A Phase II, Randomised, Double-blind, Placebo-controlled, Parallel-group, Dose-ranging, Proof-of-concept Trial of BI 730357 Given for 12 Weeks in Patients With Active Psoriatic Arthritis

This study is open to adults with active psoriatic arthritis who have tender and swollen joints. The purpose of this study is to find out whether a medicine called BI 730357 helps to reduce symptoms and to prevent damage to joints.
Three different doses of BI 730357 are tested. Participants are put into 4 groups by chance. Participants in 3 of the 4 groups take BI 730357. Participants in the fourth group take placebo. Participants take BI 730357 or placebo as tablets once a day. Placebo tablets look like BI 730357 tablets but do not contain any medicine.
Participants are in the study for about 4.5 months. During this time, they visit the study site about 8 times. At these visits, doctors check whether the swelling of inflamed joints has changed. The results between the BI 730357 and placebo groups are then compared. Doctors also regularly check the general health of the participants.

开始日期2022-05-02

申办/合作机构

Boehringer Ingelheim GmbH

NCT04679948

/ Completed临床1期

The Effect of Multiple Doses of BI 730357 on the Single Dose Pharmacokinetics of Caffeine, Warfarin, Omeprazole and Midazolam Administered Orally as a Cocktail in Healthy Subjects (an Open-label, Two-period Fixed Sequence Design Trial)

The trial will be performed to assess the influence of BI 730357 on the pharmacokinetics of caffeine, warfarin, omeprazole and midazolam.

开始日期2020-12-21

申办/合作机构

Boehringer Ingelheim GmbH

EUCTR2019-001684-77-HU

/ Not yet recruiting临床2期

A 12-weeks Phase II, randomized, double-blind, placebocontrolled, parallel-group, proof-of-concept trial of BI 730357 in patients with active ankylosing spondylitis

开始日期2020-12-07

申办/合作机构

Boehringer Ingelheim RCV GmbH & Co. KG

100 项与 Bevurogant 相关的临床结果

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100 项与 Bevurogant 相关的转化医学

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100 项与 Bevurogant 相关的专利（医药）

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项与 Bevurogant 相关的文献（医药）

2025-05-01·JOURNAL OF INVESTIGATIVE DERMATOLOGY

Revisiting RORγt Inhibition in Plaque Psoriasis: Lessons Learned from BI 730357

Article

作者: Bunick, Christopher G ; Akbarialiabad, Hossein

2025-01-01·JOURNAL OF INVESTIGATIVE DERMATOLOGY

Phase II Randomized Trial of BI 730357, an Oral RORγt Inhibitor, for Moderate-to-Severe Plaque Psoriasis

Article

作者: Papp, Kim A ; Korell, Julia ; Gooderham, Melinda J ; Mrowietz, Ulrich ; Sofen, Howard ; Drda, Kristin ; Flack, Mary ; Gu, Hui ; Kadus, Werner ; Vangerow, Harald

TRIAL DESIGN:

This 2-part, double-blinded trial assessed the RORγt inhibitor BI 730357 in plaque psoriasis.

METHODS:

In part 1, patients were randomized 2:2:2:2:1 to 25, 50, 100, and 200 mg BI 730357 or placebo once daily (fasting conditions); nonresponders were switched to higher doses. In part 2, a separate patient set was randomized 4:4:1 to receive BI 730357 (400 mg once daily, 200 mg twice daily) or a placebo (fed conditions). Patients from parts 1 and 2 could enter a long-term extension trial. Coprimary endpoints included ≥75% reduction from baseline in PASI75 and static Physician's Global Assessment score of 0/1 (clear/almost clear) at week 12.

RESULTS:

In total, 274 patients were treated (178 [part 1] and 96 [part 2]). In part 1, 12 (30.0%) patients achieved PASI75 (P = .0062), and 11 (27.5%) achieved static Physician's Global Assessment of 0/1 (P = .0095) with BI 730357 200 mg versus none receiving placebo. Exposure-response relationship plateaued at ≥200 mg once daily BI 730357. Drug-related adverse events occurred in ≤15.8% of patients. Of 165 patients who entered the long-term extension, 93 (56.4%) achieved PASI75 during treatment, and ≤18.5% experienced a drug-related adverse event.

CONCLUSIONS:

BI 730357 was well tolerated, with moderate efficacy versus placebo in plaque reduction (clinicaltrials.gov: NCT03635099 and NCT03835481).

2024-02-01·Clinical pharmacology in drug development

The Effect of BI 730357 (Retinoic Acid‐Related Orphan Receptor Gamma t Antagonist, Bevurogant) on the Pharmacokinetics of a Transporter Probe Cocktail, Including Digoxin, Furosemide, Metformin, and Rosuvastatin: An Open‐Label, Non‐randomized, 2‐Period Fixed‐Sequence Trial in Healthy Subjects

Article

作者: Huang, Fenglei ; Choi, HeeJae ; Flack, Mary

Abstract:

Evaluating Drug‐Drug Interactions (DDIs) for new investigational compounds requires several trials evaluating different drugs with different transporter specificities. By using a cocktail of drugs with different transporter specificities, a single trial could evaluate the pharmacokinetics (PKs) of each cocktail drug simultaneously, reducing the number of clinical DDI trials required for clinical development. We aimed to investigate the effect of steady‐state Boehringer Ingelheim (BI) 730357 (bevurogant) on the PKs of a validated and optimized 4‐component transporter cocktail. This open‐label, non‐randomized, 2‐period fixed‐sequence phase I trial compared transporter cocktail (0.25 mg digoxin/1 mg furosemide/10 mg metformin hydrochloride/10 mg rosuvastatin) with and without BI 730357 in healthy subjects aged 18‐55 years with body mass index 18.5‐29.9 kg/m2. During reference treatment/period 1, transporter cocktail was administered 90 minutes after breakfast. After a washout period, during test treatment/period 2, BI 730357 was dosed twice daily for 13 days, with transporter cocktail administered on day 1. The primary endpoints were the area under the concentration‐time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0‐∞) and the maximum measured concentration of the analyte in plasma (Cmax), and the secondary endpoint was the area under the concentration‐time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC0‐tz). Steady‐state BI 730357 increased digoxin (+48% to +94%), minimally affected metformin (−2% to −9%), furosemide (+12% to +18%), and rosuvastatin (+19% to +39%) exposure. Therefore, no clinically relevant inhibition of transporters OCT2/MATE‐1/MATE‐2K, OAT1/OAT3, OATP1B1/OATP1B3 was observed. Potential inhibition of breast cancer resistance protein noted as PK parameters of coproporphyrin I/III (OATP1B1/OATP1B3 biomarkers) remained within bioequivalence boundaries while rosuvastatin PK parameters (AUC0‐∞/Cmax/AUC0‐tz) exceeded the bioequivalence boundary. BI 730357 was safe and well tolerated. This trial confirms the usefulness and tolerability of the transporter cocktail consisting of digoxin, furosemide, metformin, and rosuvastatin in assessing drug‐transporter interactions in vivo.

项与 Bevurogant 相关的新闻（医药）

2024-11-21

·精准药物

靶点 RORγ 作用机制与药物分子研发进展

维甲酸受体相关孤儿受体（RORs，Retinoic acid receptor-related orphan receptors）属于核受体（NR）超家族的一个亚家族，作为转录调控因子发挥重要作用。ROR亚型包括RORα（NR1F1或RORa）、RORβ（NR1F2或RORb）、和RORγ（NR1F3或RORc）。RORγ作为RORγ1（也称为RORc1或RORγ）和RORγ2（也称为RORc2或RORγt）亚型存在，其中RORγ1在各种组织中广泛表达，而RORγt的表达局限于胸腺和免疫系统细胞。由于转录因子RORγt在分化IL-17产生T辅助细胞17（Th17）中的作用，与自身免疫密切相关（图1）。 IL-17 是一种促炎细胞因子，在炎症、自身免疫和宿主防御中起主导作用。在炎症部位，IL-17 刺激常驻细胞分泌趋化因子和其他促炎介质，从而将额外的炎症细胞募集到组织中。针对 IL-17 细胞因子本身或 IL-17 受体的单克隆抗体已证明在治疗银屑病、银屑病关节炎、和强直性脊柱炎等疾病具有临床疗效。IL-17 通路也与类风湿性关节炎等和多发性硬化症等免疫相关疾病有关。IL-17 由 T 细胞和其他免疫细胞的特定亚群产生，其中辅助性 T 细胞 17 （Th17）被认为在疾病发病机制中起主导作用。在这些细胞中，RORγt基因的免疫细胞特异性亚型表达，是 IL-17 表达和 Th17 细胞从初始 CD4+ T 细胞分化所必需的。因此，RORγt是一个非常很有前途的药物靶点，用于治疗自身免疫性疾病、病毒、代谢疾病、炎症、和癌症。此外，核受体靶向药物目前占美国和全球所有药品销售额的13%。 RORγ 结构由518个氨基酸组成，包括6个结构域（图2A，B）。与其他核受体类似，RORγ包含一个N端结构域(NTD，1−30 aa)，一个DNA结合域(DBD，31−95 aa)，一个铰链结构域(HD，96−265aa)，一个配体结合域(LBD，266−505aa)和一个C端结构域(CTD，506−518aa)。此外，在RORγ中，残基22−24是组氨酸、苏氨酸和丝氨酸，而在RORγt中，它们是蛋氨酸、精氨酸和苏氨酸（MRT）（图2B）。A/B区域被认为在DBD与DNA结合的特异性中发挥作用，但不直接与DNA相互作用。LBD可以与共激活物或辅抑制复合物相互作用，以调节基因转录；此外，通过LBD结构域可开发各种调节剂，包括激动剂、拮抗剂和反向激动剂。LBD 结构域还可以容纳变构配体。促进共激活因子复合物募集和增强基因转录的配体被称为受体激动剂（agonists）。一些甾醇配体已被报道为RORγ(t) 激动剂，包括24-脱氢胆固醇(desmosterol)、胆固醇和羟基胆固醇（图3）。代表性RORγ激动剂，如SR19355和LYC-55716(10.1021/acs.jmedchem.1c00731 )，后者已进入临床试验(针对肿瘤适应症)。拮抗剂是核受体调节的另一种药物形式，如GSK99324和SR-221127（图3）。RORγt抑制可影响与自身免疫性炎症性疾病相关的 IL-17、IL-22和粒细胞巨噬细胞集落刺激因子信号通路，如多发性硬化症、炎症性肠病、银屑病、类风湿关节炎（RA）、慢性阻塞性肺疾病和哮喘。此外，靶向 RORγt 还存在一类特殊的抑制剂。促进辅抑制因子复合物募集和减少基因转录的配体被称为反向激动剂（inverse agonists)。在药理学中是指和激动剂结合在相同的受体上，但引起相反的药理反应的分子。根据定义，反向激动剂的效能为负。反向激动剂的受体在没有结合任何配体必须有内在的基础活性。激动剂能增加其活性，而反向激动剂能降低其活性。沉默拮抗剂本身没有任何活性，但能阻止激动剂和反向激动剂的活性。这些反向激动剂表现出了有利的生物活性，包括对 RORγt 的强亲和力和抑制IL-17A细胞因子表达的能力（图3）。目前，已有许多有关 RORγt 反向激动剂的化学结构报道（图3），包括GSK2981278、GNE-3500、AZD-0284、VTP-43742、GSK805、T0901317和BMS-986251，其中一些开始临床试验。目前，除IMU-935（izumerogant，10.1002/cpdd.1243）外，其他反向激动剂，包括ABBV-157（cedirogant)和BI730357(bevurogant，10.1021/acsmedchemlett.0c00575）对银屑病不具有显著的临床疗效。 GSK2981278，设计用于局部给药，其生物利用度较低（10.1021/acs.jmedchem.8b00392）。然而，对具有合理的亲脂性和高代谢稳定性的化合物的描述是令人鼓舞的。为了提高其性能，对GSK2981278进行了大量的结构修改。Fauber等人通过磺胺基团引入脂肪族环，发现了GNE-3500（图4），它具有良好的效力、吸收、分布、代谢和排泄（ADME）。类似的研究有，通过优化取代核心结构和连接子。Liao等人通过保留磺胺基团并通过环化生成色烯环，阐明了RORγt 反向激动剂的高亲脂性（图4）。这些RORγt反向激动剂表现出与GSK2981278相似的结合模式；例如，分子的头部基团被插入“激动剂锁（agonist lock）”附近的疏水口袋，包括W317、L324、M358、L362、L391、L396和I400，尾部结构与R367相互作用，与“硫酸盐口袋”形成氢键相互作用。最近，Sun 等人通过环化技术设计并合成了苯并四氢喹啉衍生物（10.1021/acs.jmedchem.4c01727），该候选化合物（(R)-D4）具有可口服的优化药代动力学特性、和在临床前动物模型（皮炎、关节炎等）中具有体内活性。然而，RORγt靶向药物的临床试验一直受到高失败率的困扰，主要是因为缺乏疗效（外用）或安全信号（口服）。胸腺细胞异常的风险已经被多次报道，已经停止开发的BMS-986251或诺华开发的潜在临床候选药物。减轻这些风险的可能性可能涉及使用具有化学、不干扰胸腺细胞成熟的结构的RORγt反向激动剂。此外，还有最近受到关注的蛋白降解剂。声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

孤儿药临床结果信使RNA

2021-06-18

·GlobeNewswire

Axial Spondyloarthritis Pipeline: Drug Pipeline, Regulatory Events and Clinical Trials in the Spotlight| Insights by DelveInsight

Los Angeles, June 17, 2021 (GLOBE NEWSWIRE) -- Axial Spondyloarthritis Pipeline: Drug Pipeline, Regulatory Events and Clinical Trials in the Spotlight| Insights by DelveInsight The report offers the most up-to-date information on Axial Spondyloarthritis pipeline products being developed by notable companies such as Pfizer, Suzhou Zelgen Biopharmaceuticals, Clover Biopharmaceuticals, FunPep Co Ltd., Kinevant Sciences, Izana Bioscience, Mycenax Biotech, and UCB Biopharma, among others. DelveInsight’s ‘Axial Spondyloarthritis (axSpA) Pipeline Insights’ report offers exhaustive coverage of the emerging therapies in different stages of development from pre-clinical till late-stage, along with dormant, inactive, and abandoned therapeutic agents. Some of the important takeaways from the Axial Spondyloarthritis Pipeline report: Request for Sample to know more about the therapies expected to make grab the maximum patient pool @ Axial Spondyloarthritis Emerging Therapies and Forecast The Axial Spondyloarthritis Pipeline reports lay down a thorough coverage of the ongoing clinical trials, collaborations taking place in the domain, recent happenings in the Axial Spondyloarthritis pipeline space, and growth prospects across the Axial Spondyloarthritis domain. Axial Spondyloarthritis: Overview Axial Spondyloarthritis is a chronic, inflammatory rheumatic disease that affects primarily the axial joints leading to severe pain, stiffness, and fatigue. It starts with an early inflammatory phase in which there is no structural damage in the sacroiliac joints (non-radiographic disease) progressing to later stages in which structural damage is visible on X‑ray scans of the sacroiliac joints as erosions, sclerosis, or bony bridges (radiographic disease; also known as Ankylosing Spondylitis). Discover more about the disease, treatments, and pipeline therapies @ axSpA Pipeline Assessment Axial Spondyloarthritis Pipeline Drugs Request for Sample to know more @ Axial Spondyloarthritis Pipeline Analysis, Key Companies, and Futuristic Trends Axial Spondyloarthritis Therapeutics Assessment The Axial Spondyloarthritis Pipeline report presents a kaleidoscopic view of the axSpA emerging novel therapies segmented by Stage, Product Type, Route of Administration (RoA), Molecule Type, Target, and Mechanism of Action. By Product Type By Stage By Molecule Type By Route of Administration By Mechanism of Action By Targets For rich insights into merging therapies and assessment, visit Axial Spondyloarthritis Pipeline: Emerging Novel Therapies Scope of the Axial Spondyloarthritis Pipeline Report Coverage: GlobalKey Players: Izana Bioscience, UCB, Sun Pharma Global, Akeso Biopharma, Kinevant Sciences, Jiangsu Hengrui Medicine Co., Suzhou Zelgen Biopharmaceuticals, Clover Biopharmaceuticals, Mycenax Biotech, Boehringer Ingelheim, and Qyuns Therapeutics among others.Key Axial Spondyloarthritis Pipeline Therapies: Namilumab , Bimekizumab, Tofacitinib, Tildrakizumab, AK-111, NDI 031232, Gimsilumab, QX002N, SHR-0302, Jaktinib, SCB-808, FPP003, KIN-1901, ENIA11, BI 730357, and QX002N among others. Discover more about the report offerings @ axSpA Emerging Therapies, Treatments, and Ongoing Clinical Trials Table of Contents Get in touch with our Business executive for Regulatory Analysis, Licensing Services, and Consulting Solutions Related Reports Axial Spondyloarthritis MarketDelveInsight's "Axial Spondyloarthritis Market Insights, Epidemiology, and Market Forecast-2030" report. Non-Radiographic Axial Spondyloarthritis MarketDelveInsight's "Non-Radiographic Axial Spondyloarthritis (nr-AxSpA) Market Insights, Epidemiology, and Market Forecast-2030" report. Spondylolisthesis Market InsightsDelveInsight's “Spondylolisthesis Market Insights, Epidemiology, and Market Forecast-2030" report. Ankylosing Spondylitis MarketDelveInsight’s ‘Ankylosing Spondylitis Market Insights, Epidemiology, and Market Forecast–2030’ report. Global Kinase Inhibitor In Autoimmune Diseases MarketDelveInsight’s ‘Global Kinase Inhibitor in Autoimmune Diseases Market Insights and Market Forecast – 2030’ report. Adenosine Deaminase Severe Combined Immunodeficiency MarketDelveInsight's "Adenosine Deaminase-Severe Combined Immunodeficiency Market Insights, Epidemiology, and Market Forecast-2030" report. Adult-Onset Still Disease MarketDelveInsight’s “Adult-onset Still’s Disease Market Insights, Epidemiology, and Market Forecast – 2030” report. Browse through our posts ABSSSI Pipeline Analysis Parkinson's Disease Risk FactorsWearable Healthcare Devices Market About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports Pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve. For more insights, visit Pharma, Healthcare, and Biotech News

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适应症	最高研发状态	国家/地区	公司	日期
银屑病关节炎	临床2期	-	Boehringer Ingelheim GmbH	2022-05-02
慢性大斑块银屑病	临床2期	美国	Boehringer Ingelheim GmbH	2018-09-17
慢性大斑块银屑病	临床2期	加拿大	Boehringer Ingelheim GmbH	2018-09-17
慢性大斑块银屑病	临床2期	德国	Boehringer Ingelheim GmbH	2018-09-17
斑块状银屑病	临床2期	美国	Boehringer Ingelheim GmbH	2018-09-17
斑块状银屑病	临床2期	加拿大	Boehringer Ingelheim GmbH	2018-09-17
斑块状银屑病	临床2期	德国	Boehringer Ingelheim GmbH	2018-09-17
自身免疫性疾病	临床前	美国	Boehringer Ingelheim Pharmaceuticals, Inc.	2021-01-05

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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


NCT03804671 (CTgov)	临床1期	-	6	BI 730357 mixed with [C-14] BI 730357 BS	憲積襯鑰獵廠顧醖淵願(鏇獵網製觸鏇壓製鏇蓋) = 夢餘願選繭製憲襯艱憲艱憲憲顧鹽廠窪觸遞壓 (築顧積鹽選鏇蓋夢範觸, 憲顧艱淵構醖範蓋鏇壓 ~ 鑰艱簾醖艱鹽獵鬱壓遞) 更多	-	2023-07-25
NCT03886272 (CTgov)	临床1期	-	43	BI 730357 (50 mg BI 730357 iCF (T1))	膚壓鬱獵鏇醖衊廠獵網(製製艱積獵襯鬱選選範) = 獵鬱顧餘膚獵繭淵壓願顧夢鑰構蓋選觸膚艱蓋 (醖窪獵壓窪鏇憲鬱構膚, NA) 更多	-	2023-07-17
				BI 730357 (50 mg BI 730357 TF1 (R1))	膚壓鬱獵鏇醖衊廠獵網(製製艱積獵襯鬱選選範) = 鹽簾齋鑰觸網夢顧蓋鏇顧夢鑰構蓋選觸膚艱蓋 (醖窪獵壓窪鏇憲鬱構膚, NA) 更多
NCT04147260 (CTgov)	临床1期	-	85	Placebo (Placebo QD)	顧淵憲憲醖網築膚夢鏇(選網鏇築顧構壓壓艱簾) = 鏇醖膚夢製蓋艱襯構鑰觸鑰願構鏇鹽簾艱簾鹽 (觸鏇艱築憲憲齋膚襯願, 願廠鏇艱窪膚顧窪夢壓 ~ 醖醖膚膚築簾夢壓廠鏇) 更多	-	2023-07-17
				BI 730357 (400 mg QD BI 730357)	顧淵憲憲醖網築膚夢鏇(選網鏇築顧構壓壓艱簾) = 衊製餘艱鹽願艱獵願範觸鑰願構鏇鹽簾艱簾鹽 (觸鏇艱築憲憲齋膚襯願, 簾廠築夢鑰醖構糧膚襯 ~ 鏇觸鹽壓膚襯餘積夢鏇) 更多
NCT03793621 (CTgov)	临床1期	-	24	Placebo	衊顧築選艱繭齋壓蓋齋 = 壓艱獵鑰窪築繭廠築壓網醖繭獵鏇築餘範夢鑰 (餘築夢憲網鬱築選襯蓋, 築鏇構構網襯蓋鑰鏇鑰 ~ 遞範築繭製鹽鹽餘鹹築) 更多	-	2023-07-12
NCT03782987 (CTgov)	临床1期	-	14	itraconazole+BI 730357 (BI 730357 + Itraconazole (T))	糧襯築構襯鹹築構積蓋(範憲顧願鑰製鏇窪壓齋) = 鹹廠齋遞衊鹽製觸願糧艱築壓鹹膚糧糧蓋窪觸 (壓餘構淵鑰繭醖衊願積, NA) 更多	-	2023-07-12
				BI 730357 (BI 730357 (R))	糧襯築構襯鹹築構積蓋(範憲顧願鑰製鏇窪壓齋) = 淵餘夢範範願衊繭鏇齋艱築壓鹹膚糧糧蓋窪觸 (壓餘構淵鑰繭醖衊願積, NA) 更多
NCT03664011 (CTgov)	临床1期	-	6	[C-14\] BI 730357+BI 730357 BS (BI 730357)	淵願範顧夢願願構淵膚(顧餘築衊鏇淵醖鹽築膚) = 餘遞簾壓糧憲鏇範鹽窪鑰獵遞齋蓋鹹衊範願憲 (獵製簾遞糧襯淵壓獵廠, 19.2) 更多	-	2023-07-12
				BI 730357 (14C-BI 730357-EQ and BI 730357)	糧衊夢觸齋鹹艱壓遞積(膚鑰餘遞淵製繭壓鑰製) = 蓋範壓觸蓋遞鏇齋遞獵齋觸鑰積艱窪網蓋觸選 (衊憲膚鑰齋範糧廠製艱, 16.5) 更多