A Multicentre Open-label, Non-inferiority Adaptive Platform Randomised Controlled Trial to Evaluate the Efficacy, Safety, and Tolerability of Antimalarials for the Treatment of Uncomplicated Malaria in the First Trimester of Pregnancy: Master Protocol

The SAFIRE study aims to find effective treatments with acceptable safety for malaria in early pregnancy, a particularly sensitive time for the adverse consequences of malaria in pregnancy for both mother and baby. Currently, WHO recommends the antimalarial drug artemether-lumefantrine (AL) for the treatment of uncomplicated malaria in the first trimester of pregnancy. Other promising treatments are being rolled out in malaria-endemic countries for use in adults and children and data on current exposures in the first trimester are limited and insufficient to support a recommendation. This is due to the fact that pregnant women are often excluded from clinical trials to protect fetuses, unintentionally depriving them of newer, potentially better treatments. Instead, they often received older, less effective drugs. The International Council for Harmonisation (ICH E21) and stringent regulatory authorities (e.g. EMA, FDA and MHRA) now encourage pregnant women to be included in well-designed studies to ensure they can safely benefit from medical advances.
This study will compare AL with the newer antimalarial drugs that have shown no significant safety concerns in laboratory studies, accidental use during early pregnancy, or trials in later pregnancy stages. The main goal is to see if these new drugs work as well as AL in treating malaria and are safe for the mother, her pregnancy and the developing baby. The newer antimalarials being tested also offer additional benefits to pregnant women, such as preventing new malaria infections for longer after treatment than the current standard treatment (AL). Also, they can be taken just once a day instead of twice daily, like AL. A simpler dosing schedule could improve adherence to the study medication, meaning women are more likely to take the full course of treatment as prescribed. This, in turn, enhances its effectiveness in real-world settings. Future antimalarials to be tested will include those with improved resistance profiles, offering more effective options for combating drug-resistant strains.
SAFIRE uses a special "Bayesian Adaptive Platform Trial" (APT) design. This open-ended approach allows researchers to add new interventions under the same protocol, leveraging the existing trial network with infrastructure. The use of a common protocol with innovative adaptive statistical design allows the trial to stop early if it becomes clear that the new drugs are unsafe.
This multi-centre trial will be conducted in several countries in Africa where malaria is very common. Women will be randomly assigned to receive either AL or one of the new treatments. Participants will be seen daily for 4 days, then weekly for 6 weeks to assess the response to treatment, and then monthly until delivery. Their health and outcomes will be closely monitored during and after pregnancy. Newborns will be followed for 6 months. An independent data safety and monitoring board (DSMB) will regularly monitor safety data as it accumulates. By finding more treatment options, this study could improve care for pregnant women with malaria and lead to better health for mothers and babies in areas where malaria is widespread. The results will help inform global health policies and potentially change how we treat malaria in early pregnancy.

开始日期2025-07-01

申办/合作机构

Liverpool School of Tropical Medicine

NCT05974267

/ Completed临床2期

Phase 2a Proof-of-Concept, Multicenter, Randomized, Open Label Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of a Single Dose of the Combination M5717-pyronaridine as Chemoprevention in Asymptomatic Adults and Adolescents With Plasmodium Falciparum Malaria Infection (CAPTURE-2)

This study will evaluate the efficacy and safety of a single dose of M5717 plus pyronaridine tetraphosphate in clearing current Plasmodium falciparum infection and protecting against recurrent infections in asymptomatic adults and adolescents. The study will also assess the duration of protection provided by different doses of M5717 plus pyronaridine and the additional contribution of M5717 to the duration of protection using external study data.

开始日期2023-11-28

申办/合作机构

Merck Healthcare KGaA

PACTR202402599048090

/ Recruiting临床2期IIT

Efficacy and safety of pyronaridine/artesunate and pyronaridine/artesunate/praziquantel for treatment of uncomplicated Schistosoma haematobium infection in Gabonese adolescents and children

开始日期2023-09-01

申办/合作机构-

100 项与磷酸咯萘啶相关的临床结果

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100 项与磷酸咯萘啶相关的转化医学

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100 项与磷酸咯萘啶相关的专利（医药）

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567

项与磷酸咯萘啶相关的文献（医药）

2025-06-01·CLINICAL MICROBIOLOGY AND INFECTION

The non-artemisinin antimalarial drugs under development: a review

Review

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

BACKGROUND:

In 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.

OBJECTIVES:

This review summarizes recent progress in the clinical development of antimalarials particularly non-artemisinin compounds under target product profile-1.

SOURCES:

Data were gathered from Medicines for Malaria Venture (MMV)'s portfolio and clinical trial databases between 2020 and 2024.

CONTENT:

Sixteen 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.

IMPLICATIONS:

Although 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.

2025-04-01·CPT-Pharmacometrics & Systems Pharmacology

PBPK‐Led Assessment of Antimalarial Drug Concentrations in Breastmilk: A Strategy for Optimal Use of Prediction Methods to Guide Decision Making in an Understudied Population

Article

作者: Kusmider, Beata ; Pansari, Amita ; Abla, Nada ; Möhrle, Jörg J. ; Marrast, Anne Claire ; Gardner, Iain ; Faisal, Muhammad ; Abduljalil, Khaled ; Almond, Lisa M. ; Jones, Hannah M. ; El Gaaloul, Myriam ; Rowland Yeo, Karen

ABSTRACT:

Treatment of breastfeeding mothers with malaria is challenging due to the lack of information describing drug exposure in milk and the daily dose to the breastfed infant. Physiologically based pharmacokinetic (PBPK) modeling was used to predict milk‐to‐plasma (M/P) ratios, infant daily doses (IDD) and relative infant doses (RID) for five antimalarials with clinical lactation data (chloroquine, pyrimethamine, piperaquine, mefloquine and primaquine). In all cases, RID was correctly categorized as above or below the WHO proposed cut‐off of 10% using two prediction models. Predicted M/P ratios were within 2‐fold of observations for 63% of studies using both models (75% and 100% were within 3‐fold for Models 1 and 2, respectively). M/P ratios, IDD and RID were predicted prospectively for seven antimalarials. RID was < 10% for amodiaquine, dihydroartemisinin, proguanil, and pyronaridine, and > 10% for lumefantrine and tafenoquine. For atovaquone, RID was > 10% with Model 1 but not Model 2. Predicted IDD were considerably lower than licensed doses for infants except for lumefantrine (Model 2) and tafenoquine (not licensed in < 2 years). Predictions were sensitive to drug properties (plasma protein binding and lipophilicity) and milk properties (creamatocrit and pH). This analysis demonstrates the utility of PBPK to predict milk exposure in the absence of clinical lactation information. These prediction methodologies can be used, alongside any licensed dosing information for < 1 year‐olds, to evaluate whether a clinical lactation study is necessary and to inform drug label or policy recommendations. The ultimate goal is to better inform optimal treatment for lactating women supporting malaria eradication.

2025-03-18·ANALYTICAL CHEMISTRY

High-Throughput Empirical and Virtual Screening To Discover Novel Inhibitors of Polyploid Giant Cancer Cells in Breast Cancer

Article

作者: Shih, Chien-Hung ; Chen, Yu-Chih ; Chen, Hsiao-Chun ; Ma, Yushu ; Brown, Daniel D. ; Zhang, Yuan ; Wang, Li-Ju ; Cheng, Jinxiong ; Tan, Yanhao ; Lee, Adrian V. ; Oesterreich, Steffi ; Chiu, Yu-Chiao

Therapy resistance in breast cancer is increasingly attributed to polyploid giant cancer cells (PGCCs), which arise through whole genome doubling and exhibit heightened resilience to standard treatments. Characterized by enlarged nuclei and increased DNA content, these cells tend to be dormant under therapeutic stress, driving disease relapse. Despite their critical role in resistance, strategies to effectively target PGCCs are limited, largely due to the lack of high-throughput methods for assessing their viability. Traditional assays lack the sensitivity needed to detect PGCC-specific elimination, prompting the development of novel approaches. To address this challenge, we developed a high-throughput single-cell morphological analysis workflow designed to differentiate compounds that selectively inhibit non-PGCCs, PGCCs, or both. Using this method, we screened a library of 2726 FDA Phase 1-approved drugs, identifying promising anti-PGCC candidates, including proteasome inhibitors, FOXM1, CHK, and macrocyclic lactones. Notably, RNA-Seq analysis of cells treated with the macrocyclic lactone Pyronaridine revealed AXL inhibition as a potential strategy for targeting PGCCs. Although our single-cell morphological analysis pipeline is powerful, empirical testing of all existing compounds is impractical and inefficient. To overcome this limitation, we trained a machine learning model to predict anti-PGCC efficacy in silico, integrating chemical fingerprints and compound descriptions from prior publications and databases. The model demonstrated a high correlation with experimental outcomes and predicted efficacious compounds in an expanded library of over 6,000 drugs. Among the top-ranked predictions, we experimentally validated five compounds as potent PGCC inhibitors using cell lines and patient-derived models. These findings underscore the synergistic potential of integrating high-throughput empirical screening with machine learning-based virtual screening to accelerate the discovery of novel therapies, particularly for targeting therapy-resistant PGCCs in breast cancer.

项与磷酸咯萘啶相关的新闻（医药）

2025-05-30

·循因缉药

聊点不一样的！世和超万例金陵队列研究揭秘

全球视野，深度视角各位亲爱的股东，大家早上好中午好晚上好！已在星球<循因缉药 Elite>首发，加入方法如下。小编在这里！星球在这里！昨天，2025年5月29日，世和基因在南京总部举办了肿瘤早筛学术成果暨金陵队列研究数据发布会。听了，很有感触。这篇文章无广，请放心食用，且水平有限，错了欢迎打脸。我们将从2个方面入手，跟大家分享下。第一，发布了个啥？（补全）第二，技术特点是个啥？（片段组玩出花）本来想写第三点关于早筛格局的，题目太大...hold不住。好，接下来我们就聊聊。#01补全MCED(Multi-Cancer Early Detection，多癌早筛)被称为肿瘤检测领域的“圣杯”，这也是美国GRAIL Inc本来的含义。本次发布的就是世和在MCED研究的金陵队列首期数据，在聊这份数据之前，我们先稍微补充点背景资料。关于MCED，经常关注我们的老粉都知道，美国的GRAIL早就已经启动了MCED产品Galleri的商业化。现如今，Exact Sciences，Guardant Health等纷纷入局。那我们呢？其实也不少，能数得出来有世和、燃石、和瑞、小荷（微荷）、诺辉等（排名不分先后，想到哪写到哪）。如果我没有记错，这里面诺辉的PANDA研究队列最为雄心勃勃，计划入组总计50000例受试者。然而...后面的事情我们都知道了，PANDA这次恐怕挺不过寒冬了。再捋下去，就是燃石的MCED项目了。不过，最近受限于一号任务：搞钱，燃石的MCED进展缓慢。和瑞基本早就GG，退出舞台了。而小荷健康，背靠字节跳动，还在捂着自己的产品在打磨阶段。所以，这两年其实MCED临床研究出现了一个“真空”。所以，世和的金陵队列就显得格外瞩目了，也补全了国内这两年MCED临床的空缺。这次结果，包含了模型构建阶段的6853例受试者，验证阶段的1490例受试者。前瞻性研究阶段，计划入组15000例受试者，本次公布的是第一期3724例可分析受试者的结果。结果显示，模型在独立验证集中敏感性87.4%，特异性维持在97.8%，对I期癌症有近80%敏感性。前瞻性研究中，在3724例可分析受试者中，得到的敏感性为53.5%，特异性98.1%。Top2器官的溯源准确性达到89.5%（记住这个，待会要考）。这个结果还是不错的，尤其是溯源能力。那么，CanScan用的是怎么做到的？#02片段组玩出花世和CanScan使用的技术主体是片段组学（Fragmentomics），其根本的原理是健康人血液中的cell-free DNA特征与肿瘤患者体内的cell-free DNA特征是存在差异的。这里面美国的Delfi Diagnostics、国内的和瑞都采用了这个路线，当然，各有各的“花活”。片段组学方法最核心的优势是价格低廉，只需要通过提取cfDNA、文库构建、低深度WGS测序即可。一般测序深度不会超过5X，而世和CanScan此前的研究发现，即便在1X覆盖下仍然有较好的表现。按照目前的测序价格，一次检测我们即便用5X覆盖也就是100多块钱的事，这是核心竞争力了属于是。当然，也不是没有缺点。比如相较于甲基化检测，其组织溯源性就差了一些。比如Delfi的研究中，其Top2的组织实验准确性只有75%，给世和CanScan提鞋都不够格。那么，世和是咋做到的？答案就是“玩花活”。世和的CanScan会对拷贝数变异（CNV）、片段大小覆盖（FSC）、片段大小分布（FSD）、核小体足迹（NF）和基于片段的甲基化（FM）等多个维度进行分析，然后加一点点AI/ML（人工智能/机器学习），结果就很厉害。这时候就有野生刘德华和迪丽热巴要问了，你胡说，明明只做的WGS测序，哪来的甲基化？我承认你说的有道理，但也只是有一点。世和用的是基于片段的甲基化分析，通俗的说就是...猜。在其文章中引用了来自卢煜明团队的一项研究，就是通过cfDNA的片段特征反推其甲基化特征。好，看到这里，大家都学会了吧？#03最后世和CanScan用了目前来说相对最少的成本达到一个不错的早筛成绩，值得肯定。尤其是，现在这种情况下还愿意相信和投入MCED赛道，真的...泪目了。我们用这张图来结尾，通过MCED将肿瘤治疗关口前移除了能减少巨额医疗支出，更多的是惠及每一个潜在的患者。最后放张彩蛋，这是上海微荷今年在ASCO上的一篇摘要，用的是甲基化路线的MCED。当然以小荷家的狡猾，最终产品可能与之大相径庭，但是我们可以合理推测其MCED产品大概率是甲基化路线的。（错了来留言踢我）END小编在这里！星球在这里！各位股东看了么？赞了么？转发了么？别忘了点赞。谢谢！所有内容均不作为投资建议，信息均来自公开资料，星球更新更快。近期文章：重磅突发！NGS+AI龙头遭遇做空！Pillar真固、真迈亿元融资背后Illumina：坏了，Roche这是冲我来的啊创业20年，NGS肿瘤检测公司终于要上市了...小瓜|单分子免疫检测龙头被审计师蛐蛐怒换会所相关资料：注1：https://doi.org/10.1038/s41591-025-03735-2注2：https://delfidiagnostics.com/our-technology/fragmentomics/#fragmentomics注3：https://rdcu.be/cmKDL

临床结果临床研究抗体药物偶联物

2025-05-16

·生物谷

癌症放疗治疗竟有隐藏风险？！Nature｜科学家揭示高剂量辐射竟助长癌细胞转移

在癌症治疗中，放疗一直是不可或缺的利剑，其能通过高能量的辐射杀死癌细胞从而帮助无数患者控制机体中肿瘤的生长。近日，一篇发表在国际杂志《Nature》上题为“Radiation-induced amphiregulin drives tumour metastasis”的研究报告中，来自芝加哥大学医学中心等机构的科学家们通过研究揭示了放疗可能存在的“另一面”，即高剂量放疗竟会促进未直接照射的转移瘤的生长，这一发现不仅挑战了科学家们对放疗的传统认知，还为癌症治疗带来了新的思考。放疗与“坏范围效应”放疗在癌症治疗中的应用已经有很长的历史，其能通过高能量的辐射破坏癌细胞的 DNA 从而杀死癌细胞。近年来，放疗不仅用于局部肿瘤的控制，还被尝试用于治疗有限转移的癌症（称为 “寡转移”）。然而，许多患者在接受放疗后，尽管局部肿瘤得到了控制，但远处的转移瘤却继续增长，这一直是困扰医学界的难题。在这项研究中，研究人员发现，高剂量放疗可能会通过增加肿瘤细胞中一种称之为双调蛋白（Amphiregulin, AREG）的蛋白质的产生，从而意外地促进未直接照射的转移瘤的生长。AREG 是一种表皮生长因子受体（EGFR）的配体，其能够激活细胞内的信号通路从而影响细胞的生存、增殖和迁移。研究人员将这种与放疗相关的转移瘤生长现象称为 “坏范围效应”（badscopal effect），以区别于之前观察到的 “远隔效应”（abscopal effect），即放疗有时能缩小未直接照射的远处肿瘤。放疗能诱导双调节蛋白的表达和远端转移的生长关键实验流程与结果为了探索这一现象，研究人员分析了接受立体定向体部放疗（SBRT）和免疫检查点抑制剂（如帕博利珠单抗）治疗的患者的活检样本。他们发现，在接受放疗后，肿瘤细胞中 AREG 的表达会显著增加。进一步的动物实验表明，尽管放疗减少了新的转移灶的数量，但却增加了现有转移灶的大小。研究人员通过 CRISPR 基因编辑技术敲除 AREG 基因或者使用抗体阻断 AREG，就能显著减少未照射区域的肿瘤大小。研究人员还发现，AREG 的增加与免疫抑制性髓系细胞的增加有关，这些细胞能抑制免疫系统的抗肿瘤反应，从而促进肿瘤的生长。此外，AREG 还能通过上调 CD47 蛋白来增强肿瘤细胞的 “不要吃我” 信号，从而阻止巨噬细胞和髓系细胞吞噬肿瘤细胞。这一发现表明，AREG 不仅会影响免疫细胞的功能，还能直接增强肿瘤细胞的生存能力。基于这些发现，研究人员提出了新的治疗策略。他们发现，将放疗与 AREG 阻断剂或 CD47 阻断剂联合使用，能显著提高对转移瘤的控制效果。这种联合治疗不仅能减少肿瘤的大小，还能减少转移灶的数量。未来展望这一结果表明，通过检测和中和放疗诱导的 AREG 等分子，就能开发出一种新型个性化放疗方法，尤其是在转移性癌症患者中。本文研究不仅揭示了放疗可能存在的负面效应，还为癌症治疗提供了新的思路。通过深入了解放疗如何影响肿瘤细胞和免疫系统，研究人员就能更好地设计治疗方案来提高癌症的治疗效果。下一步，研究人员计划开展临床试验来验证这些发现并探索新的治疗策略。随着癌症治疗领域的不断发展，这一研究有望为患者带来更精准、更有效的治疗方案。参考文献：Piffkó, A., Yang, K., Panda, A. et al. Radiation-induced amphiregulin drives tumour metastasis. Nature (2025). doi：10.1038/s41586-025-08994-0本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！点击下方「阅读原文」，前往生物谷官网查询更多生物相关资讯~

放射疗法基因疗法

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 项与磷酸咯萘啶相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	磷酸咯萘啶	P01B	DB12975

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适应症	国家/地区	公司	日期
疟疾	-	-	-

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适应症	最高研发状态	国家/地区	公司	日期
急性淋巴细胞白血病	临床2期	肯尼亚	Armaceutica, Inc.	2022-01-30
急性髓性白血病	临床2期	肯尼亚	Armaceutica, Inc.	2022-01-30
埃博拉病毒性疾病	临床前	美国	Collaborations Pharmaceuticals, Inc.	2024-12-01

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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


NCT05287893 (CTgov)	临床1期	虫血症 \| 恶性疟	10	P. falciparum IBSM infection+Pyronaridine (Pyronaridine 360 mg)	獵觸願膚選選餘醖壓夢(膚蓋遞醖壓夢齋襯製選) = 積鑰網觸糧網顧網鹽選鹽鹽衊網蓋觸願膚顧蓋 (壓醖淵衊襯構餘網鹽築, 鑰襯鹹齋衊顧壓鹽顧鬱 ~ 衊夢觸壓鏇選壓壓鹽簾) 更多	-	2025-04-16
				P. falciparum IBSM infection+Pyronaridine (Pyronaridine 540 mg)	獵觸願膚選選餘醖壓夢(膚蓋遞醖壓夢齋襯製選) = 顧壓願築艱憲鹹憲構壓鹽鹽衊網蓋觸願膚顧蓋 (壓醖淵衊襯構餘網鹽築, 壓築繭醖廠顧願積製襯 ~ 蓋夢範鏇鏇衊構積繭醖) 更多
NCT05160363 (CTgov)	临床1期	-	37	Pyronaridine Tetraphosphate+Piperaquine tetraphosphate (PYR and PQP Combination)	夢願遞鑰膚蓋襯襯襯鬱 = 餘繭構窪蓋築觸鹽範願觸夢製壓窪淵鏇壓膚鹹 (蓋蓋構夢廠願積餘願獵, 襯淵獵願獵範獵網壓齋 ~ 窪鏇醖鑰糧簾糧齋壓繭) 更多	-	2024-05-10
				Placebo+Pyronaridine Tetraphosphate (PYR and Placebo Combination)	夢願遞鑰膚蓋襯襯襯鬱 = 網鬱襯構顧壓衊齋簾膚觸夢製壓窪淵鏇壓膚鹹 (蓋蓋構夢廠願積餘願獵, 範鹹獵壓遞遞鹽積獵鏇 ~ 鹹鏇淵鑰鑰願鹹鑰範蓋) 更多
NCT01383109 (CTgov)	临床1期	疟疾	6	14C-labeled Pyronaridine	衊廠鬱餘鬱製遞顧獵齋(獵構獵選鹽鏇壓膚蓋鑰) = 淵窪網餘壓齋獵淵壓積憲繭築淵鹽範憲繭醖膚 (鹹簾鹹築獵觸壓選範選, 0.02) 更多	-	2022-01-26