Therapeutic Potential of Targeting the JAK/STAT Pathway in Psoriasis: Focus on TYK2 Inhibition

Psoriasis is an inflammatory skin disease with a chronic relapsing course and an often-detrimental impact on patients’ quality of life. Thanks to incredible advances in research over the past few decades, the therapeutic armamentarium of psoriasis is now reasonably broad and structured, with several therapeutic agents that have demonstrated successful long-term control of this condition. However, there are still unfulfilled gaps resulting from the inherent limitations of existing therapies, which have paved the way for the identification of new therapeutic strategies or the improvement of existing ones. A great deal of attention has recently been paid to the JAK/STAT pathway, playing a crucial role in chronic inflammatory skin diseases, including psoriasis. Indeed, in a disease with such a complex pathogenesis, the possibility to antagonize multiple molecular pathways via JAK/STAT inhibition offers an undeniable therapeutic advantage. However, data from clinical trials evaluating the use of oral JAK inhibitors in immune-mediated disorders, such as RA, have arisen safety concerns, suggesting a potentially increased risk of class-specific AEs such as infections, venous thromboembolism, and malignancies. New molecules are currently under investigation for the treatment of psoriasis, such as deucravacitinib, an oral selective inhibitor that binds to the regulatory domain of TYK2, brepocitinib (PF-06700841) and PF-06826647 that bind to the active site in the catalytic domain. Due to the selective TYK2 blockade allowing the inhibition of key cytokine-mediated signals, such as those induced by IL-12 and IL-23, anti-TYK2 agents appear to be very promising as the safety profile seems to be superior compared with pan-JAK inhibitors. The aim of our review is to thoroughly explore the rationale behind the usage of JAK inhibitors in PsO, their efficacy and safety profiles, with a special focus on oral TYK2 inhibitors, as well as to provide a forward-looking update on novel therapeutic strategies targeting the TYK2 pathway in psoriasis.


Introduction
Psoriasis (PsO) is a chronic immune-mediated skin disease whose pathogenesis is only partially elucidated and based on a complex interplay between environmental and genetic factors.PsO has a significant physical, emotional, and psychosocial impact on affected patients [1].Its prevalence widely varies among populations, with approximately 3% of individuals affected in the United States [2], while higher rates are observed in regions such as the Faroe Islands [3].Conversely, certain ethnicities, like the Japanese and indigenous groups such as Aboriginal Australians and South American Indians, exhibit lower prevalence rates or even a complete absence of PsO [4].
PsO can manifest at any age, and its prevalence steadily increases over the course of life [5,6].The disease can present with several clinical variants, including plaque, guttate, inverse, erythrodermic, and pustular PsO [7].Each variant typically exhibits distinct system dysregulation is the central element in PsO pathogenesis, involving a complex interaction between genetic and immunological factors [23].
The defining characteristic of PsO is persistent inflammation, which leads to excessive proliferation and abnormal differentiation of keratinocytes [24].The inflammatory pathways involved in plaque PsO and other clinical variants are numerous; they exhibit overlapping features but also distinct differences, contributing to significant variations in phenotypes and treatment responses [23].
The inflammatory process in PsO involves both innate and adaptive immunity, working in a complex feedback loop aimed at amplifying the inflammatory cascade.This results in characteristic histopathological changes, including keratinocyte proliferation with parakeratosis, angiogenesis, neutrophil infiltration, and the enrichment of Th1/Th17 cells [25,26].
The recognition of the IL-23/IL-17 axis as the primary pathogenic pathway in PsO has significantly advanced our understanding of the disease and revolutionized its treatment approach [27].The initial responders in the immune system are the cells of innate immunity, such as macrophages and dendritic cells.These cells subsequently release several mediators, including TNF-α, IL-12, IL-23, and type I interferon (IFN).Specifically, IL-12 and IL-23 are primarily synthesized by myeloid dendritic cells (mDC) [28], promoting the differentiation of Th1 and Th17 subpopulations, respectively.Conversely, type I IFNs are produced by plasmacytoid dendritic cells (PDC) [29].The activation of PDC initiates the inflammatory cascade in PsO through the secretion of type I IFN (IFN-α and IFN-β).Type I IFN signaling, particularly IFN-α, induces mDC maturation, serving as an upstream cytokine in the IL-23/IL-17 axis [30].
IL-23 and IL-12 exploit the JAK/STAT signal transduction pathway to exert their biological effects.
Therefore, the JAK/STAT pathway, regulating a multitude of cellular processes, emerges as a pivotal convergence point for cytokine signaling implicated in PsO.

Role of JAK/STAT and TYK2 Signaling Pathways in Psoriasis
The JAK/STAT signaling pathway, which is evolutionarily conserved, mediates cellular responses to a wide array of cytokines and growth factors [35].These responses encompass various fundamental cellular processes, including proliferation, differentiation, migration, apoptosis, and cell survival.The specific outcome of the JAK/STAT pathway activation is dependent on factors such as the nature of the signal, the tissue context, and the cellular environment [36].The JAK/STAT signaling pathway progresses through several sequential steps.Initially, cytokine binding triggers the dimerization of receptors and the subsequent coupling of Janus kinases.Subsequently, tyrosine residues on receptors are phosphorylated, creating binding sites for STAT proteins containing the SH2 domain [37].Once recruited, STAT proteins undergo phosphorylation and activation, resulting in the formation of functional dimers.Ultimately, these activated STAT dimers translocate into the cell nucleus, where they regulate gene expression by binding to specific DNA elements [38].Each JAK subtype contains a specific tyrosine residue for ATP-dependent phosphorylation.Typically, the enzyme is inactive and unable to bind ATP.When a cytokine binds to its receptor on the cell surface, the receptor undergoes a conformational change that allows ATP to access its binding site in the enzyme's catalytic domain, enabling it to exert its functions [39].There are four types of JAK proteins (JAK1, JAK2, JAK3, and TYK2) and seven STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6), with each STAT protein capable of binding to various JAK family members, leading to proinflammatory cellular immune responses [40].JAK1 pairs with JAK2, JAK3, and TYK2, leading to downstream signal transduction initiated by cytokine receptors [41].Heterodimers consisting of JAK2 and TYK2 have a specific function in transmitting signals mediated by type I IFN, IL-12, and IL-23 [42].Specifically, TYK2 functions as a non-receptor tyrosine kinase involved in signaling various cytokines and interferons, regulating processes such as cell growth, migration, and both innate and adaptive immune responses [43].
In detail, TYK2, interacts with receptors for various cytokines including those of the IL-12 and IL-23 family, the type I IFN family, the IL-6 family, and the IL-10 family [44].Upon binding of these cytokines and subsequent dimerization of their receptor subunits, TYK2 undergoes phosphorylation and activation, along with its partner JAKs, JAK1 and/or JAK2 [45].To better understand the role of TYK2, a study on TYK2-/-mice was conducted.Specifically, TYK2-/-mice displayed reduced responses to IFN α/β and IL-12 and a selective deficiency in STAT3 activation in these pathways [46].Further studies on TYK2-/mice confirmed that TYK2 is necessary for IL-12 and IL-23 responses and plays a role in enhancing the sensitivity of type I interferon responses, although it is not essential for IL-6 or IL-10 [44].Comprehensively, these findings revealed that TYK2 plays a crucial role in regulating immunity, impacting both innate and adaptive immune responses.
TYK2 can modulate cytokine receptor signaling through both its enzymatic activity and a kinase-independent scaffolding function [47].For example, TYK2 has been shown to be crucial for the surface expression of the human type I IFN receptor, regardless of its enzymatic activity [48].
TYK2 plays a pivotal role in the pathophysiology of PsO by modulating downstream signaling of receptors, particularly those binding to IL-12, IL-23, type I-α IFN, and IFNβ [49].These cytokines govern the functions of diverse Th cells, including Th1, Th17, and Th22 lymphocytes, all of which are integral to shaping the PsO phenotype.Indeed, experimental findings have demonstrated that mice lacking TYK2 fail to develop epidermal hyperplasia following IL-23 activation, unlike their wild-type counterparts expressing TYK2 [42].The absence of TYK2 potentially diminishes the production of PsO-related cytokines, as well as antibacterial peptides [50].The current understanding of the significant role played by TYK2 in PsO underscores its attractiveness as a target for the development of tailored inhibitors.

JAK Inhibitors in Psoriasis
Nowadays, an enhanced understanding of the cytokine signaling through the JAK-STAT pathway, has led to increased applicability of the therapeutic interventions with JAKis in multiple diseases, including dermatological conditions [51].Despite blocking this molecular cascade have shown promising results in treating both PsO and PsA, the use of JAK1/2/3 inhibitors in PsO have been primarily halted due to concerns regarding their effectiveness and safety ratio [52].
Within oral selective JAK1 inhibitors, itacitinib, abrocitinib, solcitinib, and ivarmacitinib have been investigated for the treatment of moderate-to-severe PsO in several randomized clinical trials (RCT).
The JAK1 selective inhibitor itacitinib (INCB039110) underwent a 12-week phase 2 randomized controlled trial (RCT), on 50 moderate-to-severe psoriatic patients [53].At week 4, itacitinib at a dose of 200 mg two times a day (BID) or 600 mg once a day (QD), has demonstrated a statistically significant higher efficacy in terms of percentage of patients achieving the Physician Global Assessment (PGA) 0/1 score and PASI 75 response rates compared to placebo [53].In this trial, itacitinib has shown a positive safety profile, with the most frequently reported adverse event (AE) represented by nasopharyngitis (18.4%) [53].However, no phase III clinical trials are currently investigating itacitinib in PsO.
The efficacy and safety of abrocitinib (PF-04965842) and solcitinib (GSK2586184) have been investigated in two separate 12-week phase 2 RCTs, showing promising outcomes in patients with moderate-to-severe PsO [54,55].At week 4, a greater number of patients achieved the PASI 75 response in the abrocitinib 200 mg BID group (60%), in comparison to groups receiving 200 mg QD (17%), 400 mg QD (50%), and placebo (17%) [54].As for solcitinib, 57% of patients in the 400 mg QD group achieved a PASI 75 response, with a noticeable improvement in itching and quality of life across all doses (100 mg, 200 mg, and 400 mg), compared to placebo [55].Statistically significant differences (p < 0.001) were observed for 400 mg solcitinib BID compared with placebo at weeks 4, 8, and 12 [55].However, both JAKis are no longer being studied for PsO, since abrocitinib found broader application in AD, while the prosecution of studies on solcitinib was halted due to AEs.Specifically, across all treatment groups, headache, nasopharyngitis, nausea, diarrhea, fatigue, and upper abdominal pain were the most common AEs [55].In addition, five serious AEs related to study treatments occurred, including ureteral calculus and thrombocytopenia [55].Finally, ivarmacitinib (SHR0302) is currently under investigation in phase 3 study on 444 PsA patients, primarily aimed at assessing effectiveness and safety of this drug (NCT04957550).Results of this trial are not yet available.
Filgotinib, a selective JAK1 inhibitor with minimal JAK2 activity, which is currently approved in European Union and Japan, was primarily investigated in a phase 2 RCT for PsA [56].In this trial conducted on 131 patients, filgotinib 200 mg demonstrated a significant efficacy in achieving American College of Rheumatology (ACR) 20, ACR50, and ACR70 responses, along with a cutaneous improvement measured as PASI75 at week 16, compared to placebo (80% versus 33%, respectively), with a treatment difference of 47% (95% CI 30•2-59•6, p < 0.0001) [56].Additionally, filgotinib displayed a rapid onset of action and only mild-to-moderate AEs, such as nasopharyngitis and headache, with no statistically significant difference compared to the placebo group (57% vs. 59%) [56].
The effectiveness and safety of baricitinib, an oral small molecule targeting both JAK1 and JAK2, in PsO were investigated in a phase 2b RCT [57].By week 12, greater mean changes from baseline in their PASI were reported in patients treated with 2 mg, 4 mg, 8 mg, and 10 mg daily, in comparison to placebo (p < 0.005).Furthermore, all baricitinib treated groups, except for the 2 mg dose, had higher rates of PASI 50 compared to placebo [57].Despite being well tolerated over 24 weeks, dose-dependent alterations in laboratory values were observed.Currently, baricitinib is exclusively FDA-and EMA-approved for RA, AD, and alopecia areata, with no ongoing clinical studies assessing its use in PsO or PsA.
Ruxolitinib is another JAK1 and JAK2 inhibitor, currently approved by FDA and EMA in its oral formulation for the treatment of myelofibrosis and polycythemia vera.However, its use in PsO has been limited to topical cream formulations [58].Three clinical trials involving a total of 253 participants (NCT00617994, NCT00820950, and NCT00778700) have tried to assess its efficacy and safety in PsO, showing a statistically significant improvement in total lesion score compared to vehicle [58].Moreover, ruxolitinib was found to be noninferior compared to calcipotriene and betamethasone dipropionate [58].However, it is not approved for treating psoriatic disease and there are no ongoing studies for PsO treatment.
Peficitinib (ASP015K), a new oral inhibitor primarily targeting JAK3 over JAK1 and JAK 2, underwent a 6-week phase 2a study involving 124 patients with moderate-to-severe plaque PsO [59].Considering different dosages, including 10 mg BID, 25 mg BID, 60 mg BID, 100 mg BID, and 50 mg QD, significant improvements in PASI scores were observed in comparison to placebo (p < 0.001 for all treatment groups).Similarly, improvements in PGA 0/1 and body surface area (BSA) scores were noted compared to placebo (all p < 0.001) [59].In terms of safety, peficitinib was generally well tolerated in this trial, with no serious AEs reported [59].However, currently, there are no ongoing clinical trials focused on psoriatic disease.
Tofacitinib, a JAK1/3 inhibitor, was FDA-approved in December 2017 for the treatment of patients with moderate-to-severe PsA and an inadequate response to conventional synthetic DMARDs (csDMARDs).Two double-blind placebo-controlled phase 3 RCTs (the Oral Psoriatic Arthritis triaL [OPAL] and the Broaden and Oral Psoriatic Arthritis triaL [OPAL Beyond]) [60,61] and a long-term extension analysis of up to 48 months (OPAL Balance) [62] have shown statistically significant improvements in American College of Rheumatology 20 (ACR 20) response at 3 months and over time (48 months) in patients treated with tofacitinib 5 mg and 10 mg twice daily.Although tofacitinib was not indicated for PsO treatment due to safety concerns, its clinical efficacy has been investigated in several phase I, II, and III clinical trials, showing higher PASI75 responses compared to placebo in moderate to severe plaque PsO [62][63][64][65][66]. Also, a topical formulation of tofacitinib has been tested in chronic plaque PsO in three distinct RCTs (NCT01831466, NCT00678561, and NCT01246583) [58].
Finally, the efficacy and safety of upadacitinib, an FDA-approved oral selective JAK1 inhibitor for PsA, have been assessed in two main phase 3 trials (SELECT-PsA 1 and SELECT-PsA 2) [67,68].Those trials have demonstrated efficacy of upadacitinib in skin outcomes, including PASI75/90/100 and Static Investigator Global Assessment of Psoriasis of 0 or 1 (sIGA 0/1) response rates, suggesting promising results as a future possible treatment for PsO [67,68].A list of JAKis that have been investigated in psoriasis is provided in Table 1.

TYK2 Inhibitors in Psoriasis: A New Promising Class of Therapeutic Agents
As previously mentioned, the TYK2 signaling pathway plays an essential role in psoriatic disease, since its inhibition breaks the link between IL-23 and IL-17 axis, which is crucial in PsO pathogenesis.For the first time in 2010, TYK2 was identified as a PsO susceptibly gene in a genome-wide association study, thus further supporting its importance as potential therapeutic target for PsO treatment [29].Currently, three oral inhibitors targeting TYK2 are approved or in clinical development: deucravacitinib (FDA and PDMA approved), ropsacitinib, and brepocitinib (Table 2).Figure 1 shows a schematic representation of the mechanisms of action and selectivity of the JAKis and TYK2 inhibitors investigated in moderate-to-severe PsO.
ceptibly gene in a genome-wide association study, thus further supporting its importance as potential therapeutic target for PsO treatment [29].Currently, three oral inhibitors targeting TYK2 are approved or in clinical development: deucravacitinib (FDA and PDMA approved), ropsacitinib, and brepocitinib (Table 2).
Figure 1 shows a schematic representation of the mechanisms of action and selectivity of the JAKis and TYK2 inhibitors investigated in moderate-to-severe PsO.

Deucravacitinib
Deucravacitinib (BMS-986165) is an orally, once-daily administered selective TYK2 inhibitor, approved in September 2022 at a dose of 6 mg QD by US-FDA for adult patients with moderate-to-severe plaque PsO, who are candidates for systemic therapy or phototherapy [69].Deucravacitinib binds allosterically to the regulatory pseudo kinase domain of TYK2, unlike ropsacitinib, brepocitinib, and JAKis, which target the ATP-binding active site in the catalytic domain [70][71][72].Thereby, deucravacitinib blocks the receptor-mediated conformational change of the catalytic domain required for ATP binding, effectively inhibiting TYK2 and preventing the downstream signaling of IL-23, IL-12, or type 1 interferons, which are primarily implicated in PsO pathogenesis [71,72].
In addition, from POETYK PSO-1, it emerged that the response was maintained at week 52 in participants who received continuous deucravacitinib: 65.1% and 52.7% for PASI 75 and sPGA 0/1, respectively.Conversely, patients who switched from placebo to deucravacitinib at week 16 demonstrated PASI 75 and sPGA 0/1 responses at week 52 (68.3% and 53.8%, respectively) that were comparable to patients who received continuous deucravacitinib treatment [74].Overall, deucravacitinib exhibited a good tolerability, with nasopharyngitis, headache, diarrhea, nausea, and upper respiratory tract infection reported as the most common AEs [74,75].
Consistently, those results were confirmed in a phase 3b RCT, the POETYK long-term extension (LTE) (NCT04036435), where deucravacitinib maintained efficacy and safety with no different AEs events as previously observed over 2 years [76].
Recently, Imafuku et al. [77] published a subgroup analysis from the POETYK PSO-1 study [74] assessing the efficacy and safety of decucravacitinib in a cohort of 66 Japanese patients.These patients were randomly assigned to receive either deucravacitinib 6 mg once daily (n = 32), placebo (n = 17), or apremilast 30 mg twice daily (n = 17).Remarkably, the efficacy and safety of deucravacitinib was consistent with previous findings from the POETYK PSO-1 [74].
Another phase 3 RCT (POETYK-PSO-3) is ongoing to evaluate the efficacy and safety of deucravacitinib 6 mg QD compared to placebo in subjects with moderate-to-severe plaque PsO in China, Taiwan, and South Korea.Primary outcomes of the study are represented by (sPGA) 0/1 response and PASI 75 response.Results are not available so far (NCT04167462).

Brepocitinib
Brepocitinib (PF-06700841) is a potent oral inhibitor that targets TYK2 and JAK1.This selective inhibition leads to the modulation of multiple cytokine pathways involved in the pathogenesis of several diseases.Specifically, brepocitinib has been proposed for the treatment of systemic lupus erythematosus, Crohn's disease, ulcerative colitis (UC), alopecia areata (AA), vitiligo, and hidradenitis suppurativa (HS) [79][80][81].Also, topical administration of this small molecule had been developed for atopic dermatitis [79].Currently, brepocitinib is under development for psoriatic disorders [82].In a phase 1 trial, dosages up to 100 mg QD were found to be effective and well-tolerated for moderate-to-severe plaque PsO [83].In addition, a phase 2 RCT involving 212 psoriatic patients, has shown a statistically significant decreases in PASI score with both breprocitinib 30 mg QD and 60 mg QD doses, compared to placebo at week 12 [84].Consistently, in a phase 2b RCT including 218 PsA patients, brepocitinib 30 mg and 60 mg QD demonstrated superior efficacy in PASI75 and PASI90 at week 16, compared to placebo, with sustained responses over 52 weeks [85].Interestingly, mild AEs were reported in 66% of cases through week 16, while no major AEs such as cardiovascular events, thromboembolic events, serious infections, or deaths occurred up until week 52 [85].Finally, a phase 2b RCT demonstrated that topical brepocitinib was well tolerated but did not result in significant changes in PASI scores, when administered to mild-to-moderate PsO patients, compared with vehicle [86].

Conclusions
PsO is a chronic inflammatory skin condition whose pathogenesis is mainly driven by the IL23/1L-17 axis.Biological agents provided an excellent treatment option for patients with PsO so far, as they offer a highly selective approach with a superior safety profile compared with traditional systemic agents.Currently approved biologics target extracellular cytokines that are crucial in PsO pathogenesis, such as TNF-α (adalimumab, infliximab, certolizumab and etanercept), IL-23 (ustekinumab, guselkumab, tildrakizumab and risankizumab), and IL-17 (secukinumab, ixekizumab, bimekizumab and brodalumab).Their use has revolutionized the therapeutic landscape of PsO but is still hampered by certain limitations, including cost-related issues.Moreover, response rates may vary considerably and there is still a proportion of patients resistant, intolerant, or contraindicated to multiple therapies, representing a persistent unmet clinical need.
Recently, a great deal of attention has been paid to JAK/STAT inhibitors, since the possibility to antagonize multiple molecular pathways offers an undeniable therapeutic advantage in a complex disease such psoriasis.Additionally, the oral formulation of those drugs may bring some advantages, such as no risk of immunogenicity or injection-site reactions, but also easier transportation and storage.However, data from clinical trials assessing the administration of oral JAKis in immune-mediated disorders, such as RA, have arisen safety concerns.Indeed, these trials suggested a potential increase in the risk of class-specific AEs, including serious infections, venous thromboembolism, major adverse cardiovascular events, and malignancies.Nevertheless, in other conditions, such as AD, those risks were not entirely confirmed, thus highlighting how differences in safety profiles might also mirror differences in patient characteristics across several diseases [89].TYK2 inhibitors, such as deucravactinib, brepocitinib (PF-06700841), and ropsacitinib (PF-06826647), are a promising new class of molecules that have been recently investigated for PsO, showing a rapid onset of clinical responses and early improvements in this class of patients.A higher selectivity for TYK2 over JAK 1, 2, and 3 allows for the inhibition of crucial cytokinemediated signals, such as those induced by IL-12 and IL-23, thereby reducing the likelihood of off-target effects.Indeed, there were no alarming reports of herpes zoster, opportunistic infections, thromboembolic events in TYK2 inhibitors clinical trials, in contrast to those on JAK 1, 2, and 3 inhibitors, both in PsO and in other diseases [49,90].Furthermore, no clinically significant abnormalities in laboratory parameters were observed with deucravacitinib treatment, suggesting that routine laboratory monitoring during deucravacitinib treatment may not be strictly necessary [49,90].
On this background, anti-TYK2 agents could theoretically claim a better safety profile compared with JAKis that interact with multiple molecular pathways.However, further research and surveillance are necessary to validate the properties of these drugs in order to improve the individualized approach for the management of this challenging condition as well as to better delineate their safety profile in comparison to JAKis.

Table 1 .
Emerging JAK inhibiting agents for moderate-to-severe psoriasis.