Selective TYK2 inhibition 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.

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). 

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.