Background: Rheumatoid arthritis (RA) is characterized by synovial inflammation and joint destruction by multiple immune cell types that are driven via the NF-kB pathway. NF-kB activation leads to production of key cytokines involved in RA such as TNF, IL-1 and IL-6, as well as in the actions of many of them (TNF and IL-1). Antagonists to these cytokines (e.g. adalimumab, anakinra, tocilizumab) are known to be effective in the treatment of RA. Moreover, glucocorticoids are potent inhibitors of NF-kB and are efficacious in many autoimmune diseases including RA. 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 are critical epigenetic regulators of NF-kB-driven gene transcription in the nucleus. 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 driven by NF-kB. 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. Inhibition of IL-17 (73%), IL-23 (81%), and TNF (72%) production with VYN202 treatment vs placebo was observed in ex vivo whole blood cells stimulated with TLR agonists that signal via NF-kB in a first-in-human, phase 1a study in healthy volunteers. The drug was well tolerated in this study with no serious adverse events, no treatment discontinuations, and no laboratory abnormalities that were noted earlier with pan-BD inhibitors. VYN202 was evaluated in two animal models of arthritis to assess its potential in the treatment of RA.

Objectives: To evaluate the efficacy of orally administered VYN202 in collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA) models in rats compared to vehicle and reference compounds, dexamethasone (glucocorticoid), GSK620 (a less potent, earlier generation BD2-selective BET inhibitor), and upadacitinib (a Janus kinase inhibitor approved in RA).

Methods: CIA was induced in Lewis rats and severity of paw inflammation was evaluated over 21 days. Test agents (vehicle, VYN202 [1, 3, and 10 mg/kg], dexamethasone 0.1 mg/kg, and GSK620 10 mg/kg) were administered orally from Day 0-21. In the AIA model in Lewis rats, rats were treated orally daily from Day 0-21 with vehicle, VYN202 (0.1, 1, and 10 mg/kg/day), dexamethasone (0.1 mg/kg) or upadacitinib 10 mg/kg, and effects on paw inflammation assessed over 21 days.

Results: CIA : Treatment with 3 and 10 mg/kg of VYN202 reduced paw volume by 79% compared to vehicle at Day 21, that was close to the effect seen with dexamethasone. GSK620 10 mg/kg treatment had a modest effect on paw swelling that was not significantly different from vehicle. On histopathology, there was a significant, dose-dependent decrease in both the incidence and severity of histological signs of arthritis with VYN202 vs vehicle. Anti-collagen IgG1 antibodies were markedly decreased approaching 99% compared with vehicle at all 3 doses of VYN202, with much higher inhibition than seen with dexamethasone and GSK620 at Day 21. AIA: VYN202 at 1 and 10 mg/kg treatment reduced paw volume by over 80% compared to vehicle at Day 21. This reduction was comparable to the upadacitinib and dexamethasone treatments. Histopathology scores showed similar inhibition in ankle inflammation vs. vehicle with VYN202 10 mg/kg (67%) vs. upadacitinib (56%).

Conclusion: BD2-selective BET inhibition with VYN202 represents a novel approach to treatment of NF-κB–mediated diseases such as RA. A phase 1b study of VYN202 in RA is planned.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: 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.