Advancing Oral Therapies in Psoriasis: Targeted Innovation for Improved Disease Control and Patient Adherence
Psoriatic disease is increasingly recognized as a systemic inflammatory condition requiring more nuanced assessment beyond body surface area alone. At a recent session led by James Krueger, MD, PhD, and Brad Glick, DO, MPH, during the 2026 Masterclasses in Dermatology Annual Meeting, evolving strategies for evaluating and treating moderate-to-severe psoriasis were highlighted, with particular attention to high-impact areas such as the scalp, face, nails, palms/soles, and genitals. Even when total body surface area involvement is limited, disease in these special sites confers disproportionate psychosocial burden, functional impairment, and quality-of-life disruption. Importantly, involvement of these areas reflects ongoing systemic inflammation and warrants consideration of systemic therapy.
Dr Krueger reviewed advances in understanding psoriasis pathophysiology, emphasizing chronic activation of type 3 immunity. IL-23 drives pathogenic type 17 T cells that produce IL-17A and IL-17F, which in turn stimulate keratinocytes to release downstream mediators such as IL-19 and IL-36, amplifying epidermal hyperplasia and inflammation. Signaling through the IL-23 receptor is critically dependent on the JAK/STAT pathway, particularly TYK2 in partnership with JAK2. While JAK1, JAK2, and JAK3 participate in broader immune and homeostatic functions, TYK2-dependent pathways are more selectively tied to IL-12, IL-23, and type-1 interferon signaling. This distinction has major therapeutic implications.
Selective inhibition of TYK2 represents a refined approach to interrupting IL-23–driven inflammation while minimizing off-target effects associated with broader JAK inhibition. Unlike traditional JAK inhibitors that bind the conserved ADP binding site in the catalytic domain, allosteric TYK2 inhibitors bind the regulatory JH2 domain. This binding prevents the conformational change required for kinase activation, effectively “locking” TYK2 in an inactive state without significantly inhibiting JAK1/2/3. As a result, deeper TYK2 inhibition can be achieved without incurring the broader safety liabilities associated with pan-JAK inhibition.
Deucravacitinib was highlighted as the first US Food and Drug Administration approved allosteric TYK2 inhibitor for psoriasis. In clinical trials, it demonstrated superior efficacy compared with apremilast and favorable durability through 52 weeks. Importantly, its selective mechanism has not been associated with the same boxed warnings observed with JAK inhibitors, reflecting minimal interference with JAK1-mediated systemic pathways.
Emerging second-generation TYK2 inhibitors aim to further enhance selectivity and potency. Zasocitinib is an investigational oral allosteric TYK2 inhibitor that blocks downstream IL-12, IL-23, and type I-interferon signaling with almost no measurable impact on JAK1/2/3. Phase 2 data demonstrate significant Psoriasis Area and Severity Index (PASI)-75 responses and encouraging safety signals, with fewer gastrointestinal adverse effects than seen with PDE4 inhibition.
Similarly, envudeucitinib (ESK-001) is a highly selective allosteric TYK2 inhibitor designed for maximal 24-hour target inhibition. Phase 2 and early phase 3 data show robust efficacy, including meaningful responses in high-impact areas such as the scalp, along with improvements in patient-reported psoriasis symptom diaries addressing redness and skin sensitivity. Through week 24, no major safety signals have emerged; commonly observed adverse events include headache and upper respiratory symptoms, with laboratory abnormalities under continued monitoring.
Orthosteric TYK2 inhibitors are also in development. Ropsacitinib binds the catalytic ADP binding pocket of TYK2 and may behave more similarly to a highly selective JAK inhibitor. While this approach offers potent inhibition, long-term safety differentiation from broader JAK inhibition remains under evaluation.
Beyond TYK2, additional intracellular targets are being explored. MK2 inhibition represents a novel strategy downstream of MAPK signaling. CC-99677, an oral irreversible MAPK-activated protein kinase 2 inhibitor, suppresses TNF and IL-17A/F production in preclinical models, although human psoriasis data are still pending.
Finally, oral peptide biologics may redefine IL-23 targeting. Icotrokinra is a first-in-class oral IL-23 receptor antagonist peptide demonstrating robust PASI responses and no significant safety signals through week 24 in phase 3 trials. Its ability to deliver biologic-level IL-23 blockade without injection may significantly impact adherence and patient preference.
Collectively, these advances signal a shift toward precision immunomodulation in psoriatic disease. Selective TYK2 inhibition provides a mechanistically focused strategy to suppress IL-23/Th17 signaling while minimizing systemic JAK-related adverse effects. As oral agents increasingly approach biologic-level efficacy, individualized therapy selection, particularly for patients with high-impact site involvement, will become central to optimizing long-term disease control and quality of life.
Reference:
Krueger J, Glick B. Advancing oral therapies in psoriasis: targeted innovation for improved disease control and patient adherence. Presented at: Masterclasses in Dermatology; February 19–22, 2026; Sarasota, FL.
