Envudeucitinib, a Potent, Next-Generation, Allosteric Inhibitor of TYK2: A Narrative Review

Psoriasis is an immune-mediated inflammatory disease (IMID) impacting more than 40 million people globally and characterized by skin plaques, elevated systemic levels of inflammatory cytokines, and psychosocial burden. Many patients remain undertreated. Available topical and oral treatments are typically less effective than biologic therapies and have safety considerations that may limit long-term use. Tyrosine kinase 2 (TYK2), a Janus kinase (JAK) enzyme, is a validated target in psoriasis and is also being investigated for other IMIDs. TYK2 mediates signaling of interleukin (IL)-23 and IL-17, central proinflammatory cytokines whose dysregulation contributes to chronic inflammation associated with psoriasis, and IL-12 and type I interferons (IFNs). Therefore, selective inhibition of TYK2 offers more targeted immunomodulation vs. broader immunosuppression associated with JAK 1/2/3 inhibition. Envudeucitinib (formerly ESK-001) is a next-generation, oral, allosteric TYK2 inhibitor under investigation for the treatment of psoriasis and systemic lupus erythematosus. Envudeucitinib selectively binds to the unique regulatory domain (JAK homology 2 [JH2]) of TYK2 to induce a conformational change that prevents ATP from binding the catalytic domain (JAK homology 1 [JH1]), thereby inactivating TYK2. This approach avoids adverse events associated with classic JAK inhibition. In preclinical and phase 1 studies, oral administration of envudeucitinib twice daily achieved maximal (90% inhibitory concentration [IC₉₀]) TYK2 inhibition over 24 h, highlighting a level of sustained target engagement that distinguishes envudeucitinib from other oral immunomodulators. Envudeucitinib decreased type I IFN gene signatures in whole blood and pSTAT1 in T cells. These findings were corroborated in a phase 2 study in adults with moderate-to-severe plaque psoriasis; envudeucitinib showed maximal TYK2 inhibition at higher doses (40-80 mg daily), patients demonstrated significant and increasing efficacy responses through week 52, and the safety profile was favorable. The efficacy and safety of envudeucitinib are being further evaluated in the ongoing phase 3 ONWARD studies.