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Background: Atopic dermatitis (AD) is an inflammatory skin disease with significant unmet need. Blockade of the OX40-OX40 ligand (OX40L) costimulation pathway by targeting OX40L on antigen-presenting cells (APCs) with a fully human noncytotoxic, nondepleting anti-OX40L monoclonal antibody (amlitelimab; SAR445229; KY1005) is a novel way to modulate persistent inflammation., Objectives: To assess the safety and efficacy of amlitelimab over 16 weeks in adults with AD in a phase IIa double-blind placebo-controlled study., Methods: The study was conducted at 19 hospitals in Germany, Poland, Spain and the UK. Eligible patients with moderate-to-severe AD were randomized (1 : 1 : 1) to low-dose intravenous (IV) amlitelimab (200 mg), high-dose IV amlitelimab (500 mg) or placebo, followed by three maintenance doses (50% of loading dose) at 4, 8 and 12 weeks, with safety follow-up to week 36. The co-primary endpoints were the incidence of treatment-emergent adverse events (all patients who received ≥ 1 dose of the study drug) and mean percentage change in Eczema Area and Severity Index (EASI) to week 16 (full analysis set)., Results: Between 13 December 2018 and 12 May 2020, 89 patients were randomly assigned to low- (n = 29) or high-dose amlitelimab (n = 30) or placebo (n = 29), of whom 88 proceeded to treatment [37 women (42%), 51 (58%) men; mean (SD) age 33.6 (11.9) years]. Amlitelimab was generally well tolerated with an unremarkable safety profile; no hypersensitivity events were reported. For the primary endpoint, the least square mean percentage change in EASI from baseline to week 16 was -80.12% [95% confidence interval (CI) -95.55 to -64.68; P = 0.009 vs. placebo] and -69.97% (95% CI -85.04 to -54.60; P = 0.07 vs. placebo) for the low- (n = 27) and high-dose (n = 27) amlitelimab groups, respectively, vs. -49.37% (95% CI -66.02 to -32.72) for placebo (n = 24). Numerically greater reductions in EASI were observed for amlitelimab vs. placebo from weeks 2 to 16., Conclusions: Novel targeting of OX40L-expressing APCs with amlitelimab was well tolerated and resulted in clinically meaningful improvements in AD., Competing Interests: Conflicts of interest: S.W. reports research grants (institutional) from AbbVie, Almirall, Eli Lilly, Galderma, LEO Pharma, Pfizer and Sanofi; and consultancy fees from AbbVie, Almirall, Boehringer, Eli Lilly, Galderma, LEO Pharma, Pfizer and Sanofi. T.B. reports consultancy fees from AbbVie, Affibody, Almirall, AnaptysBio, Asana Biosciences, ASLAN Pharmaceuticals, Bayer Health, BioVerSys, Boehringer Ingelheim, Bristol-Myers Squibb, Connect Pharma, Dermavant, DIECE Therapeutics, Domain Therapeutics, EQRx, Galderma, Glenmark, GSK, Incyte, Innovaderm, IQVIA, Janssen, Kirin, Kymab, LEO, LG Chem, Lilly, L’Oréal, MSD, Novartis, Numab, OM-Pharma, Pfizer, Pierre Fabre, Sanofi/Regeneron and UCB. M.J.C. reports research grants (institutional) and consultancy fees from Hyphens Pharma, Johnson & Johnson, Kymab, L’Oréal, Leo Pharma, Perrigo (ACO Nordic), Pfizer, Regeneron and Sanofi Genzyme; and is a board member of the European Academy of Dermatology and Venereology and a voluntary medical advisor to the National Eczema Society, UK. A.R. reports research grants (personal and institutional) from AbbVie, Alvotech, Amgen, AnaptysBio, Argenx, AstraZeneca, Biothera, BMS, Celgene, Celltrion, Dermira, Galderma, Inflarx, Janssen, Kiniksa, Kymab, Leo Pharma, Novartis, Pfizer, Trevi Therapeutics and UCB; and consultancy fees from AbbVie, Chema Rzeszow, Eli Lilly, Galderma, Leo Pharma, Novartis, Sandoz, Sanofi-Aventis and Takeda. B.P.-B. was an employee of Sanofi and Sanofi stockholder during the development of this manuscript. N.B. is a former employee and shareholder in Kymab Ltd. S.G. is a former employee of Kymab Ltd and a Sanofi stockholder. S.Q. is a former employee of Kymab Ltd. M.S. is a former employee of Sanofi. R.W. has received consultancy fees from Kymab Ltd. J.T.O’M. is an employee of Sanofi and may hold stock and/or stock options in the company., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)