When We Say "OX40 Inhibition," What Do We Mean? Emma Guttman-Yassky, MD, PhD, Explains

"What does it mean to target OX40 and the OX40 ligand pathway?" Emma Guttman-Yassky, MD, PhD, phrased the question like the veteran dermatology professor and researcher that she is, during a recent interview with Patient Care. Guttman-Yassky was in Paris for the 2025 European Academy of Dermatology and Venerology Annual Meeting, held September 17-20. She and colleagues were presenting recent data on the OX40 inhibitor rocatinlimab for the treatment of atopic dermatitis from the phase 3 ROCKET clinical trial program, under the auspices of Amgen.

The therapeutic landscape for moderate-to-severe AD has evolved rapidly and significantly in the last decade as targeted therapies have been successively approved and marketed. They include dupilumab (IL-4 receptor antagonist), IL-13 inhibitors (tralokinumab, lebrikizumab), and JAK inhibitors (upadacitinib, abrocitinib, baricitinib).²,³ These agents have become guideline-recommended first-line systemic treatments, offering superior efficacy and safety compared to conventional immunosuppressants.⁴

Despite these advances, a significant unmet need remains for treatments that provide sustained remission and potentially modify disease course. Current therapies typically reach maximum efficacy by 12-16 weeks but show rapid disease return upon discontinuation, highlighting the persistence of underlying immunological memory that drives AD pathogenesis.⁵

This has led to investigation of the OX40-OX40L costimulatory pathway as a novel therapeutic target. OX40 (CD134) is a member of the tumor necrosis factor receptor superfamily expressed on activated T cells, particularly memory T cells, while OX40L (CD252) is expressed on antigen-presenting cells and other immune cells.⁶ The OX40-OX40L interaction provides critical costimulatory signals that promote T-cell activation, proliferation, and survival, with particular importance in maintaining memory T-cell responses.⁷ In atopic dermatitis, this pathway is dysregulated, with elevated expression observed in lesional skin and peripheral blood.⁸

OX40-OX40L inhibitors represent a fundamentally different therapeutic approach compared to existing treatments. Rather than blocking downstream cytokine effects or intracellular signaling cascades, these agents target upstream costimulatory signals required for T-cell activation and memory formation.⁹ This mechanism potentially offers disease-modifying capabilities through effects on immunological memory—the cellular basis for disease persistence and recurrence at consistent anatomical sites.

Two strategies are being investigated: OX40 receptor antagonism (rocatinlimab, telazorlimab) and OX40L inhibition (amlitelimab). Phase 2 trials have demonstrated promising efficacy with suggestions of continued improvement over extended periods and potential for sustained responses after treatment cessation—characteristics that distinguish these agents from current therapies.¹⁰,¹¹ The following discussion explores the mechanistic rationale for OX40 inhibition and its potential to transform AD management from chronic disease control toward disease modification.

References

1. Langan SM, et al. Atopic dermatitis. Lancet. 2020;396(10247):345-360.
2. Simpson EL, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335-2348.
3. Davis DMR, et al. Guidelines of care for the management of atopic dermatitis in adults with phototherapy and systemic therapies. J Am Acad Dermatol. 2024;90(2):e43-e56.
4. Eichenfield LF, et al. Guidelines of care for the management of atopic dermatitis in adults with phototherapy and systemic therapies. J Am Acad Dermatol. 2024;90(2):e43-e56.
5. Müller S, et al. Treatment of atopic dermatitis: Recently approved drugs and advanced clinical development programs. Allergy. 2024;79(3):576-608.
6. Croft M, et al. The significance of OX40 and OX40L to T-cell biology and immune disease. Immunol Rev. 2009;229(1):173-191.
7. Bullock K, Richmond P, McCann L. The role of OX40 ligand/OX40 axis signalling in atopic dermatitis. Br J Dermatol. 2024;191(4):488-496.
8. Zhai Y, Su J. OX40 in the pathogenesis of atopic dermatitis—a new therapeutic target. Am J Clin Dermatol. 2024;25(3):447-461.
9. Guttman-Yassky E, et al. Anti-OX40 biological therapies in the treatment of atopic dermatitis: a comprehensive review. Biomedicines. 2024;12(11):2543.
10. Silverberg JI, et al. Phase 2b randomized trial of OX40 inhibitor telazorlimab for moderate-to-severe atopic dermatitis. J Allergy Clin Immunol Glob. 2024;3(1):100191.
11. Nakagawa H, et al. Phase 2b randomized clinical trial of amlitelimab, an anti-OX40 ligand antibody, in patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol. 2024; [Epub ahead of print].