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<h2>Abstract</h2><h3>Background:</h3> Th17 and NF-kB pathways play key roles in many chronic inflammatory diseases such as psoriatic arthritis, rheumatoid arthritis, and axial spondyloarthropathies. Inhibition of these pathways by cytokine antagonists such as anti-TNF and anti-IL-17 agents are known to be effective in treatment of such diseases. Moreover, glucocorticoids are potent inhibitors of these pathways and are efficacious in these conditions. However, they have numerous non-immune adverse effects such as cardiovascular, metabolic, and bone side effects that limit their use.Bromodomain (BD) and extra-terminal domain (BET) proteins in the nucleus are critical epigenetic regulators of Th17 activation and NF-kB-driven gene transcription. Each of the four known BET proteins have BD1 and BD2 domains that play distinct roles. While BD1 regulates cell-cycling and homeostatic genes in the cell, BD2 mediates proinflammatory gene transcription. VYN202 is an oral BET inhibitor with high selectivity for the BD2 domain over the homeostatic BD1 domain. It was designed to reduce known adverse events of systemic pan-BD inhibitors that have been earlier observed in oncologic settings. <h3>Objectives:</h3> To evaluate VYN202 in a first-in-human, Phase 1 study. <h3>Methods:</h3> Healthy volunteers were dosed at single and multiple ascending oral doses with at least 6 subjects on active drug and 2 on placebo in each cohort. The safety, tolerability, pharmacokinetics, and exploratory pharmacodynamics, including stimulated whole blood assays ex vivo, were evaluated in these subjects. <h3>Results:</h3> The drug was well tolerated with no serious adverse events and no treatment discontinuations. All treatment-emergent adverse events were mild or moderate with none considered clinically significant. Unlike previously reported systemic pan-BET inhibitors, there were no meaningful changes from baseline in hematologic parameters, eg, thrombocytopenia, neutropenia. The median half-life of the drug was 36-41 hours, supporting once-daily dosing. Inhibition of TNF (72%), IL-17 (73%), IL-23 (81%), and IL-6 (49%) production, in addition to other proinflammatory cytokines, was observed in stimulated whole blood assays ex vivo with VYN202 vs placebo. Cytokine inhibition effects were comparable to those observed in preclinical models of psoriasis and rheumatoid arthritis, where efficacy was shown with oral VYN202 dosing. <h3>Conclusion:</h3> VYN202 represents a novel approach to treatment of Th17 and NF-kB–mediated diseases. A Phase 1b study of the agent in rheumatoid arthritis is planned. <h3>REFERENCES:</h3> <b>NIL</b>. <h3>Acknowledgements:</h3> <b>NIL</b>. <h3>Disclosure of Interests:</h3> Iain Stuart VYNE Therapeutics, VYNE Therapeutics, Subhashis Banerjee VYNE Therapeutics, VYNE Therapeutics, Andrew Woodland: None declared, Mark Bell: None declared, Rangeetha Jayaprakash: None declared. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.