AN OPEN-LABEL, SINGLE CENTRE TRIAL TO INVESTIGATE THE MASS BALANCE AND METABOLITE PROFILE OF A SINGLE ORAL DOSE OF AIC090019 - AIC090019 mass balance/Met-ID trial

开始日期2010-10-01

申办/合作机构

AiCuris GmbH & Co. KG

EUCTR2009-013917-91-DE / Not yet recruitingN/A

A randomized, double-blind, placebo controlled trial to evaluate the safety, tolerability and antiviral activity of 12 weeks’ treatment with a new antiviral HCMV drug

开始日期2010-02-09

申办/合作机构

AiCuris GmbH & Co. KG

EUCTR2006-006148-69-DE / Not yet recruitingN/A

Phase 2a Randomized, Controlled, Multi-center, Open-label Dose Ranging Proof of Concept Study to Evaluate the Safety, Tolerability and Antiviral Activity of AIC-001 Over 14 Days of Dosing in Patients With Positive HCMV Viremia Under the Conditions of a Pre-emptive Strategy.

开始日期2007-03-06

申办/合作机构

AiCuris GmbH & Co. KG

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项与 AiCuris GmbH & Co. KG 相关的文献（医药）

2016-02-01·The Journal of antimicrobial chemotherapy2区 · 医学

The Innovative Medicines Initiative's New Drugs for Bad Bugs programme: European public–private partnerships for the development of new strategies to tackle antibiotic resistance

2区 · 医学

Review

作者: Bonten, M J M ; Hackett, J ; O'Brien, S ; deWinter, R ; Steel, H ; Winterhalter, M ; Angyalosi, G ; Vuong, C ; Harbarth, S ; MacGowan, A ; Ross, S ; Witschi, A ; François, B ; Jafri, H S ; Goossens, H ; Elborn, J S ; Kostyanev, T ; Tacconelli, E ; Stavenger, R A ; Karlén, A

Antibiotic resistance (ABR) is a global public health threat. Despite the emergence of highly resistant organisms and the huge medical need for new drugs, the development of antibacterials has slowed to an unacceptable level worldwide. Numerous government and non-government agencies have called for public-private partnerships and innovative funding mechanisms to address this problem. To respond to this public health crisis, the Innovative Medicines Initiative Joint Undertaking programme has invested more than €660 million, with a goal of matched contributions from the European Commission and the European Federation of Pharmaceutical Industries and Associations, in the development of new antibacterial strategies. The New Drugs for Bad Bugs (ND4BB) programme, an Innovative Medicines Initiative, has the ultimate goal to boost the fight against ABR at every level from basic science and drug discovery, through clinical development to new business models and responsible use of antibiotics. Seven projects have been launched within the ND4BB programme to achieve this goal. Four of them will include clinical trials of new anti-infective compounds, as well as epidemiological studies on an unprecedented scale, which will increase our knowledge of ABR and specific pathogens, and improve the designs of the clinical trials with new investigational drugs. The need for rapid concerted action has driven the funding of seven topics, each of which should add significantly to progress in the fight against ABR. ND4BB unites expertise and provides a platform where the commitment and resources required by all parties are streamlined into a joint public-private partnership initiative of unprecedented scale.

2015-11-01·Biochimica et biophysica acta

Structural variations of the cell wall precursor lipid II in Gram-positive bacteria — Impact on binding and efficacy of antimicrobial peptides

Review

作者: Münch, Daniela ; Sahl, Hans-Georg

Antimicrobial peptides (AMPs) are natural antibiotics produced by virtually all living organisms. Typically, AMPs are cationic and amphiphilic and first contacts with target microbes involve interactions with negatively charged components of the cell envelope such as lipopolysaccharide (LPS), and wall- or lipoteichoic acids (WTA, LTA). The importance of charge-mediated interactions of AMPs with the cell envelope is reflected by effective microbial resistance mechanisms which are based on reduction of the overall charge of these polymers. The anionic polymers are linked in various ways to the stress-bearing polymer of the cell envelope, the peptidoglycan, which is made of a highly conserved building block, a disaccharide-pentapeptide moiety that also contains charged residues. This structural element, in spite of its conservation throughout the bacterial world, can undergo genus- and species-specific modifications that also impact significantly on the overall charge of the cell envelope and on the binding affinity of AMPs. The modification reactions involved largely occur on the membrane-bound peptidoglycan building block, the so-called lipid II, which is a most prominent target for AMPs. In this review, we focus on modifications of lipid II and peptidoglycan and discuss their consequences for the interactions with various classes of AMPs, such as defensins, lantibiotics and glyco-(lipo)-peptide antibiotics. This article is part of a Special Issue entitled: Bacterial Resistance to Antimicrobial Peptides.

2015-11-01·Acta neurologica Scandinavica3区 · 医学

Lacosamide cardiac safety: a thorough QT/QTc trial in healthy volunteers

3区 · 医学

Article

作者: Kropeit, D. ; Horstmann, R. ; Cawello, W. ; Johnson, M. ; Rudd, G. D.

OBJECTIVE:

To determine whether lacosamide prolongs the corrected QT interval (QTc).

MATERIALS AND METHODS:

In this randomized, double-blind, positive- and placebo-controlled, parallel-design trial, healthy volunteers were randomized to lacosamide 400 mg/day (maximum-recommended daily dose, 6 days), lacosamide 800 mg/day (supratherapeutic dose, 6 days), placebo (6 days), or moxifloxacin 400 mg/day (3 days). Variables included maximum time-matched change from baseline in QT interval individually corrected for heart rate ([HR] QTcI), other ECG parameters, pharmacokinetics (PK), and safety/tolerability.

RESULTS:

The QTcI mean maximum difference from placebo was -4.3 ms and -6.3 ms for lacosamide 400 and 800 mg/day; upper limits of the 2-sided 90% confidence interval were below the 10 ms non-inferiority margin (-0.5 and -2.5 ms, respectively). Placebo-corrected QTcI for moxifloxacin was +10.4 ms (lower 90% confidence bound >0 [6.6 ms]), which established assay sensitivity for this trial. As lacosamide did not increase QTcI, the trial is considered a negative QTc trial. There was no dose-related or clinically relevant effect on QRS duration. HR increased from baseline by ~5 bpm with lacosamide 800 mg/day versus placebo. Placebo-subtracted mean increases in PR interval at tmax were 7.3 ms (400 mg/day) and 11.9 ms (800 mg/day). There were no findings of second-degree or higher atrioventricular block. Adverse events (AEs) were dose related and most commonly involved the nervous and gastrointestinal systems.

CONCLUSIONS:

Lacosamide (≤ 800 mg/day) did not prolong the QTc interval. Lacosamide caused a small, dose-related increase in mean PR interval that was not associated with AEs. Cardiac, overall safety, and PK profiles for lacosamide in healthy volunteers were consistent with those observed in patients with partial-onset seizures.

项与 AiCuris GmbH & Co. KG 相关的新闻（医药）

2024-10-31

·PipelineReview

AiCuris Initiates First-in-Human Phase 1 Trial With Antiviral Agent AIC468 to Address BK Virus Infections in Kidney Transplant Recipients

WUPPERTAL, Germany I October 31, 2024 I AiCuris Anti-infective Cures AG today announced the initiation of its Phase 1, first-in-human trial of AIC468, a novel antisense oligonucleotide. AIC468 is an antiviral agent which aims to treat BK virus (BKV) infections in kidney transplant (KT) recipients. BKV reactivation in KT recipients is an area of high unmet medical need with no approved drug treatments. This Phase 1 trial ( 2023-510074-13-00 ) will evaluate the safety, tolerability and pharmacokinetics of AIC468 in healthy volunteers. “BK virus infections remain an urgent threat to transplant recipients, leading to graft loss and other serious complications,” said Cynthia Wat, MD, CMO of AiCuris . “Advancing AIC468 into clinical trials brings us one step closer to providing a targeted therapeutic option that directly inhibits BK virus replication, that addresses this critical unmet medical need. Our team remains committed to improving outcomes for patients dealing with the challenges of post-transplant viral infections.” “This trial marks another significant milestone in our mission to develop innovative therapies for patients with weakened immune systems, who are particularly vulnerable to serious viral infections like BK virus infections,” said Larry Edwards, CEO of AiCuris . “The initiation of this trial demonstrates the strength and diversity of our pipeline as we continue to advance cutting-edge solutions for high-risk patient populations. With multiple programs now in the clinic, we are confident that our approach can make a meaningful impact on the lives of immunocompromised patients.” The randomized, double-blind, placebo-controlled first-in-human trial will assess the safety, tolerability, and pharmacokinetics of AIC468 in 72 healthy volunteers. Conducted in Germany, the trial includes both single and multiple ascending doses of AIC468. Topline data readout from the single ascending dose part of the study is expected in 2025. About BKV BK virus (BKV) is a common polyomavirus that infects most people in early childhood, typically without symptoms. In immunocompromised individuals, such as organ transplant recipients, BKV can reactivate, leading to serious health issues. In kidney transplant (KT) patients, BKV reactivation can cause BK virus-associated nephropathy (BKVAN), affecting up to 10% 1 of recipients and potentially resulting in graft loss. Current management involves reducing immunosuppressive therapy, which increases the risk of graft rejection. Despite its prevalence, there is no approved antiviral treatment specifically for BKV. About AiCuris AiCuris is meeting the needs of the growing population of immunocompromised people who require precise therapies to effectively treat infection. Our flagship product, PREVYMIS ® , marketed by our partner MSD, prevents CMV in a defined group of transplant recipients. Our pivotal Phase 3 candidate pritelivir aims to address recurrent and resistant HSV infections in a broad population of patients with weakened immune systems. For immunocompromised people, an otherwise manageable infection can mean life or death. AiCuris, with its expertise and growing pipeline, is committed to providing therapeutic solutions for them now and in the future. 1 Imlay H. et al., Consensus Definitions of BK Polyomavirus Nephropathy in Renal Transplant Recipients for Clinical Trials, Clinical Infectious Diseases , 2022, https://doi.org/10.1093/cid/ciac071 SOURCE: AiCuris

临床3期临床1期

2024-10-14

·药通社

今日！正大天晴「明星抗病毒药」获批上市！

今日（10月14日），NMPA官网发布药品证明文件送达信息，正大天晴的来特莫韦注射液获批上市。据了解，该产品是来特莫韦注射液剂型的国内首仿。图片来源：NMPA官网来特莫韦是一款抗病毒新药，具有新型抗CMV的作用，通过抑制巨细胞病毒末端酶复合物（pUL51、pUL56和pUL89）的活性，阻止病毒DNA的加工和包装，从而发挥抗病毒的作用。主要用于接受异基因造血干细胞移植（HSCT）的巨细胞病毒（CMV）血清学阳性的成人受者[R+]预防巨细胞病毒感染和巨细胞病毒病。来特莫韦最早由德国Aicuris公司研发，2012年10月，默沙东向其支付1.1亿欧元的预付款和3.325亿欧元的里程碑费用获得了来特莫韦的全球权益。2022年，来特莫韦片剂及注射液先后在我国获批。据了解，对部分口服药不耐受的患者，注射剂型能够帮助该类患者提高药物吸收效率，片剂和注射液可根据医生的判断互换使用，更换剂型时无需调整剂量。2023年，来特莫韦片和来特莫韦注射液通过国谈被纳入国家医保乙类药物目录。根据默沙东最新财报，2023年，来特莫韦的全球销售额为6.05亿美元，同比增长41.4%。 2022年10月，正大天晴向CDE提交了来特莫韦片4类上市申请，历时近一年半获NMPA批准上市，拿下国内首仿。来特莫韦注射液是该药物的另一种剂型，其首仿同样由正大天晴斩获。图片来源：药融云数据库投稿/内容沟通：华籍美人（Ww_150525）近期精华文章

财报上市批准

2024-10-08

·精准药物

综述｜(2016–2020)上市药物中的分子手性中心构建

Asymmetric Synthesis of US - FDA Approved Drugs over Five Years (2016–2020): A Recapitulation of Chirality” 由 Rekha Tamatam 和 Dongyun Shin 撰写。论文强调了 2016 - 2020 年期间 FDA 批准的手性药物的合成方法，特别关注通过手性诱导、拆分或手性池进行的不对称合成。手性药物具有多种优势，包括：（1）由于更好的药代动力学和药效学性质，手性药物与非手性对应物相比可能具有更高的效力；（2）通过分离特定的对映体，手性药物可以减少不必要的副作用；（3）手性药物可以通过靶向特定的酶或受体来增强药物传递；（4）使用单一异构体可以降低生产成本，从而降低患者的药品价格。一个手性中心的药物的合成方法 1.1. Lifitegrast (2016) ： Lifitegrast 由美国加利福尼亚州布里斯班的 SARcode Bioscience 公司研发，用于治疗干眼症。Lifitegrast 的全合成从市售的手性底物3-溴-L-苯丙氨酸开始，经过10步反应完成，产率为 88%。 1.2. Acalabrutinib (2017)：阿卡拉布替尼由阿塞塔制药公司研发，用于治疗套细胞淋巴瘤（MCL）。从 4-溴苯甲酸（）出发，经过四步反应得到中间体。市售的手性脯氨酸衍生物与通过酰氯进行酰胺化反应，以 86% 的产率生成阿卡拉布替尼。 1.3. Pemafibrate (2017) ：培米贝特由兴和制药公司研发，用于治疗高脂血症。手性片段由对映体纯的（S）-2-羟基丁内酯（）在三甲基硅基碘存在下通过开环反应合成。的氢化还原以及使用2,6-二甲基吡啶进行的三氟甲磺酸酯加成生成。在碳酸钾和乙腈作用下发生构型翻转，以 75%的产率生成培米贝特。 1.4. Letermovir (2017) AiCuris公司开发了莱特莫韦用于治疗巨细胞病毒感染。在尿素环化步骤中，莱特莫韦中引入了一个手性中心。尿素在金鸡纳碱类相转移催化剂存在下，于磷酸钾水溶液和甲苯的双相混合物中发生环化反应，生成喹唑啉酮外消旋体（A12）。 1.5. Netarsudil(2017）艾尔建制药公司开发了奈他舒地尔用于治疗高眼压症。Evans噁唑烷酮（A15）作为手性助剂，随后在过氧化氢存在下被去除。二酯A14进行区域选择性水解，接着通过酰氯形成和酰胺化反应生成酯衍生物A16。用LiHMDS和Boc保护的苯并三唑基甲胺处理Evans噁唑烷酮化合物生成A17，奈他舒地尔的关键立体化学结构通过A17构建。 1.6. Niraparib (2017) 默克公司发现并由泰萨罗公司开发的尼拉帕利，通过酰氯形成和酰胺化反应生成酯衍生物A16。尼拉帕利用于治疗腹膜癌。具有一个手性中心的尼拉帕利从哌啶亚单元获得，由溴苯（A19）合成。亚硫酸氢盐加合物在ATA-302酶催化和吡哆醛-5-磷酸（PLP）共催化下进行转氨酶反应，生成手性哌啶A22。 1.7. Lorlatinib (2018）洛拉替尼由辉瑞公司研发，是一种肿瘤药物。洛拉替尼是一种大环化合物，由手性醇中间体A25构建而成。这个关键步骤涉及使用生物催化剂进行对映选择性还原。 1.8. Elobixibat Hydrate (2018) EA制药公司和持田制药公司开发了依洛昔巴特水合物，用于治疗慢性特发性便秘。在TBTU和甲基（R-2-氨基-2-苯基乙酸A28存在下，通过酸酯偶联生成单一手性碳。 1.9. Tezacaftor (2018) 由Vertex 制药公司发现和开发，特扎卡福是一种广泛作用的囊性纤维化跨膜传导调节因子（CFTR）。它的规模化合成（方案9）从3-氟-4-硝基苯胺A31开始。其区域选择性溴化从3-氟-4-硝基苯胺开始，与N-溴代琥珀酰亚胺（NBS）反应生成中间体A32。市售的（R）-缩水甘油基苄基醚A33通过酸催化开环在苯胺上诱导手性，接着还原硝基得到A34。后续步骤，包括Sonogashira偶联、Larock型环化和酸 - 胺偶联，以84%的产率得到特扎卡福。 1.10. Pyrotinib Maleate (2018) 恒瑞制药研发了马来酸吡咯替尼，它是一种泛ErbB受体酪氨酸激酶抑制剂，用于治疗转移性乳腺癌。马来酸吡咯替尼的千克级合成下图所示。手性片段A37由N-Boc-D-脯氨醇A36经过四步反应合成。 1.11. Encorafenib (2018) 康奈非尼与比美替尼（binimetinib）联合使用，用于治疗转移性黑色素瘤。目前，康奈非尼由辉瑞公司销售。手性的引入方式如下：在碱的存在下，用氯甲酸苄酯和氯甲酸甲酯处理(S)-(−)-1,2-二氨基丙烷二盐酸盐A39，生成氨基甲酸酯衍生物A40。经过氢化后，得到手性亚基A41。 1.12. Duvelisib Monohydrate (2018) Duvelisib一水合物最初由因泰利金（Intellikine）公司开发，后来授权给维瑞斯姆肿瘤公司（Verastem Oncology），用于治疗慢性淋巴细胞白血病和小淋巴细胞淋巴瘤。因泰利金公司公布的Duvelisib一水合物的千克级合成方法在方案12中进行了讨论。用正己基锂处理的韦恩瑞布酰胺（Weinreb amide）A44与苯甲酰胺A43结合，经过四步反应形成手性异喹啉A45。在最后一步中，在甲醇中用D-酒石酸进行盐析，然后用氨水提高A45的对映体纯度。 1.13. Elagolix sodium(2018) 艾拉戈利克斯钠用于治疗子宫内膜异位症女性患者，由艾伯维和神经分泌生物科学公司开发。与度维利塞一水合物类似，在尿嘧啶与甲磺酸酯衍生物进行烷基化的过程中引入手性；后者化合物是由(−)-N-叔丁氧羰基-D-α-苯甘氨醇与甲磺酰氯反应合成。 1.14. Tegoprazan (2018) 泰戈泊扎兰最初由辉瑞公司发现，后由乐化制药和CJ医疗进一步开发，用于治疗胃食管反流病（GERD）。泰戈泊扎兰的可扩展合成方法如方案14所示。在三正丁基膦和1,1′-(偶氮二甲酰)二哌啶（ADDP）存在下，在苯并咪唑环上引入对映纯的苯并二氢吡喃醇侧链A53是合成的关键步骤。然后，3,5-二氟苯酚（A50）与丙炔酸甲酯发生缩合反应，生成E式和Z式（1:1混合物）的烯醇醚（A51）。接着进行氢化，随后进行分子内傅克酰基化反应，并用硼杂噁唑烷催化剂（A52）进行不对称还原，生成苯并二氢吡喃醇（A53）。最后，对后者进行重结晶，得到对映纯的手性亚基A53。 1.15. Alpelisib (2019) 诺华制药开发了阿培利司。它用于治疗转移性乳腺癌。在合成的最后一步中，在三乙胺存在下，通过L-脯氨酸酰胺A56在A55的咪唑环上引入手性中心（方案15）。 1.16. Solriamfetol (2019) 索利氨酯由 SK 生物制药公司开发，用于治疗与阻塞性睡眠呼吸暂停（OSA）和发作性睡病相关的埃勒斯-当洛斯综合征（EDS）。索利氨酯的千克级合成如方案16所示。在酸的存在下，由D-苯丙氨醇（A58）和氰酸钠一步合成索利氨酯，产率为89%。 1.17. Pretomanid (2019) 普瑞玛尼是一种抗分枝杆菌药物，用于治疗结核病（TB）。它是结核病联盟开发的首个抗结核药物。环氧化物A61在二异丙基乙胺存在下与前手性硝基咪唑A60偶联，发挥其作为手性底物的作用，生成A62。 1.18. Zanubrutinib (2019) 百济神州开发了泽布替尼用于治疗套细胞淋巴瘤。与上述的手性库方法不同，泽布替尼是首个通过手性拆分方法生产的药物。泽布替尼通过用L-二苯甲酰酒石酸（LDBTA）处理，以拆分方法获得其纯对映体形式。 1.19. Darolutamide (2019) 达罗他胺用于治疗非转移性去势抵抗性前列腺癌。它由奥立安集团和拜耳医药保健有限公司开发。达罗他胺不对称合成的关键步骤是将手性异丙胺片段插入到的联芳基骨架中，然后通过酸介导脱除片段上的 Boc 保护基，生成中间体A68。 1.20. Cenobamate (2019) SK制药公司开发了西诺巴胺，用于治疗部分性发作癫痫。方案20中展示的酶催化过程概述了其在胶红酵母（一种氧化还原酶）存在下的不对称催化氢化。 1.21. Avapritinib (2020) 通过手性拆分（Chiralresolution）A73。Blueprint医药开发了阿伐替尼（avapritinib），用于治疗转移性胃肠道癌症。通过超临界流体色谱分离中间体A73进行手性拆分，以68%的产率生成对映纯的阿伐替尼。 1.22. Berotralstat (2020) 贝罗司他用于预防遗传性血管性水肿（HAE）发作。与阿伐替尼的合成方法相同，在最后一步通过超临界流体色谱法以纯对映体形式合成贝罗司他。 1.23. Lonafarnib (2020) 洛那法尼用于治疗哈钦森-吉尔福德早衰症综合征（HGPS）。与贝罗司他不同，洛那法尼的手性是通过手性分离获得的。中间体A77经二异丁基氢化铝（DIBAL）还原后进行手性分离，生成具有一个立体中心的手性亚基A78。这些连续的步骤产生洛那法尼。 1.24. Osilodrostat (2020）奥西卓司他用于治疗库欣病，是一种11β-羟化酶抑制剂。手性奥西卓司他的生成方式与贝罗司他类似。中间体A80通过手性高效液相色谱（HPLC）分离直接生成药物。 1.25. Oliceridine (2020) 奥利塞林，一种中枢神经系统（CNS）药物，用于治疗中度至重度急性疼痛。在奥利塞林的全合成中，手性中间体A83通过A82的脱羧反应获得，随后进行超临界流体色谱（SFC）手性分离。 1.26. Remimazolam (2020) Acacia制药公司开发了瑞马唑仑，一种超短效苯二氮䓬类药物。在氯仿中用手性底物A86处理A85，生成了取代产物，该产物经过碱促进的F-moc脱保护和乙酸促进的缩合反应，经过三步生成环化中间体A87。 1.27. Ozanimod (2020) 奥扎尼莫德用于治疗复发型多发性硬化症。手性亚磺酰胺片段A90作为手性辅助基团，通过在A91的茚上插入一个手性中心来发挥作用（方案27）。片段A90与茚衍生物A89作为手性辅助基团，通过在茚上插入一个手性中心来发挥作用。奥扎尼莫德由中间体通过连续步骤合成A91. 两个手性中心的药物的合成方法未完待续！声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

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