Primaquine Phosphate

LONDON, UK I December 04, 2024 I GSK plc (LSE/NYSE: GSK) and Medicines for Malaria Venture (MMV) announced today that the World Health Organization (WHO) has awarded prequalification to tafenoquine , the first single-dose medicine for the prevention of relapse of Plasmodium vivax (P. vivax) malaria. Tafenoquine , co-administered with chloroquine, is now also included in WHO’s updated Guidelines for malaria, in South America, marking the first time the medicine has been recommended by WHO. This milestone is a significant step toward closing the treatment gap for P. vivax malaria. The WHO prequalification and updated guidelines include both adults and children aged 2 years and older, weighing at least 10 kg. A single-dose medicine provides an opportunity to overcome challenges with adherence to the existing longer, one-two week regimen of the standard of care, which can be a challenge for patients with relapsing malaria whose symptoms improve shortly after treatment initiation 1 . P. vivax is the dominant malaria parasite in most countries outside of sub-Saharan Africa, prevalent in most tropical and sub-tropical areas in the world, with children under five and migrant populations at particular risk. Among these vulnerable groups, infants and children carry a disproportionate burden, being highly vulnerable to severe disease, recurrence and anaemia 2 . The complex lifecycle of the P. vivax parasite includes a blood stage and an undetectable dormant liver stage, which can reactivate, causing repeated episodes of malaria following a single infectious bite of a mosquito carrying this parasite. Thomas Breuer, Chief Global Health Officer, GSK, said: “WHO prequalification of tafenoquine opens new possibilities to positively impact and protect more lives; lives of children and vulnerable populations who continue to bear the burden of this devastating disease. Inclusion of tafenoquine in the updated Guidelines for malaria is an equally important step forward in efforts to eliminate this preventable and treatable disease. Making treatments simpler for people to take is an ambition of ours across much of our Global Health pipeline and portfolio. Alongside our partners, we remain committed to enabling affordable and equitable access to this new single-dose treatment option for those in need in malaria-endemic countries.” Martin Fitchet, Chief Executive Officer, MMV, said: “Today marks a historic milestone in the fight against malaria. The WHO’s prequalification of tafenoquine and its inclusion in the updated Guidelines for malaria is a groundbreaking advancement on the road to elimination, which will transform lives by providing a well-tolerated, effective, and single-dose cure to prevent malaria relapses in some of the world’s most vulnerable communities. This achievement is a testament to the power of innovation and collaboration in global health, to bring us closer to our vision of a malaria-free world.” Tafenoquine , an 8-aminoquinoline antimalarial drug targeting the liver-stage of P. vivax malaria, is recommended as an alternative to primaquine (3.5 mg/kg total dose) for preventing malaria relapses in children over the age of two in South America. A single dose of tafenoquine administered to P. vivax patients who receive chloroquine treatment provides what is known as radical cure: the treatment of both the blood- and liver-stages of the disease. Tafenoquine , like all 8-aminoquinolines, has the potential to cause haemolytic anaemia in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency, therefore G6PD testing must be performed before prescribing. This is possible with the ‘STANDARD’ G6PD test, developed in collaboration between SD Biosensor and PATH, which provides a measure of a patient’s G6PD enzyme activity levels in two minutes based on a drop of blood from a finger-prick. WHO prequalification of medicines is crucial as it ensures that the medicine meets standards of quality, safety and efficacy, and is suitable for the target population. The prequalification programme has played a vital role in improving the access to life-saving medications used by millions in low- and middle-income countries. The WHO Guidelines for malaria are regularly reviewed and updated by the world’s leading malaria experts under WHO’s convening. This update includes a first recommendation for tafenoquine (150mg tablets and 50mg dispersible tablets) with chloroquine in South America. WHO prequalification and Guideline inclusion follows the launch of tafenoquine in Brazil and Thailand in June this year. Approvals for tafenoquine have been granted in Australia, Brazil, Colombia, Ethiopia, Guyana, Myanmar, Pakistan, Peru, the Philippines, Thailand, Vietnam and the United States, and the drug is undergoing marketing authorisation evaluation in a number of other countries where P. vivax is endemic. About tafenoquine Tafenoquine is an 8-aminoquinoline with activity against all stages of the P. vivax lifecycle, including hypnozoites. It was first synthesised by scientists at the Walter Reed Army Institute of Research in 1978. GSK’s legacy in the research and development of tafenoquine as a potential medicine for malaria commenced over 20 years ago.  In 2008, GSK entered into a collaboration with the not-for-profit drug research partnership, MMV, to develop tafenoquine as an anti-relapse medicine for patients infected with P. vivax . The tafenoquine clinical programme is part of GSK’s global health programme aimed at improving healthcare for vulnerable populations. About Standard G6PD test The STANDARD G6PD test was developed in collaboration between SD Biosensor and PATH. The handheld device provides a measure of a patient’s G6PD enzyme activity levels in two minutes based on a drop of blood from a finger-prick. The Test has been approved by the Australian TGA, and by the Global Fund Expert Review Panel on Diagnostics (ERPD) and is distributed to over 30 countries. Important safety information Tafenoquine can cause haemolytic anaemia in patients with G6PD deficiency. The most common side effects are difficulty sleeping, headache, dizziness, nausea and vomiting. Allergic hypersensitivity reactions can occur after taking the drug. Please refer to the Consumer Medicine Information (CMI) summary for important dosage, administration, and safety information available at this link: kozenis-cmi-au.pdf (gsk.com) About Plasmodium vivax malaria The Plasmodium parasite is a complex organism with a lifecycle spanning both humans and mosquitoes. After an infected mosquito bite, the P. vivax parasite infects the blood and causes an acute malaria episode. It also has the ability to lie dormant in the liver (in a form known as hypnozoite) from where it periodically reactivates to cause relapses of P. vivax malaria. Hence, a single P. vivax infection can give rise to multiple episodes of malaria, in the absence of a new mosquito bite. These relapses can occur weeks, months or even years after the initial infection. The dormant liver forms of the parasite cannot be readily treated with most anti-malarial treatments active against the blood-stage parasite. The current treatment (primaquine) for the dormant liver stage must be taken for 7 to 14 days to be effective, a regimen that is associated with poor compliance in unsupervised patients 3,4,5 . The use of a medicine that targets the dormant liver forms of the parasite, co-administered with a medicine to treat the blood stage, is known as radical cure. P. vivax malaria has a significant public health and economic impact, primarily in South-Asia, South-East Asia, Latin America and the horn of Africa. The disease is estimated to cause around 8.5 million clinical infections every year. The clinical features of P. vivax malaria include fever, chills, vomiting, malaise, headache and muscle pain, and in some cases, can lead to severe malaria and be fatal. About GSK GSK is a global biopharma company with a purpose to unite science, technology, and talent to get ahead of disease together. Find out more at gsk.com. About Medicines for Malaria Venture MMV is a Swiss-based not-for-profit organization working to deliver a portfolio of accessible medicines with the power to treat, prevent and eliminate malaria. Born in 1999, out of a need for greater health equity, we close critical gaps in research, development and access – working “end-to-end” to expand the use of existing antimalarials and innovate new compounds to protect public health. This starts with women and children. It’s working. As of 2023, MMV-supported products have effectively treated an estimated 680 million people and saved around 15.4 million lives. We cannot stop now. With a quarter of a billion malaria cases and more than 600,000 deaths reported in 2022, progress towards disease elimination has stalled. MMV is part of an ecosystem of partners determined to change this. Bringing public and private sector partners together, we pioneer new solutions that align with local and global health priorities and promote the equitable development of effective and affordable products that work to help end malaria and advance health for all. For more information, visit http://www.mmv.org . References SOURCE: GlaxoSmithKline

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~