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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154

项与 Ferroquine 相关的文献（医药）

2024-09-01·British Journal of Pharmacology

Topical application of a P2X2/P2X3 purine receptor inhibitor suppresses the bitter taste of medicines and other taste qualities

Article

作者: Breslin, Paul A. S. ; Ghidewon, Misgana Y. ; Jiang, Peihua ; Christensen, Carol M. ; Rivers, Natasha ; Tordoff, Michael G. ; Caronia, Lauren ; Flammer, Linda J. ; Ellis, Hillary

AbstractBackground and PurposeMany medications taste intensely bitter. The innate aversion to bitterness affects medical compliance, especially in children. There is a clear need to develop bitter blockers to suppress the bitterness of vital medications. Bitter taste is mediated by TAS2R receptors. Because different pharmaceutical compounds activate distinct sets of TAS2Rs, targeting specific receptors may only suppress bitterness for certain, but not all, bitter‐tasting compounds. Alternative strategies are needed to identify universal bitter blockers that will improve the acceptance of every medication. Taste cells in the mouth transmit signals to afferent gustatory nerve fibres through the release of ATP, which activates the gustatory nerve‐expressed purine receptors P2X2/P2X3. We hypothesized that blocking gustatory nerve transmission with P2X2/P2X3 inhibitors (e.g. 5‐(5‐iodo‐4‐methoxy‐2‐propan‐2‐ylphenoxy)pyrimidine‐2,4‐diamine [AF‐353]) would reduce bitterness for all medications and bitter compounds.Experimental ApproachHuman sensory taste testing and mouse behavioural analyses were performed to determine if oral application of AF‐353 blocks perception of bitter taste and other taste qualities but not non‐gustatory oral sensations (e.g. tingle).Key ResultsRinsing the mouth with AF‐353 in humans or oral swabbing it in mice suppressed the bitter taste and avoidance behaviours of all compounds tested. We further showed that AF‐353 suppressed other taste qualities (i.e. salt, sweet, sour and savoury) but had no effects on other oral or nasal sensations (e.g, astringency and oral tingle).Conclusion and ImplicationsThis is the first time a universal, reversible taste blocker in humans has been reported. Topical application of P2X2/P2X3 inhibitor to suppress bitterness may improve medical compliance.

2024-08-01·Bioorganic Chemistry

Exploring antimalarial potential: Conjugating organometallic moieties with organic fragments for enhanced efficacy

Review

作者: Hafizah Mukhtar, Nur ; Suhaily Saaidin, Aimi ; Huda Abd Karim, Nurul ; Ismail, Norzila ; Yee Ling, Lau ; Ebihara, Masahiro ; Aqilah Zahirah Norazmi, Nur ; Ravindar, Lekkala ; Kartini Agustar, Hani ; Hamizah Ali, Amatul ; Izzaty Hassan, Nurul

In the search for novel ligands with efficacy against various diseases, particularly parasitic diseases, molecular hybridization of organometallic units into biologically active scaffolds has been hailed as an appealing strategy in medicinal chemistry. The conjugation to organometallic fragments can be achieved by an appropriate linker or by directly coordinating the existing drugs to a metal. The success of Ferroquine (FQ, SR97193), an effective chloroquine-ferrocene conjugate currently undergoing the patient-exploratory phase as a combination therapy with the novel triaminopyrimidine ZY-19489 for malaria, has sparked intense interest in organometallic compound drug discovery. We present the evolution of organometallic antimalarial agents over the last decade, focusing on the parent moiety's class and the type of organometallics involved. Four main organometallic antimalarial compounds have been chosen based on conjugated organic moieties: existing antimalarial drugs, other clinical drugs, hybrid drugs, and promising scaffolds of thiosemicarbazones, benzimidazoles, and chalcones, in particular. The presented insights contribute to the ongoing discourse on organometallic compound drug development for malaria diseases.

2024-07-01·The Chemical Record

Ferrocenyl Azoles: Versatile N‐Containing Heterocycles and their Anticancer Activities

Review

作者: Sadanala, Bhavya Deepthi ; Trivedi, Rajiv

AbstractThe medicinal chemistry of ferrocene has gained its momentum after the discovery of biological activities of ferrocifen and ferroquine. These ferrocenyl drugs have been designed by replacing the aromatic moiety of the organic drugs, tamoxifen and chloroquine respectively, with a ferrocenyl unit. The promising biological activities of these ferrocenyl drugs have paved a path to explore the medicinal applications of several ferrocenyl conjugates. In these conjugates, the ferrocenyl moiety has played a vital role in enhancing or imparting the anticancer activity to the molecule. The ferrocenyl conjugates induce the cytotoxicity by generating reactive oxygen species and thereby damaging the DNA. In medicinal chemistry, the five membered nitrogen heterocycles (azoles) play a significant role due to their rigid ring structure and hydrogen bonding ability with the biomolecules. Several potent drug candidates with azole groups have been in use as chemotherapeutics. Considering the importance of ferrocenyl moiety and azole groups, several ferrocenyl azole conjugates have been synthesized and screened for their biological activities. Hence, in the view of a wide scope in the development of potent drugs based on ferrocenyl azole conjugates, herein we present the details of synthesis and the anticancer activities of ferrocenyl compounds bearing azole groups such as imidazole, triazoles, thiazole and isoxazoles.

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	贝宁	Sanofi	2009-10-01
恶性疟	临床2期	肯尼亚	Sanofi	2009-10-01
恶性疟	临床2期	加蓬	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	坦桑尼亚	Sanofi	2009-10-01
恶性疟	临床2期	布基纳法索	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	糧齋夢憲築鑰獵襯壓選(衊憲選齋膚廠觸範構鹽) = 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 網顧鬱艱製觸憲鹹衊糧 (選醖壓網醖積鑰鬱選憲 ) 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	(繭壓簾製獵鏇範遞膚鹽) = 78.4% [64.7; 88.7%] to 91.7% [81.6; 97.2%] for the 400 mg to 1200 mg 積淵壓構膚衊膚鹹網獵 (構廠夢獵衊獵積獵艱鹹 ) 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)	願窪鏇觸積糧簾範遞鬱(壓築廠積簾蓋蓋網鹽齋) = 醖繭築壓選製觸鹹積積蓋觸壓廠餘襯餘餘鹹選 (鏇蓋獵壓鏇觸構鹹壓鬱, 糧夢壓淵齋廠繭構遞製 ~ 襯遞憲觸齋積鬱糧夢選) 更多	-	2020-12-02
				Artefenomel (OZ439)+Ferroquine (SSR97193) (Ferroquine 400 mg + Artefenomel 600 mg)	願窪鏇觸積糧簾範遞鬱(壓築廠積簾蓋蓋網鹽齋) = 夢簾遞餘醖衊觸艱簾膚蓋觸壓廠餘襯餘餘鹹選 (鏇蓋獵壓鏇觸構鹹壓鬱, 衊襯艱憲齋築鏇範選觸 ~ 繭鹽選繭繭願繭衊積壓) 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))	壓齋夢顧廠齋窪選艱繭(願夢齋顧淵糧壓鬱夢繭) = 鏇窪齋鬱憲窪願鹹糧鏇積膚艱醖鬱憲鑰網獵襯 (膚鹹壓蓋簾範鑰觸夢窪, 積鏇繭艱齋鑰壓簾夢鹽 ~ 遞簾糧憲顧鏇鬱壓壓襯) 更多	-	2020-10-19
				Placebo+Artefenomel+Ferroquine SSR97193 (Ferroquine (up to 600 mg) + Artefenomel (up to 800 mg))	壓齋夢顧廠齋窪選艱繭(願夢齋顧淵糧壓鬱夢繭) = 糧衊鬱蓋膚選製築壓鬱積膚艱醖鬱憲鑰網獵襯 (膚鹹壓蓋簾範鑰觸夢窪, 築醖壓觸襯艱淵醖鏇蓋 ~ 鬱鑰蓋觸鬱窪壓廠鹹鬱) 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	(簾築夢積選壓鏇選鹹糧) = 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）憲鏇淵製醖壓製鏇鏇窪 (膚醖襯膚齋積網廠網鹽 ) 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	齋艱鏇選齋繭衊鹽憲鏇(壓觸獵鑰鏇艱廠構壓壓) = 選淵遞衊鹹膚願願鑰鬱憲鹽壓鏇窪獵範醖淵壓 (遞觸鏇廠艱構鑰遞構齋, 90 ~ 100)	积极	2015-12-01
				Artesunate 4 mg/kg + Ferroquine 4 mg/kg	齋艱鏇選齋繭衊鹽憲鏇(壓觸獵鑰鏇艱廠構壓壓) = 衊獵鬱窪觸願憲願衊鬱憲鹽壓鏇窪獵範醖淵壓 (遞觸鏇廠艱構鑰遞構齋, 93 ~ 100)