Background: Envudeucitinib (formerly ESK-001) is an oral, selective small molecule allosteric inhibitor of TYK2, a validated therapeutic target for immune-mediated disease currently being investigated in adults with active systemic lupus erythematosus (SLE) in the Phase 2b LUMUS trial. In the Phase 2 STRIDE trial, envudeucitinib achieved high clinical response rates in moderate-to-severe psoriasis in a dose-dependent manner, greatest at the highest doses.

Objectives: STRIDE incorporated extensive biomarker assessments, including skin biopsies for transcriptomic profiling, to characterize cell-specific modulation of disease-relevant cytokine pathways. Importantly, this analysis also assessed signaling axes not traditionally considered central to psoriasis, such as type I interferon (IFN) activity in skin, to elucidate the broader immunologic impact of TYK2 inhibition.

Methods: Patient skin punch biopsies from 40mg twice daily, 40mg daily, and placebo dose arms were collected at baseline and Week 12 from non-lesional and lesional skin locations. Biopsies were cut in half: with one half placed in preservative for bulk RNA extraction while the other half was embedded in paraffin for spatial transcriptomics. Spatial transcriptomics were performed using the 10X Genomics Visium HD platform and analyzed with Space Ranger. Downstream analyses, including pseudobulk expression analysis at the cell-type level, was performed using the Suerat package in R.

Results: Spatial transcriptomics show high expression of type I IFN genes in keratinocytes, melanocytes, and myeloid/T cells of lesional patient samples at baseline. Expression of these markers was markedly inhibited to near non-lesional levels after 12 weeks of envudeucitinib treatment compared to placebo. Additionally, expression of genes in established type I IFN scores (DxTerity, Brkic) showed similar inhibition in lesional skin after 12 weeks of envudeucitinib administration compared to placebo. This was consistent with dose-dependent inhibition of type I IFN observed in blood.

Conclusions: In STRIDE, spatial transcriptomics showed envudeucitinib achieved robust suppression of SLE-relevant type I IFN gene expression in skin cell types that are dysregulated in immune-mediated disease such as keratinocytes and myeloid/T cell subsets. Given the central role of type I IFN gene expression in the pathogenesis of SLE, there is a mechanistic rationale to expect a clinical effect of envudeucitinib in patients with SLE, especially at higher doses. This is being investigated in the 52-week SLE LUMUS study which evaluates doses of up to 40 mg BID with a 52-week long term extension. Topline results from LUMUS are expected Q3 2026.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: Nicole Narayan Alumis, Alumis, Joshua Hoffman Alumis, Alumis, Claire L Langrish Alumis, Alumis, Raj Punwaney Alumis, Alumis, Pedro R Corpuz Jr Alumis, Alumis, Nicholas E Vlahakis Alumis, Alumis, Mera Tilley Alumis, Alumis.