Tyrosine Kinase 2 Inhibitor Research Articles

Development and Therapeutic Implications of Tyrosine Kinase 2 Inhibitors.

Janus kinases (JAKs) are central components in cytokine signaling pathways. A number of small molecule JAK inhibitors have been approved to treat a wide range of inflammatory and autoimmune diseases. Due to safety concerns of pan-JAK inhibition, the thrust of current research is toward the discovery of isoform-selective JAK inhibitors. Selective inhibition of tyrosine kinase 2 (TYK2) has the potential to balance efficacy and safety. Substantial efforts have been made to develop selective TYK2 inhibitors: Deucravacitinib (BMS-986165) is a representative allosteric inhibitor that has been approved by the FDA, and ropsacitinib (PF-06826647) is an active site-directed inhibitor currently being evaluated in clinical trials. Herein, we outline the key roles of TYK2 in diseases, review the advances of selective TYK2 inhibitors, and finally discuss future perspectives and challenges in the development of TYK2 inhibitors.

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

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.

Efficacy and safety of deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, in patients with active systemic lupus erythematosus: Results from a phase 2, randomized, double-blind, placebo-controlled study

Introduction: Tyrosine kinase 2 (TYK2) mediates signaling of Type I interferons and IL-23, key cytokines involved in systemic lupus erythematosus (SLE) pathogenesis. Deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, is approved in multiple countries for the treatment of adults with plaque psoriasis. This analysis assessed the efficacy and safety of deucravacitinib in patients with active SLE.
 Methods: This 48-week, double-blind, phase 2 trial (NCT03252587) randomized patients 1:1:1:1 to deucravacitinib (3 mg BID, 6 mg BID, 12 mg QD) or placebo. Oral corticosteroid tapering was required from weeks 8-20; further tapering was optional from weeks 32-40. The primary endpoint was the proportion of patients achieving SLE Responder Index-4 (SRI[4]) at week 32. Key secondary endpoints at week 48 included percentage of patients achieving SRI(4) and decrease of ≥50% from baseline Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI-50), in patients with baseline CLASI ≥10. Change from baseline in CLASI Activity Score (CLASI-A) over time was also assessed.
 Results: Of 363 randomized patients, 275 (76%) completed 48 weeks of treatment. Baseline demographic and disease characteristics were balanced across treatment groups, with baseline mean CLASI-A scores ranging from 8.0 to 8.6. The primary endpoint at week 32 was met, with significantly greater proportions of patients in deucravacitinib 3 mg BID and 6 mg BID groups vs placebo achieving SRI(4) responses (placebo: 34.4%; deucravacitinib 3 mg BID: 58.2%, P=0.0006; 6 mg BID: 49.5%, P=0.021; 12 mg QD: 44.9%, P=0.078). Patients treated with deucravacitinib demonstrated improvement across all secondary endpoints compared with placebo. In patients with CLASI ≥10 at baseline, greater mean changes from baseline in CLASI-A were observed in deucravacitinib vs placebo over 48 weeks of treatment (placebo: 16.7%; deucravacitinib 3 mg BID: 69.6%, P=0.0006; 6 mg BID: 56.0%, P=0.0058; 12 mg QD: 62.1%, P=0.0009). Rates of adverse events (AEs), serious AEs, and AEs of interest were similar between deucravacitinib and placebo groups. Most common AEs with deucravacitinib were upper respiratory tract infection, nasopharyngitis, headache, and urinary tract infection. No deaths, major adverse cardiac events, thrombotic events, systemic opportunistic infections, or active tuberculosis occurred.
 Conclusion: Deucravacitinib demonstrated sustained, meaningful clinical efficacy in SRI(4), improvement in mucocutaneous activity as measured by CLASI-A responses, and was well tolerated in patients with active SLE up to 48 weeks.

Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, in moderate to severe plaque psoriasis: evaluation of lipid parameters in the phase 3 POETYK PSO-1 and PSO-2 trials

Introduction: Tyrosine kinase 2 (TYK2), an intracellular kinase, mediates signaling of cytokines (IL-23 and Type I interferons) involved in psoriasis pathogenesis. Deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, is approved by the US Food and Drug Administration for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Deucravacitinib was significantly more efficacious than placebo or apremilast and was well tolerated in the phase 3 POETYK PSO-1 and PSO-2 trials. We evaluated changes in lipid parameters in these trials.
 Methods: PSO-1 (NCT03624127) and PSO-2 (NCT03611751) were 52-week, double-blind trials conducted globally. Patients with moderate to severe plaque psoriasis (PASI ≥12, sPGA ≥3, BSA involvement ≥10%) were randomized 1:2:1 to oral placebo, deucravacitinib 6 mg once daily, or apremilast 30 mg twice daily. This analysis evaluated serum lipids in patients taking placebo, deucravacitinib, or apremilast during Weeks 0-16 and those taking deucravacitinib continuously during Weeks 0-52 in PSO-1 and PSO-2. Mean changes in total cholesterol, HDL cholesterol, LDL cholesterol, and triglyceride levels are reported, as are shifts from baseline in CTCAE v5 severity grade of hypercholesterolemia and hypertriglyceridemia.
 Results: 666 and 1020 patients were randomized in PSO-1 and PSO-2, respectively. Mean baseline levels of total cholesterol, HDL cholesterol, and LDL cholesterol were comparable between treatment groups. Mean changes from baseline to Week 16 were small; none was clinically meaningful. Worsening of hypercholesterolemia grade from baseline was observed with similar frequencies among patients receiving placebo, deucravacitinib, and apremilast (10.6%, 11.7%, and 8.4%, respectively); nearly all shifts were 1 grade, and there was no grade ≥3 event. Baseline triglyceride levels were near the upper limit of normal (150 mg/dL) across treatment groups. A 10.3 mg/dL increase in mean triglycerides from baseline to Week 16 was observed with deucravacitinib, but worsening in hypertriglyceridemia >1 grade from baseline was rare (1.2%) and comparable to placebo (1.4%). Most deucravacitinib-treated patients maintained the same or shifted to a lower grade of hypertriglyceridemia from baseline to Week 16. Among patients treated with deucravacitinib continuously for 52 weeks, mean changes in total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides were small. Shifts in >1 grade from baseline for hypercholesterolemia and hypertriglyceridemia were uncommon (0.2% and 1.9%, respectively). No patient discontinued deucravacitinib due to a lipid-related adverse event.
 Conclusion: There were no meaningful changes in total cholesterol, HDL cholesterol, and LDL cholesterol levels with deucravacitinib treatment. Minimal increases in mean triglyceride levels from baseline to Weeks 16 and 52 were accompanied by very few worsening shifts >1 grade.

Deucravacitinib (Sotyktu) for Plaque Psoriasis

The FDA has approved deucravacitinib (Sotyktu – BMS), an oral tyrosine kinase 2 (TYK2) inhibitor, for once-daily treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. Deucravacitinib is the first selective TYK2 inhibitor to be approved in the US for any indication.

Role of tyrosine kinase 2 signals during progression of psoriasis

Psoriasis is a skin disease characterized by scaly erythema, parakeratosis, and epidermal hyperplasia. Application of imiquimod (IMQ), a ligand for Toll-like receptor 7, produces a mouse model for psoriasis. IMQ application induces scaling, erythema, and thickness in skin lesions, and the symptoms are milder in interleukin-23 p19 (Il23p19)-deficient and Il17a-deficient mice than in wild-type mice; this suggests that the interleukin-23 (IL-23)/T helper 17 (Th17) axis and Th17 cell-secreting cytokines play essential roles in the IMQ-induced psoriasis model. It is notable that a genome-wide association study identified the human tyrosine kinase 2 (TYK2) gene within the psoriasis susceptibility locus. After IMQ application, mice lacking Tyk2, a mouse homologue of the human TYK2 gene, exhibited significantly lower symptom scores of psoriasis and diminished inflammatory cell infiltration in the skin lesions. Tyk2-deficient mice also failed to increase CD4+IL-17+ or CD4+ interferon-γ+ (IFN-γ+) T cells in the draining lymph nodes or to produce Th17 cell-related cytokines after IMQ application. Furthermore, Tyk2 deficiency led to diminished skin inflammation induced by IL-23 and IL-22 injections. These results indicate that Tyk2-mediated signals in mice contribute to multiple steps of immune and inflammatory responses during the development of psoriasis; therefore, TYK2 targeting may be a promising strategy to treat patients with psoriasis. Recent clinical trials have shown that TYK2 inhibitors have a high overall response rate with good tolerability in the management of psoriasis. This review describes the fundamental mechanisms of Tyk2 inhibition in immune/inflammatory diseases.

Trends in prescriptions of oral medications for psoriasis: A single-center retrospective study.

The systemic treatment of psoriasis has changed markedly with the introduction of many novel drugs. However, clinicians have had limited opportunities to evaluate these new therapies. One of the new drugs, apremilast (a phosphodiesterase-4 inhibitor), was approved in 2017 in Japan. We previously reported oral treatment for psoriasis before the introduction of apremilast. In this study, we investigated the impact of apremilast on oral medication for psoriasis by comparing data obtained before and after apremilast became available. This retrospective study enrolled patients who visited the Department of Dermatology, Fukuoka University Hospital, who were diagnosed with psoriasis and treated with anti-psoriatic oral medications. Patients were divided into two groups: Group 1, who first visited our clinic between January 2010 and March 2016; and Group 2, who first visited our clinic between April 2016 and March 2022. The information collected included patient demographics, drug use (apremilast, cyclosporine, methotrexate, and etretinate), and treatment duration. In Group 1 (n=149 patients), cyclosporine, methotrexate, and etretinate were prescribed to 59.1%, 16.6%, and 24.3% of the patients, respectively. In Group 2 (n=129 patients), apremilast was prescribed to 52.5% of patients, while the number of prescriptions for cyclosporine and etretinate had decreased to 17.1% and 8.3%, respectively. The number of methotrexate prescriptions did not change significantly. Apremilast, methotrexate, and etretinate had longer continuation rates than cyclosporine in Group 2. In conclusion, apremilast replaced cyclosporine and etretinate mainly because of its better safety profile, whereas methotrexate remained in constant demand in both eras. New oral treatments for psoriasis, such as tyrosine kinase-2 inhibitors, are now in the pipeline, and our data will serve as a control for oral anti-psoriatic medicine before the coming era.

Novel TYK2 Inhibitors with an N-(Methyl-d 3)pyridazine-3-carboxamide Skeleton for the Treatment of Autoimmune Diseases.

Tyrosine kinase 2 (TYK2) mediates the interleukin-23 (IL-23), IL-12, and type I interferon (IFN)-driven signal responses that are critical in autoimmune diseases. Here, a series of novel derivatives with an N-(methyl-d 3)pyridazine-3-carboxamide skeleton that bind to the TYK2 pseudokinase domain were designed, synthesized, and evaluated. Among them, compound 30 demonstrated more excellent inhibitory potency against STAT3 phosphorylation than the positive control deucravacitinib. In addition to JAK isoform selectivity, compound 30 exhibited good in vivo and in vitro pharmacokinetic properties. Furthermore, compound 30 was orally highly effective in both IL-23-driven acanthosis and anti-CD40-induced colitis models. Together, these findings support compound 30 as a promising candidate for therapeutic applications in autoimmune diseases.

S876 Efficacy of Deucravacitinib, an Oral, Selective, TYK2 Inhibitor, in Patients With Moderately to Severely Active Ulcerative Colitis and Prior Exposure to Biologic Therapy: Subanalysis From the Phase 2 LATTICE-UC Study

Introduction: Deucravacitinib (DEUC) is an oral, selective, allosteric inhibitor of tyrosine kinase 2 (TYK2), which mediates signaling of key cytokines in UC pathogenesis. In a phase 2 trial of DEUC in moderate to severe active UC, the primary endpoint was not met; however, a treatment effect was observed in patients with prior exposure to ≥1 biologic agent. Methods: LATTICE-UC (NCT03934216), a double-blind phase 2 trial, randomized patients with moderate to severe active UC (modified Mayo score [MMS] 5-9 with endoscopic score [MES] ≥2, rectal bleeding score [RBS] ≥1, stool frequency score [SFS] ≥2) 2:1 to DEUC 6 mg or placebo (PBO) twice daily (BID). This post-hoc analysis in biologic-exposed patients assessed clinical remission (MMS ≤2, with SFS ≤1, RBS=0, MES ≤1); clinical response (decrease from baseline [BL] in MMS ≥2 points and ≥30% with decrease in RBS ≥1 point or absolute RBS ≤1); endoscopic improvement (MES ≤1); and change from BL (CFB) in symptomatic Mayo score (RBS + SFS). Colonic tissue transcriptomes were assessed via bulk RNA sequencing in a subset of biologic-exposed patients (DEUC n=17; PBO n=9). Differential expression with limma-voom and pathway enrichment analysis via Gene Set Enrichment Analysis were performed. Results: Of 131 patients randomized, 48 (36.6%) were biologic-exposed (DEUC, 32/88 [36.4%]; PBO, 16/43 [37.2%]). At week 12, higher response rates were seen in patients receiving DEUC vs PBO in clinical remission (16.1% vs 0.0%), clinical response (29.0% vs 12.5%), and endoscopic improvement (25.8% vs 12.5%). Greater mean CFB in symptomatic Mayo score was observed at week 12 with DEUC (-2.1) vs PBO (-0.1) (Table). Type I interferon (IFN)‒regulated genes (IRG) were significantly reduced in colonic tissues at week 12 compared to BL in DEUC (FDR < 0.1) but not in PBO. Pathway enrichment analysis confirmed that the IFN pathway was down-regulated with DEUC treatment. In patients receiving DEUC who achieved clinical response at week 12, IRG expression was reduced compared with nonresponders; similar trends were seen in clinical remitters and in endoscopic improvers. Conclusion: Biologic-exposed patients treated with DEUC had greater improvements in clinical outcomes compared to PBO and had greater decreases in colonic IRG. The biomarker decreases were associated with clinical response or remission, suggesting inhibition of TYK2 pathways may be beneficial for UC. These results provide evidence the target was engaged and suggest a higher dose may have greater efficacy. Table 1. - Clinical Endpoints at Week 12 in Bio-Exposed Patients Endpoint Deucravacitinib6 mg BID (n = 31) Placebo (n = 16) Clinical remission response rate, mean 16.1% 0.0% Clinical response rate, mean 29.0% 12.5% Endoscopic improvement response rate, mean 25.8% 12.5% Symptomatic Mayo score, mean change from baseline (a) -2.1% -0.1 Table: (a) n for deucravacitinib and placebo is 16 and 9, respectively. BID, twice daily.

TYK2 in Immune Responses and Treatment of Psoriasis.

Tyrosine kinase 2 (TYK2), a key part of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, plays an integral role in the differentiation and immune responses of intrinsic immune cells and regulates the mediation of cytokines. TYK2 leads to inflammatory cascade responses in the pathogenesis of immune-mediated inflammatory diseases (IMIDs), especially psoriasis. Small-molecule TYK2 inhibitors are considered to be an effective strategy for modulating psoriasis. Here, we attempt to review the pro-inflammatory mechanisms of the JAK-STAT signaling pathway, the regulatory roles of TYK2 in the pathogenesis of psoriasis, and provide updates on ongoing and recently completed trials of TYK2 inhibitors.

317 Characterization of pharmacokinetics, pharmacodynamics, tolerability and clinical activity in phase I studies of the novel allosteric tyrosine kinase 2 (TYK2) inhibitor NDI-034858

Tyrosine kinase 2 (TYK2) is an obligate mediator of signaling via IL-23, IL-12 and the type I interferon receptors, and is a validated therapeutic target in psoriasis and psoriatic arthritis. NDI-034858 is a novel, oral, allosteric, investigational TYK2 inhibitor with high selectivity for TYK2 over JAK1, JAK2, and JAK3 kinases. NDI-034858 was studied in multiple placebo-controlled Phase I studies. These included two trials in healthy volunteers receiving single ascending doses (six dose groups, N = 5-6 per group; versus placebo, N = 12) and multiple ascending doses (four dose groups, N = 6 per group; versus two placebo groups, N = 4 per group) for 2 weeks. NDI-034858 was also studied in patients with moderate to severe psoriasis treated daily for 4 weeks (three dose groups, N = 21 total; versus placebo, N = 5). Across the studies, the pharmacokinetic parameters of NDI-034858 were calculated. Pharmacodynamic effect was tested in a cytokine-induced ex vivo assay using whole blood samples, which demonstrated that exposure to NDI-034858 correlated with activity. No serious adverse events or deaths were observed in the studies, and treatment emergent adverse events were as expected for inhibition of TYK2. Exploratory efficacy endpoint analysis in patients with moderate to severe psoriasis using the Psoriasis Area and Severity Index (PASI) score suggested improvement in the disease. These data support further development of NDI-034858. Phase 2b trials in psoriasis and psoriatic arthritis are ongoing.

700 Tyrosine kinase 2 inhibition rescues hair follicles from IL-12–mediated immune privilege collapse and reverses the induction of human alopecia areata in a humanized mouse model

Alopecia areata (AA), an immune-mediated hair follicle (HF) disorder, leads to hair loss due to collapse of the HF’s physiologic immune privilege (IP), induced by elevated IFNγ levels and a Tc1-driven inflammatory response dominated by T and NK cells. Given that IL-12 signaling is crucial for IFNγ production by immune cells, we explored for the first time the role of IL-12 and tyrosine kinase 2 (TYK2)-mediated signaling in the induction and prevention of HF IP collapse via a selective TYK2 inhibitor (BMS-986202).

Novel Small Molecule Tyrosine Kinase 2 Pseudokinase Ligands Block Cytokine-Induced TYK2-Mediated Signaling Pathways.

A member of the Janus kinase (JAK) family, Tyrosine Kinase 2 (TYK2), is crucial in mediating various cytokine-signaling pathways such as interleukin-23 (IL23), interleukin-12 (IL12) and type I Interferons (IFN) which contribute to autoimmune disorders (e.g., psoriasis, lupus, and inflammatory bowel disease). Thus, TYK2 represents an attractive target to develop small-molecule therapeutics for the treatment of cytokine-driven inflammatory diseases. Selective inhibition of TYK2 over other JAK isoforms is critical to achieve a favorable therapeutic index in the development of TYK2 inhibitors. However, designing small molecule inhibitors to target the adenosine triphosphate (ATP) binding site of TYK2 kinase has been challenging due to the substantial structural homology of the JAK family catalytic domains. Here, we employed an approach to target the JAK homology 2 (JH2) pseudokinase regulatory domain of the TYK2 protein. We developed a series of small-molecule TYK2 pseudokinase ligands, which suppress the TYK2 catalytic activity through allosteric regulation. The TYK2 pseudokinase-binding small molecules in this study simultaneously achieve high affinity-binding for the TYK2 JH2 domain while also affording significantly reduced affinity for the TYK2 JAK homology 1 (JH1) kinase domain. These TYK2 JH2 selective molecules, although possessing little effect on suppressing the catalytic activity of the isolated TYK2 JH1 catalytic domain in the kinase assays, can still significantly block the TYK2-mediated receptor-stimulated pathways by binding to the TYK2 JH2 domain and allosterically regulating the TYK2 JH1 kinase. These compounds are potent towards human T-cell lines and primary immune cells as well as in human whole-blood specimens. Moreover, TYK2 JH2-binding ligands exhibit remarkable selectivity of TYK2 over JAK isoforms not only biochemically but also in a panel of receptor-stimulated JAK1/JAK2/JAK3-driven cellular functional assays. In addition, the TYK2 JH2-targeting ligands also demonstrate high selectivity in a multi-kinase screening panel. The data in the current study underscores that the TYK2 JH2 pseudokinase is a promising therapeutic target for achieving a high degree of biological selectivity. Meanwhile, targeting the JH2 domain represents an appealing strategy for the development of clinically well-tolerated TYK2 inhibitors that would have superior efficacy and a favorable safety profile compared to the existing Janus kinase inhibitors against autoimmune diseases.

Efficacy and safety of selective TYK2 inhibitor, deucravacitinib, in a phase II trial in psoriatic arthritis

ObjectiveTo evaluate the efficacy and safety of an oral selective tyrosine kinase 2 (TYK2) inhibitor, deucravacitinib, in patients with active psoriatic arthritis (PsA).MethodsIn this double-blind, phase II trial, 203 patients...

Selective TYK2 inhibitors as potential therapeutic agents: a patent review (2019–2021)

ABSTRACT Introduction Tyrosine kinase 2 (TYK2) is a member of the JAK family class of kinases that is responsible for mediating the immune response to IL-12, IL-23, and IFNα. The therapeutic value of targeting this pathway in autoimmune diseases is supported by human genetics and multiple companies are developing small-molecule inhibitors as potential new treatments. Areas covered This article seeks to give a comprehensive review of the applications related to selective small-molecule TYK2 inhibition since the last publication in this journal in 2019. Recent regulatory activity, emerging clinical data, and new companies entering the clinic with selective TYK2 inhibitors will also be discussed. Expert opinion Over the past 3 years there has been an increase in the number of companies and patent applications claiming selective TYK2 inhibitors. Deucravacitinib, an allosteric TYK2 inhibitor discovered by BMS, is the most advanced molecule in clinical development and in 2021, it received positive phase 3 data for the treatment of plaque psoriasis. . This development has spurred a renewed interest in targeting TYK2 with selective inhibitors and several new molecules have recently entered phase 1 trials. The research interest in this area is likely to further increase as additional clinical data with deucravacitinib and other TYK2 inhibitors continue to emerge.

TYK2 in Cancer Metastases: Genomic and Proteomic Discovery.

Simple SummaryCancer deaths are predominantly due to metastases rather than the primary tumors, and thus there is an urgent need for the discovery of more effective drug therapies for metastatic cancer. Recent genomics, transcriptomics, and proteomics studies have identified tyrosine kinase 2 (TYK2) as an oncogene that is frequently mutated or overexpressed in many types of cancer and metastases. A member of the Janus kinase (JAK) family, TYK2 mediates the signals of numerous cytokines involved in immune and inflammatory signaling. In cancer cells, activation of TYK2 can lead to decreased cell death as well as increased cell growth and invasion. Multiple drugs that specifically block TYK2 or JAKs are currently FDA-approved or in clinical trials. In this review, we provide an overview of the screening, molecular, and animal studies that have characterized the role of TYK2 in cancer and metastases, and the potential of TYK2 inhibitors as effective cancer therapies. Advances in genomic analysis and proteomic tools have rapidly expanded identification of biomarkers and molecular targets important to cancer development and metastasis. On an individual basis, personalized medicine approaches allow better characterization of tumors and patient prognosis, leading to more targeted treatments by detection of specific gene mutations, overexpression, or activity. Genomic and proteomic screens by our lab and others have revealed tyrosine kinase 2 (TYK2) as an oncogene promoting progression and metastases of many types of carcinomas, sarcomas, and hematologic cancers. TYK2 is a Janus kinase (JAK) that acts as an intermediary between cytokine receptors and STAT transcription factors. TYK2 signals to stimulate proliferation and metastasis while inhibiting apoptosis of cancer cells. This review focuses on the growing evidence from genomic and proteomic screens, as well as molecular studies that link TYK2 to cancer prevalence, prognosis, and metastasis. In addition, pharmacological inhibition of TYK2 is currently used clinically for autoimmune diseases, and now provides promising treatment modalities as effective therapeutic agents against multiple types of cancer.

From Science to Success? Targeting Tyrosine Kinase 2 in Spondyloarthritis and Related Chronic Inflammatory Diseases.

Spondyloarthritis (SpA) is a family of inflammatory arthritic diseases, which includes the prototypes of psoriatic arthritis and ankylosing spondylitis. SpA is commonly associated with systemic inflammatory diseases, such as psoriasis and inflammatory bowel disease. Immunological studies, murine models and the genetics of SpA all indicate a pathogenic role for the IL-23/IL-17 axis. Therapeutics targeting the IL-23/IL-17 pathway are successful at providing symptomatic relief, but may not provide complete protection against progression of arthritis. Thus there is still tremendous interest in the discovery of novel therapeutic targets for SpA. Tyrosine kinase 2 (TYK2) is a member of the Janus kinases, which mediate intracellular signaling of cytokines via signal transducer and activator of transcription (STAT) activation. TYK2 plays a crucial role in mediating IL-23 receptor signaling and STAT3 activation. A plethora of natural mutations in and around TYK2 have provided a wealth of data to associate this kinase with autoimmune/autoinflammatory diseases in humans. Induced and natural mutations in murine Tyk2 largely support human data; however, key inter-species differences exist, which means extrapolation of data from murine models to humans needs to be done with caution. Despite these reservations, novel selective TYK2 inhibitors are now proving successful in advanced clinical trials of inflammatory diseases. In this review, we will discuss TYK2 from basic biology to therapeutic targeting, with an emphasis on studies in SpA. Seminal studies uncovering the basic science of TYK2 have provided sound foundations for targeting it in SpA and related inflammatory diseases. TYK2 inhibitors may well be the next blockbuster therapeutic for SpA.

Selective Tyrosine Kinase 2 Inhibition for Treatment of Inflammatory Bowel Disease: New Hope on the Rise.

Conventional systemic and biologic agents are the mainstay of inflammatory bowel disease (IBD) management; however, many of these agents are associated with loss of clinical response, highlighting the need for effective, novel targeted therapies. Janus kinase (JAK) 1-3 and tyrosine kinase 2 (TYK2) mediate signal transduction events downstream of multiple cytokine receptors that regulate targeted gene transcription, including the interleukin-12, interleukin-23, and type I interferon receptors for TYK2. This review summarizes the role of TYK2 signaling in IBD pathogenesis, the differential selectivity of TYK2 inhibitors, and the potential clinical implications of TYK2 inhibition in IBD. A PubMed literature review was conducted to identify studies of JAK1-3 and TYK2 inhibitors in IBD and other immune-mediated inflammatory diseases. Key efficacy and safety information was extracted and summarized. Pan-JAK inhibitors provide inconsistent efficacy in patients with IBD and are associated with toxicities resulting from a lack of selectivity at therapeutic dosages. Selective inhibition of TYK2 signaling via an allosteric mechanism, with an agent that binds to the regulatory (pseudokinase) domain, may reduce potential toxicities typically associated with JAK1-3 inhibitors. Deucravacitinib, a novel, oral, selective TYK2 inhibitor, and brepocitinib and PF-06826647, TYK2 inhibitors that bind to the active site in the catalytic domain, are in development for IBD and other immune-mediated inflammatory diseases. Allosteric TYK2 inhibition is more selective than JAK1-3 inhibition and has the potential to limit toxicities typically associated with JAK1-3 inhibitors. Future studies will be important in establishing the role of selective, allosteric TYK2 inhibition in the management of IBD.

Safety, tolerability, efficacy, pharmacokinetics, and pharmacodynamics of the oral TYK2 inhibitor PF-06826647 in participants with plaque psoriasis: a phase 1, randomised, double-blind, placebo-controlled, parallel-group study

Summary Background Blockade of tyrosine kinase 2 (TYK2) signalling has previously shown therapeutic potential in the treatment of psoriasis. The primary objective of this study was to assess the safety and tolerability of the TYK2 inhibitor PF-06826647. Methods This phase 1, randomised, double-blind, placebo-controlled, parallel-group study assessed once daily oral dosing of PF-06826647 in participants with plaque psoriasis, at a single clinical research site in the USA. Eligible participants (aged 18–65 years) had plaque psoriasis covering at least 15% of total body surface area and a psoriasis area and severity index (PASI) score of at least 12 at baseline. Participants received PF-06826647 (100 mg or 400 mg), or placebo once daily for 28 days. Using a computer-generated randomisation schedule with a block size of 3, participants were sequentially randomly assigned into two cohorts by the investigator; in the first cohort, participants were randomly assigned in a 2:1 ratio to receive either oral PF-06826647 400 mg or placebo once daily, whereas participants in the second cohort were randomly assigned in a 2:1 ratio to receive either oral PF-06826647 100 mg or placebo once daily. Site, investigator, Pfizer personnel, and participants, were masked to treatment. The primary endpoint was the safety of multiple-dose PF-06826647 in participants with plaque psoriasis. Secondary endpoints were the characterisation of the pharmacokinetics of multiple-dose PF-06826647 in plasma and the change in PASI score at day 28. Safety analysis was done in all participants who received at least one dose of study drug. Efficacy analysis was done in all participants who received at least one dose of randomised study drug, and had a baseline and at least one post-baseline measurement. This study is registered as a randomised, controlled trial with ClinicalTrials.gov , NCT03210961 and is completed. Findings The trial was done between July 14, 2017, and Jan 25, 2019. Overall from 91 participants assessed, 40 participants with moderate-to-severe psoriasis were randomly assigned to treatment (placebo 14 [35%] of 40; PF-06826647 100 mg, 11 [28%] of 40; PF-06826647 400 mg, 15 [38%] of 40). Treatment-emergent adverse events (TEAEs) were reported in 12 (80%) of 15 participants in the PF-06826647 400 mg group, seven (50%) of 14 in the placebo group and five (45%) of 11 in the 100 mg group. All TEAEs were mild in severity, except one moderate TEAE of vomiting reported in the placebo group. There were no deaths, serious TEAEs, severe TEAEs, dose reductions, or temporary discontinuations. Compared with placebo, the change from baseline in PASI score at day 28 showed a significant reduction in least squares mean difference for the PF-06826647 400 mg group (−13·05; 90% CI −18·76 to −7·35; p=0·00077) but not for the PF-06826647 100 mg group (−3·49; −9·48 to 2·50; p=0·33). Both the area under the concentration–time curve over the dosing interval and the maximum concentration increased in a less than dose proportional manner with increasing dose from 100 mg to 400 mg PF-06826647. Interpretation PF-06826647 showed significant improvement in disease activity within 4 weeks of dosing with an acceptable safety profile. PF-06826647 holds promise over conventional oral treatments for psoriasis that have shown limited efficacy or unfavourable safety profiles. Funding Pfizer.

13601 BMS-986165, an oral selective TYK2 inhibitor, in the treatment of moderate to severe psoriasis as assessed by the static Physicians Global Assessment/body surface area composite tool, a clinically useful alternative to the Psoriasis Area and Severity Index score

Background: In a phase 2 trial of the oral, selective tyrosine kinase 2 (TYK2) inhibitor BMS-986165, in 267 patients with moderate to severe plaque psoriasis (NCT02931838), 67%-75% achieved PASI75 at wk 12 (primary end point) at doses ≥3 mg twice daily (bid) versus 7% with placebo (P < .001). The product of the static Physicians Global Assessment and body surface area (sPGA×BSA) accounts for extent and severity of psoriasis and may be a simple, clinically useful alternative to PASI.