Recent advances in oral therapies for psoriasis are reshaping treatment approaches, with tyrosine kinase 2 (TYK2) inhibitors emerging as particularly promising options. These developments were presented by April W. Armstrong, MD, MPH, professor and chief of the Division of Dermatology at UCLA, at the 2025 Midwinter Clinical Hawaii Dermatology Conference.
TYK2 Inhibition: A Game-Changing Approach
Deucravacitinib, a selective TYK2 inhibitor, has demonstrated remarkable efficacy in treating moderate-to-severe plaque psoriasis. "TYK2 is important because it's an intracellular molecule that helps to transmit the signal of IL-23, which is critical to psoriasis pathogenesis," explained Dr. Armstrong. The drug's unique mechanism targets the regulatory domain of the TYK2 molecule.
The POETYK PSO-1 and PSO-2 trials revealed deucravacitinib's superior performance compared to both placebo and apremilast. At week 16, 53.6% and 58.4% of patients receiving deucravacitinib achieved static Physician's Global Assessment (sPGA) scores of 0/1, significantly outperforming apremilast's results of 32.1% and 31.0% (P < .0001).
Apremilast's Continued Role
Apremilast, an oral phosphodiesterase-4 (PDE4) inhibitor, maintains its significance in treating mild-to-moderate plaque psoriasis. The phase 3 ADVANCE trial showed that 21% of bio-naïve patients achieved an sPGA score of 0 or 1 with a ≥2-point improvement over 16 weeks. The drug remains particularly valuable for patients with a history of malignancy or those unable to tolerate systemic immunosuppressants.
Pipeline Developments
Several promising oral therapies are in development, targeting various pathways involved in psoriasis. JNJ-77242114, an IL-23 receptor blocker, has shown impressive results in the FRONTIER 2 study, with PASI 75 and PASI 90 response rates exceeding 65% and 50%, respectively, at week 52.
Second-generation TYK2 inhibitors, including zasocitinib (TAK-279) and ESK-001, are being developed with enhanced specificity to minimize off-target JAK inhibition. Phase 2b trials of zasocitinib have demonstrated significant improvements in PASI scores across multiple endpoints.
Dr. Armstrong also highlighted ongoing development of oral tumor necrosis factor (TNF) inhibitors, noting their novel mechanism of action: "This molecule interacts with soluble TNF alpha and distorts the cytokine so it cannot bind to the receptor."
Patient Selection and Clinical Implementation
For deucravacitinib, Dr. Armstrong emphasized optimal patient selection: "The sweet spot for this oral medication is someone who is systemic-naïve and their severity is more on the moderate end of the spectrum." The drug has shown particular efficacy in treating psoriasis in challenging areas, including the scalp, nails, and palmoplantar regions.
