Primaquine Phosphate

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~

The Tafenoquine for Babesiosis clinical trial will be conducted at three sites: Yale University, Rhode Island Hospital and Tufts Medical CenterPatient enrollment has begun; interim results anticipated by September, 2025In the Northeast U.S., the incidence of babesiosis has been increasing; babesiosis is an emerging, tick-borne, potentially life-threatening illnessCase studies in recent medical literature suggest that tafenoquine combined with standard-of-care treatment exhibits a high cure rate in immunosuppressed patients who have relapsing babesiosis and for whom prior treatment has failedTotal cumulative accessible market through the end of patent protection in the U.S. for ARAKODA® (tafenoquine) for babesiosis is approximately 400,000 patients WASHINGTON, July 19, 2024 (GLOBE NEWSWIRE) -- 60 Degrees Pharmaceuticals, Inc. (NASDAQ: SXTP; SXTPW) (the “Company”), a pharmaceutical company focused on developing new medicines for infectious diseases, announced today it has signed clinical trial agreements with all three of the planned clinical trial sites for the Tafenoquine for Babesiosis study now enrolling. Tufts Medical Center, Yale University, and Rhode Island Hospital will conduct the world's first randomized, double-blind, placebo-controlled clinical trial evaluating the efficacy and safety of tafenoquine in treating human babesiosis patients. At least 24, and potentially up to 33, hospitalized patients diagnosed with relapsing babesiosis will be recruited for the study, with interim results anticipated by September, 2025. “Babesiosis is becoming a top concern within the infectious diseases healthcare community given the fact that accurate diagnosis and treatment are crucial to preventing progression to very serious phases of this illness,” said Dr. Geoff Dow, chief executive officer of 60 Degrees Pharmaceuticals. “Today, a patient who reaches the relapsing stage of babesiosis has few effective treatment options. The Tafenoquine for Babesiosis clinical trial currently enrolling patients is anticipated to shed new light on how best to address the babesiosis treatment needs of this group. The team at 60 Degrees Pharmaceuticals is pleased to partner with Tufts Medical Center, Yale University, and Rhode Island Hospital – three of the world’s leading medical centers – in this effort.” A recently published study suggested that tafenoquine combined with standard-of-care treatment exhibits a high cure rate in immunosuppressed patients who have relapsing babesiosis and for whom prior treatment has failed. Babesiosis is a steadily emerging, infectious disease transmitted by a microscopic parasite, Babesia, through the bite of the black-legged (deer) tick, the vector that spreads Lyme disease. Babesiosis may be life-threatening in elderly and immunosuppressed patients. Cases of babesiosis are rising in the Northeast U.S. The total cumulative accessible market through the end of U.S. patent protection in December 2035, for ARAKODA® (tafenoquine) for babesiosis is approximately 400,000 patients. Tafenoquine is approved for malaria prophylaxis in the United States under the product name ARAKODA®. The safety of the approved regimen of tafenoquine for malaria prophylaxis has been assessed in five separate randomized, double-blind, active comparator or placebo-controlled trials for durations of up to six months. Tafenoquine has not been proven to be effective for treatment or prevention of babesiosis and is not approved by the U.S. Food and Drug Administration for such an indication. About the Study of Tafenoquine for Patients Hospitalized with Babesiosis The study is a randomized, double-blind, placebo-controlled trial that will compare the safety and efficacy of tafenoquine versus placebo in patients hospitalized for babesiosis and administered standard of care medications. The two main study endpoints will be the time to sustained clinical resolution of symptoms and the time to molecular cure as determined by an FDA-approved nucleic acid test (NAT). At least 24, and as many as 33 patients, will be recruited before an interim analysis is conducted. Sufficient enrollment capacity is planned to allow all study subjects to be recruited before the end of the 2025 tick season (traditionally, from June to September). The interim analysis will include both a test of significance, as well as size re-estimation to allow additional recruitment if required. The efficacy and safety of 8-aminoquinolines, a class of drugs that includes tafenoquine and primaquine, for prevention and treatment of malaria is well documented. Several case reports of tafenoquine use for babesiosis indicate that the drug is already being used for this purpose in the practice of medicine in the U.S. About ARAKODA® (tafenoquine) Tafenoquine was discovered by Walter Reed Army Institute of Research. Tafenoquine was approved for malaria prophylaxis in 2018 in the United States as ARAKODA® and in Australia as KODATEF®. Both were commercially launched in 2019 and are currently distributed through pharmaceutical wholesaler networks in each respective country. They are available at retail pharmacies as a prescription-only malaria prevention drug. According to the Centers for Disease Control and Prevention, the long terminal half-life of tafenoquine, which is approximately 16 days, may offer potential advantages in less- frequent dosing for prophylaxis for malaria. ARAKODA is not suitable for everyone, and patients and prescribers should review the Important Safety Information below. Individuals at risk of contracting malaria are prescribed ARAKODA 2 x 100 mg tablets once per day for three days (the loading phase) prior to travel to an area of the world where malaria is endemic, 2 x 100 mg tablets weekly for up to six months during travel, then 2 x 100 mg in the week following travel. ARAKODA® (tafenoquine) Important Safety Information ARAKODA® is an antimalarial indicated for the prophylaxis of malaria in patients aged 18 years of age and older. Contraindications ARAKODA® should not be administered to: Glucose-6-phosphate dehydrogenase (“G6PD”) deficiency or unknown G6PD status;Breastfeeding by a lactating woman when the infant is found to be G6PD deficient or ifG6PD status is unknown;Patients with a history of psychotic disorders or current psychotic symptoms; orKnown hypersensitivity reactions to tafenoquine, other 8-aminoquinolines, or any component of ARAKODA®. Warnings and Precautions Hemolytic Anemia: G6PD testing must be performed before prescribing ARAKODA® due to the risk of hemolytic anemia. Monitor patients for signs or symptoms of hemolysis. G6PD Deficiency in Pregnancy or Lactation: ARAKODA® may cause fetal harm when administered to a pregnant woman with a G6PD-deficient fetus. ARAKODA® is not recommended during pregnancy. A G6PD-deficient infant may be at risk for hemolytic anemia from exposure to ARAKODA® through breast milk. Check infant’s G6PD status before breastfeeding begins. Methemoglobinemia: Asymptomatic elevations in blood methemoglobin have been observed. Initiate appropriate therapy if signs or symptoms of methemoglobinemia occur. Psychiatric Effects: Serious psychotic adverse reactions have been observed in patients with a history of psychosis or schizophrenia, at doses different from the approved dose. If psychotic symptoms (hallucinations, delusions, or grossly disorganized thinking or behavior) occur, consider discontinuation of ARAKODA® therapy and evaluation by a mental health professional as soon as possible. Hypersensitivity Reactions: Serious hypersensitivity reactions have been observed with administration of ARAKODA®. If hypersensitivity reactions occur, institute appropriate therapy. Delayed Adverse Reactions: Due to the long half-life of ARAKODA® (approximately 17 days), psychiatric effects, hemolytic anemia, methemoglobinemia, and hypersensitivity reactions may be delayed in onset and/or duration. Adverse Reactions: The most common adverse reactions (incidence greater than or equal to 1 percent) were: headache, dizziness, back pain, diarrhea, nausea, vomiting, increased alanine aminotransferase (ALT), motion sickness, insomnia, depression, abnormal dreams, and anxiety. Drug Interactions Avoid co-administration with drugs that are substrates of organic cation transporter-2 (OCT2) or multidrug and toxin extrusion (MATE) transporters. Use in Specific Populations Lactation: Advise women not to breastfeed a G6PD-deficient infant or infant with unknown G6PD status during treatment and for 3 months after the last dose of ARAKODA®. To report SUSPECTED ADVERSE REACTIONS, contact 60 Degrees Pharmaceuticals, Inc. at 1- 888-834-0225 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The full prescribing information of ARAKODA® is located here. About 60 Degrees Pharmaceuticals, Inc. 60 Degrees Pharmaceuticals, Inc., founded in 2010, specializes in developing and marketing new medicines for the treatment and prevention of infectious diseases that affect the lives of millions of people. 60 Degrees Pharmaceuticals, Inc. achieved FDA approval of its lead product, ARAKODA® (tafenoquine), for malaria prevention, in 2018. 60 Degrees Pharmaceuticals, Inc. also collaborates with prominent research organizations in the U.S., Australia, and Singapore. The 60 Degrees Pharmaceuticals, Inc. mission has been supported through in-kind funding from the U.S. Department of Defense and private institutional investors including Knight Therapeutics Inc., a Canadian-based pan-American specialty pharmaceutical company. 60 Degrees Pharmaceuticals, Inc. is headquartered in Washington D.C., with a majority-owned subsidiary in Australia. Learn more at www.60degreespharma.com. The statements contained herein may include prospects, statements of future expectations and other forward-looking statements that are based on management's current views and assumptions and involve known and unknown risks and uncertainties. Actual results, performance or events may differ materially from those expressed or implied in such forwardlooking statements. Cautionary Note Regarding Forward-Looking Statements This press release may contain “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. Forward‐looking statements reflect the current view about future events. When used in this press release, the words “anticipate,” “believe,” “estimate,” “expect,” “future,” “intend,” “plan,” or the negative of these terms and similar expressions, as they relate to us or our management, identify forward‐looking statements. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based only on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, projections, anticipated events and trends, the economy, activities of regulators and future regulations and other future conditions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict and many of which are outside of our control. Our actual results and financial condition may differ materially from those indicated in the forward-looking statements. Therefore, you should not rely on any of these forward-looking statements. Important factors that could cause our actual results and financial condition to differ materially from those indicated in the forward-looking statements include, among others, the following: there is substantial doubt as to our ability to continue on a going-concern basis; we might not be eligible for Australian government research and development tax rebates; if we are not able to successfully develop, obtain FDA approval for, and provide for the commercialization of non- malaria prevention indications for tafenoquine (ARAKODA® or other regimen) or Celgosivir in a timely manner, we may not be able to expand our business operations; we may not be able to successfully conduct planned clinical trials or patient recruitment in our trials might be slow or negligible; and we have no manufacturing capacity which puts us at risk of lengthy and costly delays of bringing our products to market. More detailed information about the Company and the risk factors that may affect the realization of forward- looking statements is set forth in the Company’s filings with the Securities and Exchange Commission (“SEC”), including the information contained in our Annual Report on Form 10-K filed with the SEC on April 1, 2024, and our subsequent SEC filings. Investors and security holders are urged to read these documents free of charge on the SEC’s web site at www.sec.gov. As a result of these matters, changes in facts, assumptions not being realized or other circumstances, the Company’s actual results may differ materially from the expected results discussed in the forward-looking statements contained in this press release. Any forward-looking statement made by us in this press release is based only on information currently available to us and speaks only as of the date on which it is made. We undertake no obligation to publicly update any forward-looking statement, whether written or oral, that may be made from time to time, whether as a result of new information, future developments or otherwise. Media Contact:Sheila A. BurkeSheilaBurke-consultant@60degreespharma.com(484) 667-6330 Investor Contact:Patrick Gaynespatrickgaynes@60degreespharma.com(310) 989-5666