-severe atopic dermatitis: a multicentre, double-blind, placebo-controlled phase 2b study. Lancet. 2023 Jan 21;401(10372):204-214. doi: 10.1016/S0140-6736(22)02037-2. Epub 2022 Dec 9. Erratum in: Lancet. 2023 Jan 21;401(10372):194. doi: 10.1016/S0140-6736(22)02581-8. PMID: 36509097.

10. Weidinger S, Bieber T, Cork MJ, Reich A, Wilson R, Quaratino S, Stebegg M, Brennan N, Gilbert S, O'Malley JT, Porter-Brown B. Safety and efficacy of amlitelimab, a fully human nondepleting, noncytotoxic anti-OX40 ligand monoclonal antibody, in atopic dermatitis: results of a phase IIa randomized placebo-controlled trial. Br J Dermatol. 2023 Oct 25;189(5):531-539. doi: 10.1093/bjd/ljad240. PMID: 37463508.

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Benjamin Hidalgo-Matlock
Skin Care Physicians of Costa Rica

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