Next-Generation TYK2 Inhibitors in Psoriasis

Key Takeaways

• Zasocitinib and envudeucitinib demonstrated levels of skin clearance previously associated primarily with biologic therapies, potentially narrowing the efficacy gap between oral and injectable treatments. 
• By targeting the TYK2 JH2 pseudokinase domain rather than the catalytic JAK domain, these agents inhibit IL-23/IL-17 signaling while preserving JAK1/2/3 pathways, potentially reducing adverse effects seen with broader JAK inhibitors. 
• The most common adverse events were mild infections, headache, nasopharyngitis, and acneiform eruptions, with no significant laboratory abnormalities or major safety signals observed to date. 
• If long-term safety and durability data remain positive, these agents could provide biologic-like efficacy with the convenience of oral administration and less intensive laboratory monitoring, potentially reshaping future psoriasis treatment algorithms.

Psoriasis is a multifactorial, chronic immune-mediated skin disease that affects approximately 2% to 3% of the global population and is associated with substantial impairment in quality of life and significant comorbidities, including psoriatic arthritis, cardiovascular disease, metabolic syndrome, depression, and anxiety.¹ For patients with moderate-to-severe disease, long-term management frequently requires systemic therapy to achieve sustained disease control and minimize cumulative inflammatory burden.

Over the past two decades, advances in psoriasis therapeutics have been driven by an improved understanding of immune signaling pathways involved in disease pathogenesis. While biologic therapies targeting tumor necrosis factor (TNF)-α, IL-17, and IL-23 have dramatically improved treatment outcomes, many patients continue to seek effective oral treatment options due to concerns regarding injections, treatment burden, cost, or accessibility.²

Among emerging oral therapies (see Table 1), tyrosine kinase 2 (TYK2) inhibition has emerged as one of the most promising therapeutic approaches. TYK2 is a member of the Janus kinase (JAK) family and plays a critical role in intracellular signaling downstream of IL-23, IL-12, and type I interferons.³ Selective inhibition of TYK2 disrupts the IL-23/IL-17 inflammatory axis central to psoriasis pathogenesis while avoiding many of the off-target effects associated with broader JAK inhibition.

Deucravacitinib became the first US Food and Drug Administration (FDA)-approved TYK2 inhibitor for moderate-to-severe plaque psoriasis in 2022 and established proof-of-concept for selective TYK2 blockade. Since then, next-generation TYK2 inhibitors have advanced through late-stage clinical development. Recent phase 3 clinical trial data suggest that zasocitinib (TAK-279) and envudeucitinib (ESK-001) may fundamentally redefine expectations for oral psoriasis therapy by achieving levels of skin clearance previously associated primarily with biologic therapies while maintaining favorable safety profiles. This review summarizes the mechanism of action, efficacy, safety, and clinical implications of these next-generation TYK2 inhibitors and discusses their potential role within the evolving psoriasis treatment paradigm.

Selective TYK2 Inhibition: Mechanism of Action

The hallmark epidermal hyperproliferation and plaque formation characteristic of psoriasis are largely driven by dysregulation of the IL-23/IL-17 inflammatory axis. Pathogenic T helper 17 (Th17) cells produce IL-17 in response to upstream cytokines, particularly IL-23, which signals through the JAK-STAT pathway.⁴ TYK2 is a member of the JAK family responsible for mediating intracellular signal transduction downstream of cytokines including IL-23, IL-12, type I interferons, and members of the IL-10 cytokine family.⁵ Given its central role in immune signaling, selective TYK2 inhibition has emerged as a promising therapeutic strategy for disrupting IL-23-mediated inflammation and limiting immune-mediated disease activity.

In contrast to traditional JAK inhibitors that target the catalytic kinase (JH1) domain, selective TYK2 inhibitors bind the regulatory JH2 pseudokinase domain. This allosteric mechanism exploits structural differences among JAK family members and confers substantially greater selectivity. Consequently, TYK2 inhibitors preserve signaling through JAK1, JAK2, and JAK3 while maintaining potent inhibition of TYK2-dependent cytokine pathways. Preservation of JAK1/2/3 signaling may reduce the risk of hematologic abnormalities, lipid elevations, thromboembolic events, and other adverse events historically associated with broader JAK inhibition.⁶

Both zasocitinib and envudeucitinib employ allosteric inhibition of the TYK2 JH2 pseudokinase domain, stabilizing an inactive conformation of TYK2 and preventing downstream STAT phosphorylation. 

Zasocitinib

Zasocitinib is a highly selective oral TYK2 inhibitor currently undergoing regulatory review for moderate-to-severe plaque psoriasis. Early phase 2 studies demonstrated robust proof-of-concept efficacy; however, the pivotal phase 3 LATITUDE PsO 3001 and PsO 3002 trials have established the agent as one of the most effective oral therapies evaluated in psoriasis to date. The LATITUDE studies were randomized, multicenter, double-blind phase 3 trials comparing once-daily zasocitinib with placebo and apremilast in adults with moderate-to-severe plaque psoriasis. Across both studies, approximately 70% of patients achieved static Physician Global Assessment (sPGA) scores of 0 or 1 at Week 16, compared with approximately 30% of patients receiving apremilast and 11% to 13% receiving placebo.⁸

PASI90 responses reached 61.3% and 51.9% across the two phase 3 studies, while complete skin clearance (Psoriasis Area and Severity Index [PASI] 100) was achieved by 25.2% to 33.4% of treated patients by Week 16. Importantly, efficacy continued to improve through Week 24, suggesting progressive disease control with continued treatment.⁸ These results significantly exceed efficacy historically reported for most oral systemic therapies and approach outcomes observed with several biologic agents. The magnitude of PASI 90 and PASI 100 responses has generated considerable enthusiasm regarding the potential of TYK2 inhibition to narrow the traditional efficacy gap between oral and injectable therapies.

Zasocitinib was generally well tolerated. The most reported adverse events included upper respiratory tract infection, nasopharyngitis, and acneiform eruptions. No major safety signals emerged during the phase 3 program, and laboratory abnormalities commonly associated with conventional JAK inhibitors were not observed.⁸

Envudeucitinib

Envudeucitinib is another highly selective oral TYK2 inhibitor that has demonstrated impressive efficacy in the phase 3 ONWARD clinical development program. The ONWARD1 and ONWARD2 trials were randomized, placebo-controlled phase 3 studies evaluating envudeucitinib in adults with moderate-to-severe plaque psoriasis. Both studies successfully met all primary and secondary efficacy endpoints.⁹

At Week 16, approximately 74% of treated patients achieved PASI 75 responses, while approximately 59% achieved sPGA scores of 0 or 1. Clinical responses continued to deepen through Week 24, with PASI 90 responses reaching 68.0% and 62.1% and PASI 100 responses reaching 41.0% and 39.5% in ONWARD1 and ONWARD2, respectively.⁹ These findings represent some of the highest levels of skin clearance reported for any oral psoriasis therapy. Beyond improvements in plaque psoriasis severity, envudeucitinib also demonstrated significant benefits in scalp psoriasis, itch reduction, and patient-reported quality-of-life measures. Clinical improvements emerged rapidly, with meaningful responses observed within the first month of treatment.⁹

The safety profile remained favorable and consistent with prior studies. Common adverse events included headache, nasopharyngitis, and upper respiratory tract infections. No major laboratory abnormalities or new safety concerns emerged during the phase 3 program.⁹

Comparative Positioning of Next-Generation TYK-2 Inhibitors 

The emergence of zasocitinib and envudeucitinib has substantially altered the therapeutic landscape of oral psoriasis treatment (see Table 2). Historically, oral systemic agents such as methotrexate, cyclosporine, acitretin, apremilast, and deucravacitinib have required varying tradeoffs between efficacy, safety, convenience, and monitoring burden. While biologic therapies have generally achieved superior skin clearance, oral therapies have remained attractive due to ease of administration and patient preference.

Phase 3 data suggest that next-generation TYK2 inhibitors may substantially narrow the efficacy gap between oral therapies and biologics. Zasocitinib achieved PASI 90 responses exceeding 50% by Week 16, while envudeucitinib achieved PASI 90 rates exceeding 60% and PASI100 rates approaching 40% by Week 24. These efficacy outcomes compare favorably with those reported historically for many biologic therapies.

Furthermore, these efficacy gains have thus far been achieved without evidence of the laboratory abnormalities or safety concerns associated with traditional JAK inhibition. If long-term safety findings remain favorable, next-generation TYK2 inhibitors may emerge as favorable oral therapeutic options for patients seeking biologic-level efficacy without injectable administration.

Safety Considerations and Laboratory Monitoring

A major distinction between selective TYK2 inhibitors and conventional JAK inhibitors lies in their mechanism of target engagement. Traditional JAK inhibitors, including tofacitinib, upadacitinib, and abrocitinib, inhibit the catalytic JH1 kinase domain and variably affect JAK1, JAK2, JAK3, and TYK2 signaling pathways. While effective, broader JAK inhibition has been associated with laboratory abnormalities including anemia, neutropenia, lymphopenia, elevated hepatic transaminases, lipid abnormalities, and creatine phosphokinase elevations. Additionally, concerns regarding serious infections, venous thromboembolism, major adverse cardiovascular events, and malignancy prompted the addition of boxed warnings across the JAK inhibitor class.¹⁰

In contrast, deucravacitinib, zasocitinib, and envudeucitinib selectively bind the regulatory TYK2 JH2 pseudokinase domain while preserving signaling through JAK1, JAK2, and JAK3. This selectivity minimizes interference with hematopoiesis, lipid metabolism, and other physiologic pathways believed to contribute to many adverse events observed with broader JAK inhibition.⁶ Clinical data to date support this mechanistic distinction. Across phase 2 and phase 3 studies of selective TYK2 inhibitors, clinically meaningful changes in hemoglobin, neutrophil counts, lymphocyte counts, platelet counts, hepatic transaminases, serum creatinine, and lipid parameters have generally not been observed.^7-9 Reported adverse events have predominantly consisted of mild-to-moderate infections, headache, nasopharyngitis, acneiform eruptions, and gastrointestinal symptoms.

From a practical standpoint, selective TYK2 inhibitors may offer an advantage over conventional JAK inhibitors by reducing the need for intensive laboratory surveillance. Although continued monitoring for infection risk remains appropriate, current evidence suggests that routine laboratory monitoring requirements may be substantially less burdensome than those associated with traditional JAK inhibitors. Nevertheless, continued post-marketing surveillance and long-term extension studies will therefore be critical to fully characterize the safety profile of next-generation TYK2 inhibitors.

Future Directions

The success of the LATITUDE and ONWARD programs has positioned TYK2 inhibition as one of the most promising areas of therapeutic development in inflammatory disease. Beyond psoriasis, TYK2 inhibitors are currently being investigated across a growing spectrum of immune-mediated disorders, including psoriatic arthritis, inflammatory bowel disease, systemic lupus erythematosus, hidradenitis suppurativa, and other chronic inflammatory conditions.

Future studies will help determine whether the efficacy observed in psoriasis can be replicated across these diseases and whether TYK2 inhibition may emerge as a broadly applicable therapeutic platform. Additionally, long-term extension studies will be critical for evaluating durability of response, treatment persistence, and cumulative safety outcomes. Head-to-head trials comparing next-generation TYK2 inhibitors against biologic therapies may ultimately determine whether these agents can challenge existing treatment hierarchies and become first-line systemic therapies for selected patients.

Conclusion

The successful phase 3 development programs for zasocitinib and envudeucitinib represent a significant advancement in psoriasis therapeutics. By selectively targeting the TYK2 JH2 pseudokinase domain, these agents provide potent suppression of IL-23-driven inflammation while preserving the selectivity advantages that distinguish TYK2 inhibition from broader JAK blockade. The efficacy demonstrated in the LATITUDE and ONWARD programs challenges traditional assumptions regarding the limitations of oral psoriasis therapies. Both agents achieved high rates of skin clearance, with envudeucitinib demonstrating PASI 100 responses approaching 40% and zasocitinib demonstrating PASI 90 responses exceeding 60% in pivotal studies. Equally important, the favorable safety and laboratory monitoring profiles observed thus far may offer a meaningful advantage over conventional JAK inhibitors. If ongoing studies continue to demonstrate durable efficacy with minimal laboratory abnormalities and low rates of serious adverse events, next-generation TYK2 inhibitors could emerge as favorable oral therapeutic options for patients seeking biologic-like efficacy without injectable administration or intensive laboratory monitoring. Overall, next-generation TYK2 inhibitors are poised to become major components of future treatment algorithms for moderate-to-severe plaque psoriasis and may ultimately continue to redefine expectations for oral systemic therapy. 

Disclosures: Calvin Nguyen, BSA, and Carlson Nguyen, BS, have no conflicts of interest to declare. Dr. Harrison Nguyen reports relationships with Abbvie, Alumis, Amgen, Apogee, Arcutis, Boehringer Ingelheim, Bristol Myers Squibb, Castle Biosciences, Galderma, Incyte, Johnson & Johnson, Leo Pharma, Novartis, Organon, Pfizer, Regeneron, Sanofi, Sun Pharmaceuticals, UCB, Takeda, Verrica Pharmaceuticals.

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