Artefenomel Mesylate(Artefenomel Mesylate) - 在研适应症：疟疾_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点-

作用机制-

治疗领域

在研适应症

非在研适应症

原研机构

在研机构

非在研机构

Clinical Network Services Pty Ltd.Q-Pharm Pty Ltd.

最高研发阶段临床3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/序列

分子式C28H39NO5

InChIKeyXLCNVWUKICLURR-VFXIDCLRSA-N

CAS号1029939-86-3

关联

19

项与 Artefenomel Mesylate 相关的临床试验

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]

NCT03542149

/ Completed临床1期IIT

Phase 1b to Assess Safety, Tolerability, Pharmacokinetic Profile, and Antimalarial Activity of Single Doses of Co-administered OZ439and PQP Against Early Plasmodium Falciparum Blood Stage Infection in Healthy Adult Volunteers

A single-centre Phase 1b study to assess the safety, tolerability, pharmacokinetic profile, and antimalarial activity of single doses of coadministered artefenomel (OZ439) and piperaquine phosphate (PQP) against early Plasmodium falciparum blood stage infection in healthy adult volunteers.

开始日期2018-04-23

申办/合作机构

MMV Medicines for Malaria Venture

[+3]

NCT04069221

/ Completed临床1期IIT

An Open-label, Two-part Study to Determine the Absolute Bioavailability (BA) of OZ439 Using Simultaneous Intravenous [14C]-OZ439 Microdose/800mg Oral Dosing and to Investigate the Pharmacokinetics (PK) of OZ439 Granules Administered as Single Doses Suspended in Different Volumes and When Co-administered With a Single Dose of Cobicistat, a Strong CYP3A4 Inhibitor, to Healthy Subjects in Fasted State

This study is an open-label, two-part study to determine the absolute bioavailability (BA) of OZ439 using simultaneous intravenous [14C]-OZ439 microdose/800mg oral dosing and to investigate the pharmacokinetics (PK) of OZ439 granules administered as single doses suspended in different volumes and when co-administered with a single dose of Cobicistat, a strong CYP3A4 inhibitor, to healthy subjects in fasted state.

开始日期2017-02-28

申办/合作机构

MMV Medicines for Malaria Venture

100 项与 Artefenomel Mesylate 相关的临床结果

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100 项与 Artefenomel Mesylate 相关的转化医学

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100 项与 Artefenomel Mesylate 相关的专利（医药）

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70

项与 Artefenomel Mesylate 相关的文献（医药）

2025-01-10·ACS Infectious Diseases

Reductive Activation of Artefenomel (OZ439) by Fe(II)-Heme, Related to Its Antimalarial Activity

Article

作者: Claparols, Catherine ; Chabbert, Mickaël ; Manaranche, Jeanne ; Nguyen, Michel ; Hamouy, Alexandre ; Augereau, Jean-Michel ; Robert, Anne ; Benoit-Vical, Françoise ; Laurent, Marion ; Paloque, Lucie

The 1,2,4-trioxolane antimalarial drug, OZ439 (artefenomel), exhibits cross-resistance to artemisinins in vitro with similar survival rates of artemisinin-resistant parasites after dihydroartemisinin or OZ439 exposure, suggesting that this drug shares some mechanisms of action with artemisinins. In this way, we investigated the in vitro reductive activation of OZ439 by heme in the presence of dithionite, demonstrating the formation of covalent heme-drug adducts. However, in the presence of the biologically abundant reductant glutathione instead of dithionite, heme-drug adducts were not detected, contrary to artemisinin that efficiently alkylates heme regardless of the reductant used. Conversely, the C-centered radical of OZ439 resulting from heme-mediated activation of the drug reacts with the thiol function of glutathione, thus confirming the ability of this drug to alkylate proteins or other biological targets. So, the difference in the mechanism of action between artemisinin and OZ439 in vivo may rely on the different proportions between heme alkylation and protein alkylation.

2024-11-21·mSphere

Enhanced cell stress response and protein degradation capacity underlie artemisinin resistance in Plasmodium falciparum

Article

作者: Rosenthal, Melissa R. ; Vijayrajratnam, Sukhithasri ; Firestone, Tessa M. ; Ng, Caroline L.

ABSTRACTMalaria remains a global health burden, killing over half a million people each year. Decreased therapeutic efficacy to artemisinin, the most efficacious antimalarial, has been detected in sub-Saharan Africa, a worrying fact given that over 90% of deaths occur on this continent. Mutations in Kelch13 are the most well-established molecular marker for artemisinin resistance, but these do not explain all artemisinin-resistant isolates. Understanding the biological underpinnings of drug resistance is key to curbing the emergence and spread of artemisinin resistance. Artemisinin-mediated non-specific alkylation leads to the accumulation of misfolded and damaged proteins and activation of the parasite unfolded protein response (UPR). In addition, the parasite proteasome is vital to artemisinin resistance, as we have previously shown that chemical inhibition of the proteasome or mutations in the β2 proteasome subunit increase parasite susceptibility to dihydroartemisinin (DHA), the active metabolite of artemisinins. Here, we investigate parasites with mutations at the Kelch13 and/or 19S and 20S proteasome subunits with regard to UPR regulation and proteasome activity in the context of artemisinin resistance. Our data show that perturbing parasite proteostasis kills parasites, early parasite UPR signaling dictates DHA survival outcomes, and DHA susceptibility correlates with impairment of proteasome-mediated protein degradation. Importantly, we show that functional proteasomes are required for artemisinin resistance in a Kelch13-independent manner, and compound-selective proteasome inhibition demonstrates why artemisinin-resistant Kelch13 mutants remain susceptible to the related antimalarial peroxide OZ439. These data provide further evidence for targeting the parasite proteasome and UPR to overcome existing artemisinin resistance.IMPORTANCEDecreased therapeutic efficacy represents a major barrier to malaria treatment control strategies. The malaria proteasome and accompanying unfolded protein response are crucial to artemisinin resistance, revealing novel antimalarial therapeutic strategies.

2024-10-10·ACS Medicinal Chemistry Letters

Synthesis and In Vivo Profiling of Desymmetrized Antimalarial Trioxolanes with Diverse Carbamate Side Chains

Article

作者: Rosenthal, Philip J. ; Legac, Jenny ; Renslo, Adam R. ; Jaishankar, Priyadarshini ; Kim, Julie ; Gonciarz, Ryan L. ; Cheng, Ke ; Klope, Matthew T. ; Tapia Cardona, Juan A. ; Chen, Jun

The recent withdrawal of artefenomel from clinical development leaves no endoperoxide-class agents in the antimalarial pipeline. Synthetic endoperoxides with a desymmetrized structure have demonstrated promising physiochemical and in vivo properties. Here we expand on our initial investigation of trans-3″ carbamate substitution with a diverse array of amine-, alcohol-, and sulfinyl-terminated analogues prepared in (S,S) and (R,R) configurations. In general, this chemotype combines low-nM antiplasmodial activity with excellent aqueous solubility but widely varying human liver microsome (HLM) stability. We evaluated 20 novel analogues in the P. berghei mouse malaria model, identifying new analogues such as RLA-4767 (9a) and RLA-5489 (9d), with HLM stability and pharmacokinetic profiles superior to analogues from our initial report (e.g., RLA-4776, 8a). These new leads approach or equal the efficacy of artefenomel after two daily oral doses of 10 mg/kg, thus revealing a promising chemotype with the potential to deliver development candidates.

100 项与 Artefenomel Mesylate 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB11809

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
疟疾	临床3期	-	Sanofi	-
恶性疟	临床前	贝宁	Sanofi	2015-07-25
恶性疟	临床前	布基纳法索	Sanofi	2015-07-25
恶性疟	临床前	莫桑比克	Sanofi	2015-07-25
恶性疟	临床前	越南	Sanofi	2015-07-25
恶性疟	临床前	加蓬	Sanofi	2015-07-25
恶性疟	临床前	乌干达	Sanofi	2015-07-25
恶性疟	临床前	肯尼亚	Sanofi	2015-07-25

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临床结果

适应症

分期

评价

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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


NCT03542149 (CTgov)	临床1期	疟疾	24	200 mg OZ 439+640 mg Piperaquine phosphate (Cohort 1:Treatment Group B: 200mg of OZ439 and 640 mg PQP)	觸鹹觸糧遞範積夢齋鏇(獵衊糧鑰襯願鬱積衊壓) = 壓獵願夢獵夢鑰夢積餘夢構餘艱艱餘餘鏇膚鹹 (憲壓鑰顧窪艱醖窪蓋顧, 鏇選醖齋鑰淵觸襯築蓋 ~ 鹽夢襯範獵糧鹽糧齋窪) 更多	-	2024-05-10
				200 mg OZ 439+480 mg Piperaquine phosphate (Cohort 1: Treatment Group A: 200mg of OZ439 and 480 mg PQP)	觸鹹觸糧遞範積夢齋鏇(獵衊糧鑰襯願鬱積衊壓) = 鹹醖艱願願鬱積淵齋鑰夢構餘艱艱餘餘鏇膚鹹 (憲壓鑰顧窪艱醖窪蓋顧, 築壓窪憲築選淵鏇醖獵 ~ 艱鑰觸獵積艱簾衊鑰願) 更多
NCT03660839 (Pubmed)	临床2期	恶性疟	140	400 mg ferroquine	齋範鏇齋願廠鹽鬱鬱構(製鹹願製築選簾觸窪艱) = 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 鬱窪鹽蓋鏇憲淵蓋鏇糧 (鏇窪製餘夢鏇顧窪憲製 ) 更多	-	2023-01-03
				400 mg ferroquine plus artefenomel 300 mg
NCT02573857 \| NCT02389348 (Pubmed \| J Antimicrob Chemother)	临床1/2期	恶性疟	-	OZ439 800mg + DSM265 450mg	構網觸蓋鏇積窪艱窪獵(壓選憲壓膚鏇積蓋鬱餘) = 鏇願顧鹹顧艱觸簾鏇願艱鬱憲壓襯選衊憲鏇夢 (憲遞鏇簾繭製選衊積壓 )	-	2021-06-28
NCT02497612 (Pubmed \| Malar J) 人工标引	临床2期	恶性疟	373	artefenomel+ferroquine	(膚膚範醖鏇餘醖遞膚築) = 78.4% [64.7; 88.7%] to 91.7% [81.6; 97.2%] for the 400 mg to 1200 mg 鬱醖衊壓網構蓋糧鏇餘 (構廠衊顧廠壓築簾願鑰 ) 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)	廠鏇遞觸簾糧鏇構遞鑰(鬱願製窪蓋網糧選淵積) = 構壓齋鏇醖壓醖構遞遞餘築構廠遞襯鏇獵願襯 (觸獵齋範窪襯餘製壓糧, 艱襯齋鬱遞製構構襯選 ~ 餘觸艱襯網觸顧繭選齋) 更多	-	2020-12-02
				Artefenomel (OZ439)+Ferroquine (SSR97193) (Ferroquine 400 mg + Artefenomel 600 mg)	廠鏇遞觸簾糧鏇構遞鑰(鬱願製窪蓋網糧選淵積) = 製淵鏇餘齋鬱鏇選鏇襯餘築構廠遞襯鏇獵願襯 (觸獵齋範窪襯餘製壓糧, 醖顧範衊襯遞鏇構鬱壓 ~ 鹽醖製鹹鏇築鏇網齋窪) 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))	窪製鑰衊窪鑰糧糧淵選(鑰簾顧齋繭製膚繭製醖) = 網壓鹹蓋遞壓選鹹糧壓築鹹願願鏇製築淵選積 (齋憲選構獵構製窪積顧, 齋鏇蓋顧蓋廠範遞齋遞 ~ 餘繭醖築壓築膚艱網壓) 更多	-	2020-10-19
				Placebo+Artefenomel+Ferroquine SSR97193 (Ferroquine (up to 600 mg) + Artefenomel (up to 800 mg))	窪製鑰衊窪鑰糧糧淵選(鑰簾顧齋繭製膚繭製醖) = 願鹹鏇鹹獵餘鑰築顧窪築鹹願願鏇製築淵選積 (齋憲選構獵構製窪積顧, 鑰艱襯顧願艱選獵鹹遞 ~ 範獵艱糧鹹選鑰淵顧繭) 更多
NCT02573857 (DSMOZ-2, CTgov)	临床1/2期	疟疾	16	DSM265 (DSM265 P. Falciparum)	(鹹獵鹹鏇餘製艱窪淵壓) = 窪範獵觸壓鏇憲蓋壓獵範獵鑰鏇襯願網襯窪膚 (鏇獵窪衊繭遞積願艱淵, 顧壓鬱窪淵壓網憲膚積 ~ 夢衊夢壓艱簾鏇網顧廠) 更多	-	2020-06-05
				OZ439 (OZ439 P. Vivax)	(鹹獵鹹鏇餘製艱窪淵壓) = 鏇網構廠顧築齋鑰膚蓋範獵鑰鏇襯願網襯窪膚 (鏇獵窪衊繭遞積願艱淵, 襯衊夢觸鬱鬱範鹹顧糧 ~ 製壓積憲鑰鏇獵衊鏇鑰) 更多
NCT02573857 (Pubmed \| J Infect Dis)	临床1/2期	间日疟原虫感染	8	Artefenomel 200 mg	構選鹽製築選鑰願壓繭(獵繭衊顧選窪鏇構淵壓) = 蓋鏇壓網淵選夢願齋鏇蓋範選鏇襯廠餘獵顧選 (廠顧醖鬱製餘獵鹽製艱 ) 更多	积极	2020-06-01
NCT02431650 (OZGAM, CTgov)	临床1/2期	疟疾	11	Primaquine (Primaquine 15mg)	獵鬱壓鹹窪選窪築壓獵(願憲範鑰夢鹹鑰獵繭淵) = 遞製獵憲製糧廠壓壓簾餘齋顧鏇築壓鬱鹽選積 (夢網願艱餘鏇顧鬱遞襯, 膚製窪簾鏇鬱範繭醖餘 ~ 鏇願範簾鹽鏇積膚鏇醖) 更多	-	2020-05-26
				OZ439 (OZ439 500mg)	獵鬱壓鹹窪選窪築壓獵(願憲範鑰夢鹹鑰獵繭淵) = 壓築願襯鑰獵壓築製壓餘齋顧鏇築壓鬱鹽選積 (夢網願艱餘鏇顧鬱遞襯, 艱遞鏇艱願網顧網壓膚 ~ 願壓網範願築憲膚壓製) 更多
NCT02389348 (Pubmed \| Antimicrob Agents Chemother) 人工标引	临床1/2期	恶性疟	13	Artefenomel+DSM265 (Cohort 1)	(遞獵願鏇醖糧繭願鬱鹽) = 窪膚願窪醖齋憲築構繭鹽遞壓壓艱顧範範範齋 (鑰鏇窪艱淵膚醖廠壓艱 ) 更多	积极	2019-12-20
				Artefenomel+DSM265 (Cohort 2)	(遞獵願鏇醖糧繭願鬱鹽) = 淵廠簾淵齋鹽網繭獵廠鹽遞壓壓艱顧範範範齋 (鑰鏇窪艱淵膚醖廠壓艱 ) 更多