Pharmacodynamic Response to Deucravacitinib, an Oral, Selective, Allosteric TYK2 Inhibitor, in a Global, Phase 2, Randomized, Double-Blind, Placebo-Controlled Psoriasis Trial

IF 3.5 3区医学 Q1 DERMATOLOGY

Dermatology and Therapy Pub Date : 2024-09-16 DOI:10.1007/s13555-024-01262-5

Ian M. Catlett, Lu Gao, Yanhua Hu, Subhashis Banerjee, James G. Krueger

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引用次数: 0

Abstract

Background

Psoriasis, a chronic, immune-mediated, inflammatory disease, affects 2‒3% of the population. Tyrosine kinase 2 (TYK2) mediates cytokine signaling involved in adaptive [interleukin (IL)-12, IL-23] and innate (type-I interferons) immune responses; IL-23–driven T-helper (Th)17 pathways play a key role in chronic inflammation in psoriasis. In a phase 2 trial, deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, reduced IL-23/Th17 and type-I interferon pathway expression in the skin of patients with moderate to severe plaque psoriasis, reductions that were accompanied by clinical improvement of psoriatic lesions.

Objectives

The aim of this study was to identify biomarkers of psoriatic disease in serum from patients enrolled in the phase 2 trial and to assess the effects of deucravacitinib on those biomarkers.

Methods

Serum biomarkers from Olink proteomics and other quantitative assays were evaluated for a pharmacodynamic response to deucravacitinib treatment and correlation with psoriasis disease activity measures.

Results

Serum biomarkers associated with the IL-23/Th17 pathway [IL-17A, IL-17C, IL-19, IL-20, beta-defensin, and peptidase inhibitor 3 (PI3)] were upregulated in patients with psoriasis versus healthy controls. Deucravacitinib treatment reduced IL-17A (adjusted mean change from baseline at Day 85; 12 mg once daily versus placebo; −0.240 versus −0.067), IL-17C (−14.850 versus −1.664), IL-19 (−96.445 versus −8.119), IL-20 (−0.265 versus −0.064), beta-defensin (−65,025.443 versus −7553.961), and PI3 (−14.005 versus −1.360) expression. Reductions in serum biomarker expression occurred in a dose- and time-dependent manner, with significant reductions from baseline seen with deucravacitinib doses ≥ 3 mg twice daily (P ≤ 0.05). Biomarker expression correlated with disease activity measures such as Psoriasis Area and Severity Index (PASI) at baseline. Biomarker expression also correlated with PASI scores at Week 12.

Conclusion

IL-23/Th17 pathway expression in the serum of patients with psoriasis is an indicator of disease activity and response to deucravacitinib treatment.

Trial registration number

NCT02931838.

Abstract Image

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在一项全球性、第 2 期、随机、双盲、安慰剂对照银屑病试验中，对口服、选择性、异位 TYK2 抑制剂 Deucravacitinib 的药效学反应

背景牛皮癣是一种免疫介导的慢性炎症性疾病，发病率占总人口的 2-3%。酪氨酸激酶2（TYK2）介导细胞因子信号转导，参与适应性[白细胞介素（IL）-12、IL-23]和先天性（I型干扰素）免疫反应；IL-23驱动的T-helper（Th）17通路在银屑病的慢性炎症中起着关键作用。在一项2期试验中，口服选择性异位TYK2抑制剂deucravacitinib降低了中度至重度斑块状银屑病患者皮肤中IL-23/Th17和I型干扰素通路的表达，同时银屑病皮损的临床症状也得到了改善。结果与健康对照组相比，银屑病患者与IL-23/Th17通路相关的血清生物标记物[IL-17A、IL-17C、IL-19、IL-20、β-防御素和肽酶抑制剂3 (PI3)]上调。Deucravacitinib治疗可降低IL-17A（第85天时与基线相比的调整后平均变化；12毫克，每日一次与安慰剂相比；-0.240与-0.067）、IL-17C（-14.850与-1.664）、IL-19（-96.445与-8.119）、IL-20（-0.265与-0.064）、β-防御素（-65,025.443与-7553.961）和PI3（-14.005与-1.360）的表达。血清生物标志物表达的降低呈剂量和时间依赖性，在deucravacitinib剂量≥3毫克、每天两次时，生物标志物表达较基线显著降低（P≤0.05）。生物标志物的表达与基线时的银屑病面积和严重程度指数（PASI）等疾病活动指标相关。结论银屑病患者血清中IL-23/Th17通路的表达是疾病活动性和对deucravacitinib治疗反应的指标。

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来源期刊

Dermatology and Therapy Medicine-Dermatology

CiteScore

6.00

自引率

8.80%

发文量

187

审稿时长

6 weeks

期刊介绍： Dermatology and Therapy is an international, open access, peer-reviewed, rapid publication journal (peer review in 2 weeks, published 3–4 weeks from acceptance). The journal is dedicated to the publication of high-quality clinical (all phases), observational, real-world, and health outcomes research around the discovery, development, and use of dermatological therapies. Studies relating to diagnosis, pharmacoeconomics, public health and epidemiology, quality of life, and patient care, management, and education are also encouraged. Areas of focus include, but are not limited to all clinical aspects of dermatology, such as skin pharmacology; skin development and aging; prevention, diagnosis, and management of skin disorders and melanomas; research into dermal structures and pathology; and all areas of aesthetic dermatology, including skin maintenance, dermatological surgery, and lasers. The journal is of interest to a broad audience of pharmaceutical and healthcare professionals and publishes original research, reviews, case reports/case series, trial protocols, and short communications. Dermatology and Therapy will consider all scientifically sound research be it positive, confirmatory or negative data. Submissions are welcomed whether they relate to an International and/or a country-specific audience, something that is crucially important when researchers are trying to target more specific patient populations. This inclusive approach allows the journal to assist in the dissemination of quality research, which may be considered of insufficient interest by other journals. The journal appeals to a global audience and receives submissions from all over the world.