TYK2 Inhibitors Redefine Systemic Options in Moderate-to-Severe Psoriasis: Mechanism, Selectivity, and Long-Term Response
At the Fall Clinical 2025 session, “Seminar-in-Depth: Encapsulating Progress with New and Emerging TYK2 Inhibitors for Psoriasis,” presenters James Q. Del Rosso, DO, and Benjamin Lockshin, MD, delivered an evidence-anchored discussion of TYK2 inhibitors and their positioning in the therapeutic landscape. The session clarified mechanistic distinctions, clinical relevance, and patient-centered endpoints, with a strong emphasis on selectivity, durability, and the evolving role of oral agents in moderate-to-severe psoriasis.
Dr Lockshin opened the session by reviewing a representative case of a 28-year-old man with 11% body surface area (BSA) involvement and severe itch in sensitive areas. The patient had cycled through topical therapies with limited relief. “I would’ve jumped right to a systemic agent,” Dr Lockshin noted, underscoring a shift in treatment philosophy toward earlier systemic intervention in high-burden presentations.
Dr Del Rosso followed with an explanation of the key differences between TYK2 and other Janus kinases (JAK1/2/3). TYK2 is primarily involved in IL-12, IL-23, and type I interferon signaling—pathways central to psoriasis—whereas JAK1/2/3 regulate broader functions like hematopoiesis and lipid metabolism.
“What sets TYK2 inhibition apart is not only what it inhibits, but how it inhibits it,” Dr Del Rosso explained. “If the drug binds to the regulatory domain, it stays selective for TYK2. If it binds to the active domain, it can cross-react with other JAK pathways.”
The current approved TYK2 inhibitor, deucravacitinib, uses an allosteric mechanism, avoiding cross-target effects and contributing to its favorable safety profile. Selectivity, the presenters emphasized, is foundational to both efficacy and tolerability.
They revisited cytokine signaling to frame TYK2’s place in the psoriasis cascade. “Biologics act extracellularly, while small molecules like TYK2 inhibitors act intracellularly,” Dr Lockshin said. He walked attendees through the IL-23 receptor binding process: dimerization, kinase recruitment (e.g., TYK2), phosphorylation, and STAT activation—all culminating in gene transcription of pro-inflammatory cytokines.
Drugs with poor selectivity—so-called “dirty bombs,” as Dr Lockshin called them—may inhibit beneficial processes and cause off-target effects. “This agent binds TYK2 without JAK crossover,” he stressed, “which is critical for doing exactly what we want: decreasing inflammation in psoriasis without triggering unrelated side effects.”
The conversation shifted to clinical trial data for deucravacitinib, the first and only approved TYK2 inhibitor. In phase 3 trials, the agent outperformed apremilast and showed durable efficacy:
- At 16 weeks, 53% to58% of patients achieved Psoriasis Area and Severity Index (PASI) 75, and 55% reached an Investigator’s Global Assessment score of 0/1
- At 24 weeks, ~70% achieved PASI 75 in the POETYK-1 study
- At 5 years, about 50% of patients maintained PASI 90, using multiple statistical imputations (as-observed, non-responder imputation, and multiple imputation)
“The steady state is around 24 weeks,” Dr Lockshin said. “I tell patients: if you’re doing well at 24 weeks, and still well at 12 months, there’s a good chance you’ll continue to do well for years.”
Dr Del Rosso highlighted the importance of consistency across statistical models. “Whether it’s as-observed or imputed data, the results hold up,” he said. “That’s important when patients inevitably miss visits.Real-world performance still aligns with clinical trial results.”
The panel noted the challenges in treating high-impact anatomic sites. Dr Lockshin presented a scalp psoriasis case showing significant clearance by week 24. “These areas are tough to treat, and they upstage patients,” he said. International Psoriasis Council guidelines now factor location, treatment history, and impact, not just BSA.
Dr Del Rosso agreed, referencing atopic dermatitis parallels. “Like in chronic hand eczema, appearance doesn’t always reflect the pain or functional impairment,” he said. Patients with fissures or palm involvement may not appear severely affected but may have profound quality-of-life burden.
Dr Lockshin shared long-term follow up of the earlier case, with post-inflammatory erythema and complete disease control. “This gentleman’s life has changed,” he said.
Dr Del Rosso highlighted a shift in understanding patient-reported symptoms, particularly itch, which was historically underappreciated in psoriasis. “We were taught that itching wasn’t common in psoriasis,” he said. “But that’s absolutely not true.”
The rise of patient-reported outcomes in trials and practice has changed clinician understanding. “They’ve humbled us,” Dr Del Rosso added. “We’re learning that what we thought we knew doesn’t always match what patients experience.”
Drs Del Rosso and Lockshin concluded by encouraging clinicians to embrace the evolving role of oral TYK2 inhibitors in moderate-to-severe psoriasis care. With increased clarity around mechanism, safety, and long-term outcomes, TYK2 inhibitors represent a powerful addition to the therapeutic toolbox, especially for patients who prioritize oral agents or have challenging-to-treat disease locations.
“These patients want to know what’s going to happen to them,” Dr Lockshin said. With deucravacitinib and emerging agents like ESK-001 in development, the TYK2 space is set to further expand, offering precision options for a broad range of clinical scenarios.
Reference
Del Rosso J, Lockshin B. Seminar-in-depth: encapsulating progress with new and emerging TYK2 inhibitors for psoriasis. Presented at: 2025 Fall Clinical Dermatology Conference. October 23–26, 2025; Virtual.
