TYK2 as a novel therapeutic target in psoriasis

ABSTRACT

Introduction

Psoriasis is a chronic inflammatory skin disease affecting approximately 60 million people worldwide. Genome-wide association studies (GWAS) have allowed identification of novel therapeutic targets in psoriasis including tyrosine kinase 2 (TYK2) where an exonic variant within the gene increases the risk of developing psoriasis.

Areas covered

This review discusses the role of TYK2 in psoriasis pathogenesis, how that relates to genetic variants and recently published ground-breaking clinical trials of novel TYK2 inhibitors. Keyword searches of PubMed were made until January 2023, using the terms: ‘TYK2 inhibitor,’ ‘TYK2 inhibitor AND psoriasis’ and ‘TYK2 AND GWAS.’ Articles and references have been thoroughly reviewed by the authors.

Expert opinion

The TYK2 inhibitor deucravacitinib shows promise as an effective oral agent for treating psoriasis. Longer term data are needed to know if thrombotic risk/cancer risk is distinct from other Janus kinase (JAK) inhibitors. Psoriasis is a complex genetic disease for which risk is influenced by genes and environmental factors. GWAS studies have identified several regions of DNA associated with increased risk of disease. We believe that pathway analysis by genetic and genomic means will be key to optimizing TYK2 therapy for the right person at the right time.

KEYWORDS:

• Psoriasis
• chronic plaque psoriasis
• TYK2 inhibitors
• deucravacitinib
• precision medicine

Article highlights

• There are four members of the JAK family – JAK1, JAK2, JAK3, and TYK2. JAK inhibitors mediate their effects via the JAK/STAT pathway

• Genome wide association studies have linked the TYK2 gene to psoriasis susceptibility

• Blocking TYK2 activity inhibits the major downstream signaling effects of IL-12 and IL-23, which play a critical role in multiple autoimmune diseases

• The TYK2 inhibitor deucravacitinib is more specific compared to the other JAK inhibitors, and associated with a more desirable safety profile. This oral treatment has been approved by the FDA in 2022

• The data suggest deucravacitinib avoids laboratory changes due to its selectivity for TYK2, and overall, its safety profile is different from less selective therapies

• By determining the genetic architecture of the TYK2 psoriasis pathway we may be able to score patients with an empirical genetic risk score to improve the efficacy and safety of therapies targeting this pathway

Declaration of interest

RB Warren reports research grants from AbbVie, Almirall, Amgen, Celgene, Janssen, Lilly, Leo, Novartis, Pfizer, and UCB as well as consulting fees from AbbVie, Almirall, Amgen, Arena, Astellas, Avillion, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, DiCE, GSK, Janssen, Lilly, Leo, Novartis, Pfizer, Sanofi, Sun Pharma, UCB and UNION. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed receipt of research, speaking and/or consulting support from Eli Lilly and Company, GlaxoSmithKline/Stiefel, AbbVie, Janssen, Alovtech, vTv Therapeutics, Bristol-Myers Squibb, Samsung, Pfizer, Boehringer Ingelheim, Amgen, Dermavant, Arcutis, Novartis, Novan, UCB, Helsinn, Sun Pharma, Almirall, Galderma, Leo Pharma, Mylan, Celgene, Ortho Dermatology, Menlo, Merck & Co, Qurient, Forte, Arena, Biocon, Accordant, Argenx, Sanofi, Regeneron, the National Biological Corporation, Caremark, Teladoc, BMS, Ono, Micreos, Eurofins, Informa, UpToDate and the National Psoriasis Foundation. They are a part owner of Causa Research and hold stock in Sensal Health. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.