VYNE Therapeutics Announces Positive Phase 1a MAD Results for VYN202, a BD2-Selective BET Inhibitor

VYNE Therapeutics Inc., a clinical-stage biopharmaceutical company, has announced promising results from the multiple ascending dose (MAD) segment of its Phase 1a clinical trial for VYN202. This innovative oral treatment is aimed at addressing a variety of immune-mediated disorders and has shown potential as a novel, once-daily therapeutic option. The trial was structured as a two-part, double-blind, placebo-controlled study in healthy volunteers and included single ascending dose (SAD) and MAD components. The primary objectives were to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of VYN202.

The outcomes of the Phase 1a MAD study for VYN202 reveal that the treatment has a favorable safety profile. Notably, no drug-related adverse events were observed, which are commonly linked with earlier, less selective BET inhibitors. These adverse events typically include thrombocytopenia, neutropenia, or gastrointestinal issues. The trial reported no severe adverse events, no discontinuations due to adverse events, and all treatment-emergent adverse events (TEAEs) were mild or moderate. Importantly, no drug-related adverse events were associated with laboratory results, including any relating to thrombocytopenia, a known dose-limiting toxicity of earlier BET inhibitors.

VYN202 displayed a favorable PK profile, supporting a once-daily dosing regimen. It demonstrated dose-dependent exposure, reaching a steady-state after seven consecutive daily doses. VYN202's blood levels remained within the key inhibitory thresholds of IC50 to IC90 against BD2 BRD4 for at least 24 hours at all doses. Additionally, no drug-drug interaction was observed when VYN202 was administered alongside methotrexate, a common treatment for chronic immuno-inflammatory conditions.

In terms of pharmacodynamic activity, VYN202 showed robust performance in ex vivo assays, indicating strong target engagement and inhibition of inflammatory biomarkers. It induced a dose-dependent increase in the target engagement biomarker HEXIM-1, with maximum effect observed at doses ranging from 0.5mg to 1.0mg QD. The drug also inhibited the production of multiple inflammatory biomarkers associated with Th17, Th1/myeloid, and Th1/Tc dysregulated activity, supporting findings from preclinical models of VYN202.

The MAD segment of the trial involved 14-day administration of multiple ascending doses of VYN202 to healthy volunteers. Four study cohorts were established, assessing VYN202 dosed at 0.5mg every other day, 0.5mg daily, 1mg daily, and 1mg daily combined with methotrexate 7.5mg weekly. The cohort receiving 0.5mg every other day was aimed at approximating a 0.25mg daily dose. The combination cohort with methotrexate explored potential drug interactions, given methotrexate's frequent use in treating chronic inflammatory conditions.

According to David Domzalski, President and CEO of VYNE, the trial's PK, pharmacodynamic, and safety data support further development of VYN202 as a potential treatment for immune-mediated diseases. The drug has been designed to mitigate adverse events associated with earlier BET inhibitors, and the Phase 1a trial results validate the company's drug design approach. VYNE plans to finalize clinical trial plans for VYN202, focusing on longer treatment durations.

VYN202 is described as a promising BET inhibitor with high selectivity and potency for BD2 over BD1, distinguishing it structurally from VYNE's pan-BET inhibitor, VYN201. This differentiation aims to provide a more convenient non-biologic treatment option for acute and chronic management of immune-mediated conditions, potentially overcoming the limitations of earlier BET inhibitors through improved selectivity and alternative administration routes.