No to little data exists on penetration of antiretroviral drugs in breastmilk. Too high concentrations may lead to infant toxicity and too low concentrations may lead to development of resistance in case the infant inadvertently becomes infected with the virus.
The aim of this trial is to determine the concentration of currently often used ARV (doravirine, raltegravir, bictegravir, tenofovir alafenamide, emtricitabine) in breast milk after administration of a single dose Study design: This is a single centre, single dose, open label, pharmacokinetic study in healthy volunteers.
Study population: Adult, healthy volunteers at the end of their breastfeeding period Intervention: Administration of one dose of either doravirine (DOR) 100mg, raltegravir (RAL) 1200mg or a combination of tenofovir alafenamide 25mg, emtricitabine 200mg and bictegravir 50mg (BIC/FTC/TAF).
Main study parameters/endpoints: Area under the plasma and milk concentration curve are used to calculate milk to plasma ratio.

开始日期2023-03-01

申办/合作机构

Radboud University Medical Center

[+2]

NCT05751031

/ Unknown statusN/AIIT

Pregnancy and Neonatal Outcomes Following Antenatal Exposure to Raltegravir: a Pooled Analysis From the European Pregnancy and Paediatric Infections Cohort Collaboration (EPPICC)

Raltegravir is the preferred INSTI for for treatment of antiretroviral-naïve pregnant women in the US Perinatal Guidelines, alongside Dolutegravir, and for late pregnancy. There are relatively limited information available on its use during early pregnancy, particularly the peri-conception period. The aim of the study is to assess "real-world" maternal, fetal and newborn outcomes following RAL use during pregnancy through pooled analysis of individual patient data from observational studies participating in the European Pregnancy and Paediatric Infections Cohort Collaboration.

开始日期2023-02-20

申办/合作机构-

NCT03954327

/ Completed临床2期IIT

Randomized Controlled Trail (RCT) of Emtricitabine, Tenofovir Disoproxil and Raltegravir for Patients With Primary Biliary Cholangitis Unresponsive to Ursodeoxycholic Acid (UDCA)

Placebo Controlled, double-blind randomized controlled trial (RCT) with 12 months Tenofovir Disoproxil and Raltegravir for primary biliary cholangitis (PBC) patients unresponsive to Ursodeoxycholic Acid (UDCA). Placebo patients will be offered 12 months open label therapy at unblinding. All patients will be offered an additional 12 months open label therapy. Observational, open label study will be performed in parallel using Emtricitabine (FTC)/Tenofovir Disoproxil (TDF) & Raltegravir in liver transplant recipients meeting all entry criteria except for use of immunosuppression.

开始日期2021-03-01

申办/合作机构

University of Alberta

[+1]

100 项与拉替拉韦钾相关的临床结果

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100 项与拉替拉韦钾相关的转化医学

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100 项与拉替拉韦钾相关的专利（医药）

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项与拉替拉韦钾相关的文献（医药）

2025-12-01·Medicinal Chemistry

A Comprehensive Review: Synthesis and Pharmacological Activities of 1,3,4-Oxadiazole Hybrid Scaffolds

Article

作者: Pandit, Amit ; Lata, Suman ; Choudhary, Lucky ; Abbot, Vikrant ; Bharwal, Ankita

Introduction::

Heterocyclic derivatives, particularly those containing heteroatoms such as oxygen and nitrogen, represent a significant portion of currently marketed drugs. Among these, the aromatic heterocycle 1,3,4-oxadiazole, characterized by an N=C=O-linkage, stands out due to its remarkable biological activities. These activities include anti-inflammatory, anti-cancer, antioxidant, anti-tubercular, antiviral, anti-diabetic, and antibacterial effects. Notably, several commercially available medications, such as tiodazosin, raltegravir, zibotentan, and nesapidil, incorporate this structural motif.

Methods::

This review compiles and analyzes existing synthetic methods for preparing 1,3,4- oxadiazole and its derivatives. By examining various synthetic routes and methodologies, the review provides a detailed overview of the strategies employed to generate these biologically active compounds.

Results::

The review highlights the potential of 1,3,4-oxadiazole derivatives in addressing the toxicity, side effects, and drug resistance commonly associated with existing anticancer therapies. By combining the 1,3,4-oxadiazole moiety with other heteroatoms, novel hybrid derivatives have been synthesized, demonstrating enhanced pharmacological activities across various therapeutic areas.

Conclusion::

This comprehensive review offers valuable insights into the synthesis and pharmacological applications of 1,3,4-oxadiazoles. It serves as a crucial resource for researchers exploring the development of new therapeutic compounds, with the ultimate goal of improving public health. The review builds on existing literature from the last two decades to present an exhaustive examination of the potential of 1,3,4-oxadiazole derivatives in drug development.

2025-12-01·BIOCHEMICAL PHARMACOLOGY

Role of organic anion transporter 2 in the efflux of raltegravir glucuronide from the endoplasmic reticulum in the liver

Article

作者: Kato, Yukio ; Peng, Hanwei ; Dai, Shengyu ; Arakawa, Hiroshi

Endoplasmic reticulum (ER) type organic anion transporter 2 (OAT2) plays an essential role in the glucuronidation of certain drugs by mediating their uptake across ER membranes. However, the mechanism by which glucuronide conjugates generated in the ER lumen are excreted to the cytoplasm remains unclear. As plasma membrane-type OAT2-546aa has bidirectional transport properties, we hypothesized that glucuronide generated in the ER lumen may be exported from the ER via OAT2-548aa. In this study, we aimed to elucidate the role of OAT2-548aa in drug efflux from the ER. The immunostaining of OAT2 was merged with ER marker calnexin in human hepatocarcinoma differentiated HepaRG cells. The formation of glucuronide by the anti-human immunodeficiency virus agent raltegravir in hepatocellular carcinoma HepaRG cells was reduced by the OAT2 inhibitor valproic acid. In contrast, valproic acid did not affect the uptake of raltegravir into HepaRG cells or the formation of raltegravir glucuronide (RAL-Glu) in human hepatic microsomes permealized by pore-forming agent alamethicin. An uptake study using OAT2-546aa-expressing Xenopus laevis oocytes revealed that RAL-Glu was a substrate for OAT2, but parental raltegravir was not. Valproic acid inhibited OAT2-546aa-mediated uptake of RAL-Glu. Furthermore, the efflux of RAL-Glu injected into OAT2-546aa-expressing oocytes was enhanced compared with that in non-OAT2-546aa-expressing oocytes. Additionally, RAL-Glu production in HepaRG cells was decreased by OAT2 knockdown using small interfering RNA (siRNA) targeting both 546aa and 548aa. These results suggest that OAT2-548aa regulates raltegravir glucuronidation in the ER by mediating the efflux of its glucuronide conjugate generated in the ER.

2025-11-01·EClinicalMedicine

Mortality using raltegravir versus other integrase strand-transfer inhibitors in people with HIV in Europe and Australia: a prospective multicentre study

Article

作者: Mussini, Cristina ; Lundgren, Jens ; Jaschinski, Nadine ; Vannappagari, Vani ; Ryom, Lene ; Vehreschild, Jörg Janne ; Castagna, Antonella ; Tusch, Erich ; Martin, Charlotte ; Tallada, Joan ; Zangerle, Robert ; Reekie, Joanne ; Wit, Ferdinand ; Peters, Lars ; Begovac, Josip ; Rooney, Jim ; Günthard, Huldrych F ; Wallner, Elmar ; Hoffmann, Christian ; Dos Santos Mendes, Sofia ; Kusejko, Katharina ; Giacomelli, Andrea ; Degen, Olaf ; Kowalska, Justyna

Background:

Integrase strand-transfer inhibitors (INSTI) are a key part of contemporary antiretroviral therapy (ART). Raltegravir (RAL) was the first INSTI and remains recommended for some people with HIV. We investigated all-cause mortality between RAL-based ART and other INSTIs in the RESPOND cohort consortium among both ART-naïve and treatment experienced individuals.

Methods:

RESPOND, a multicenter prospective cohort study, includes approximately 40,000 adults (≥18 years) with HIV from 17 cohorts across Europe and Australia. Individuals eligible for inclusion into RESPOND had ≥1 clinical visit at a site participating in RESPOND after January 01, 2012, and a CD4 count and HIV viral load measurement available at inclusion. Participants in RESPOND who started their first INSTI between JAN 01, 2012 and DEC 31, 2021 were included. All-cause mortality among those starting RAL was compared to those starting any other INSTI using Cox proportional hazards regressions: one model adjusting for age and another weighted by inverse probability of treatment weights (IPTW). Predictors of starting RAL were estimated by logistic regression.

Findings:

Among 20,349 participants starting an INSTI (15,429 (75.8%) male, 4879 (24.0%) female, and 41 (0.2%) transgender), 938 (4.6%) died during 94,677 person-years of follow-up (PYFU). Crude mortality rates (MR) were higher for participants starting RAL (MR 12.9 per 1000 PYFU; 95% CI 11.5-14.5) than other INSTIs (MR 9.1 per 1000 PYFU; 95% CI 8.4, 9.8). Starting RAL was significantly associated with higher mortality when controlling for age (adjusted hazard ratio (aHR) 1.43; 95% CI 1.25, 1.65). However, after applying IPTW, there was insufficient evidence for a difference in mortality in the full cohort (hazard ratio (HR) 1.13; 95% CI 0.93, 1.34) or among ART-naïve participants (HR 1.23; 95% CI 0.71, 2.12). Starting RAL was associated with higher HIV viral load, hepatitis C positive status (aOR 2.07; 95% CI 1.82, 2.37), prevalent end-stage renal disease (aOR 2.58; 95% CI 1.58, 4.19), chemotherapy near baseline (aOR 1.58; 1.01, 2.48), and cardiovascular disease (aOR 1.58; 95% CI 1.30, 1.91).

Interpretation:

In this large and well-characterised cohort we found no evidence of an association between all-cause mortality and use of RAL compared to other INSTIs after accounting for confounding at the time of starting the INSTI. Our findings suggest that prior reports of such an association could have been confounded by indication and channelling bias. While a large number of potential confounders were accounted for, the results presented are an estimation of average treatment effect using IPTW which is still vulnerable to uncontrolled confounding.

Funding:

CHU St Pierre Brussels HIV Cohort, Austrian HIV Cohort Study, Australian HIV Observational Database, AIDS Therapy Evaluation in the Netherlands National Observational HIV cohort, EuroSIDA cohort, Frankfurt HIV Cohort Study, Georgian National AIDS Health Information System, Nice HIV Cohort, ICONA Foundation, Modena HIV Cohort, PISCIS Cohort Study, Swiss HIV Cohort Study, Swedish InfCare HIV Cohort, Royal Free HIV Cohort Study, San Raffaele Scientific Institute, University Hospital Bonn HIV Cohort, University of Cologne HIV Cohort, Brighton HIV Cohort, and the National Croatian HIV cohort, ViiV Healthcare, Merck Life Sciences, Gilead Sciences, and the Centre of Excellence for Health, Immunity Infections (CHIP).

项与拉替拉韦钾相关的新闻（医药）

2025-09-11

·漫游药化

全球最畅销的十款小分子药物！

小分子药物已过时？显然没有！随着抗体、基因疗法、细胞疗法等新兴药物模式的兴起，小分子药物一度被认为即将过时，事实上，小分子药物仍有其不可替代性，相对生物制剂来说，小分子在生产制造、运输、患者依从性、可用靶点范围、免疫原性等方面仍具有明显优势。在全球范围内的上市药物中，小分子药物的占比仍然高达近90%。而在2023年前三季度FDA批准的40个新药中，也有21个小分子。下面就让我们一起盘点小分子药物中的优等生，看看在销售榜单中的top 10都有哪些明星分子。根据Arizona大学Jon Njardarson课题组的统计，2022年前十大销售额的小分子药物总计销售超966亿美元，治疗领域涵盖病毒感染、心血管、肿瘤等。从公司来看，辉瑞不愧为小分子药物开发先驱，共有4款药物入围前十，其次是BMS，有阿哌沙班、来那度胺两款小分子药进入前十，合计贡献217亿美元营收。表1, 2022销售额 top 10小分子药物 01 奈玛特韦（Paxlovid，Nirmatrelvir）由辉瑞研发的一款3CL蛋白酶抑制剂，可以抑制3CL蛋白酶的作用，从而阻止新冠病毒后续的一系列复制活动。在临床试验中，Paxlovid可将新冠肺炎非住院患者的住院或死亡率降低89%。该药于2021年12月成为首款获得FDA紧急批准的新冠口服药，上市第一年，销售额便达到了189亿美元，一举超越阿哌沙班成为最畅销小分子药物。奈玛特韦是在先前开发的针对非典（SARS）的特效药PF-00835231基础上改造得来，辉瑞的研究人员发现，PF-00835231与SARS-CoV的结合位点，同样存在于新冠病原SARS-CoV-2，这意味着PF-00835231也许对新冠病毒同样有效，经测试证明确实如此，但静脉注射剂型太过繁琐，辉瑞便对PF-00835231进行结构优化并引入三氟乙酰胺基团，提高了生物利用度，使其可通过口服吸收。图1，由SARS特效药改造得到SARS-CoV-2特效药Paxlovid 02 阿哌沙班（Eliquis，apixaban）由BMS和辉瑞公司联合研发的一种新型凝血因子Xa（Factor Xa）抑制剂，分别于2011和2012年在欧洲和美国上市，用于患者术后静脉血栓栓塞症（VTE）预防及房颤患者脑卒中预防。虽然专利还未到期（2026年），但2022年销售额同比2021年仍降低了约30%，为117亿美元。阿哌沙班由BMS经过高通量筛选优化得到，对人FXa的Ki 0.08 nM，对 FXa 的选择性比其他人凝血蛋白酶高 30000 倍以上。与维生素K拮抗剂华法林等相比，阿哌沙班具有疗效更好，安全性更高的特点。图2, 阿哌沙班的结构优化过程 03 必妥维（Biktarvy）由吉利德科学公司研发，于2018年获FDA批准上市的用于治疗HIV的三合一复方新药，含有比克替拉韦（bictegravir）50mg/恩曲他滨（emtricitabine）200mg/丙酚替诺福韦（tenofovir alafenamide）25mg，bictegravir是HIV-1整合酶抑制剂，emtricitabine和tenofovir alafenamide都是核苷类似物，用作逆转录酶抑制剂。2020/2021/2022年的销售额分别为72.59亿、86.24亿、103亿美元，放量十分迅速。恩曲他滨和丙酚替诺福韦在2003和2015年就已经上市，只有比克替拉韦为Biktarvy复方新药中的NME成分，其化学结构与多替拉韦（Dolutegravir， GSK开发的HIV药物）类似，同为整合酶抑制剂，但Biktarvy安全性更佳。图3, Bictegravir（BIC）和Dolutegravir（DTG） 04 来那度胺（Revlimid, Lenalidomide）来那度胺由新基制药开发，是老药新用的经典案例，前身是臭名昭著的“反应停“沙利度胺。上世纪90年代，科学家发现沙利度胺有抗癌疗效，对其进行分子改造后得到来那度胺，后者于2005年获批上市，用于治疗多发性骨髓瘤（MM）、骨髓瘤增生异常综合征（MDS）等疾病。该药2020/2021/2022年的销售额分别为121亿、129亿、100亿美元，2023年进一步降至61亿美元，但上市至今累计销售额已达1050亿美元。图4, 沙利度胺与来那度胺后来，经过更广泛的研究，科学家发现来那度胺是通过分子胶水的机制诱导E3连接酶Cereblon (CRBN) 降解靶蛋白来发挥治疗作用，由此开发出了一项全新的小分子药物技术—蛋白水解靶向嵌合体（PROTAC），其能够弥补传统小分子药物难以靶向不可成药靶点的缺陷，诱导致病蛋白的降解。 05 恩格列净（Jardiance, Empagliflozin）由勃林格殷格翰公司研发的钠-葡萄糖协同转运蛋白-2 (SGLT2)抑制剂，于2014年8月获FDA批准上市，用于控制2型糖尿病成人患者的血糖和降低患者的心血管风险。SGLT2主要在肾脏表达，负责从肾小管腔重吸收过滤后的葡萄糖和钠，当SGLT2被抑制后，肾脏对葡萄糖和钠的重吸收都会减少，降低体内血糖浓度。该药2020/2021/2022年销售额为41.08亿、58.29亿、82.15亿美元。图5, 恩格列净作用机制 06 伊布替尼（Imbruvica，Ibrutinib）该药于2013年在美国上市，是全球首个BTK共价抑制剂，用于治疗套细胞淋巴瘤（MCL）、慢性淋巴细胞白血病/小淋巴细胞淋巴瘤（CLL/SLL）和华氏巨球蛋白血症（WM）等血液肿瘤。然而，伊布替尼作为一代抑制剂，对BTK选择性不够好，存在脱靶效应，并可能抑制其他具有相同保守的Cys残基的激酶从而导致过敏和腹泻等不良反应。图6, 已上市的BTK抑制剂结构该药2020/2021/2022年销售额为94.42亿、97.77亿、83亿美元，核心专利将于2026年到期，但由于泽布替尼和其他后来者的强力竞争，伊布替尼的市场急剧下滑，2023年销售额仅为36亿美元。而2022年刚获FDA批准的泽布替尼，2023年销售额已达到13亿美元。 07 多替拉韦（Tivicay，Dolutegravir）由GSK和ViiV Healthcare共同研发，与bictegravir一样，是HIV整合酶抑制剂，阻断HIV病毒DNA整合来限制HIV的复制，于2013年8月获FDA批准上市。多替拉韦还是GSK其他三款HIV产品——Triumeq(多替拉韦/阿巴卡韦/拉米夫定)、Juluca(多替拉韦/利匹韦林）和Dovato（多替拉韦/拉米夫定)的成分之一，该药2022年销售额达到了81亿美元。在dolutegravir之前，已经有raltegravir、elvitegravir等整合酶抑制剂上市，对整合酶药物结合口袋的构效关系研究也已经比较清楚，于是盐野义和GSK的研究人员在总结前期发表的分子结构基础上引入氧原子设计了化合物5，以增强化何物对整合酶的结合能力，之后又对生物利用度、半衰期和突变体结合活性进行了优化，得到了dolutegravir，半衰期为6 h，生物利用度达到了34%。图7, Dolutegravir（3）结构优化历程 08 Trikafta (Elexacaftor, Tezacaftor, Ivacaftor) 由福泰制药研发，于2019年10月获FDA批准上市，用于治疗6岁及以上囊性纤维化跨膜电导调节蛋白（CFTR）的基因至少有一个F508del突变或其它有效突变的囊性纤维化（cystic fibrosis, CF）患者。 Trikafta由三个小分子复方组成，他们同时结合致病的CFTR突变蛋白，彼此之间有协同作用，elexacaftor是新一代CFTR蛋白校正剂，帮助恢复携带F508del突变的CFTR蛋白的功能；tezacaftor帮助组装和运输CFTR蛋白至细胞表面来增强它的功能，ivacaftor则通过增加位于细胞表面CFTR通道的开放率（门控通道），提高CFTR蛋白的活性，增加氯化物的转运。三种分子联合应用能增加CFTR蛋白的数量并增强蛋白的功能。图8，Trikafta含有的三个小分子结构及其作用机制囊性纤维化是一种遗传性疾病，由CFTR的基因突变引起，在美国有3万多名囊性纤维化患者，全世界约有7万名患者。Trikafta则是福泰制药的当家产品，该药在2020/2021/2022/2023年销售额分别为39亿、57亿、76亿、89亿美元，年均增长率达32%，在2023年更是贡献了福泰全年总营收的90%。 09 利伐沙班（Xarelto，Rivaroxaban）利伐沙班由拜耳制药开发，为首个上市的Factor Xa抑制剂（分别于2008和2011年在欧洲和美国获批），它通过抑制因子Xa可以中断凝血瀑布的内源性和外源性途径，抑制凝血酶的产生和血栓形成。 Bayer于1998年便启动了直接抑制FXa小分子抗凝药物研发项目，经过高通量筛选20万化合物后得到了一个IC50为70 nM、选择性抑制FXa体外酶活的苗头化合物，并对其进行结构优化以提升抑制活性和口服生物利用度，最终优化得到含有吡咯烷酮结构的利伐沙班，IC50为0.7 nM，口服生物利用度接近60%。图9，利伐沙班抗凝血机制 10 恩杂鲁胺（Xtandi, Enzalutamide）由美国Medivation公司研发，是一款成功的me-better的非甾体雄激素受体（androgen receptor，AR）抑制剂，于2012年获FDA批准上市，用于治疗去势性前列腺癌和转移性激素敏感性前列腺癌。最初的药化工作是由UCLA大学的Jung和Memorial Sloan-Kattering癌症中心的Sawyers合作进行, Jung等以药物尼鲁米特和雄激素激动剂RU59063为出发点, 试图优化得到AR拮抗剂，最终从合成的200多个化合物中优选出恩杂鲁胺。图10 恩杂鲁胺及其先导化合物结构恩杂鲁胺2020/2021/2022年销售额51亿、56.36、62亿，销售额仍处于稳定爬坡中。 Ref： Wong PC, Pinto DJ, Zhang D. Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor. J Thromb Thrombolysis. 2011 May;31(4):478-92. Owen DR, Allerton CMN, Zhu Y. An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science. 2021 Dec 24;374(6575):1586-1593. Liu J, Chen C, Wang D, Zhang J, Zhang T. Emerging small-molecule inhibitors of the Bruton's tyrosine kinase (BTK): Current development. Eur J Med Chem. 2021 May 5;217:113329. Perzborn, E., Roehrig, S., Straub, A.et al. The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor. Nat Rev Drug Discov 10, 61–75 (2011). https://www.xareltohcp.com/ Fiedorczuk K, Chen J. Molecular structures reveal synergistic rescue of Δ508 CFTR by Trikafta modulators. Science. 2022 Oct 21;378(6617):284-290. Yoshiyuki Taoda, Shuichi Sugiyama & Takahiro Seki. (2023) New designs for HIV-1 integrase inhibitors: a patent review (2018-present). Expert Opinion on Therapeutic Patents 33:1, pages 51-66. 作者：betaloc

上市批准细胞疗法基因疗法紧急使用授权

2025-06-11

·生物制品圈

吉利德 HIV 组合疗法被暂停不影响 Lenacapavir 审批进程

吉利德科学（Gilead Sciences）近日宣布其试验性 HIV 组合疗法遭遇监管暂停，引发市场对其 HIV 产品线的关注。不过分析人士指出，这一事件不会影响该公司备受期待的长效 HIV 药物 lenacapavir 的审批进程，后者即将迎来美国 FDA 的关键决策。组合疗法暂停：安全信号引发五项临床试验搁置周二上午，吉利德发布公告称，其研究性每周 HIV 组合药片的五项临床试验已被 FDA 暂停，原因是在部分患者中观察到 CD4+ T 细胞和绝对淋巴细胞计数下降，这可能表明 HIV 患者的免疫系统减弱。受影响的试验包括两项 II/III 期研究 WONDERS-1 和 WONDERS-2，以及三项 I 期研究。该组合疗法包含整合酶链转移抑制剂 GS-1720 和 / 或衣壳抑制剂 GS-4182。值得注意的是，GS-4182 是一种前药形式，与吉利德已获批的 lenacapavir（商品名 Sunleca）相关。Sunleca 目前用于治疗多重耐药 HIV 患者，每半年注射一次，同时其预防 HIV 的适应症正在 FDA 审查中。吉利德在公告中强调对该组合疗法的信心，并承诺与监管机构合作解决暂停问题。公司同时指出，此次暂停不影响其 HIV 产品线中的其他资产。市场反应与分析：Lenacapavir 审批预期不变尽管消息公布后，吉利德股价在周二早盘下跌 2% 至 110.75 美元，但分析师们普遍认为这一事件对即将到来的 lenacapavir 审批影响有限。杰富瑞（Jefferies）分析师在报告中写道：“虽然这可能会增加投资者对 6 月 19 日 lenacapavir 预防适应症 PDUFA 日期的不确定性，但我们认为没有重大影响，预计 FDA 将按时且顺利批准。” 该机构指出，若 FDA 真的担忧，可能会暂停吉利德更多正在开发的配方和整合酶抑制剂，但目前情况并非如此。蒙特利尔银行资本市场（BMO Capital Markets）也持相同观点，但表示投资者消化这一消息时，吉利德的股价仍可能面临一些压力。Lenacapavir：吉利德 HIV 帝国的新希望吉利德正寻求批准 lenacapavir 作为每半年一次的注射剂用于 HIV 暴露前预防（PrEP）。FDA 定于 6 月 19 日做出的决定，受到分析师、患者和吉利德的热切期待，该公司正为大规模上市做准备。这款药物有望进一步巩固吉利德在 HIV 领域的地位。其现有旗舰产品 Biktarvy 在 2024 年录得 134 亿美元的销售额，BMO 预测 lenacapavir 用于 PrEP 的峰值销售额将达到 65 亿美元。更广泛地说，吉利德的目标是到 2033 年推出九种新的 HIV 药物。lenacapavir 的最新申请基于 III 期 PURPOSE 1 和 PURPOSE 2 研究的数据。PURPOSE 1 专注于顺性别女性，显示出 100% 的预防 HIV 感染效果。PURPOSE 2 则纳入了更多样化的人群，包括顺性别男性、跨性别男性、跨性别女性和非二元性别个体，结果显示每半年一次的 lenacapavir 将 HIV 发病率降低了 96%。杰富瑞指出，这一适应症与现在被暂停的组合疗法所针对的问题截然不同，目前尚不清楚 lenacapavir 前药是否是问题所在。行业背景：HIV 药物开发中的安全挑战吉利德并非唯一在 HIV 药物开发中面临安全信号的公司。例如，默克（Merck）2007 年推出的 Isentress 在试验中也因观察到 CD4 T 细胞计数下降而被 FDA 暂停。几年前，Isentress 与吉利德的 lenacapavir 联合用于 HIV 治疗的试验也被暂停，但最终在 2022 年通过降低默克药物的剂量得以解除。杰富瑞对此次临床暂停并不太担心，该机构更看重 lenacapavir 与注射用整合酶抑制剂 GS-1219 和 GS-3242 联合使用的 I 期数据。吉利德计划在今年年底前选择其中一种药物，与 lenacapavir 组成联合疗法。这些药物在第一个月和第六个月各给药一次（每半年一次）。“如果吉利德能够在本十年后半期将 150 亿美元的 Biktarvy 市场转换为长效每半年一次的注射剂，这将是真正改变游戏规则的价值主张，” 杰富瑞写道。随着 6 月 19 日的临近，市场将密切关注 FDA 对 lenacapavir 的决定，而吉利德与监管机构合作解决组合疗法暂停问题的进展也将成为焦点。这两个事件共同描绘了吉利德在 HIV 领域持续创新与应对监管挑战的现状。这篇报道从事件本身、市场反应、重点药物进展及行业背景四个方面，全面呈现了吉利德 HIV 组合疗法暂停事件及其影响。若你希望对某个部分进一步展开或调整结构，可随时告知。参考来源：https://www.biospace.com/drug-development/gileads-hiv-combo-on-hold-with-no-impact-on-fdas-pending-lenacapavir-decision识别微信二维码，添加生物制品圈小编，符合条件者即可加入生物制品微信群！请注明：姓名+研究方向！版权声明本公众号所有转载文章系出于传递更多信息之目的，且明确注明来源和作者，不希望被转载的媒体或个人可与我们联系(cbplib@163.com)，我们将立即进行删除处理。所有文章仅代表作者观点，不代表本站立场。

临床2期临床3期

2025-06-10

·BioSpace

Gilead’s HIV Combo on Hold, With No Impact on FDA’s Pending Lenacapavir Decision

iStock, Nuthawut Somsuk Gilead underscored its faith in the combo therapy and pledged to work with regulators to resolve the hold, which has paused five clinical trials. Gilead also stressed that the hold does not impact any other assets in its HIV pipeline. Five clinical trials for Gilead’s investigational weekly HIV combo pill have been placed on hold by the FDA after a safety signal emerged. While the combo includes a version of Gilead’s lenacapavir, which is approved as Sunleca for twice-yearly treatment of people with multi-drug-resistant HIV and currently under FDA review for the prevention of HIV, Jefferies analysts said the pause will not affect the looming decision date. Gilead announced the clinical hold Tuesday morning, explaining in a release that two Phase II/III trials named WONDERS-1 and -2 had been paused, plus three Phase I studies. The combination therapy features the integrase strand transfer inhibitor GS-1720 and/or the capsid inhibitor GS-4182. While Gilead did not mention lenacapavir in the release, Jefferies analysts explained that GS-4182 is a pro-drug formulation of the investigational therapy, which is separately under review for HIV pre-exposure prophylaxis (PrEP). “While it might increase some investor uncertainty into the all-important June 19 PDUFA for [lenacapavir] for PrEP, we see no major read-through and expect an on-time and clean FDA approval,” Jefferies wrote on Tuesday morning. BMO Capital Markets agreed but said that Gilead’s shares could still face some pressure Tuesday as investors digest the news. The company’s stock declined 2% to $110.75 as of 10:50 a.m. ET. Gilead said that the hold was placed after decreases in CD4+ T cell and absolute lymphocyte counts were identified in a subset of patients who received both drugs. This can be a signal of a weakened immune system in patients with HIV. The Phase II/III WONDERS-1 trial is comparing the combo with Gilead’s approved HIV medicine Biktarvy in people with HIV who are taking medication to suppress the virus. The Phase II/III WONDERS-2 study similarly features Biktarvy as the comparator but has enrolled patients with HIV who are treatment-naive. The company underscored its faith in the combo therapy and pledged to work with regulators to resolve the hold. Gilead also stressed that the hold does not impact any other assets in its HIV pipeline. Jefferies agreed with this assessment, noting that had the FDA been concerned, it would have stalled more of Gilead’s formulations and integrase inhibitors currently under development. Any Day Now Gilead is seeking approval of lenacapavir as a twice-yearly injection for PrEP for HIV. The FDA’s decision, due June 19, has been eagerly anticipated by analysts, patients and Gilead, which is gearing up for a massive launch. The company is looking to the drug to build on its HIV empire, which is anchored by Biktarvy—a drug that recorded sales of $13.4 billion in 2024. BMO predicts peak sales of $6.5 billion for the PrEP indication. More broadly, Gilead is aiming to launch nine new HIV drugs by 2033. Gilead backed lenacapavir’s latest application with data from the Phase III PURPOSE 1 and PURPOSE 2 studies. PURPOSE 1, which focused on cisgender women, demonstrated 100% efficacy in preventing HIV infection. PURPOSE 2 enrolled a more diverse population of cisgender men, transgender men, transgender women and nonbinary individuals who have sex with partners assigned male at birth. Results showed that twice-yearly lenacapavir cut HIV incidence by 96% . Jefferies said this indication is very different from what the combo has been aimed at addressing in the now-stalled trials. It’s also unclear if the lenacapavir pro-drug is even the issue at this point. Other companies in the HIV space have had similar safety signals arise. Merck, for example, had trials of Isentress, launched in 2007, placed on hold by the FDA after CD4 T cell count reductions were observed. A combo of Isentress and Gilead’s lenacapavir for HIV treatment was also placed on hold several years ago but was ultimately released in 2022 using lower doses of Merck’s drug. Altogether, Jefferies is not too worried about the clinical hold. The firm places more weight on Phase I data for lenacapavir in combination with the injectable integrase inhibitors GS-1219 and GS-3242. Gilead intends to pick one of those medicines to move forward in a combo regimen with lenacapavir by the end of the year. The drugs are administered as a single dose at the first month and sixth month (Q6M). “This would be the real game changer and value proposition for Gilead if they are able to swap the $15B Biktarvy market onto long-acting Q6M injectable in the later half of the decade,” Jefferies wrote.

临床3期临床结果上市批准临床1期临床2期

100 项与拉替拉韦钾相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D07133	拉替拉韦钾	J05AX08	DB06817

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
HIV感染	美国	Merck Sharp & Dohme Corp.	2007-10-12

未上市

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
获得性免疫缺陷综合征	申请上市	欧盟	Viatris Ltd. (New Zealand)	-
终末期肾脏病	临床3期	法国	Merck Sharp & Dohme Corp.	2011-12-01
高甘油三酯血症	临床3期	美国	Merck Sharp & Dohme Corp.	2009-05-01
艾滋病相关机会致病菌感染	临床3期	美国	Merck Sharp & Dohme Corp.	2008-07-01
艾滋病相关机会致病菌感染	临床3期	加拿大	Merck Sharp & Dohme Corp.	2008-07-01
艾滋病相关机会致病菌感染	临床3期	法国	Merck Sharp & Dohme Corp.	2008-07-01
艾滋病相关机会致病菌感染	临床3期	意大利	Merck Sharp & Dohme Corp.	2008-07-01
艾滋病相关机会致病菌感染	临床3期	波兰	Merck Sharp & Dohme Corp.	2008-07-01
艾滋病相关机会致病菌感染	临床3期	波多黎各	Merck Sharp & Dohme Corp.	2008-07-01
艾滋病相关机会致病菌感染	临床3期	西班牙	Merck Sharp & Dohme Corp.	2008-07-01

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临床结果

适应症

分期

评价

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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


NCT03311945 (CTgov)	临床3期	HIV血清阳性	33	Lamivudine+raltegravir	廠築顧鑰選觸窪積鑰齋 = 鬱餘夢製鏇選夢鑰獵窪淵築積艱範觸糧鏇窪範 (範鹹鏇淵淵膚餘齋積積, 艱積製範齋窪簾鬱衊選 ~ 鬱網選憲獵觸築獵夢鏇) 更多	-	2025-07-18
NCT03029689 (RAGTIME, CTgov)	临床3期	HIV感染	61	Current ART+raltegravir (Current ART + Raltegravir)	鏇觸艱蓋範衊淵夢廠獵(壓餘壓遞遞遞齋鏇窪醖) = 醖壓鹽齋膚顧蓋簾鏇獵鹹繭鏇壓醖窪鹽艱憲窪 (鹹願鏇淵獵夢窪網窪鬱, 繭窪選願繭製壓憲願醖 ~ 膚淵鑰糧遞觸醖觸積蓋) 更多	-	2025-04-13
				Current ART (Current ART + Placebo)	鏇觸艱蓋範衊淵夢廠獵(壓餘壓遞遞遞齋鏇窪醖) = 餘膚構繭積廠壓獵觸廠鹹繭鏇壓醖窪鹽艱憲窪 (鹹願鏇淵獵夢窪網窪鬱, 鹽網繭繭鏇積選繭憲鹹 ~ 顧鹹夢製鬱窪觸壓選膚) 更多
NCT01854762 (PregnantHIV, CTgov)	临床2/3期	怀孕 \| HIV感染	33	Raltegravir (Raltegravir)	築築遞憲獵觸齋選襯獵 = 齋積製網憲積壓遞窪蓋夢夢獵築糧製艱齋醖廠 (遞鏇繭糧壓膚蓋醖衊願, 衊簾艱簾醖網顧壓鹽淵 ~ 鏇膚襯齋簾襯顧膚廠襯) 更多	-	2024-10-15
				Lopinavir/Ritonavir (Lopinavir/Ritonavir)	築築遞憲獵觸齋選襯獵 = 獵齋餘夢蓋築衊繭顧範夢夢獵築糧製艱齋醖廠 (遞鏇繭糧壓膚蓋醖衊願, 襯鹹夢顧範鑰鑰製鏇繭 ~ 遞遞膚鬱衊艱夢鹽餘齋) 更多
NCT01641367 (ACTG A5288, Pubmed)	临床4期	三线	257	RAL	網襯鹽襯壓願壓夢範廠(淵構衊築壓餘獵壓鑰糧) = 膚築製獵鑰艱築壓築遞糧繭齋顧膚鹽蓋遞餘繭 (網鑰獵糧夢襯廠簾衊遞 ) 更多	-	2022-06-01
				DRV/r	製網餘夢憲廠鬱觸壓壓(鑰願鏇獵艱獵憲衊繭窪) = 廠鑰繭壓衊網觸鹽艱網獵製襯鏇憲糧鹹繭積遞 (積夢窪鬱獵製憲艱構餘 )
NCT03374358 (Pubmed \| AIDS Patient Care STDS)	临床4期	-	43	Switch to Raltegravir	遞齋範齋網鑰構築繭願(積膚醖淵網繭顧積鑰遞) = 製鑰衊壓範獵獵襯繭夢窪鏇廠簾淵鑰積淵鏇壓 (簾鏇遞製膚醖廠鏇觸糧 ) 更多	-	2021-09-01
				Continue unchanged antiretroviral therapy	窪顧範網壓遞糧壓鏇齋(憲構淵構蓋鑰鏇鏇觸鹹) = 選淵窪顧遞衊窪繭鬱憲膚醖憲鹹夢鹽齋襯蓋鬱 (窪製鬱餘鏇蓋網淵構願 )
NCT01147107 (CTgov)	临床4期	HIV感染 \| 慢性丙型肝炎	80	raltegravir (Raltegravir Based Therapy)	齋艱築窪構壓襯製願膚 = 艱築願範積淵鹹夢糧鏇餘遞鹹壓繭窪顧廠觸範 (齋醖壓淵鹹糧膚餘簾齋, 夢遞艱鹽壓糧範憲觸餘 ~ 餘構淵繭餘鏇壓簾夢鹽) 更多	-	2021-08-13
				Efavirenz (Efavirenz Based Therapy)	齋艱築窪構壓襯製願膚 = 簾餘鑰膚鹽餘鹹蓋糧積餘遞鹹壓繭窪顧廠觸範 (齋醖壓淵鹹糧膚餘簾齋, 艱構選衊齋繭鏇遞齋顧 ~ 襯餘構築膚構網積淵繭) 更多
NCT03374358 (OBERAL, CTgov)	临床4期	代谢综合征 \| 脂肪肝 \| HIV血清阳性	45	raltegravir	壓衊築觸糧遞窪選簾製(製網製憲繭蓋繭艱窪觸) = 遞願餘簾鬱選壓鏇鹹蓋願簾糧淵願網網顧淵繭 (觸簾鹽鹽鹹繭鬱襯鹹壓, 餘艱淵廠積鬱繭壓窪獵 ~ 獵觸構窪積窪襯醖壓衊) 更多	-	2021-07-07
NCT03205566 (R-PrEP, CTgov)	临床4期	HIV感染	38	Raltegravir (Raltegravir)	選廠網遞築鏇憲構餘齋(築製廠蓋遞構願鏇鹹築) = 夢壓醖鑰構廠壓壓獵憲鬱構選網窪顧憲衊壓繭 (蓋鹹襯淵範簾鑰蓋獵願, NA) 更多	-	2021-02-21
				Raltegravir (Raltegravir During Combination Treatment)	選廠網遞築鏇憲構餘齋(築製廠蓋遞構願鏇鹹築) = 築糧遞顧願壓鑰齋壓繭鬱構選網窪顧憲衊壓繭 (蓋鹹襯淵範簾鑰蓋獵願, 231.40) 更多
NCT01751568 (CTgov)	临床1/2期	结核 \| 获得性免疫缺陷综合征 \| 肺结核 ... 更多	40	raltegravir (Cohort 1: ≥ 2 to < 6 Years of Age on TB Treatment)	製鏇壓製觸製糧齋齋築 = 範鹹選簾艱築選餘醖壓餘獵簾醖製蓋窪窪壓蓋 (築遞衊淵築淵觸廠衊糧, 廠簾鏇夢範壓簾鏇獵獵 ~ 選選繭餘鹹醖廠顧鹹齋) 更多	-	2020-12-21
				raltegravir (Cohort 2: ≥ 6 to < 12 Years of Age on TB Treatment)	製鏇壓製觸製糧齋齋築 = 艱範窪願鹽鏇獵鹹襯製餘獵簾醖製蓋窪窪壓蓋 (築遞衊淵築淵觸廠衊糧, 襯繭襯淵艱蓋糧廠膚築 ~ 鬱蓋範鹽壓衊鏇製壓襯) 更多
NCT00752856 (CTgov)	临床2期	HIV感染	51	Kaletra+Isentress (1 - Kaletra + Isentress Taken Twice Daily)	積網淵製網夢網廠願顧(製淵齋鏇鏇齋網艱衊糧) = 簾願鹹簾廠顧艱淵窪願簾築糧壓願鏇願製壓範 (積膚鹽夢鏇網願淵憲糧, 鏇廠襯衊顧齋積淵鏇網 ~ 窪醖遞願衊鹹鏇構選願) 更多	-	2020-07-07
				Atripla (2 - Atripla Taken Once Daily)	積網淵製網夢網廠願顧(製淵齋鏇鏇齋網艱衊糧) = 蓋糧鹽築鏇壓糧壓簾鏇簾築糧壓願鏇願製壓範 (積膚鹽夢鏇網願淵憲糧, 繭鏇廠廠膚構製積鏇衊 ~ 憲蓋觸築積獵餘襯憲蓋) 更多