Psoriasis is a chronic, immune-mediated inflammatory condition that significantly impacts patients’ quality of life. As an alternative to conventional therapies and biologics, oral small molecule inhibitors have emerged as a promising new class of treatments. Tyrosine kinase 2 (TYK2) inhibitors represent a highly selective and effective therapeutic approach.

This page provides an in-depth look at the mechanism of action, key clinical trial data, and the potential impact of this therapeutic class, with a specific focus on deucravacitinib.

Mechanism of Action

The pathogenesis of psoriasis is driven by the dysregulation of the immune system, particularly the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. This pathway mediates downstream signaling of pro-inflammatory cytokines, including interleukin (IL)-23, IL-12, and type I interferons, which are central to psoriasis inflammation.

TYK2 inhibitors are a class of agents that specifically target this pathway. They are categorized into two types based on their mechanism:

Orthosteric Inhibitors: These agents compete directly with adenosine triphosphate (ATP) to bind to the enzyme’s catalytic domain, blocking its activation.
Allosteric Inhibitors: These inhibitors, including deucravacitinib, bind to a site on the enzyme other than the active site. This allosteric binding to the regulatory domain of TYK2 prevents the necessary conformational change for activation and downstream signaling. This selective mechanism helps avoid off-target effects that may be associated with less selective JAK inhibitors.

Efficacy and Safety of Deucravacitinib

As a first-in-class, oral, once-daily, selective TYK2 inhibitor, deucravacitinib has been extensively studied in clinical trials, including Phase II, Phase III, and long-term extension trials.

Key Clinical Trial Data (POETYK-PSO-1 & POETYK-LTE)

In the Phase III POETYK-PSO-1 trial, deucravacitinib demonstrated superior efficacy compared to both placebo and apremilast.

Week 16: A higher proportion of patients treated with deucravacitinib achieved the co-primary endpoints of ≥75% reduction in Psoriasis Area and Severity Index (PASI 75) and a static Physician’s Global Assessment score of 0 or 1 (sPGA 0/1).
Long-Term Efficacy: In the POETYK-LTE trial, patients who continued deucravacitinib treatment maintained or improved their response rates up to Week 112, demonstrating sustained efficacy.

Scalp Psoriasis

A subgroup analysis of the POETYK-PSO-1 and POETYK-PSO-2 trials showed that deucravacitinib was highly effective in treating moderate-to-severe scalp psoriasis. At Week 16, a significantly higher proportion of patients treated with deucravacitinib achieved a scalp-specific Physician Global Assessment score of 0 or 1 (ss-PGA 0/1) and a ≥90% improvement from baseline in the Psoriasis Scalp Severity Index (PSSI 90) compared to placebo and apremilast.

Safety Profile

The safety profile of deucravacitinib was consistent across clinical trials. The most common adverse events (AEs) reported were mild to moderate and included upper respiratory tract infections. The overall rate of AEs was comparable between the deucravacitinib, placebo, and apremilast groups.

Clinical Impact

The convenience of a once-daily oral administration, combined with demonstrated efficacy and a favorable safety profile, positions TYK2 inhibitors as a promising therapeutic option for patients with psoriasis.

Network meta-analyses have shown that deucravacitinib can achieve similar long-term efficacy to certain biologics and is associated with higher rates of PASI 75 response compared to other oral small molecules like apremilast. This suggests that TYK2 inhibitors, particularly deucravacitinib, represent a significant advancement in the management of psoriasis.