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Selective TYK2 inhibition for the treatment of psoriatic disease
Ulrich Mrowietz
Paolo Gisondi
Peter Nash
Yukari OkuboDo you know... Which of the following is an allosteric TYK2 inhibitor currently in development for the treatment of psoriatic disease?
During the PsOPsA Hub Steering Committee Meeting on July 16, 2025, Paolo Gisondi, University Hospital of Verona, Verona, IT, chaired a discussion on selective TYK2 inhibition for the treatment of psoriatic disease. The discussion also featured Ulrich Mrowietz, Peter Nash, and Yukari Okubo.
Selective TYK2 inhibition for the treatment of psoriatic disease
Selective TYK2 inhibition for the treatment of psoriatic disease
Presentation
Gisondi provided an overview of TYK2 inhibitors, describing their mechanism of action and distinguishing between allosteric and orthosteric types, with a particular focus on the allosteric inhibitors deucravacitinib and zasocitinib.1
Deucravacitinib
Deucravacitinib is approved for the treatment of plaque psoriasis (PsO) based on efficacy demonstrated in the POETYK-PSO-1 (NCT03624127) and POETYK-PSO-2 (NCT03611751) trials. Two-year follow-up results from the ongoing phase IIIb, open-label POETYK PSO-LTE (NCT04036435) trial indicated that treatment with deucravacitinib maintained or further improved efficacy through Week 112 compared with the start of the extension trial (Week 52) in adults with moderate-to-severe PsO.2
Deucravacitinib has also yielded positive results in the phase III POETYK PsA-1 (NCT04908202) and POETYK PsA-2 (NCT04908189) trials, giving higher Week 16 ACR20 response rates compared with placebo.3,4
Zasocitinib
Zasocitinib is a TYK2 inhibitor in late-stage clinical development (Table 1)5–13 and has been found to be efficacious and tolerable in both PsO14 and PsA15 (Figure 1 and Figure 2).
Table 1. Zasocitinib clinical trial landscape*
Figure 1. Zasocitinib in PsO: Efficacy results from a randomized, multicenter, double-blind, placebo-controlled, phase IIb trial (NCT04999839)*
Figure 2. Zasocitinib in PsA: Efficacy results from a randomized, multicenter, double-blind, phase IIb trial (NCT05153148)*
Discussion
- The clinical utility of TYK2 inhibitors is often questioned, given their moderate efficacy (PASI 90 response rates <50%), and relatively higher incidence of AEs (e.g. folliculitis, nasopharyngitis) and infections, especially when compared with IL-23 p19 inhibitors.
- Oral administration of deucravacitinib and zasocitinib offers practical advantages, though patient preferences vary by region. Oral agents are favored in Japan and Australia for convenience, easier storage, or for patients recovering from AEs associated with biologics (especially with tumor necrosis factor inhibitors), while in Germany, injectables are preferred for their greater efficacy, less frequent dosing, and lower psychological burden.
- In Australia, oral agents remain integral to PsA management, particularly as bridging therapies before biologics. Deucravacitinib is generally well-tolerated in patients with mild-to-moderate PsA and is often used off-label in combination with traditional biologics for treatment-refractory cases.
- In Japan, apremilast is typically prescribed first due to its lower cost, with TYK2 inhibitors considered upon failure. For moderate-to-severe PsO, earlier initiation of TYK2 inhibitors is being explored, while biologics remain the preferred option in PsA.
- Real-world data from Germany indicate the highest drug survival with IL-23 p19 inhibitors, followed by IL-17 inhibitors and adalimumab. In contrast, oral treatments including apremilast and deucravacitinib show lower drug survival, due to factors such as limited efficacy and AEs, meaning they are less favorable from both clinical and economic perspectives.
This independent educational activity is supported by Takeda. All content was developed independently. The funder was allowed no influence on the content of this activity.
References
Martin G. Novel Therapies in plaque psoriasis: A review of tyrosine kinase 2 inhibitors. Dermatol Ther (Heidelb). 2023;13(2):417-435. DOI: 10.1007/s13555-022-00878-9
Lebwohl M, Warren RB, Sofen H, et al. Deucravacitinib in plaque psoriasis: 2-year safety and efficacy results from the phase III POETYK trials. Br J Dermatol. 2024;190(5):668-679. DOI: 10.1093/bjd/ljae014
van der Heijde D. Efficacy and safety of deucravacitinib up to Week 16 from POETYK PsA-1: A multicenter, randomized, double blind, placebo-controlled, phase 3 study in patients with active psoriatic arthritis. Oral Abstract #LB0001. Presented at: European Alliance of Associations for Rheumatology 2025 Congress; Jun 11–14, 2025; Barcelona, ES.
Mease PJ. Efficacy and safety of deucravacitinib up to week 52 from POETYK PsA-2: A multicenter, randomized, double-blind, placebo-controlled, phase III study in patients with psoriatic arthritis. Presentation #OP0095. Presented at: European Alliance of Associations for Rheumatology (EULAR) Congress 2025; Jun 11–14, 2025; Barcelona, ES.
ClinicalTrials.gov. Study of NDI-034858 in participants with moderate to severe plaque psoriasis. https://clinicaltrials.gov/study/NCT04999839?term=NCT04999839&rank=1. Updated Sep 28, 2023. Accessed Aug 26, 2025.
ClinicalTrials.gov. A study about how well TAK-279 Works and its safety in participants with moderate-to-severe plaque psoriasis during 52 weeks of treatment. https://clinicaltrials.gov/study/NCT06088043?term=NCT06088043&rank=1. Updated Oct 16, 2024. Accessed Aug 26, 2025.
ClinicalTrials.gov. A study about how well TAK-279 works and its safety in participants with moderate-to-severe plaque psoriasis during 60 weeks of treatment with a withdrawal and retreatment period. https://clinicaltrials.gov/study/NCT06108544?term=NCT06108544&rank=1. Updated Jan 27, 2025. Accessed Aug 26, 2025.
ClinicalTrials.gov. A study comparing zasocitinib (TAK-279) with deucravacitinib in adults with plaque psoriasis. https://clinicaltrials.gov/study/NCT06973291?term=NCT06973291&rank=1. Updated May 15, 2025. Accessed Aug 26, 2025.
ClinicalTrials.gov. A study of TAK-279 in participants with moderate-to-severe plaque psoriasis. https://clinicaltrials.gov/study/NCT06550076?term=NCT06550076&rank=1. Updated Apr 17, 2025. Accessed Aug 26, 2025.
ClinicalTrials.gov. A study of TAK-279 in adult participants with generalized pustular psoriasis or erythrodermic psoriasis. https://clinicaltrials.gov/study/NCT06323356?term=NCT06323356&rank=1#study-plan. Updated Jan 10, 2025. Accessed Aug 26, 2025.
ClinicalTrials.gov. A study to evaluate the efficacy, safety, and tolerability of NDI-034858 in participants with active psoriatic arthritis. https://clinicaltrials.gov/study/NCT05153148?term=NCT05153148&rank=1. Updated May 31, 2024. Accessed Aug 26, 2025.
ClinicalTrials.gov. A study of zasocitinib in adults with psoriatic arthritis who have not taken biologic medicines. https://clinicaltrials.gov/study/NCT06671483?term=NCT06671483&rank=1. Updated May 4, 2025. Accessed Aug 26, 2025.
ClinicalTrials.gov. A study of zasocitinib in adults with psoriatic arthritis who have or have not been treated with biologic medicines. https://clinicaltrials.gov/study/NCT06671496?term=NCT06671496&rank=1. Updated Apr 17, 2025. Accessed Aug 26, 2025.
Armstrong AW, Gooderham M, Lynde C, et al. Tyrosine Kinase 2 inhibition with zasocitinib (tak-279) in psoriasis: A randomized clinical trial. JAMA Dermatol. 2024;160(10):1066-1074. DOI: 10.1001/jamadermatol.2024.2701
Kivitz A. Efficacy and safety outcomes of TAK-279, a selective oral tyrosine kinase 2 (TYK2) inhibitor, from a randomized, double-blind, placebo-controlled phase 2b trial in patients with active psoriatic arthritis. European Alliance of Associations for Rheumatology Congress 2024. Abstract #0138; Jun 12–15, 2024; Vienna, AT.
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