Phase Ib, Single-center, Randomized, Study to Determine Safety, Tolerability, and Pharmacokinetics of Different Orally Administered Regimens of the Combination ZY19489-Ferroquine in Adult Asymptomatic Plasmodium Falciparum Carriers

Malaria is caused by protozoan parasites of the genus Plasmodium and it is the most important parasitic disease in terms of mortality and morbidity. Estimates of 247 million malaria cases and 619.000 deaths worldwide were reported by WHO for the year 2021 (1). Plasmodium falciparum can lead to severe malaria and accounts for 90% of malaria deaths that mainly occur in children below the age of 5 years in Sub-Saharan Africa.
A simplified treatment regimen, ideally a single-day cure (or at most 2-day dosing regimen), of uncomplicated malaria due to P. falciparum would be the magic in the antimalarial armamentarium. Improving treatment adherence is one of the key factors in reducing mortality and morbidity and also the transmission of malaria, and such a regimen would substantially increase adherence. To find a new non-artemisinin combination therapy with a shorter regimen, ideally, a single-dose cure, with low resistance potential would be the aim. The two compounds tested here are ZY19489, a triaminopyrimidine, and ferroquine (FQ), a next-generation 4-aminoquinoline. Both compounds show unique features in terms of long half-life, and activity against current drug-resistant strains.
Therefore, the main goal of this clinical trial is to assess the safety of the ZY19489-FQ combination given as a 1- or 2-day dose regimen.

开始日期2024-08-30

申办/合作机构

Zydus Lifesciences Ltd.

NCT03660839

/ Completed临床2期

A Randomized, Open Label, Parallel-group, Single Dose Regimen, Phase 2a Study, to Investigate the Clinical and Parasiticidal Activity and the Pharmacokinetics of 3 Dose Levels of Artefenomel (OZ439) Given in Combination With Ferroquine (FQ) and FQ Alone, in African Patients With Uncomplicated Plasmodium Falciparum Malaria

Primary Objective:
To show the contribution of artefenomel (OZ439) to the clinical and parasiticidal effect of OZ439/Ferroquine (FQ) combination by analyzing exposure-response of OZ439 measured by Day 28 polymerase chain reaction (PCR)-corrected adequate clinical and parasitological response (ACPR) for the effect and the area under the curve (AUC) of OZ439 as pharmacokinetic (PK) predictor.
Secondary Objectives:
To evaluate the exposure-response of OZ439 combined with FQ on crude Day 28 ACPR.
To evaluate the dose response of OZ439 combined with FQ on PCR-corrected and crude Day 28 ACPR.
To evaluate the dose-response of OZ439 combined with FQ on selected secondary endpoints.
To evaluate the safety and tolerability of different dosages of OZ439 in combination with FQ and FQ alone.
To characterize the PK of OZ439 in plasma, and of FQ and its active metabolite SSR97213 in blood.

开始日期2018-09-11

申办/合作机构

Sanofi

[+1]

NCT02497612

/ Terminated临床2期

A Randomized, Double-blind, Phase IIb Study to Investigate the Efficacy, Safety, Tolerability and Pharmacokinetics of a Single Dose Regimen of Ferroquine (FQ) With Artefenomel (OZ439) in Adults and Children With Uncomplicated Plasmodium Falciparum Malaria

Primary Objective:
To determine whether a single dose combination of OZ439 (Artefenomel)/FQ (Ferroquine) was an efficacious treatment for uncomplicated Plasmodium falciparum malaria in adults and children.
Secondary Objectives:
To evaluate the efficacy of OZ439/FQ:
To determine the incidence of recrudescence and re-infection.
To determine the time to relief of fever and parasite clearance.
To evaluate the safety and tolerability of OZ439/FQ in adults and children.
To characterize the pharmacokinetics of OZ439 in plasma, FQ and its active metabolite SSR97213 in blood.
To determine the blood/plasma ratio for FQ and SSR97213 in some participants at limited time points in selected sites.

开始日期2015-07-25

申办/合作机构

Sanofi

[+1]

100 项与 Ferroquine 相关的临床结果

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100 项与 Ferroquine 相关的转化医学

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100 项与 Ferroquine 相关的专利（医药）

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156

项与 Ferroquine 相关的文献（医药）

2025-03-01·Applied Organometallic Chemistry

Advances in the Potential of Quinoline‐Derived Metal Complexes as Antimalarial Agents: A Review

作者: Gonçalves, Raoni Schroeder Borges ; Peron, Carla ; Moura, Sidnei

ABSTRACTQuinolines obtained from native trees of South and Central America, of the genus Cinchona, have been used since the 17th century for the treatment of malaria. However, it was only in 1820 that quinine had its structure elucidated, and subsequently, during the 20th century, several synthetic derivatives were produced with quinine superior activities. In parallel, the search for the synthesis of metal complex compounds for the treatment of malaria dates from 1994, with the development of ferroquine, an iron complex derived from chloroquine, developed by Biot and collaborators at Lille University. After, there are several metal complexes synthesized from quinine with various metals, such as ruthenium, gold, iridium, and platinum, over the last 30 years, which are the aims of this review. This review identified 84 quinoline–metal complexes reported across 25 studies, with the gold complex (Complex 63) showing significant potency against the FcBI strain (IC50 10 nM), outperforming chloroquine (CQ, 50 nM), indicating that metal coordination enhances the drug's action. The ruthenium complex (Complex 03) exhibited activity against PFB but was less effective than CQ (IC50 22.5 vs. 8.2 nM). Other complexes, such as Au(III) (Complex 61), Ir(I) (Complex 52), and Ir(II) (Complex 50), also demonstrated promising results with varying effectiveness across different strains. Structural features, including linear geometry in Au(I) complexes and square planar or piano stool geometries in Ru(II) and Ir complexes, play crucial roles in influencing their biological activity. These findings highlight the potential of metal coordination in improving antimalarial efficacy.

2025-03-01·Clinical Microbiology and Infection

The non-artemisinin antimalarial drugs under development: a review

Review

作者: Mombo-Ngoma, Ghyslain ; Ramharter, Michael ; Okwu, Dearie Glory ; Duparc, Stephan ; Zoleko Manego, Rella ; Kremsner, Peter Gottfried

BACKGROUNDIn 2022, malaria caused approximately 249 million cases and 608,000 deaths, primarily in Africa. Current treatments target asexual blood-stage parasites, gametocytes, and liver hypnozoites. Standard guidelines recommend a 3-day course of artemisinin-based combination therapies as a first-line treatment of uncomplicated malaria and parenteral artesunate for severe malaria. However, the emergence of partial resistance to artemisinin derivatives threatens the treatment efficacy, highlighting the urgent need for novel antimalarial drugs.OBJECTIVESThis review summarizes recent progress in the clinical development of antimalarials particularly non-artemisinin compounds under target product profile-1.SOURCESData were gathered from Medicines for Malaria Venture (MMV)'s portfolio and clinical trial databases between 2020 and 2024.CONTENTSixteen clinical trials were reviewed, including safety and efficacy studies involving healthy volunteers, experimentally infected volunteers, asymptomatic Plasmodium falciparum carriers and malaria patients. Six trials evaluated the safety and tolerability of MMV533, ZY19489, INE963, GSK701/MMV367 and intravenous KAE609 in healthy volunteers. Efficacy trials involving experimentally infected volunteers assessed ZY19489 and GSK701/MMV367, whereas studies on asymptomatic carriers tested ZY19489/ferroquine and cabamiquine/pyronaridine. Trials on malaria patients investigated combinations of ganaplacide/lumefantrine-SDF, cabamiquine/pyronaridine, both oral and intravenous cipargamin and INE963.IMPLICATIONSAlthough attrition remains a possibility, several promising candidate drugs with novel modes of action are advancing through clinical development. Many are expected to become available for treating uncomplicated and severe malaria within the next decade. These new antimalarials could significantly enhance malaria treatment, reduce resistance, and support global health efforts towards malaria control, elimination and, potentially, eradication.

2024-10-28·JACS Au

Pyrimidine Azepine Targets the Plasmodium bc₁ Complex and Displays Multistage Antimalarial Activity

Article

作者: Silva-Mendonça, Sabrina ; Usui, Miho ; Aguiar, Anna Caroline C. ; Moura, Igor M. R. ; Long, Carole A. ; Benavente, Ernest D. ; da Silva Araujo, Maisa ; Calit, Juliana ; Eastman, Richard T. ; Bargieri, Daniel Y. ; Williamson, Kim C. ; Miura, Kazutoyo ; Araújo, Jessica E. ; Simeonov, Anton ; Andrade, Carolina H. ; Medeiros, Jansen F. ; Deng, Bingbing ; Prajapati, Surendra K. ; Annunciato, Yasmin

Malaria control and elimination efforts would benefit from the identification and validation of new malaria chemotherapeutics. Recently, a transgenic Plasmodium berghei line was used to perform a series of high-throughput in vitro screens for new antimalarials acting against the parasite sexual stages. The screens identified pyrimidine azepine chemotypes with potent activity. Here, we validate the activity of PyAz90, the most potent pyrimidine azepine chemotype identified, against P. falciparum and P. vivax in the asexual and sexual stages. PyAz90 blocked parasite transmission to the mosquito vector at nanomolar concentrations and inhibited in vitro asexual parasite multiplication with a fast-action profile. Through the generation of P. falciparum PyAz90-resistant parasites and in vitro assays of mitochondrial activity, we identified cytochrome b as a molecular target of PyAz90. This work characterizes a promising chemotype that can be explored for the future development of new antimalarials targeting the Plasmodium cytochrome bc ₁ complex.

项与 Ferroquine 相关的新闻（医药）

2024-11-29

·CPHI制药在线

抗疟疾药物研发进展

关注并星标CPHI制药在线在全球健康的版图中，疟疾一直是一块难以攻克的“顽疾”。据世界卫生组织（WHO）统计，2021年全球约有2.47亿疟疾病例，61.9万人因此失去生命，其中95%的病例和96%的死亡发生在撒哈拉以南非洲地区。疟疾不仅严重威胁人类健康，还对经济发展造成巨大阻碍，每年导致该地区约120亿美元的经济损失。今天，就让我们深入了解疟疾的现状、抗疟药物的研发进展，以及未来面临的挑战与希望。 1、现有抗疟疗法及耐药困境（1）常用药物与疗法当前，治疗非重症恶性疟原虫疟疾，主要依靠以青蒿素为基础的联合疗法（ACTs）。其中，蒿甲醚 - 苯芴醇（artemether lumefantrine，AL）在非洲市场占据了75%的份额，青蒿琥酯 - 阿莫地喹（artesunate amodiaquine）则作为二线选择，拥有24%的市场占有率。这些药物在一定程度上有效控制了疟疾的发展，但它们也面临着日益严峻的耐药问题。除了ACTs，还有双氢青蒿素 - 哌喹（dihydroartemisinin piperaquine，DHA - PPQ）、阿托伐醌 - 氯胍（atovaquone proguanil，Malarone）等药物组合，但使用相对较少。对于重症疟疾，静脉注射青蒿琥酯（artesunate）是首选治疗方法，金鸡纳霜（quinine）也可作为替代选择。而针对间日疟原虫疟疾的根治，氯喹（Chloroquine）与伯氨喹（primaquine）或他非诺喹（tafenoquine）的联合使用是常见方案；孕期间歇性预防治疗则采用磺胺多辛 - 乙胺嘧啶（sulfadoxine-pyrimethamine，SP）；在非洲的季节性疟疾高发地区，对于6个月至5岁（部分国家至10岁）的儿童，每月使用SP和阿莫地喹进行季节性疟疾化学预防（SMC）（图1）。（2）药物耐药性问题疟原虫耐药问题由来已久，20世纪初有对奎宁耐药的报告，50年代起氯喹和SP耐药性在疟疾流行区扩散，致死亡人数上升。21世纪ACTs虽为一线疗法，但耐药问题仍存。东南亚大部分地区DHA - PPQ因耐药失效，非洲大陆AL虽仍有效，但卢旺达已现青蒿素部分耐药，乌干达恶性疟原虫临床分离株对咯萘啶（pyronaridine）和DHA敏感性降低，这些耐药现象严重威胁全球疟疾防控成效。图1.在疟原虫生命周期下的疟疾治疗来源：出自参考文献【1】 2、抗疟药物研发进展（1）传统与现代的研发策略在抗疟药物研发的漫长历程中，传统策略主要包括从天然产物中分离和修饰活性成分，以及筛选化合物库、设计已知靶点抑制剂等。然而，这种基于天然产物的研发方式面临着诸多挑战，如供应不稳定、成分多变、生物测定引导分馏后复杂混合物相关的实际挑战。此外，对现有天然产物进行改进以克服耐药性的难度较大，这使得研发人员不得不寻求新的方法。随着科学技术的发展，现代抗疟药物研发主要采用表型筛选和基于靶点和虚拟药效团的方法。表型筛选：通过对全细胞寄生虫培养进行大规模化学库筛选，可发现具有新颖作用模式的化合物，许多在研药物由此发现，但靶点未知会给后续优化带来困难。基于靶点和虚拟药效团方法：基于靶点的方法可开发新的生化测定，合理设计化合物，但可能成本高且存在耐药风险；虚拟筛选虽初期成本低，但需大量后续工作确认化合物与靶点的结合及对寄生虫的功能抑制，目前尚未产生具有强细胞活性的新化合物。（2）新靶点及治疗药物为了开发更有效的抗疟药物，科学家们已经发现了一些具有潜力的靶点，如细胞色素B（CytB）、二氢蝶酸合成酶（DHPS）、二氢叶酸还原酶 - 胸苷酸合成酶（DHFR - TS）和血红素等，这些都是已有的临床验证靶点（图2）。此外，还有一些较新的靶点，如ATP酶4（ATP4）、延伸因子2（eEF2）、脯氨酰tRNA合成酶（PRS）和磷脂酰肌醇4 - 激酶（PI4K）等。图2.具有临床验证的抗疟靶点来源：出自参考文献【1】在抗疟药物的研发进程中，众多药物处于不同的研究阶段（图3），给我们带来了新的希望。患者探索阶段： ZY - 19489是一种快速杀伤无性血液阶段寄生虫且耐药倾向低的化合物，在志愿者感染研究中，其安全性、药代动力学和抗疟活性表现优异，支持其进一步开发。 ferroquine是一种含二茂铁基环的4 - 氨基喹啉类药物，具有快速杀伤和长半衰期的特点，与ZY - 19489组合使用，有望实现儿童疟疾的单剂量治疗，为应对ACTs耐药性提供了潜在解决方案。 cabamiquine对寄生虫无性肝、血和性阶段均有活性，但其耐药性发展较快，因此与咯萘啶联用，以增强疗效并延缓耐药性的产生。 ganaplacide对无性肝、血和性阶段的恶性疟原虫均有强效作用，与优化配方的苯芴醇联用，在临床研究中取得了积极结果，有望成为自2000年以来首个非ACT治疗药物。 cipargamin可使寄生虫僵化并快速清除，对传播阻断也有效，但由于存在耐药风险，目前正在探索注射用新配方，以确保其长期有效性。临床I期阶段： atoguanil是阿托伐醌 - 氯胍的新配方，旨在提高药物的疗效和安全性。 MMV688533是通过基于同源性的筛选策略发现的TCP - 1候选药物，其作用机制虽尚未完全明确，但耐药风险低，在实验室条件下难以产生耐药性，目前正在进行临床I期研究。 INE963是诺华发现的快速杀伤化合物，对无性血液阶段寄生虫具有高效作用，且耐药倾向低，近期已进入临床I期试验，后续还将在治疗组合的II期试验中进行评估。临床前阶段：共有11种候选小分子和1种抗体正在深入研究。其中， MMV183是一种抑制AcAS的抗代谢物，具有显著的传播阻断和无性血液阶段活性； GSK701是酰基辅酶A合成酶ACS10和ACS11的新型抑制剂，具有TCP - 1活性特征； WM382和BRD5018分别是 plasmepsins IX和X以及FRS的抑制剂，具有多阶段活性，对寄生虫的多个生命周期阶段均有作用； SC83288是一种新型注射候选药物，用于治疗重症疟疾，但其作用机制尚不清楚； GSK484和IWY357是通过表型筛选发现的快速杀伤化合物，具有低耐药倾向，虽然其结构和作用机制尚未公布，但在抗疟药物研发中具有潜在价值； MMV371是阿托伐醌前药，ELQ - 331是ELQ - 300的口服前药，两者均通过抑制寄生虫CytB发挥作用； S011 - 1793是下一代4 - 氨基喹啉，能够克服氯喹和PPQ耐药性； MMV1793609是PfATP4抑制剂，具有低剂量高效的特点，是2022年发现的备选药物。图3.抗疟药物研发进展和研发管线来源：出自参考文献【1】 3、抗疟之路的未来挑战与展望疟疾防控工作面临着诸多复杂的挑战，疟原虫耐药机制研究复杂，实验室研究多基于单基因变化，但实际临床分离株往往涉及多个突变，且寄生虫遗传背景对耐药性产生的影响机制尚不明确，不同地区疟原虫的遗传差异也导致耐药性表现和传播方式各异。此外，药物递送与药代动力学也存在难题，例如长效注射剂面临疗效持续时间、体积和安全性等挑战，不同人群对药物代谢和反应的差异也增加了研发复杂性...... 尽管挑战重重，但过去15年在疟疾防控方面取得了一定成果，新靶点不断被发现，候选药物进入研发管线，新治疗方法如首个疟疾疫苗获批问世。这些成绩的取得离不开全球各方的紧密合作，未来仍需进一步加强合作，整合资源、加大研发投入、鼓励创新，通过共享数据、技术和经验来加速抗疟药物研发进程，实现疟疾的有效控制和消除。疟疾防控是全球性持久战，每一次突破都使我们向战胜疟疾的目标更近一步，我们应共同关注和支持抗疟工作，期待人类能早日摆脱疟疾威胁。参考文献 [1]Siqueira-Neto, Jair L et al. “Antimalarial drug discovery: progress and approaches.” Nature reviews. Drug discovery vol. 22,10 (2023): 807-826. doi:10.1038/s41573-023-00772-9 [2]Carter, Richard, and Kamini N Mendis. “Evolutionary and historical aspects of the burden of malaria.” Clinical microbiology reviews vol. 15,4 (2002): 564-94. doi:10.1128/CMR.15.4.564-594.2002 [3]Rasmussen, Charlotte et al. “Current and emerging strategies to combat antimalarial resistance.” Expert review of anti-infective therapy vol. 20,3 (2022): 353-372. doi:10.1080/14787210.2021.1962291 END 【智药研习社近期直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

临床研究孤儿药

100 项与 Ferroquine 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
恶性疟	临床2期	肯尼亚	Sanofi	2009-10-01
恶性疟	临床2期	喀麦隆	Sanofi	2009-10-01
恶性疟	临床2期	贝宁	Sanofi	2009-10-01
恶性疟	临床2期	布基纳法索	Sanofi	2009-10-01
恶性疟	临床2期	坦桑尼亚	Sanofi	2009-10-01
恶性疟	临床2期	加蓬	Sanofi	2009-10-01

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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


NCT03660839 (Pubmed)	临床2期	恶性疟	140	400 mg ferroquine	憲願醖艱壓觸網夢餘選(憲鏇鹹網獵壓構獵夢衊) = Adverse events (AEs) of any cause occurred in 51.4% (18/35) of patients with ferroquine 400 mg alone, and 58.3% (21/36), 66.7% (24/36), and 72.7% (24/33) with 300, 600, and 1000 mg artefenomel, respectively 製餘鹹鏇艱簾選選繭繭 (壓製壓糧餘蓋鏇簾簾遞 ) 更多	-	2023-01-03
				400 mg ferroquine plus artefenomel 300 mg
NCT02497612 (Pubmed \| Malar J) 人工标引	临床2期	恶性疟	373	artefenomel+ferroquine	(構顧鹽壓鏇窪廠壓選築) = 78.4% [64.7; 88.7%] to 91.7% [81.6; 97.2%] for the 400 mg to 1200 mg 願製鑰夢積觸齋繭憲構 (鹹鏇鬱願積淵觸築鏇衊 ) 更多	不佳	2021-05-19
NCT03660839 (CTgov)	临床2期	恶性疟	140	Artefenomel (OZ439)+Ferroquine (SSR97193) (Ferroquine 400 mg + Artefenomel 300 mg)	憲簾鏇夢範齋夢壓構窪(蓋遞鬱鬱範築餘餘網鑰) = 製築選鬱廠蓋窪齋範壓遞獵憲製選願蓋簾憲糧 (襯簾鬱廠鏇遞壓淵顧鹹, 觸衊鬱網鑰窪築膚醖襯 ~ 繭鹽糧壓選夢網鹹遞鏇) 更多	-	2020-12-02
				Artefenomel (OZ439)+Ferroquine (SSR97193) (Ferroquine 400 mg + Artefenomel 600 mg)	憲簾鏇夢範齋夢壓構窪(蓋遞鬱鬱範築餘餘網鑰) = 鏇醖醖壓鑰築艱鬱糧鏇遞獵憲製選願蓋簾憲糧 (襯簾鬱廠鏇遞壓淵顧鹹, 齋積築淵衊齋蓋齋範鏇 ~ 壓鹽選淵簾淵繭壓鑰鹽) 更多
NCT02497612 (FALCI, CTgov)	临床2期	恶性疟	377	Placebo+Artefenomel+Ferroquine SSR97193 (Ferroquine (up to 400 mg) + Artefenomel (up to 800 mg))	築網範艱齋夢餘鏇構簾(壓構齋壓窪齋憲蓋壓糧) = 範鬱選衊觸獵廠繭遞築簾夢淵網廠獵衊憲範餘 (顧鬱糧願獵鑰範鑰積夢, 網醖餘選鹽鹽選繭鑰網 ~ 製窪膚窪襯簾獵築齋鹹) 更多	-	2020-10-19
				Placebo+Artefenomel+Ferroquine SSR97193 (Ferroquine (up to 600 mg) + Artefenomel (up to 800 mg))	築網範艱齋夢餘鏇構簾(壓構齋壓窪齋憲蓋壓糧) = 鑰齋艱淵窪範鑰夢網淵簾夢淵網廠獵衊憲範餘 (顧鬱糧願獵鑰範鑰積夢, 鏇齋範夢窪鬱獵鑰網構 ~ 鹹築餘襯衊獵餘憲鬱簾) 更多
NCT00563914 (Pubmed \| Trans R Soc Trop Med Hyg \| Am J Trop Med Hyg) 人工标引	临床2期	恶性疟	72	Artesunate+Ferroquine	(醖淵觸鹽襯廠積蓋網廠) = mild increases（grade 1 toxicity）in ALT levels with a dose trend starting at 400 mg；two grade 2 ALT events（200 mg 1 pt，600 mg 1 pt）鹽廠憲觸醖鬱襯觸鹹齋 (淵蓋鬱餘壓願獵築窪範 ) 更多	积极	2017-08-01
				Artesunate+Amodiaquine
NCT00988507 (Pubmed \| Lancet Infect Dis)	临床2期	恶性疟	326	Artesunate 4 mg/kg + Ferroquine 2 mg/kg	壓鏇範廠膚鑰衊憲淵鏇(顧壓簾繭衊廠築簾淵膚) = 繭壓蓋願簾鹽淵艱齋糧蓋繭膚鹽觸窪淵淵壓選 (範淵製顧遞簾鏇選築鑰, 90 ~ 100)	积极	2015-12-01
				Artesunate 4 mg/kg + Ferroquine 4 mg/kg	壓鏇範廠膚鑰衊憲淵鏇(顧壓簾繭衊廠築簾淵膚) = 簾壓壓鑰膚積顧襯鏇製蓋繭膚鹽觸窪淵淵壓選 (範淵製顧遞簾鏇選築鑰, 93 ~ 100)