A phase I double-blind, placebo controlled (part B only), randomised trial to evaluate the safety, tolerability and pharmacokinetics of single dose in fed state, and repeated doses of DNDI-6899 in healthy participants.

开始日期2024-09-30

申办/合作机构

Drugs for Neglected Diseases initiative

NCT03874234 / Terminated临床1期

A Randomized, Double-blind (Sponsor Unblinded), Placebo-controlled, First Time in Human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of Single (in Both Fed and Fasted States) and Repeat Doses of GSK3186899 in Healthy Participants

The purpose of this study is to evaluate the safety, tolerability and PK profile of single and repeat ascending doses of GSK3186899 in healthy subjects. This is a Phase 1 first time in human study, to investigate the effect of food on PK of GSK3186899. This study will consists of two parts. Part A (dose escalation phase) will be a single ascending, sequential cross-over design in cohorts 1, 2 and 3 of subjects. Cohort 1 and 2 will be 4-way cross-over which includes 4 dosing regimens of GSK3186899 and placebo (3:1 ratio) under fasted conditions. Cohort 3 will be 2-way cross-over which includes 2 treatment periods, 2 dosing regimens in fasted and fed conditions. In Part B (repeat dose escalation phase) subjects will be randomized to receive repeat doses of either GSK3186899 or placebo (3:1 ratio) in either fed or fasted conditions. Part B will be conducted based on the review of all safety, tolerability and PK data from Part A. The study duration includes screening, treatment periods and follow-up.

开始日期2019-04-30

申办/合作机构

GSK Plc

100 项与 GSK-3186899 相关的临床结果

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100 项与 GSK-3186899 相关的转化医学

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100 项与 GSK-3186899 相关的专利（医药）

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项与 GSK-3186899 相关的文献（医药）

2019-02-14·Journal of medicinal chemistry1区 · 医学

Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis

1区 · 医学

Article

作者: Ferrer, Santiago ; Thomas, John ; Reid, Iain H. ; Stojanovski, Laste ; Miguel-Siles, Juan ; De Rycker, Manu ; Miles, Timothy J. ; Revill, Charlotte ; Brand, Stephen ; Thompson, Stephen ; Albrecht, Sébastian ; Woodland, Andrew ; MacKenzie, Claire J. ; Simeons, Frederick R.C. ; Hindley, Sean J. ; Shishikura, Yoko ; Gilbert, Ian H. ; Ghidelli-Disse, Sonja ; Daugan, Alain ; Osuna-Cabello, Maria ; Fiandor, Jose M. ; Drewes, Gerard ; Cantizani-Perez, Juan ; Norval, Suzanne ; Martin, Franck ; Smith, Alasdair ; Ruiz-Gomez, Jose Ramon ; Gray, David W. ; Boesche, Markus ; Quesada-Campos, Maria Teresa ; Thomas, Michael G. ; Pena, Imanol ; Campbell, Lorna ; Spinks, Daniel ; Lowe, Rhiannon M. ; Cleghorn, Laura A.T. ; Ajakane, Myriam ; Riley, Jennifer ; Hill, Alan P. ; Nguyen, Van Loc ; Underwood, Tim ; Wyatt, Paul G. ; Gonzalez, Silvia ; Patterson, Stephen ; Smith, Victoria C. ; Copley, Royston C.B. ; Manthri, Sujatha ; Álvarez-Pedraglio, Ana Isabel ; Gresham, Stephanie L. ; Read, Kevin D. ; MacLean, Lorna ; Crouch, Sabrinia D.

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (1) for VL.

2018-08-09·Nature1区 · 综合性期刊

Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis

1区 · 综合性期刊

Article

作者: Sastry, Lalitha ; Zuccotto, Fabio ; Dixon, Susan ; Thomas, Michael ; De Rycker, Manu ; Miles, Timothy J ; Manthri, Sujatha ; Otto, Thomas D ; Ferguson, Michael A J ; Ghidelli-Disse, Sonja ; Drewes, Gerard ; Pflaumer, Hannah ; Homeyer, Nadine ; Boesche, Markus ; Gray, David W ; Lowe, Rhiannon ; Fiandor, Jose M ; Simeons, Frederick R C ; Read, Kevin D ; Fairlamb, Alan H ; Albrecht, Sebastian ; Crouch, Sabrinia ; Gilbert, Ian H ; Stojanovski, Laste ; Berriman, Matt ; Connolly, Paul ; Urbaniak, Michael D ; Wyllie, Susan ; Gresham, Stephanie ; Wyatt, Paul G ; Patterson, Stephen ; MacLean, Lorna M

Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis.

Biomolecules3区 · 生物学

A Molecular Modeling Approach to Identify Potential Antileishmanial Compounds Against the Cell Division Cycle (cdc)-2-Related Kinase 12 (CRK12) Receptor of Leishmania donovani

3区 · 生物学

ArticleOA

作者: Asiedu, Seth O. ; Kwofie, Samuel K. ; Miller, Whelton A. ; Broni, Emmanuel ; Wilson, Michael D.

The huge burden of leishmaniasis caused by the trypanosomatid protozoan parasite Leishmania is well known. This illness was included in the list of neglected tropical diseases targeted for elimination by the World Health Organization. However, the increasing evidence of resistance to existing antimonial drugs has made the eradication of the disease difficult to achieve, thus warranting the search for new drug targets. We report here studies that used computational methods to identify inhibitors of receptors from natural products. The cell division cycle-2-related kinase 12 (CRK12) receptor is a plausible drug target against Leishmania donovani. This study modelled the 3D molecular structure of the L. donovani CRK12 (LdCRK12) and screened for small molecules with potential inhibitory activity from African flora. An integrated library of 7722 African natural product-derived compounds and known inhibitors were screened against the LdCRK12 using AutoDock Vina after performing energy minimization with GROMACS 2018. Four natural products, namely sesamin (NANPDB1649), methyl ellagic acid (NANPDB1406), stylopine (NANPDB2581), and sennecicannabine (NANPDB6446) were found to be potential LdCRK12 inhibitory molecules. The molecular docking studies revealed two compounds NANPDB1406 and NANPDB2581 with binding affinities of −9.5 and −9.2 kcal/mol, respectively, against LdCRK12 which were higher than those of the known inhibitors and drugs, including GSK3186899, amphotericin B, miltefosine, and paromomycin. All the four compounds were predicted to have inhibitory constant (Ki) values ranging from 0.108 to 0.587 μM. NANPDB2581, NANPDB1649 and NANPDB1406 were also predicted as antileishmanial with Pa and Pi values of 0.415 and 0.043, 0.391 and 0.052, and 0.351 and 0.071, respectively. Molecular dynamics simulations coupled with molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) computations reinforced their good binding mechanisms. Most compounds were observed to bind in the ATP binding pocket of the kinase domain. Lys488 was predicted as a key residue critical for ligand binding in the ATP binding pocket of the LdCRK12. The molecules were pharmacologically profiled as druglike with inconsequential toxicity. The identified molecules have scaffolds that could form the backbone for fragment-based drug design of novel leishmanicides but warrant further studies to evaluate their therapeutic potential.

项与 GSK-3186899 相关的新闻（医药）

2024-11-08

·被忽视疾病药物研发倡议组织

这种被忽视的疾病可能导致毁容，中国仍有病例报告

2023年，孟加拉国成为全球第一个获得世界卫生组织（WHO）消除内脏利什曼病认证的国家。而其他受该疾病严重影响的南亚和东非地区的国家也在朝着消除目标稳步前进——这部分归功于DNDi过去20年的研究工作帮助人们获得了更安全和更简单的治疗。当前， DNDi及其合作伙伴正专注于为内脏利什曼病患者提供全新的口服药物，从而支持全球实现和维持内脏利什曼病的消除。 //认识内脏利什曼病：现状与危害// 利什曼病（Leishmaniasis）可由20多种利什曼虫属原生动物寄生虫引起，目前已知有90多种白蛉可以传播这些利什曼虫属寄生虫。该病有三种主要形式：内脏利什曼病（Visceral leishmaniasis，VL）、皮肤利什曼病（Cutaneous leishmaniasis, CL）和皮肤粘膜利什曼病（Mucocutaneous leishmaniasis）。其中，内脏利什曼病（又名黑热病）是最严重的形式，它可能出现暴发并导致死亡，是继疟疾之后第二致命的寄生虫病。据估计，全世界有6亿多人面临感染VL的风险，每年新发病例数在5万至9万之间，大约50%的VL患者为儿童群体。研究表明，大多数患者分布在巴西、东非和印度。而在中国，近年来病例报告主要集中于新疆、甘肃和四川等地。VL患者通常会出现发烧、体重下降、肝脾肿大等症状，如果不及时治疗，超过95%的患者会发生死亡。其中，携带艾滋病毒的VL患者尤其难以治愈，具有很高的复发率和死亡率。与其他人群相比，携带艾滋病毒的人群罹患VL的风险高出100倍以上。 [图源：DNDi] //推动进步：内脏利什曼病的治疗创新// 东非的VL患者迫切需要比现有标准治疗更安全、更简单的替代方案，特别是当地占比70%的儿童患者。2003年，DNDi创建了东非利什曼病平台（Leishmaniasis East Africa Platform，LEAP），来自20个机构的60名专家参与研究，并帮助推动了肯尼亚、埃塞俄比亚、乌干达和苏丹抗击VL的进展。 2018年，DNDi与AfriKADIA联盟合作在埃塞俄比亚、肯尼亚、苏丹和乌干达开展了一项III期临床研究，比较米替福辛和帕罗霉素（miltefosine and paromomycin，MF+PM）联合治疗与目前的标准治疗——硬葡萄糖酸钠和帕罗霉素（sodium stibogluconate and paromomycin，SSG+PM）的结局。研究结果显示，MF+PM与SSG+PM一样有效，但所需注射次数较少，治疗周期较短，没有SSG相关毒性风险，并且继发黑热病后皮肤利什曼病（Post-Kala-Azar Dermal Leishmaniasis，PKDL）的风险也更低。为确保MF+PM在儿科用药中的适当剂量，研究团队开展了进一步的工作，研究结果支持在儿童和成人患者中均实施较短的14天治疗方案。 [图源：DNDi] DNDi与第七届利什曼病世界大会和第28届LEAP平台会议的与会专家以及开展研究的区域和社区的利什曼病技术和咨询小组分享了试验结果。与此同时，世卫组织指南制定小组开始审查DNDi的 III期临床试验产生的证据，为东非地区成人和儿童VL患者的治疗指南的修订提供信息。 //打破传播链条：PKDL患者的治疗// 据报告，5-10%的VL患者会继发PKDL。该病症通常表现为面部、上臂和躯干部位出现斑点、丘疹或结节，还可能导致毁容和给患者造成极大的病耻感。此外，PKDL患者仍可以作为VL的传染源，因此，早期和有效的PKDL治疗对于持续减少VL传播至关重要。基于此前完成的两项II期临床研究——在苏丹开展的旨在测试脂质体两性霉素B (LAmB)+MF和MF+PM的研究，以及在印度和孟加拉国开展的测试LAmB单药疗法和LAmB+MF组合疗法的研究，DNDi及其合作伙伴分别于2023年11月和2024年6月在期刊PLOS Neglected Tropical Diseases上发表了研究结果。由于这些新的科学证据，预计更短期、更安全的治疗方法将在未来被推荐给PKDL患者。 [图源：DNDi] //全新的口服药物：合作与创新// 2023年，DNDi与合作伙伴在开发新的分子实体方面取得了重大进展，这些实体有可能彻底改变VL的治疗方法，并支持其消除目标的实现。 LXE408是一种由DNDi与Novartis联合开发的首创新药化合物。2023年8月，印度的第二个研究点已经启动，并在当年招募了39名患者。与此同时，在埃塞俄比亚进行的一项类似的II期研究已于2024年4月入组了首位受试者。预计到2025年，这两项研究将总共招募140名参与者。 GSK245具有与LXE408相似的作用模式，由DNDi、GSK全球健康部门和邓迪大学药物发现部门合作开发。2023年，针对该化合物的研究继续进行，并完成了健康志愿者单次剂量递增的I期研究。 [图源：DNDi] 此外，DNDi及其合作伙伴也恢复了具有独特的作用机理的化合物DNDI-6899的开发。储存在药明康德的活性药物成分已完成重新加工和配制，以支持2024年启动的多次剂量递增I期研究。在上月举行的第43届DNDi科学咨询委员会会议上，DNDI-6899研发项目从40多个研发项目中脱颖而出，入选“2024年度项目”（2024 Projects of the Year），以表彰该项目在临床前研究中的突出进展。在DNDi的所有利什曼病药物组合中，DNDI-6174提供了一种全新的作用模式，并且预期具有较低的人用剂量和有前景的安全边际。该化合物由DNDi与GSK和邓迪大学合作发现，并于2019年被提名为VL候选药物，该成果已于2023年12月发表在期刊Science Translational Medicine上。自2019年来，DNDi和Eisai一直在合作开发该化合物，并于2023年继续合作研究以扩大对该化合物非临床特征的了解，从而推进首次人体临床试验。 [图源：DNDi] 我们非常感激这一路同行的合作伙伴们，他们在为被忽视的患者群体推进医学创新方面发挥了重要作用。未来，我们将继续在利用现有药物提供更安全、更短周期的治疗的同时，完成全新药物的长期开发，以拯救生命，减少与内脏利什曼病有关的社会歧视和病耻感，并最终消除内脏利什曼病。点击“阅读原文”，可了解更多DNDi为最被忽视的病人推动的医学创新。关于DNDi 被忽视疾病药物研发倡议组织（DNDi）是一个以病患需求为出发点的非营利性药物研发组织。DNDi主要为被忽视的疾病患者研发新的治疗方法，其中包括昏睡病、南美锥虫病、利什曼病、淋巴丝虫病、足菌肿、儿童艾滋病/艾滋病以及丙型肝炎的治疗方法。DNDi同时也在协调ANTICOV临床试验，为非洲的轻度至中度新冠肺炎（COVID-19）患者寻找治疗方法。自2003年成立以来，DNDi迄今已交付了13种全新的治疗方案，其中包括用于治疗利什曼病的新药物组合、两种固定剂量的抗疟药，首次成功研发的新化学实体药物非昔硝唑（fexinidazole）用于治疗昏睡病，以及通过南南合作研发的丙肝药物拉维达韦（ravidasvir），旨在为全球丙肝患者提供可负担的药物选择。 *点击下方图片，了解更多有关DNDi的介绍。

临床3期

100 项与 GSK-3186899 相关的药物交易

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