ZPL-389(ZPL-389) - 药物靶点：H4 receptor_专利_临床

概要

基本信息

药物类型

小分子化药

别名

Adriforant

+ [4]

靶点

H4 receptor

作用机制

H4 receptor拮抗剂(组胺H4受体拮抗剂)

治疗领域

免疫系统疾病遗传病与畸形皮肤和肌肉骨骼疾病+ [1]

在研适应症-

非在研适应症

哮喘中度特应性皮炎斑块状银屑病+ [2]

原研机构

Ziarco, Inc.

在研机构-

非在研机构

Novartis Pharmaceuticals Corp.

Pfizer Inc.Ziarco Pharma Ltd.

最高研发阶段终止临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C13H22N6

InChIKeyISBHYKVAFKTATD-SNVBAGLBSA-N

CAS号943057-12-3

关联

12

项与 ZPL-389 相关的临床试验

EUCTR2017-002176-75-FR / Not yet recruiting临床2期

A randomized, double blind, placebo controlled multicenter dose ranging study to assess the safety and efficacy of multiple oral ZPL389 doses in patients with moderate to severe Atopic Dermatitis (ZEST trial) - A study to assess the safety and efficacy of ZPL389 doses in patients with moderate to severe AD

开始日期2019-12-20

申办/合作机构

Novartis Pharma AG

NCT03948334 / Terminated临床2期

A Randomized, Double Blind, Multicenter Extension to CZPL389A2203 Dose-ranging Study to Assess the Short-term and Long-term Safety and Efficacy of Oral ZPL389 With Concomitant Use of TCS and/or TCI in Adult Patients With Atopic Dermatitis.

This extension study (CZPL389A2203E1) was designed as a 2-year (100 weeks) extension to the core study (CZPL389A2203/ NCT03517566) which is disclosed separately. It aimed to assess the short-term and long-term safety of (blinded) 30 mg o.d and 50 mg o.d ZPL389 with concomitant or intermittent use of topical corticosteroids (TCS) and/or topical calcineurin inhibitors (TCI).

开始日期2019-04-04

申办/合作机构

Novartis Pharmaceuticals Corp.

NCT03517566 / Terminated临床2期

A Randomized, Double-blind, Placebo-controlled Multicenter Dose Ranging Study to Assess the Safety and Efficacy of Multiple Oral ZPL389 Doses in Patients With Moderate to Severe Atopic Dermatitis (ZEST Trial)

This was a randomized, double-blind, placebo-controlled, parallel-group study to assess safety and efficacy of ZPL389 in subjects with moderate to severe atopic dermatitis with a total study duration up to 24 weeks

开始日期2018-11-14

申办/合作机构

Novartis Pharmaceuticals Corp.

100 项与 ZPL-389 相关的临床结果

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100 项与 ZPL-389 相关的转化医学

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100 项与 ZPL-389 相关的专利（医药）

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5

项与 ZPL-389 相关的文献（医药）

2023-04-01·European Journal of Pharmacology

Adriforant is a functional antagonist of histamine receptor 4 and attenuates itch and skin inflammation in mice

Article

作者: Urban, Beatrice ; Hauchard, Alice ; Goetschy, Jean-Francois ; Wang, Yichen ; Roussel, Elsa ; Röhn, Till A ; Raulf, Friedrich ; Kaupmann, Klemens ; Bäumer, Wolfgang ; Uluckan, Özge ; Bruno, Sandro ; Wack, Nathalie ; Zerwes, Hans Günter ; Stark, Holger ; Wilzopolski, Jenny ; Fehlmann, Dominique ; Delucis-Bronn, Corinne ; Kempf, Dominique

BACKGROUNDHistamine has been postulated to play a role in atopic dermatitis via histamine receptor 4, mediating pruritic and inflammatory effects. The H4R antagonist adriforant (PF-3893787 or ZPL389) indicated clinical efficacy in a Ph2a study in atopic dermatitis. Preclinical investigations of adriforant had been scarce as experiments in transfectants with H4R from several species suggested partial agonism, not seen in human cells.OBJECTIVEDuring the Ph2b trial in AD, we performed experiments to understand the pharmacology of adriforant in primary murine cells and in vivo models. We assessed its effects on ERK phosphorylation and transcriptional changes in bone marrow-derived mast cells, histamine-dependent Ca²⁺ flux in neurons and histamine-induced itch response. In addition, its impact on MC903-induced skin inflammation was evaluated.RESULTSWe show that, contrary to transfectants, adriforant is a competitive antagonist of the murine histamine receptor 4, antagonizes histamine-induced ERK phosphorylation, normalizes histamine-induced transcriptional changes in mast cells and reduces histamine-dependent Ca²⁺ flux in neurons. Administration to mice reduces acute histamine-induced itch response. In addition, adriforant ameliorates inflammation in the mouse MC903 model.CONCLUSIONSOur results suggest that functional inhibition of histamine receptor 4 by adriforant reduces itch and inflammation in vivo. The effects observed in mice, however, did not translate to clinical efficacy in patients as the Ph2b clinical trial with adriforant did not meet pre-specified efficacy endpoints. Given the complex pathogenesis of AD, antagonism of histamine receptor 4 alone appears insufficient to reduce disease severity in AD patients, despite the effects seen in mouse models.

2019-05-01·Journal of Allergy and Clinical Immunology1区 · 医学

Efficacy and safety of the histamine H4 receptor antagonist ZPL-3893787 in patients with atopic dermatitis

1区 · 医学

Article

作者: Purkins, Lynn ; Lynch, Victoria ; Werfel, Thomas ; Asher, Aliya ; Layton, Gary ; Whitlock, Lyndsey ; Tsianakas, Athanasios ; Jimenez, Pablo ; Yeadon, Michael ; Osterloh, Ian ; Liu, Wai

BACKGROUNDH₄ receptor antagonists are potential novel treatments for inflammatory skin diseases, including atopic dermatitis (AD).OBJECTIVEWe sought to study the efficacy and safety of ZPL-3893787 (a selective H₄ receptor antagonist) in patients with moderate-to-severe AD.METHODSA randomized, double-blind, placebo-controlled, parallel-group study was conducted to evaluate ZPL-3893787 (30 mg) once-daily oral therapy in adults with moderate-to-severe AD. Patients were randomized (2:1) to ZPL-3893787 (n = 65) or placebo (n = 33) for 8 weeks. Patients had a history of AD for more than 12 months, Eczema Area and Severity Index (EASI) scores of 12 or greater and 48 or less, Investigator's Global Assessment (IGA) scores of 3 or greater, pruritus scores of 5 or greater (0- to 10-point scale), and AD on 10% or greater of body surface area. Efficacy parameters included EASI, IGA, SCORAD, and pruritus assessment.RESULTSTreatment with oral ZPL-3893787 showed a 50% reduction in EASI score compared with 27% for placebo. The placebo-adjusted reduction in EASI score at week 8 was 5.1 (1-sided P = .01). Clear or almost-clear IGA scores were 18.5% with ZPL-3893787 versus 9.1% with placebo. SCORAD scores exhibited 41% reduction with ZPL-3893787 versus 26% with placebo (placebo-adjusted reduction of 10.0, P = .004). There was a 3-point reduction (scale, 1-10) in pruritus with ZPL-3893787, but there was a similar reduction with placebo, resulting in a nonsignificant difference (P = .249). Patient-reported pruritus subscores obtained from SCORAD were reduced with ZPL-3893787 compared with placebo at week 8 (nonsignificant). ZPL-3893787 was well tolerated.CONCLUSIONFor the first time, these results showed that ZPL-3893787 improved inflammatory skin lesions in patients with AD, confirming H₄ receptor antagonism as a novel therapeutic option.

2018-03-01·Journal of the American Academy of Dermatology1区 · 医学

New therapies for atopic dermatitis: Additional treatment classes

1区 · 医学

Article

作者: Vakharia, Paras P ; Silverberg, Jonathan I

BACKGROUNDA wide array of miscellaneous agents is being studied for the treatment of atopic dermatitis (AD), including targeted topical, oral systemic, and biologic agents.OBJECTIVETo review the known efficacy and safety to date for such agents being studied for the treatment of AD.METHODSA nonsystematic review of the literature was performed. PubMed and ClinicalTrials.gov were searched for studies assessing agents not described previously for the treatment of AD. Randomized controlled trials were primarily sought, but other study types were also included if they contained pertinent data. Agents are presented by mechanism of action, with analysis of mechanism of action and data regarding efficacy and safety in patients with AD.RESULTSData regarding the following agents are presented: omiganan (an antimicrobial peptide), tapinarof (a nonsteroidal anti-inflammatory agent), PR022 (hypochlorous acid), asimadoline (a κ-opioid agonist), DS107 (dihomo-γ-linolenic acid), ZPL-389 (a histamine H4 receptor antagonist), secukinumab (an interleukin 17A inhibitor), and fezakinumab (interleukin 22 inhibitor).LIMITATIONSLimited clinical data exist for many of the described agents.CONCLUSIONSAs recent research has improved our understanding of AD pathogenesis, various agents with unique mechanisms of action have been studied for the treatment of AD. Many of these hold great therapeutic promise for AD, and continued research and development is warranted.

100 项与 ZPL-389 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB15027

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
中度特应性皮炎	临床2期	捷克	Novartis Pharmaceuticals Corp.	2018-11-14
中度特应性皮炎	临床2期	美国	Novartis Pharmaceuticals Corp.	2018-11-14
斑块状银屑病	临床2期	德国	Ziarco Pharma Ltd.	2016-01-11
斑块状银屑病	临床2期	比利时	Ziarco Pharma Ltd.	2016-01-11
斑块状银屑病	临床2期	波兰	Ziarco Pharma Ltd.	2016-01-11
斑块状银屑病	临床2期	英国	Ziarco Pharma Ltd.	2016-01-11
瘙痒	临床2期	比利时	Ziarco Pharma Ltd.	2015-05-18
瘙痒	临床2期	德国	Ziarco Pharma Ltd.	2015-05-18
瘙痒	临床2期	英国	Ziarco Pharma Ltd.	2015-05-18
瘙痒	临床2期	波兰	Ziarco Pharma Ltd.	2015-05-18

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT02618616 (CTgov)	临床2期	斑块状银屑病	129	ZPL-3893787 (ZPL-389)	蓋醖鬱鏇積選鹽廠範顧(淵獵選製觸糧顧獵網繭) = 觸襯鑰構襯鏇築積鏇鏇鑰願網憲製遞衊鬱遞鬱 (繭淵鬱夢獵積鹽憲醖憲, 餘膚壓壓願顧築鹹糧醖 ~ 淵艱鑰遞鹹糧壓鏇願選) 更多	-	2021-07-20
				Placebo (Placebo)	蓋醖鬱鏇積選鹽廠範顧(淵獵選製觸糧顧獵網繭) = 鑰壓淵膚積鹹顧遞淵齋鑰願網憲製遞衊鬱遞鬱 (繭淵鬱夢獵積鹽憲醖憲, 鹽廠繭製憲廠鏇築廠顧 ~ 醖糧繭網鹹醖齋憲鑰繭) 更多
NCT03948334 (ZESTExt, CTgov)	临床2期	特应性皮炎	123	TCS and/or TCI+ZPL389 30mg (ZPL389 30mg)	構壓觸網網襯願築範構(範醖糧選餘齋窪觸選網) = 鑰蓋襯淵窪衊夢積網廠鑰願製鑰窪獵繭膚淵衊 (夢壓醖淵糧糧醖齋衊餘, 夢遞網繭鑰積網簾憲鑰 ~ 觸醖築製壓鏇壓遞願鹽) 更多	-	2021-07-20
				ZPL389 50mg+TCS and/or TCI (ZPL389 50mg)	構壓觸網網襯願築範構(範醖糧選餘齋窪觸選網) = 膚鬱鏇齋夢衊鬱觸鑰製鑰願製鑰窪獵繭膚淵衊 (夢壓醖淵糧糧醖齋衊餘, 製獵鹹獵鹽願繭觸願網 ~ 願夢鏇壓蓋鬱製衊構網) 更多
NCT02424253 (CTgov)	临床2期	瘙痒 \| 中度特应性皮炎 \| 重度特应性皮炎	98	ZPL-3893787 (ZPL-3893787)	遞積蓋窪鑰淵築醖觸壓(窪鹽窪繭網夢壓願鹽鬱) = 襯艱顧蓋襯鑰淵憲衊鹽選廠壓製夢築簾憲築衊 (鹹繭衊鑰鬱糧網齋製願, 製蓋網夢簾鏇構衊鏇壓 ~ 糧選夢廠醖遞襯網網鹹) 更多	-	2021-05-13
				Placebo (Placebo)	遞積蓋窪鑰淵築醖觸壓(窪鹽窪繭網夢壓願鹽鬱) = 鏇壓蓋選醖窪遞襯構艱選廠壓製夢築簾憲築衊 (鹹繭衊鑰鬱糧網齋製願, 獵鏇願積廠壓鏇憲觸鏇 ~ 鏇衊製網衊壓簾鏇夢鬱) 更多
NCT02424253 (Pubmed \| J Allergy Clin Immunol Pract) 人工标引	临床2期	特应性皮炎	98	ZPL-3893787	(製繭膚觸觸構糧艱鑰構) = 壓衊簾淵淵築遞顧構築繭齋壓願淵廠獵窪網鬱 (顧鏇鹹鬱獵選艱鹹鹹窪 ) 更多	积极	2019-05-01
				Placebo	(製繭膚觸觸構糧艱鑰構) = 襯製鹽顧網憲糧選獵糧繭齋壓願淵廠獵窪網鬱 (顧鏇鹹鬱獵選艱鹹鹹窪 ) 更多