Deucravacitinib, a TYK2 inhibitor, safety in psoriasis and psoriatic arthritis: What should a dermatologist know?

Abstract

The search for therapeutic options in psoriasis that are effective, safe and convenient for patients has led to the development of new drugs. Selective tyrosine kinase 2 (TYK2) inhibitors, namely deucravacitinib, are recent therapeutic weapons, whose role is to inhibit key cytokines, such as interleukin (IL)-12, IL-23 and type I interferon, involved in the pathogenesis of immune-mediated diseases, such as psoriasis and psoriatic arthritis. This new small molecule acts by allosteric binding to the regulatory rather than the active catalytic domain of TYK2, being more selective for TYK2 than to other JAKs, thus not affecting the JAK 1, 2 or 3 signalling pathway.1 Because of its higher selectivity, better therapeutic effects can be achieved with fewer associated adverse effects (AEs). Given the recent information available on this promising drug, this letter aims to alert dermatologists to the most frequent and relevant AEs associated with deucravacitinib. Deucravacitinib demonstrated a favourable safety profile in phase 2 and 3 clinical trials in 1723 patients with moderate-to-severe plaque psoriasis and psoriatic arthritis (Table 1). In two phase 2 trials,2, 3 the most commonly reported AEs included nasopharyngitis, upper respiratory tract infection (URTI), headache, diarrhoea and nausea. The rates of serious AEs (SAEs) and AEs leading to discontinuation were similar between placebo and active-treatment groups. No cases of clinically meaningful laboratory changes or herpes zoster were reported. When considering dermatological AEs, the occurrence of mild-to-moderate acne was higher in patients in the active-treatment group, mostly in the highest-dose group (9%), showing a dose-dependent correlation. This is in accordance and expected as other JAK inhibitors, mainly upadacitinib, present the same cutaneous AEs.4 In a 52-week phase 3 trial (POETYK PSO-1),5 which compared the efficacy and safety of deucravacitinib with apremilast and placebo in patients with psoriasis, the types and rates of AEs and SAEs were similar across the groups. The most frequent AEs were nasopharyngitis and URTI, and the frequency of discontinuations due to AEs was lower in the deucravacitinib-treated patients. Except for pericarditis and cholecystitis which occurred in 2 deucravacitinib-treated patients, all SAEs occurred in single patients, with no deaths reported in the active-treatment group. The most common laboratory abnormality was an increase in creatine phosphokinase, however, all cases were mild and resolved without treatment. There was an increase in viral infections, especially herpes zoster reactivation, with five cases reported. Nevertheless, every event was mild to moderate, localized, and followed a benign course. The phase 3 trial (POETYK PSO-2)6 showed similar results in AEs, SAEs and AEs-related discontinuation rates. There were two deaths reported in deucravacitinib-treated patients, none of which was considered treatment-related, and all SAEs occurred in single patients, except for pneumonia in three patients. Besides a slight increase in creatine phosphokinase, there were no clinically relevant laboratory changes. Herpes zoster reactivation rates were higher in the active-treatment group, with no severe cases reported. Regarding skin events, there was also an increase in acne and folliculitis. In all of the above clinical trials, no tuberculosis or opportunistic infections were reported, and malignancy, thrombosis, and cardiovascular event rates were similar between groups and in the general population. The described safety profile was consistent with a long-term extension, with no emerging safety signals.7 Overall, the use of the new TYK2 inhibitor appears to be well tolerated. Its mechanism of action provides a high degree of selectivity and reduces the off-target effects associated with other JAK inhibitors, such as laboratory changes (namely haematological parameters, lipid level or other chemistry parameters),1 which limits their use. Of note, this drug is associated with increased cutaneous AEs, mostly in the form of mild-to-moderate acne. The use of topical therapy alone for acne (e.g., adapalene and combination with benzoyl peroxide as first-line) seems to be an effective treatment for these patients, with no need to discontinue treatment with deucravacitinib.8 As this is an oral drug administered once daily, it combines convenience with a favourable efficacy and safety profile. Further clinical trials and real-world evidence are essential to support the scientific data available. Data collection: Inês Pereira Amaral. Research design: Inês Pereira Amaral. Manuscript write-up and review: Inês Pereira Amaral, Joana Antunes, Ivânia Soares, Madalena Pupo Correia, Paulo Filipe. Manuscript submission: Inês Pereira Amaral. Overall supervision: Inês Pereira Amaral, Joana Antunes, Paulo Filipe. Data validation: Joana Antunes, Ivânia Soares, Madalena Pupo Correia, Paulo Filipe. Critical revision and approval of the final version of the manuscript: Joana Antunes, Ivânia Soares, Madalena Pupo Correia, Paulo Filipe. Research idea: Paulo Filipe. No funding source. The authors declare no conflict of interest. Not applicable. The data that support the findings of this study are available from the corresponding author upon reasonable request.