TYK2 inhibition: changing the treatment landscape for psoriasis?

Abduelmula, Abrahim; Gooderham, Melinda

doi:10.1080/1744666x.2022.2008240

Cited by 9 publications

(8 citation statements)

References 6 publications

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“…However, oral options bring some advantages, such as no risk of immunogenicity or injection-site reactions, easier transportation and storage and may be more comfortable for patients who prefer an oral treatment they can take at home or for those with trypanophobia. Although they do not need expert personnel drug administration or patient training, treatment response might be easily compromised as a result of incorrect adherence [55]. Further pharmacoeconomic studies are required.…”

Section: Discussionmentioning

confidence: 99%

Deucravacitinib for the Treatment of Psoriatic Disease

2022

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Psoriasis is an immune-mediated disease, with the interleukin (IL)-23/IL-17 axis currently considered its main pathogenic pathway. Tyrosine kinase 2 (TYK2) is responsible for mediating immune signalling of IL-12, IL-23 and type I interferons, without interfering with other critical systemic functions as other JAK proteins do. This article aims to review the current knowledge on deucravacitinib, a new oral drug that selectively inhibits TYK2, granting it a low risk of off-target effects. After good efficacy and safety results in a phase II, placebo-controlled trial, two phase III, 52-week trials evaluated deucravacitinib 6 mg against placebo and apremilast-an active comparator. POETYK PSO-1 and PSO-2 involved 1688 patients with moderate-to-severe psoriasis. After 16 weeks, in both studies, over 50% of patients treated with deucravacitinib reached PASI75, which was significantly superior to placebo and apremilast. In POETYK PSO-1, these results improved until week 24 and were maintained through week 52, with over 65% of patients achieving PASI75 at this point. A reduction in signs and symptoms was also reported by patients, with greater impact on itch. Deucravacitinib was well tolerated and safe. There were no reports of serious infections, thromboembolic events, or laboratory abnormalities, which are a concern among other JAK inhibitors. Persistent efficacy and consistent safety profiles were reported for up to 2 years. Despite advances in the treatment of psoriasis, namely among biologic agents, an oral, effective and safe new drug can bring several advantages to prescribers and patients. Further investigation is required to understand where to place deucravacitinib among current psoriasis treatment options.

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Section: Discussionmentioning

confidence: 99%

Deucravacitinib for the Treatment of Psoriatic Disease

2022

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“…[33][34][35] TYK2 pairs with JAK2 to mediate the signaling of IL-12 and IL-23 receptors. 36 As previously mentioned, IL-12 and IL-23 are two critical pathogenic mediators of psoriasis. IL-12 is essential in the differentiation and proliferation of Th1 cells that produce IFN-γ and TNF-α, and IL-23 is central to the survival and proliferation of Th17 cells.…”

Section: Jak-stat Signaling Pathway and The Role Of Tyk2 In Psoriasismentioning

confidence: 95%

“…3,24 TYK2 also pairs with JAK1 to mediate the signaling of type I IFNs receptors, namely IFNα and IFN-β. 36 Type I IFNs have several effects that also contribute to the pathogenesis of psoriasis: Th1 and Th17 cells polarization, dendritic cells maturation and activation, reduced regulatory T cells function, and increased B cells activation with subsequent antibody production. 37 In 2010, TYK2 was identified in a genome-wide association study as a psoriasis susceptibility gene.…”

Section: Jak-stat Signaling Pathway and The Role Of Tyk2 In Psoriasismentioning

confidence: 99%

Deucravacitinib in the treatment of psoriasis

Estevinho

Lé

Torres

2022

Journal of Dermatological Treatment

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Introdução: A psoríase é uma doença inflamatória crónica da pele, imunomediada e comum, que apresenta um impacto negativo e significativo na qualidade de vida dos doentes. Habitualmente, a doença moderada a grave requere o uso de terapêuticas sistémicas. Os agentes sistémicos atualmente disponíveis, apesar de serem largamente utilizados, apresentam inúmeras desvantagens. Desta forma, novos tratamentos eficazes e seguros são necessários. O deucravacitinib é um inibidor seletivo da tyrosine kinase 2 (TYK2) de administração oral, atualmente em ensaios clínicos de fase 3 para o tratamento da psoríase, que se apresenta como uma alternativa promissora às terapêuticas sistémicas disponíveis.Objetivos: Esta revisão bibliográfica visa explorar e sintetizar a literatura científica atual acerca do deucravacitinib, o seu mecanismo de ação, bem como a sua eficácia e segurança no tratamento da psoríase, apresentando e sumariando os resultados dos ensaios clínicos que têm vindo a ser publicados.Metodologia: Procedeu-se a uma pesquisa bibliográfica, recorrendo às bases de dados PubMed, Google Scholar, Science Direct, Cochrane Library e ClinicalTrials.gov. Foram selecionados artigos originais e de revisão escritos em língua inglesa ou portuguesa. A recuperação de artigos relevantes da lista de referências bibliográficas de artigos originais foi também realizada.Discussão: A patogénese da psoríase é complexa e não está totalmente esclarecida. Contudo, acredita-se que esta doença constitua um distúrbio complexo tanto do sistema imune inato como do adaptativo, em que o eixo interleucina (IL)-23/IL-17 tem um papel preponderante. A via de sinalização Janus kinase and signal transducer and activator of transcription (JAK-STAT) desempenha um papel central na sinalização intracelular de citocinas envolvidas em processos fisiológicos e patológicos, inclusive na psoríase. A TYK2, membro da família Janus kinase (JAK), está envolvida na sinalização de recetores de citocinas críticas na patogénese da psoríase, especialmente a IL-23, IL-12 e os interferons (IFNs) tipo I. O deucravacitinib apresenta um mecanismo de ação distinto dos outros inibidores JAK, que lhe confere uma elevada seletividade para a TYK2, sendo expectável que, por conseguinte, possua um melhor perfil de segurança comparativamente com outros inibidores JAK menos seletivos. Ensaios clínicos de fase 2 e 3 avaliaram a segurança e eficácia do deucravacitinib no tratamento da psoríase moderada a grave e os seus resultados são encorajadores.Conclusões: O deucravacitinib demonstrou uma clara superioridade relativamente ao placebo e ao apremilast nos ensaios clínicos, tanto a nível de segurança como de eficácia, tendo o potencial para se tornar um tratamento seguro, eficaz e bem tolerado para pacientes com doença moderada a grave. Futuros estudos serão importantes para determinar o papel exato deste fármaco no tratamento da psoríase.

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“…With these successes, deucravacitinib was approved for the treatment of plaque psoriasis in the United States . Additional clinical information for deucravacitinib has been recently reviewed. , …”

Section: Small-molecule Targeting Of the Jak Pseudokinasesmentioning

confidence: 99%

Progress on the Pharmacological Targeting of Janus Pseudokinases

Henry

Jorgensen

2023

J. Med. Chem.

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The Janus kinases (JAKs) are key components of the JAK-STAT signaling pathway and are involved in myriad physiological processes. Though they are the molecular targets of many FDA-approved drugs, these drugs manifest adverse effects due in part to their inhibition of the requisite JAK kinase activity. However, the JAKs uniquely possess an integrated pseudokinase domain (JH2) that regulates the adjacent kinase domain (JH1). The therapeutic targeting of JH2 domains has been less thoroughly explored and may present an avenue to modulate the JAKs without the adverse effects associated with targeting the adjacent JH1 domain. The potential of this strategy was recently demonstrated with the FDA approval of the TYK2 JH2 ligand deucravacitinib for treating plaque psoriasis. In this light, the structure and targetability of the JAK pseudokinases are discussed, in conjunction with the state of development of ligands that bind to these domains. ■ SIGNIFICANCEThe JAK pseudokinase (JH2) domains present attractive targets for modulation of JAK-STAT pathways to circumvent adverse side effects of traditional Jakinibs. This has been demonstrated by the recent FDA approval of the TYK2 JH2 ligand deucravacitinib. Understanding the structure of these domains and the state of development of their ligands is important for future development of the JAK pseudokinases as therapeutic targets.

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TYK2 inhibition: changing the treatment landscape for psoriasis?

Cited by 9 publications

References 6 publications

Deucravacitinib for the Treatment of Psoriatic Disease

Deucravacitinib for the Treatment of Psoriatic Disease

Deucravacitinib in the treatment of psoriasis

Progress on the Pharmacological Targeting of Janus Pseudokinases

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