From Convenience to Clinical Efficacy: Selective TYK2 Inhibition in Psoriasis and the Evolving Role of Next-Generation Oral Targeted Therapies

Psoriasis is a chronic, immune-mediated inflammatory skin disease requiring effective long-term systemic treatment. Current options, including using conventional small molecules and biological therapies, are limited by adverse events, suboptimal efficacy, or poor adherence due to inconvenient administration. This highlights an unmet need for safe, convenient, and effective oral self-administered dosage form therapies aligned with patient preferences. This review evaluates the mechanism, safety, and efficacy of next-generation tyrosine kinase 2 (TYK2) inhibitors and compares them to currently available therapeutic options. The pathogenesis of psoriasis is driven by chronic systemic inflammation mediated by the interleukin-23 (IL-23)/Th17/interleukin-17 (IL-17) axis. Selective TYK2 inhibitors, such as deucravacitinib, envudeucitinib, and zasocitinib, act through a unique allosteric mechanism by binding to the regulatory pseudokinase domain (JH2) rather than the enzyme's catalytic domain. This enables highly selective suppression of IL-23-mediated inflammation while mitigating systemic toxicity seen with nonselective Janus kinase (JAK) inhibitors. Clinical trials (POETYK PSO-1 and PSO-2) and long-term extension studies demonstrate that deucravacitinib provides superior efficacy compared to the first-generation oral small molecule apremilast, with high and sustained response rates. It maintains durable efficacy for up to four years in patients with moderate to severe plaque psoriasis and shows a stable long-term safety profile, with low incidence of major adverse cardiovascular events (MACEs), venous thromboembolism (VTE), serious infections, and malignancies. Selective TYK2 inhibition bridges the therapeutic gap, providing an optimal balance of efficacy and oral convenience. With the potential to improve patient adherence and quality of life, these agents represent a promising option to become a first-line oral systemic therapy for psoriasis.