A Single Centre, Randomised, Double-blind, Placebo-controlled, Phase Ib Study to Evaluate the Safety, Tolerability and Chemoprotective Antimalarial Activity of P218 Against Controlled Human Malaria Infection With Plasmodium Falciparum Sporozoite Challenge in Non-immune Healthy Adult Volunteers

This was a single centre, randomised, double-blind, placebo-controlled Phase Ib study, to evaluate the safety, tolerability and chemoprotective activity of P218 in a controlled P. falciparum sporozoite infection model.
Healthy men and women, aged 18 to 45 years were to be enrolled in 3 study cohorts and to be administered either P218 or placebo twice, 48 hours apart. Subjects in cohorts 2 and 3 were to be inoculated with P. falciparum sporozoites. Enrolment in cohorts was to proceed sequentially, to facilitate review of data by a Safety Review Team (SRT) before proceeding with a subsequent cohort.
In cohort 1, safety and tolerability of P218 was assessed. In cohorts 2 and 3, chemoprotective activity of P218 against malaria infection was assessed, as well as the Influence of time of initiation of the P218 treatment on the protective effect.

开始日期2018-11-16

申办/合作机构

MMV Medicines for Malaria Venture

[+8]

NCT02885506

/ Completed临床1期IIT

A Phase I Study to Investigate the Safety, Tolerability and Pharmacokinetic Profile and Food Effect of P218 in Healthy Adult Volunteers

The First in Human (FIH) study is separated into two parts:
* The first part is a Single Ascending Dose (SAD), double-blinded, randomized and placebo-controlled, including 8 cohorts of 8 subjects (2 placebo and 6 on active drug).
* The second part is a food effect cohort with an open-labelled, randomized fed/fasted cross-over design.
The main objectives of the study are to confirm safety, tolerability and Pharmacokinetics (PK) of P218 in healthy volunteers.

开始日期2016-08-24

申办/合作机构

MMV Medicines for Malaria Venture

[+1]

100 项与 P-218 相关的临床结果

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100 项与 P-218 相关的转化医学

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100 项与 P-218 相关的专利（医药）

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项与 P-218 相关的文献（医药）

2024-12-01·BIOORGANIC CHEMISTRY

Flexible 2,4-diaminopyrimidine bearing a butyrolactone as Plasmodium falciparum dihydrofolate reductase inhibitors

Article

作者: Vanichtanankul, Jarunee ; Jantra, Tararat ; Thiabma, Ratthiya ; Decharuangsilp, Sasithorn ; Arwon, Uthai ; Yuthavong, Yongyuth ; Kamchonwongpaisan, Sumalee ; Rattanajak, Roonglawan ; Hoarau, Marie ; Kongkasuriyachai, Darin ; Sooksai, Nawarat ; Saeyang, Thanaya

Recently, P218, a new flexible antifolate targeting Plasmodium falciparum dihydrofolate reductase (PfDHFR), has entered its clinical trial with good safety profile and effective Pf infection prevention. However, it carries a free carboxyl terminal, which is hydrophilic and prone to metabolic glucuronidation. Here, a new series of P218 analogues carrying butyrolactone has been synthesized with the purpose of enhancing lipophilicity and minimizing metabolic instability. The inhibition constants against the mutant PfDHFR enzymes are in sub-nanomolar level and the antimalarial activity against antifolate-resistant parasites are in the low micromolar range. The crystal structure of the most potent analogue LA1 bound enzyme complex indicates interaction with multiple residues, including Arg122 and Phe116 in the active site. In vitro log D_7.4 and kinetic solubility confirmed a higher lipophilicity of this butyrolactone series as compared to P218. These outcomes suggest the possibility to further develop butyrolactone derivatives as non-carboxyl antiplasmodial antifolates.

2024-11-14·JOURNAL OF MEDICINAL CHEMISTRY

Rational Exploration of 2,4-Diaminopyrimidines as DHFR Inhibitors Active against Mycobacterium abscessus and Mycobacterium avium, Two Emerging Human Pathogens

Article

作者: Duncan, Christina ; Read, Kevin D. ; Behr, Marcel A. ; Pilli, Ronaldo A. ; Andrade Meirelles, Matheus ; Ferguson, Liam ; Woodward, Elijah L. ; Shim, Abraham ; Battaile, Kevin P. ; dos Reis, Caio Vinicius ; Sankaran, Banumathi ; Staker, Bart L. ; Zigweid, Rachel ; Sullivan, Jaryd R. ; Seibold, Steve ; Mian, Mohammad Rasel ; Cunha, Micael Rodrigues ; Riley, Jennifer ; de Toledo, Ian ; Almeida, Vitor M. ; Joji, Halimatu ; Lovell, Scott ; Couñago, Rafael M. ; Liu, Lijun ; Simeons, Frederick R. C.

Nontuberculous mycobacteria (NTM) are emerging human pathogens linked to severe pulmonary diseases. Current treatments involve the prolonged use of multiple drugs and are often ineffective. Bacterial dihydrofolate reductase (DHFR) is a key enzyme targeted by antibiotics in Gram-negative bacterial infections. However, existing DHFR inhibitors designed for Gram-negative bacteria often fail against mycobacterial DHFRs. Here, we detail the rational design of NTM DHFR inhibitors based on P218, a malarial DHFR inhibitor. We identified compound 8, a 2,4-diaminopyrimidine exhibiting improved pharmacological properties and activity against purified DHFR, and whole cell cultures of two predominant NTM species: Mycobacterium avium and Mycobacterium abscessus. This study underscores the potential of compound 8 as a promising candidate for the in vivo validation of DHFR as an effective treatment against NTM infections.

2023-07-07·The Journal of organic chemistry

Functionalization of 2,4-Dichloropyrimidines by 2,2,6,6-Tetramethylpiperidyl Zinc Base Enables Modular Synthesis of Antimalarial Diaminopyrimidine P218 and Analogues.

Article

作者: Couñago, Rafael M ; Barreiro, Gabriela ; de Toledo, Ian ; Pilli, Ronaldo A ; Thurow, Samuel ; Meirelles, Matheus A

Two routes to the antimalarial diaminopyrimidine P218 were developed based on the C-6 metalation of suitable 2,4-dichloro-5-alkoxy pyrimidines using (TMP)₂Zn·2MgCl₂·2LiCl base. One approach involves a late-stage modification of the C-6 position, while the other allows for tail fragment modification of P218. Both routes have proven reliable in synthesizing P218, as well as eight analogues. These innovative strategies have the potential to contribute to the search for new antimalarial drugs.

项与 P-218 相关的新闻（医药）

2025-12-03

·Med有心人

【CTAD 2025前沿】从预测模型到居家治疗：礼来构建阿尔茨海默病“全生态”护城河

在正在举办的 2025 年阿尔茨海默病临床试验大会（CTAD）上，礼来（Eli Lilly and Company）展现了其在 AD 领域的深厚统治力。从临床前期的精准预测，到治疗阶段的安全性精细化管理，再到给药方式的革命性突破，礼来通过一系列扎实的研究，回应了 AD 诊疗面临的“诊断难、风险高、治疗繁”三大痛点。本文将解读此次大会的几项关键数据，透视礼来如何用循证证据重塑 AD 的临床实践标准。一、诊断与预后：让 P-tau217 成为临床决策的“罗盘” 血液生物标志物 P-tau217 已经不再仅仅是一个科研工具，CTAD 上的多项数据表明，它已经具备了改变临床路径的 “定量分层” 和 “精准预测” 能力。1. 临床实用性：用数据验证“诊断变轨” 引入血液检测真的能改变医生的行为吗？这项针对 609 名多元化人群的随机对照研究给出了肯定答案：诊断修正率翻倍：数据显示，在获得 P-tau217 结果后的第 4 周，检测组（Tested Arm）有 28.5% 的患者其工作诊断（Working Diagnosis）发生了改变，而未检测组仅为 15.4% 。医疗资源分流：对于检测结果为阴性的患者，医生后续开具 PET 扫描或腰穿（CSF）检查的比例大幅下降。这证明 P-tau217 具有极高的阴性预测价值，能有效充当“守门人”，将昂贵的 PET 资源精准导向阳性患者。 2. 临床前预测：精准识别“沉默的风险” 针对无症状（临床前）AD 人群，礼来基于 A4 和 LEARN 队列构建了高精度的 Cox 比例风险模型，为“预防窗口期”提供了量化工具：极高的区分度（C-index 0.822）：在认知正常且淀粉样蛋白阴性的人群中，一个包含基线 P-tau217、年龄和受教育程度的简单模型，预测未来 5 年内病理转阳的 C-index 高达 0.822。风险量化：模型显示，APOE ε4 纯合子携带者发生病理改变的风险是非携带者的 2.25 倍（HR=2.251）。 “主观+客观”双重验证：在已经出现淀粉样蛋白阳性的无症状人群中，如果基线血浆 P-tau217 > 0.282 U/mL，其 5 年内出现临床症状的风险增加了 81% （HR 1.81）。更有趣的是，如果患者自述认知功能指数（CFI）总分 > 5.3，这一进展风险将飙升至 2.51 倍。这些数据将 AD 的筛查前移了一大步。特别是 CFI 评分的高权重提示我们，在生物标志物时代，患者的主观主诉依然是预测临床转归的黄金指标。未来的社区筛查可能就是简单的“抽血 + 问卷”。二、治疗优化：多奈单抗的安全性“加减法” 随着多奈单抗疗效的确立，如何进一步降低 ARIA（淀粉样蛋白相关影像学异常）风险成为临床关注的焦点。礼来通过回顾性挖掘和前瞻性设计，打出了一套组合拳。1. 真实世界挖掘：降压药带来的意外获益通过对 TRAILBLAZER-ALZ 系列试验 2,721 名参与者的汇总分析，研究者发现了一个具有高度临床指导意义的数据关联：风险显著降低：基线使用任何抗高血压药物的患者，发生 ARIA-E 的比值比（OR）为 0.650（p<0.001），即风险降低了 35% 。症状性风险“腰斩”：更为关键的是，有症状 ARIA-E 的风险显著降低了约 50% （OR 0.496）。钙通道阻滞剂（CCB）表现抢眼：在亚组分析中，CCB 类药物显示出极强的保护作用（OR 0.279），意味着风险降低了 72% ，且这一效应独立于患者的基线血压水平。 2. 前瞻性策略：激素预处理方案设计除了回顾性发现，礼来还公布了 TRAILBLAZER-ALZ 6 研究新增列队（Addendum）的设计方案。设计背景：该研究的主试验数据已经证实，采用“调整滴定法”（Modified Titration）可将 ARIA-E 的相对风险降低 41% （发生率从 23.7% 降至 13.7%）。新方案：基于此，礼来启动了新的 N=375 队列，旨在评估在“调整滴定”基础上，进一步给予 10 mg 地塞米松静脉推注预处理，能否将 ARIA-E 和输注反应（IRR）的发生率压得更低。这标志着 AD 免疫治疗的安全性管理正向“主动干预”进阶。激素预处理研究设计降压药（特别是 CCB）能降低 ARIA 风险的发现，可能直接改变临床实践指南。这提示我们在启动抗体治疗前，优化患者的血管健康不仅是为了心脑血管获益，更是AD 免疫治疗的标准护航策略。三、给药革新：Remternetug 验证“居家模式”可行性下一代抗体 Remternetug 的核心使命是解决给药便利性。此次公布的 TRAILRUNNER-ALZ 1 研究数据 (P-040)，用详实的数据回应了“痴呆患者能否居家治疗”的质疑。高成功率：在 197 名症状性 AD（3-4 期）患者中，56.9% 的患者成功进行了至少一次非医护人员（HCP）执行的皮下注射。患者赋能：在家庭注射场景中，43.1% 完全由患者自我注射，45.4% 由研究伙伴协助。人群画像：数据进一步显示，认知功能相对较好（MMSE > 26分）的患者自我注射比例显著更高（48.3% vs 21.4%）。这一数据是 AD 治疗模式转型的里程碑。接近六成的居家注射率意味着 AD 药物有望摆脱对输注中心的依赖，像糖尿病胰岛素一样实现慢病化、居家化管理。这对于缓解医疗资源挤兑、提高患者长期依从性具有决定性意义。四、总结与展望纵观 2025 CTAD 大会，礼来展示了一幅超越单一药物研发的宏大图景。通过 P-tau217 的精准预测模型、Donanemab 的安全性优化策略以及 Remternetug 的皮下制剂创新，礼来不仅回应了 AD 诊疗中“诊断难、风险高、给药繁”的现实痛点，更为行业定义了一套以数据驱动的全病程管理新标准。这种从“经验医学”向“精准医学”的跨越，标志着阿尔茨海默病诊疗生态正在快速走向成熟，为未来的临床实践和患者获益奠定了坚实基础。参考文献： Burnham SC, et al. P-tau217 Testing Impact on Patient Management... CTAD 2025 Poster P-218. Yaari R, et al. Prognostic Models for Development of Elevated Plasma P-tau217... CTAD 2025 Poster P231. Payakachat N, et al. Development of Prognostic Models for Five-Year Risk... CTAD 2025 Poster P322. Ardayfio P, et al. Baseline Antihypertensive Medication Use is Associated with Lower Frequency of ARIA-E... CTAD 2025 Poster P-059. Nery ESM, et al. The Effect of Corticosteroid Pretreatment... TRAILBLAZER-ALZ 6 Addendum Design. CTAD 2025 Poster P042. Hufford M, et al. Feasibility of Participants With Symptomatic AD to Self-Administer Remternetug... CTAD 2025 Poster P-040. 免责声明：本文内容仅供医疗卫生专业人士进行学术交流使用，不构成任何医疗建议或治疗推荐。文中涉及的药物及部分适应症可能尚未在中国获批，最终临床获益与安全性需以监管机构批准的说明书为准。关键词： #CTAD2025 #阿尔茨海默病 #礼来 #Donanemab #Ptau217 #AD诊疗生态

100 项与 P-218 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
疟疾	临床1期	英国	MMV Medicines for Malaria Venture	2016-08-24

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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


NCT03707041 (CTgov)	临床1期	疟疾	32	P218 (1000 mg) Oral Capsules (P218 1000 mg (Oral Capsules) - Cohort 1)	範窪夢顧願鹹願遞鏇衊(網壓選獵廠醖鏇網齋糧) = 遞壓衊膚願衊鹽觸鹽衊夢壓衊遞襯構窪壓壓餘 (衊觸淵憲繭網顧衊網鹹, 6958) 更多	-	2021-04-09
				Placebo Oral Capsules (P218 Placebo Oral Capsules - Cohort 1)	膚壓齋觸憲範夢遞積簾 = 憲簾願遞憲鏇積鏇鬱壓範繭製積淵鑰蓋願製鏇 (餘範艱夢鹽糧糧廠鬱糧, 膚壓糧顧淵憲願願積願 ~ 壓範範願艱蓋廠顧糧觸) 更多