LAUSR

Psoriasis is a common immune-mediated inflammatory disease affecting approximately 2% of individuals living in Western countries. Patients with psoriasis suffer from a multitude of comorbidities such as psoriatic arthritis, inflammatory bowel disease, anxiety and depression, metabolic syndrome and cardiovascular disease[1]. The inflammatory process in psoriasis is driven in part by pathogenic Th17 cells, which produce interleukin (IL)-17 in response to the regulatory cytokine, IL-23, along with other key players of inflammation including tumor necrosis factor α (TNF-α) and interferons[2]. The signaling of IL-23 is known to be transmitted through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway. One important JAK involved is tyrosine kinase 2 (TYK2) which makes it a suitable target for inhibition. TYK2 pairs with JAK2 for the signaling of IL-12 and −23, and TYK2 pairs with JAK1 for signaling downstream of Type 1 interferon (IFN) receptors [3,4]. TYK2 inhibition presents itself as a promising avenue for the management of psoriasis. This editorial examines the role of a new selective TYK2 inhibitor, deucravacitinib (BMS-986165), as well as reviewing its clinical efficacy and safety. As TYK2 inhibitors are a relatively new treatment modality, there is not yet a commercially available TYK2 inhibitor for clinical use. There are also other TYK2 inhibitors in development, such as brepocitinib (TYK2/JAK1) and PF06826647 (TYK2/JAK2), but deucravacitinib is furthest in development and will be the focus of this editorial. The other TYK2 inhibitors for use in dermatology have recently been reviewed[5]. Deucravacitinib is a novel, oral, selective TYK2 inhibitor with a unique mechanism of action through allosteric binding of the pseudokinase (JH2) domain which is regulatory in nature and lacks catalytic activity. This contrasts with other JAK inhibitors which bind to the adenosine triphosphate (ATP) site of the catalytic domain thereby blocking ATP and the downstream phosphorylation and signal transduction [6,7]. Cellbased assays have shown deucravacitinib has demonstrated higher selectivity for TYK2 versus JAK 1–3, reducing the chance of off-target effects [6,7]. Selective targeting of TYK2 results in the inhibition of signaling of IL-12, −23 and Type 1 IFN, the key cytokines involved in psoriasis pathogenesis. Deucravacitinib demonstrated efficacy and tolerability in two phase 2 trials investigating moderate-to-severe plaque psoriasis (NCT02931838) and active psoriatic arthritis (NCT03881059) [8,9]. Two pivotal phase 3, double-blinded, clinical trials (POETYK PSO-1, POETYK PSO-2) compared deucravacitinib 6 mg once daily (OD) to placebo and apremilast 30 mg twice daily (BID) over 52 weeks in patients with moderate-to-severe plaque psoriasis (NCT03624127, NCT03611751) [10]. POETYK PSO-1 included a total of 666 participants. The coprimary endpoints at week 16 were the proportion of participants achieving a 75% or greater reduction in the psoriasis area and severity index (PASI75) and a static physician global assessment (sPGA) 0/1. At week 16, PASI75 was reached by 58.7% receiving 6 mg OD deucravacitinib compared to 12.7% receiving placebo and 35.1% receiving apremilast (P < 0.0001). sPGA 0/1 was reached by 53.6% of participants receiving deucravacitinib compared to 7.2% receiving placebo and 32.1% receiving apremilast (P < 0.0001). The ranked secondary endpoints of PASI90 and PASI100 improvement at week 16 compared to placebo were also met[10]. By week 24, deucravacitinib was found superior to apremilast with 69% of the deucravacitinib group achieving PASI75 compared to only 38.1% of the apremilast group. Similarly, for sPGA 0/1 at week 24, 58.4% and 31.0% achieved clear or almost clear for deucravacitinib and apremilast, respectively[10]. Deucravacitinib participants who achieved PASI 75 at Week 24 and continued treatment to week 52 maintained PASI 75 response at rates of 82.5%[10]. Results for POETYK PSO-2, which enrolled 1020 participants were similar to that of POETYK PSO-1 and have also been presented but have not yet been published[10]. Eligible patients from the phase 3 program will continue to receive deucravacitinib in a longterm extension study (NCT04036435). Deucravacitinib was well tolerated and had a similar safety profile in the phase 3 trials to previously published phase 2 results. Deucravacitinib showed a similar number of adverse events (AEs) and serious AEs (SAEs) across treatment groups. In the integrated POETYK PSO-1 and POETYKPSO-2, at least one AE was reported by 55.7% of the deucravacitinib group versus 49.6% and 57.6% of the placebo and apremilast group, respectively. AEs leading to discontinuation were numerically