新药Deucravacitinib在中重度银屑病中的治疗作用

摘要/Abstract

摘要： 银屑病是一种慢性、复发性、免疫介导的皮肤和关节疾病，全球范围内广泛分布，对人的身心健康造成极大损害。目前银屑病的治疗方案主要是控制症状为主，尚无有效治愈银屑病的方法。2022年9月9日，美国食品药品管理局(FDA)批准Deucravacitinib（BMS-986165）用于成人中重度斑块银屑病的治疗；2022年9月26日，日本药品和医疗器械管理局（PMDA）批准Deucravacitinib用于斑块型银屑病、泛发性脓疱型银屑病和红皮病型银屑病的治疗。Deucravacitinib通过与酪氨酸激酶2（TYK2）调控域的特异性结合对TYK2发挥抑制作用，抑制TYK2变构，进而抑制TY2活性；对TYK2具有高选择性和高亲和力，对JAK激酶1-3(JAK1-3)无明显抑制效应，可有效抑制银屑病相关的I 型干扰素（IFN）、白细胞介素（IL）-12和 IL-23通路。临床研究中Deucravacitinib常见不良反应为上呼吸道感染、血肌酸激酶升高、单纯疱疹、口腔溃疡等。 Deucravacitinib 6 mg·d-1 QD能显著减少银屑病皮损面积和改善患者生活质量，有效性和安全性良好，药动学特征良好，有望成为治疗银屑病等自身免疫性疾病的治疗药物。

关键词: 银屑病, Deucravacitinib, TYK2抑制剂, 作用机制

Abstract: Psoriasis， a chronic， recurrent， immune mediated skin and joint disease， have great significant impact on people's physical and mental health. At present， there is no effective therapeutic options to cure psoriasis. The current treatment strategy is mainly to control its symptoms. On 9 September 2022， FDA approved deucravacitinib (BMS-986165) for the treatment of moderate to severe psoriasis. On 26 September 2022， deucravacitinib was subsequently approved by Japan Pharmaceuticals and Medical Divices Agency（PMDA） for the treatment of plaque psoriasis， generalized pustular psoriasis and erythrodermic psoriasis. Deucravacitinib inhibit the activity of tyrosine kinase-2 （TYK2） through specific binding with the regulatory domain of TYK2 pseudokinase， strongly inhibiting isomerization of TYK2 and inhibit immune signaling of IL-12， IL-23， and type I interferons without interfering with other critical systemic functions. Deucravacitinib has high selectivity and affinity for TYK2， and has no obvious inhibitory effect on The Janus kinase 1-3 (JAK1-3)， effectively inhibiting psoriasis related type I interferon (IFN)， interleukin（IL）-12 and IL-23 pathways. Common adverse action of deucravacitinib in clinical studies were upper respiratory tract infection， elevated creatine kinase， herpes simplex， and oral ulcers. Deucravacitinib QD 6 mg·d-1 significantly reduce psoriasis skin lesions and improve patients′ quality of life. Deucravacitinib has good efficacy， safety and good pharmacokinetic characteristics， and it is expected to become a therapeutic drug for autoimmune diseases such as psoriasis.

Key words: Psoriasis, Deucravacitinib, TYK2 inhibitors, Mechanism of action

中图分类号:

R977.1

邢俊香, 侯立强, 孙燕, 陈萍. 新药Deucravacitinib在中重度银屑病中的治疗作用[J]. 中国医药导刊, 2023, 25(12): 1230-1235.

XING Junxiang, HOU Liqiang, SUN Yan, CHEN Ping. Research Progress of A New Drug， Deucravacitinib for Psoriasis Treatment[J]. CHINESE JOURNAL OF MEDICINAL GUIDE, 2023, 25(12): 1230-1235.

参考文献

[1]WHO.WHO publishes new report on psoriasis 2016 [EB/OL]. （2016-02-26） [2023-06-10]. https：//www.who.int/news/item/26-02-2016-who-publishes-new-report-on-psoriasis.
     [2]Langley RG， Krueger GG， Griffiths CE. Psoriasis： epidemiology， clinical features， and quality of life[J]. Ann Rheum Dis， 2005， 64（Suppl 2）：ii18-23；discussion ii4-5.
     [3]Krueger JG， McInnes IB， Blauvelt A.Tyrosine kinase 2 and Janus kinase signal transducer and activator of transcription signaling and inhibition in plaque psoriasis[J]. J Am Acad Dermatol， 2022， 86(1)：148-157.
     [4]Nogueira M， Puig L， Torres T. JAK inhibitors for treatment of psoriasis：focus on selective TYK2 inhibitors[J].Drugs， 2020， 80(4)：341-352.
     [5]Armstrong AW， Read C. Pathophysiology， clinical presentation， and treatment of psoriasis：a review[J]. JAMA， 2020， 323(19)：1945-1960.
     [6]Boehncke WH， Schon MP. Psoriasis[J]. Lancet， 2015， 386(9997)：983-994.
     [7]Deng Y， Chang C， Lu Q. The Inflammatory response in psoriasis：a comprehensive review[J]. Clin Rev Allergy Immunol， 2016， 50(3)：377-389.
     [8]Roskoski R.Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases[J]. Pharmacol Res， 2016， 111：784-803.
     [9]Raychaudhuri SK， Abria C， Raychaudhuri SP. Regulatory role of the JAK STAT kinase signalling system on the IL-23/IL-17 cytokine axis in psoriatic arthritis[J].Ann Rheum Dis， 2017， 76(10)：e36.
     [10]Moslin R， Gardner D， Santella J， et al. Identification of imidazo[1， 2-b] pyridazine TYK2 pseudokinase ligands as potent and selective allosteric inhibitors of TYK2 signalling[J].Medchemcomm， 2017， 8(4)：700-712.
     [11]U.S. Food and Drug Administration approves SotyktuTM (deucravacitinib)， oral treatment for adults with moderate-to-severe plaque psoriasis [press release] [EB/OL].(2022-09-09) [2023-06-10]. https：//www.fda.gov/media/164429/download.
     [12]Japan Pharmaceuticals and Medical Devices Agency. received manufacturing and marketing approval for TYK2 inhibitor SOTYKTU tablets 6 mg [EB/OL]. (2022-09-26) [2023-06-10]. https：//www. bms. com/assets/bms/japan/pressrelease/20220926. pdf.
     [13]Wrobleski ST， Moslin R， Lin S， et al. Highly selective inhibition of tyrosine kinase 2 (TYK2) for the treatment of autoimmune diseases：discovery of the allosteric inhibitor BMS-986165[J].J Med Chem， 2019， 62(20)：8973-8995.
     [14]Chimalakonda A， Burke J， Cheng L， et al.Selectivity profile of the tyrosine kinase 2 inhibitor deucravacitinib compared with janus kinase 1/2/3 inhibitors[J]. Dermatol Ther (Heidelb)， 2021， 11(5)：1763-1776.
     [15]Burke JR， Cheng L， Gillooly KM， et al. Autoimmune pathways in mice and humans are blocked by pharmacological stabilization of the TYK2 pseudokinase domain[J]. Sci Transl Med， 2019， 11：1-16.
     [16]Catlett IM， Hu Y， Gao L， et al. Molecular and clinical effects of selective tyrosine kinase 2 inhibition with deucravacitinib in psoriasis[J]. J Allergy Clin Immunol， 2022， 149(6)：2010-2020.
     [17]Catlett IM， Aras U， Hansen L， et al. First-in-human study of deucravacitinib：a selective， potent， allosteric small-molecule inhibitor of tyrosine kinase 2[J]. Clin Transl Sci， 20223， 16(1)：151-164.
     [18]Squibb BM.SOTYKTUTM (deucravacitinib) tablets， for oral use： US prescribing information [EB/OL]. (2022-09-12) [2023-06-10]. https：//packageinserts.bms.com/pi/pi_sotyktu.pdf.
     [19]Thaci D， Strober B， Gordon KB， et al. Deucravacitinib in moderate to severe psoriasis：clinical and quality-of-life outcomes in a phase 2 trial[J]. Dermatol Ther (Heidelb)， 2022， 12(2)：495-510.
     [20]Mease PJ， Deodhar AA， van der HD， et al. Efficacy and safety of selective TYK2 inhibitor， deucravacitinib， in a phase II trial in psoriatic arthritis[J]. Ann Rheum Dis， 2022， 81(6)：815-822.
     [21]Papp K， Gordon K， Thaci D， et al. Phase 2 trial of selective tyrosine kinase 2 inhibition in psoriasis[J]. N Engl J Med， 2018， 379(14)：1313-1321.
     [22]Armstrong AW， Gooderham M， Warren RB， et al. Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis： efficacy and safety results from the 52-week， randomized， double-blinded， placebo-controlled phase 3 POETYK PSO-1 trial[J]. J Am Acad Dermatol， 2023， 88(1)：29-39.
     [23]Strober B， Thaci D， Sofen H， et al. Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis：efficacy and safety results from the 52-week， randomized， double-blinded， phase 3 POETYK PSO-2 trial[J]. J Am Acad Dermatol， 2023， 88(1)：40-51.
     [24]Qiu J, Liu J, Liu W, et al. The efficacy and safety of tyrosine kinase 2 inhibitor deucravacitinib in the treatment of plaque psoriasis: a systematic review and meta-analysis of randomized controlled trials[J]. Front Med, 2023, 29(9):1-11.
     [25]Yarmolinsky J， Amos CI， Hung RJ， et al. Association of germline TYK2 variation with lung cancer and non-Hodgkin lymphoma risk[J]. Int J Cancer， 2022， 151(12)：2155-2160.
     [26]Chimalakonda A， Singhal S， Darbenzio R， et al. Lack of electrocardiographic effects of deucravacitinib in healthy subjects[J]. Clin Pharmacol Drug Dev， 2022， 11(4)：442-453.
     [27]刘绿野，梗立东.托法替尼治疗银屑病的研究进展[J]. 临床药物治疗杂志， 2022， 20(3)：22-26.
     [28]Tokarski JS， Zupa-Fernandez A， Tredup JA， et al. Tyrosine kinase 2-mediated signal transduction in T lymphocytes is blocked by pharmacological stabilization of its pseudokinase domain[J]. J Biol Chem， 2015， 290(17)：11061-11074.

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