This clinical trial aims to confirm the efficacy and safety of Vemlia® tablets (Tenofovir alafenamide) in liver transplant patients with hepatitis B, focusing on their effects on renal function.
HBV reactivation post-liver transplantation can result in a post-transplant mortality rate of up to 50% within two years, making prophylaxis critical. Currently, a combination therapy of HBIG and nucleotide analogues is commonly used. Among the nucleotide analogues (NA), entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are frequently used as first-line therapies. However, both ETV and TDF have nephrotoxicity, requiring caution in patients with chronic kidney disease. Specifically, 18% of liver transplant patients develop chronic kidney disease due to immunosuppressant use, making the appropriate use of antiviral drugs to preserve renal function crucial.
TAF has been reported through RCTs to be more effective than TDF in preserving renal function and bone density, while showing similar antiviral effects. However, these studies have been conducted exclusively on general chronic liver disease patients. Although multicenter studies have been reported for liver transplant patients, they were retrospective and involved a limited number of patients.
Therefore, the primary objective of this study is to assess the impact of converting to TAF on renal function preservation in liver transplant patients taking antivirals for HBV prophylaxis. The secondary objectives are to evaluate the antiviral effect on HBV, the impact on lipid profiles, and the effectiveness in preserving bone density.

开始日期2025-03-01

申办/合作机构

Samsung Medical Center

NCT05652478

/ Recruiting临床2期IIT

A Phase 2 Randomized Cross-Over Design Study of the Early Metabolic Effects of Dolutegravir or Tenofovir Alafenamide in Healthy Volunteers

Background:
People with HIV take drugs to keep the amount of virus in their body low. One type of these drugs, called integrase strand transfer inhibitors (INSTIs), can cause weight gain over time. Weight gain can cause diabetes, heart disease, and other serious issues. Researchers want to understand how INSTIs cause weight changes.
Objective:
To see how a common INSTI, dolutegravir (DTG), affects how the body uses energy. DTG will be compared with a non-INSTI drug, tenofovir alafenamide (TAF).
Eligibility:
Healthy people aged 18 to 55.
Design:
Participants will be screened. They will have a physical exam and blood tests. They will have a nutritional assessment and tests of their heart function.
Participants will have 2 inpatient stays at the clinic. Each stay will be for 11 nights, with a 3-week break between.
Both DTG and TAF are gel caps swallowed once per day by mouth. Participants will take 1 drug for 8 days during each stay.
Participants will have tests to see how their body uses energy:
They will spend 23 continuous hours in a special room that measures how much oxygen they breathe in and how much carbon dioxide they breathe out. They will do this a total of 6 times.
They will have a DEXA (dual-energy X-ray absorptiometry). DEXA is a kind of X-ray that measures body fat and bone density.
They will lie on a table. Electrodes will be placed on their hands and feet to measure body fat and lean body mass.
They will stand still on a platform for about 30 seconds. High-resolution laser cameras will scan their bodies.

开始日期2025-02-24

申办/合作机构

National Institute of Allergy & Infectious Diseases

NCT06338826

/ Not yet recruiting临床2期IIT

Interventional, Multicenter, Open-label, Randomized, Non-comparative Trial Evaluating the Safety, in Terms of HBV Virological Control At 96 Weeks, of 2 Antiviral Treatment Relief Strategies, in Patients Co-infected with the HIV-1 and HBV Viruses

The main objective of this study is to evaluate at 96 weeks the safety with respect to hepatitis B control of 2 treatment reduction strategies for patients with previously controlled HIV-HBV co-infection on continuous triple therapy

开始日期2025-02-01

申办/合作机构

ANRS, Emerging Infectious Diseases

100 项与富马酸丙酚替诺福韦相关的临床结果

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100 项与富马酸丙酚替诺福韦相关的转化医学

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100 项与富马酸丙酚替诺福韦相关的专利（医药）

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1,965

项与富马酸丙酚替诺福韦相关的文献（医药）

2025-12-31·HIV Research & Clinical Practice

Evaluation of the effect of 48 weeks of BIC/F/TAF and DRV/c/F/TAF on platelet function in the context of rapid ART start

Article

作者: Boffito, Marta ; Henderson, Merle ; Whitlock, Gary ; Khawaja, Akif A. ; Taylor, Graham P. ; Fidler, Sarah ; Soler-Carracedo, Alfredo ; Emerson, Michael

INTRODUCTION:

The BIC-T&T study aimed to determine the efficacy of bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF) and darunavir/cobicistat/emtricitabine/tenofovir alafenamide (DRV/c/F/TAF) at suppressing viral load in a two-arm, open-label, multi-centre, randomised trial under a UK test-and-treat setting. This sub-study aimed to evaluate potential off-target cardiovascular impact by examining ex vivo platelet function.

METHODS:

Platelets were isolated by centrifugation of citrated blood from participants attending Chelsea and Westminster Hospital or St Mary's Hospital at Week 48 following enrolment. Platelet activation was assessed by real-time flow cytometry to examine integrin activation and granule release and platelet aggregation was evaluated by light transmission aggregometry. Statistical significance was determined by 2-way ANOVA with a Šidák's multiple comparisons post-test.

RESULTS:

An analysis of 21 participants was performed at Week 48 (96% male and 48% white; mean (range) age was 37 (23-78) years). No difference between arms was observed in ADP-, collagen- or thrombin receptor activator for peptide (TRAP)-6-evoked platelet α_IIbβ₃ integrin activation, granule release or platelet aggregation in response to any of the agonists tested. Despite differences in the demographics between treatment arms, the presence of an unboosted integrase inhibitor or boosted protease inhibitor in a test-and-treat setting did not impact platelet function.

CONCLUSIONS:

Our study provides no evidence of differences in downstream platelet responses between participants taking BIC/F/TAF compared to DRV/c/F/TAF following 48 wk of treatment. Further data are required to explore whether there are biologically significant off-target effects, including effects on platelets and other components of the cardiovascular system between these two test-and-treat regimens.

CLINICAL TRIAL NUMBER:

NCT04653194.

2025-03-01·AIDS

Impact of switching from efavirenz/emtricitabine/tenofovir disoproxil fumarate to bictegravir/emtricitabine/tenofovir alafenamide on psychiatric symptoms and neurocognition

Article

作者: Vergori, Alessandra ; Esvan, Rozenn ; Grilli, Elisabetta ; Ottou, Sandrine ; Del Duca, Giulia ; Camici, Marta ; Gagliardini, Roberta ; Bellagamba, Rita ; Antinori, Andrea ; Paulicelli, Jessica ; Mazzotta, Valentina ; Lorenzini, Patrizia ; Plazzi, Maria Maddalena ; De Zottis, Federico ; Fusto, Marisa ; Brita, Anna Clelia ; Pinnetti, Carmela ; Mastrorosa, Ilaria

Objectives::

The aim was to investigate whether switching from efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/F/TDF) to bictegravir/emtricitabine/tenofovir alafenamide (BIC/F/TAF) may improve neuropsychiatric symptoms and neurocognition.

Design::

Pilot, single-arm, prospective study of persons with HIV (PWH) on the efficacy and safety of switching from EFV/F/TDF to BIC/F/TAF.

Methods::

Participants underwent neuropsychological assessment (NPA) at switch (T0) and after 48 weeks (T1). NPA was carried out through a standardized battery of 12 tests. Neurocognitive impairment (NCI) was defined by a score of at least 1 standard deviation (SD) below the normal mean on at least two tests or ≥2 SD below on one test. Individual z scores were determined, NPZ-12 was calculated as the average of 12 test z scores and change of NPZ-12 was the outcome. HIV-associated neurocognitive disorder (HAND) was classified by Frascati's criteria. Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI-II), and Pittsburgh Sleep Quality Index (PSQI) were administered. Paired-Wilcoxon and McNemar tests were used for comparisons, and logistic regression for associations with NCI changes.

Results::

Out of 126 participants, BAI, BDI-II, and PSQI questionnaires revealed an improvement at T1. NPA revealed NCI in 40.5% of persons at T0 and 42.1% at T1 (P = 0.746). Specifically, at T0, among participants with NCI, 35% improved; among those without, 26% worsened at T1; NPZ-12 score worsened at T1. 5.6% of ANI was observed at T0 and 7.9% at T1. No factor associated with these changes was found.

Conclusion::

Our results suggest switching from EFV/F/TDF to B/F/TAF significantly improves psychiatric symptoms and sleep quality. Neurocognitive performance remained stable, although a decline in NPZ-12 and in specific domains was observed.

2025-03-01·JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES

Pharmacokinetics and Safety of Bictegravir in Pregnant and Postpartum Persons With HIV and Their Infants

Article

作者: Best, Brookie M. ; Greene, Elizabeth ; Brooks, Kristina M. ; McMorrow, Flynn ; Momper, Jeremiah D. ; Browning, Renee ; Shapiro, David E. ; Eke, Ahizechukwu C. ; Agwu, Allison ; Huang, Xiaoying ; Topete, Lourdes ; Knowles, Kevin ; Pinilla, Mauricio ; Arora, Priyanka ; Stek, Alice ; Mirochnick, Mark ; Chakhtoura, Nahida ; Powis, Kathleen M.

Background::

Limited data exist on bictegravir pharmacokinetics in pregnancy among persons with HIV (PWH) and infant washout.

Setting::

Nonrandomized, open-label, multicenter phase-IV prospective study of bictegravir pharmacokinetics and safety in pregnant PWH and their infants.

Methods::

Steady-state 24-hour pharmacokinetic sampling of oral bictegravir 50 mg once daily (a component of fixed-dose combination bictegravir/emtricitabine/tenofovir alafenamide) during the second and third trimesters and postpartum was performed. Cord blood and infant washout samples were collected. Total and free bictegravir concentrations were measured by validated liquid chromatography with tandem mass spectrometry methods. Within-participant geometric mean ratios (GMR) with 90% confidence intervals (CI) were calculated to compare pharmacokinetics between second and third trimester versus postpartum. Infant HIV testing results were obtained.

Results::

Twenty-seven maternal–infant pairs were enrolled. Bictegravir area under the concentration–time curve from time 0 through 24 hours post-dose was 46% lower in the second trimester (n = 12; P = 0.002; GMR 0.54; 90% CI: 0.43 to 0.69) and 52% lower in the third trimester (n = 24; P < 0.0001; GMR 0.48; 90% CI: 0.43 to 0.55), compared with postpartum. C24 concentrations were above the estimated bictegravir protein-adjusted 95% effective concentration of 0.162 μg/mL. The median ratio of cord-to-maternal blood concentration was 1.38 (n = 17; quartiles: 1.17–1.63). Median T1/2 for infant bictegravir washout was 33.2 hours (quartiles: 25.7–45.9) with a Cmax of 2.06 μg/mL (quartiles: 1.37–2.72). Overall, 88%–92% of participants maintained suppression <40 copies/mL throughout pregnancy and postpartum. All available infant HIV testing results were negative. The safety profile for pregnant PWH and infants was acceptable.

Conclusions::

Bictegravir exposure was lower during pregnancy compared with postpartum, yet C24 concentrations were greater than the bictegravir protein-adjusted 95% effective concentration.

401

项与富马酸丙酚替诺福韦相关的新闻（医药）

2025-02-18

·行舟Drug

CDE老师文章 | 富马酸丙酚替诺福韦仿制药药学研究的一般考虑

点击上方的行舟Drug ▲ 添加关注作者：张歆，吴小飞，王宏亮（国家药品监督管理局药品审评中心）来源：《药学研究》2024年第12期摘要：近年来，以富马酸丙酚替诺福韦(tenofovir alafenaide fumarate，TAF)为代表的核苷(酸)类抗乙型肝炎药物仿制药申报获得广泛关注。本文通过对富马酸丙酚替诺福韦的理化性质、合成路线、质量研究、制剂的工艺特点等进行汇总整理，结合相关文献专利和审评经验，综合提出富马酸丙酚替诺福韦(TAF)药学研究的建议，旨在为后续研发提供一些参考。关键词：核苷(酸)类抗乙型肝炎药物；富马酸丙酚替诺福韦；仿制药英文摘要：略 1 常见核苷(酸)类抗乙型肝炎药物仿制药申报情况慢性乙型肝炎病毒(hepatitis B virus，HBV)感染是严重危害我国人民健康及国家经济发展的重要传染性疾病，是现阶段最为突出的公共卫生问题之一[1]。抗病毒是慢性乙型肝炎(chronic hepatitis B，CHB)患者治疗的关键，持续及充分抑制乙肝病毒的复制是治疗的核心。根据各大指南的推荐，口服核苷(酸)类似物[nucleos(t)ide analogues，NAs]已成为治疗CHB的主流药物，其主要通过抑制乙肝病毒的反转录和DNA合成发挥抗病毒作用[2]。根据中华医学会肝病学会于2022年更新的《慢性乙型肝炎防治指南(2022年版)》，以恩替卡韦(ETV)、富马酸替诺福韦二吡呋酯(TDF)和富马酸丙酚替诺福韦(TAF)等为代表的核苷(酸)类似物因其强效、低耐药等优点而成为我国治疗CHB的主流药物[3]。恩替卡韦(ETV)是由美国百时美施贵宝公司在20纪90年代研制开发的一种强效选择性鸟嘌呤核苷类似物，具有显著的抗乙型肝炎病毒的活性，于2005年被FDA批准上市，有普通片、分散片、胶剂等多种剂型。替诺福韦是由Gilead公司开发的开环膦酸核苷类化合物，具有良好的抗乙型肝炎病毒活性，但因其无法经消化道吸收而影响药效的发挥，因此将替诺福韦制备成前体药物TDF或TAF后口服给药[4]。TDF是替诺福韦的第一代口服前体药物，在替诺福韦基础上加二吡呋酯基，在体内吸收后被降解成为替诺福韦，后转变为活性代谢产物替诺福韦双磷酸盐，发挥抗病毒作用，TDF于2008年被EMA和FDA分别批准用于治疗成人慢性乙型肝炎，于2013年被CFDA批准用于CHB患者的抗病毒治疗。TAF是替诺福韦的第二代口服前体药物，在已上市的TDF结构的基础上变换了磷酸中两个羟基上的前药基团，即将二吡呋酯变换为一个酰胺和一个苯酚酯，是一种酯化酰胺化前药。该改构克服了TDF在血浆中不稳定、易被酯酶水解的缺点，进而提高了替诺福韦至肝细胞、外周血单核细胞(PBMC)和淋巴器官的递送率，达到了明显的减毒增效的效果，其有效剂量比TDF低约25倍。作为TDF的改良，TAF仅用十分之一的用药量就能达到相同的疗效，而且抗病毒疗效更强，不良反应有所减轻，研究表明，TAF的靶向性、安全性、血浆稳定性都优于TDF[5]。经检索国家药品监督管理局(NMPA)药品审评中心公开的受理品种目录[6]，笔者简要整理了我国2021—2023年常见核苷(酸)类抗乙型肝炎药物仿制药品申报受理情况(见表1)，由受理情况可知，以 TAF为代表的核苷(酸)类抗乙型肝炎药物仿制药申报获得广泛关注，笔者结合药物特点、相关文献专利、品种特点和审评经验，综合提出TAF药学研究的建议，旨在为后续的研发提供一些参考。 2 富马酸丙酚替诺福韦原料药药学研究探讨 2.1 合成路线的研究有关TAF的合成路线中外均有报道。部分相关文献报道的合成路线以吉利德公司原研专利文献为基础，以腺嘌呤为起始原料，经与R-碳酸丙烯酯缩合后再与甲苯磺酸盐试剂发生取代反应并经水解生成替诺福韦(PMPA)，经酯化反应生成PMPA单苯酯，经氯代后与L-丙氨酸异丙酯盐酸盐发生磷酰胺化反应生成丙酚替诺福韦，再经成盐制成终产品[8]。起始物料是原料药分子结构的重要组成部分。同时，工艺路线的长短及工艺过程能力是衔接起始物料与终产品质量的重要桥梁[9]。如果起始物料结构比较复杂，后续生产工艺需要的杂质清除能力和相关风险随之增加[10]。TAF有3个手性中心，其异构体较多，而PMPA作为TAF的结构片段，其复杂的化学结构涉及了手性中心的构建，且PMPA并非已获批原料药，如果以PMPA作为起始物料则意味着PMPA的合成无需在CMP条件下进行，且生产过程可能没有充分的杂质控制策略，这将增加后续工艺对终产品杂质控制的风险[10]。因此，为降低起始物料对原料药杂质产生较大影响，建议选择腺嘌呤作为TAF的起始物料。同时，建议结合起始物料生产商出具的制备工艺对起始物料可能含有的有机杂质、潜在致突变杂质、无机杂质、元素杂质、残留溶剂等进行分析和研究，并根据对后续工艺和终产品质量的影响对起始物料的杂质进行必要的控制。如所选起始物料的手性中心引入至原料药TAF的结构中，建议关注起始物料的手性研究，加强对该起始物料光学纯度的控制。选择起始物料时，建议参考ICH Q11，选择合理的起始原料，合成路线应包括TAF手性中心的构建。同时，建议关注起始物料供应商的长期商业化供货能力，加强起始原料供应商审计、起始物料的控制、中间体的控制等。 2.2 结构确证研究 TAF含有3个手性中心，建议对其平面结构、立体构型及成盐比进行全面研究。平面结构确证可采用元素分析、质谱、IR、UV、核磁共振谱、热分析、X射线粉末衍射等方法；成盐比可通过对富马酸含量的测定进行确认；立体构型可通过X射线单晶衍射进行确认；也可综合比旋度、与法定对照品进行手性对比研究、结合起始物料的构型及合成机理分析等予以确证。 2.3 原料药的杂质分析不同制备方法引入的工艺杂质可能不同。仿制药研发应结合产品的合成路线、起始原料以及降解途径，对可能存在于起始原料中杂质在后续反应中的衍生物、起始原料和中间体残留、副产物、降解质等进行全面分析和研究。 TAF有3个手性中心(RSS)，理论上可以产生3对非对映异构体和1个对映异构体，建议结合工艺路线对手性杂质的来源进行分析，分阶段对多个手性杂质进行控制，在工艺过程中除监测对映异构体外，还应研究和监控非对映异构体[14]。除关注起始物料引入的手性杂质外，还应通过工艺控制在磷上产生的异构体杂质。对于潜在致突变杂质，建议对起始原料和生产工艺中可能引入的潜在致突变杂质进行分析和研究，结合研究结果，按照ICH M7拟定合理的控制策略。 3 富马酸丙酚替诺福韦片药学研究探讨在保证仿富马酸丙酚替诺福韦原料药质量控制符合要求的基础上，进行仿制制剂的药学研发相对更容易成功。目前富马酸丙酚替诺福韦在国内外仅有普通片剂上市。 3.1 理化性质研究在进行制剂药学研究时原料药的关键理化性质对制剂研究有重要影响，尤其是原料药的粒度控制。无论原料药BCS分类如何，粒度作为影响产品的质量的因素之一，均应该进行必要的评估和论证[11]。根据EMA相关审评报告[12]，TAF为BCS 3类药物。在制剂研究中，建议关注原料药粒径对制剂生产及制剂溶出行为的影响，根据原料药粒度分布对制剂的影响研究结果对原料的粒径进行合理控制。固体药物不同品型理化性质的差异会对药物的生产、临床使用及安全性等方面造成不同的影响。因此，药物生产制备的过程中晶型的选择对于品型药物的研发有十分重要的意义。根据文献调研及原研专利信息[13]，TAF存在多晶型现象，非溶剂化无水晶型(Ⅰ型)为热力学稳定形式，晶型Ⅱ在干燥条件下去溶剂化形成晶型Ⅰ。在原料药工艺开发中建议关注结晶溶剂和条件的筛选，并采用中试及以上规模样品对晶型的批间一致性及稳定性进行研究。在制剂工艺开发中，建议对原料的晶型在制剂制备及稳定性研究中是否发生转晶进行考察。 3.2 处方工艺研究化学药品仿制药的研发，可在对参比制剂充分调研的基础上，确定目标产品质量概况( quality target product profile，QTPP)和 CQAs。根据富马酸丙酚替诺福韦片原研相关文献和欧盟CHMP审评报告[12]，原研处方中包含的辅料有乳糖、微晶纤维素、交联羧甲基纤维素钠、硬脂酸镁及薄膜包衣预混剂。进行富马酸丙酚替诺福韦片仿制药处方研究时，建议以相关的专利文献为基础，重点对所选辅料的种类、用量、加入方式进行讨论，并将降解产物、溶出行为等关键质量属性作为评估指标，最终所选处方应有充分的数据作为支持[11]。各辅料用量应在其每日安全用量范围内，原辅料相容性应符合要求。关于工艺方面，应对过程控制方法和中间体的控制标准进行全面研究，明确关键工艺步骤、工艺参数及其制定依据，关注工艺验证中关键工艺参数的验证情况。除了上述的常规工艺研究外，还有以下考虑富马酸丙酚替诺福韦原料对热相对不稳定，仿制制剂如采用湿法制粒工艺，建议关注制剂在生产制备过程中的稳定性，以及对干燥后颗粒水分的控制。仿制制剂如采用干法制粒工艺，一般会存在颗粒或粉末形式的中间体，粉末和颗粒的粉体力学性质如流动性、颗粒的分布等，常常会进一步影响到后续压片产品的均一性[11]，建议对干法制粒所得颗粒的粒度分布、粉体密度、休止角等粉体学性质对压片过程可压性以及制剂溶出行为的影响进行研究，根据研究结果增加对中间体的控制。另外，如富马酸丙酚替诺福韦片主药含量小于单剂重量的25%，建议重点关注其混合工艺对含量均匀度的影响，对混合均匀度进行研究，在工艺验证中对总混粉的含量均勾度进行验证，必要时根据验证结果在中间体颗粒增订混合均匀度的控制。 3.3 制剂的杂质分析《中国药典》尚未收载富马酸丙酚替诺福韦片剂标准。建议结合制剂的处方工艺、降解途径等对富马酸丙酚替诺福韦片制备过程中可能引入杂质以及降解杂质进行全面分析。在杂质谱分析的基础上，采用相应的杂质对照品对分析方法进行系统的方法学验证，以证明所用的分析方法确实能有效地检出相应的杂质。非特定杂质限度应符合ICH Q3B的规定。同时，TAF原料药含伯胺结构，如处方中使用了乳糖，建议对潜在美拉德反应所产生的乳糖加合物进行研究和控制。此外，应根据ICH Q3D的规定，通过科学和基于风险的评估来确定制剂中元素杂质的控制策略，包括原辅包、生产设备等可能引人的元素杂质。 4 结语富马酸丙酚替诺福韦作为替诺福韦的第二代口服前体药物，因其强效、低耐药等优点而成为我国治疗CHB的主流药物，近年来在国内抗乙型肝炎药物仿制药市场获得广泛关注。对于富马酸丙酚替诺福韦原料药及片剂的研发，建议在充分调研国内外相关文献资料的基础上，结合富马酸丙酚替诺福韦自身特性提出科学的质量控制策略，确保仿制药工艺稳健性和质量可控性。参考文献：略本文引用方式：张歆,吴小飞,王宏亮.富马酸丙酚替诺福韦仿制药药学研究的一般考虑[J].药学研究,2024,43(12):1200-1202,1219. 本文链接：http://www.yaoxueyanjiu.org.cn/ch/reader/view_abstract.aspx?file_no=202412011&flag=1 文章信息源于药学研究，登载该文章目的为更广泛的传递行业信息，不代表赞同其观点或对其真实性负责。文章版权归原作者及原出处所有，文章内容仅供参考。本网拥有对此声明的最终解释权，若无意侵犯版权，请联系小编删除。学如逆水行舟，不进则退；心似平原走马，易放难收。行舟Drug 每日更新欢迎订阅+ 医药大数据|行业动态|政策解读

上市批准

2025-02-18

·Pharmaceutical Technology

Gilead’s lenacapavir moves closer to FDA approval for HIV PrEP use

If approved, lenacapavir would be the first twice-yearly HIV prevention choice. Credit: Ulrich Baumgarten via Getty Images. Gilead is edging closer to an approval for its twice-yearly injectable human immunodeficiency virus-1 (HIV-1) capsid inhibitor, lenacapavir, as a pre-exposure prophylaxis (PrEP) option. The US Food and Drug Administration (FDA) has accepted Gilead’s new drug application (NDA) for lenacapavir and set a prescription drug user fee act (PDUFA) target action date of 19 June 2025. Lenacapavir is already approved under the name Sunlenca as an HIV treatment for patients resistant to other medication options. Gilead is a major player in the HIV and AIDS research space and currently markets several HIV treatments, including Biktarvy (bictegravir /emtricitabine/tenofovir alafenamide) and Descovy (emtricitabine/tenofovir). These drugs pulled in $15.5bn in sales for Gilead in 2024, as announced by the company earlier this month. Gilead is also planning its broader access strategy for lenacapavir as PrEP. In the 18 February announcement, the company said it submitted a marketing authorisation application to the European Commission and an EU-Medicines for All (EU-M4all) application to the European Medicines Agency (EMA). The EU-M4all procedure is designed to support regulatory pathways in low- and lower-middle-income countries by allowing national authorities to use the EU opinion to accelerate their own review processes, potentially expediting access to lenacapavir for PrEP in these regions. A twice-yearly injectable PrEP option like lenacapavir could offer significant advantages over the commonly used daily oral PrEP options, like Gilead’s Truvada (emtricitabine/tenofovir), particularly in terms of adherence and accessibility, said Linda-Gail Bekker, director of the Desmond Tutu HIV Center at the University of Cape Town, South Africa, in a previous announcement. “While we know traditional HIV prevention options are highly effective when taken as prescribed, twice-yearly lenacapavir for PrEP could help address the stigma and discrimination some people may face when taking or storing oral PrEP pills, as well as potentially help increase PrEP adherence and persistence given its twice-yearly dosing schedule,” Bekker stated. The FDA’s review is based on data from the Phase III PURPOSE 1 and PURPOSE 2 trials conducted by Gilead. PURPOSE 1 (NCT04994509) showed zero HIV infections in the lencapavir group, indicating a 100% risk reduction compared to background HIV incidence (bHIV) among cisgender women. PURPOSE-2 (NCT04925752) reported two HIV infections in the lenacapavir group, translating to a 96% risk reduction. The drug also demonstrated superior efficacy over Gilead’s daily oral PrEP option Truvada (emtricitabine/tenofovir). Researchers have long spoken about ending the HIV/AIDS crisis. The World Health Organization (WHO) has a 2022–2030 global health sector strategy on HIV, which aims to reduce HIV infections from 1.5 million in 2020 to 335,000 by 2030, and deaths from 680,000 in 2020 to under 240,000 in 2030. In May 2024, a group of public figures, scientists, medical professionals, and celebrities called on Gilead to improve access to HIV drugs in low- and middle-income countries (LMICs). In October 2024, Gilead Sciences announced that it had signed voluntary licensing agreements with six generic pharmaceutical manufacturers to expand access to lenacapavir in 120 resource-limited and high-incidence countries.

临床3期临床结果引进/卖出申请上市上市批准

2025-02-14

·医药地理

新增4款！2024全球百亿美元畅销药榜单大洗牌

随着各大药企财报纷纷出炉，2024年共有12款药物登上百亿美元畅销药的榜单，总体数量相比2023年新增了2款。从整体情况来看，共有4款药物在2024年首次销售额突破百亿美元，成为新的超级重磅炸弹产品，分别是TOP 4礼来的替尔泊肽（164.66亿美元）、TOP 8艾伯维的利生奇珠单抗（117.18亿美元）、TOP 9强生的达雷妥尤单抗（116.7亿美元）、TOP 11 Vertex的Trikafta（102.39亿美元）；与2023年对比，艾伯维的阿达木单抗和辉瑞COMIRNATY疫苗跌出榜单，2024年销售额分别为89.93亿美元（-37.6%）和53.53亿美元（-52.3%）。表：2024年百亿美元畅销药排行榜来源：各大药企财报，中国医药工业信息中心整理表：2023年百亿美元畅销药排行榜从治疗领域来看，这12款药品分布在肿瘤（3）、代谢（3）、自免（3）、心血管（1）、抗病毒（1）以及罕见病（1）等领域。肿瘤领域肿瘤领域的3款产品均为抗体大分子，分别是2款PD-1抗体和1款CD38抗体。帕博利珠单抗 TOP 1 2023年的药王Keytruda（帕博利珠单抗）营收高达294.82亿美元，同比增长18%，其销售额约占默沙东全年总营收的46%，成功卫冕2024年的全球药王。其增长主要源于全球范围内对转移适应症的需求持续强劲，包括新增膀胱癌、子宫内膜癌适应症以及包括三阴性乳腺癌和非小细胞肺癌等在内的早期适应症。不过，K药的部分关键专利将在2028年到期，生物类似药的涌入和国产PD-1的“出海”都将蚕食其市场份额。达雷妥尤单抗 TOP 9 强生的达雷妥尤单抗（Darzalex）作为治疗多发性骨髓瘤的靶向CD38单抗，2024年全球销售额达116.70亿美元，同比增长19.8%，首次突破百亿美元大关。达雷妥尤单抗的组合物专利将于2026年3月到期，国内药企中，正大天晴、复宏汉霖、九源基因都有在研的生物类似药。表：达雷妥尤单抗生物类似药竞争格局来源：Pharma ONE药物研发大数据分析平台纳武利尤单抗 TOP 12 2024年，BMS的Opdivo（纳武利尤单抗）销售收入93.04亿美元，加上来自小野制药的8.40亿美元，总销售额达到101.44亿美元。纳武利尤单抗目前已在包括美国、欧盟、日本和中国在内的超过65个国家和地区获得批准上市，涵盖12个瘤种，包括肺癌、头颈癌、胃癌、食管癌、肝癌、肾癌、结直肠癌、尿路上皮癌、黑色素瘤、霍奇金淋巴瘤、胸膜肿瘤、不明原发部位肿瘤。纳武利尤单抗的专利将于2028年到期，BMS正通过推出皮下制剂等方式延长产品生命周期。2024年12月28日，FDA批准了Opdivo皮下注射剂Opdivo Qvantig（nivolumab加透明质酸酶）上市，用于所有已批准的Opdivo适应症，意味着Opdivo成为全球首款获批上市的PD-1皮下制剂。代谢领域代谢领域的3款产品包含2款GLP-1类多肽和1款SGLT2抑制剂小分子。司美格鲁肽 TOP 2 2024年司美格鲁肽大卖 292.96亿美元，占到了诺和诺德总营收的约69.5%。其中，Ozempic （降糖注射版）销售额为1203.42亿丹麦克朗，约为174.66亿美元（+26%）；Rybelsus（降糖口服版）销售额约为33.82亿美元（+26%）；Wegovy（减重版）销售额约为84.48亿美元（+86%）。三款产品中，Wegovy带来了核心增长动力，增幅高达87%。司美格鲁肽在中国的核心序列专利将于2026年3月到期，势必会有一大批生物类似药上市，抢夺这一巨大的市场份额，据Pharma ONE药物研发数据库统计，截至目前，已有近20家企业的司美格鲁肽生物类似药加入战局，其中丽珠医药、杭州九源、珠海联邦的产品均已处于注册申请阶段。表：司美格鲁肽生物类似药竞争格局来源：Pharma ONE药物研发大数据平台替尔泊肽 TOP 4 降糖版替尔泊肽Mounjaro在2024年的销售额突破百亿美元大关，达到115.401亿美元，同比增长124%。与此同时，减重版替尔泊肽Zepbound也贡献了49.257亿美元的收入。两款药物销售额合计164.66亿美元，占礼来全年总收入的约36%。 2024年12月，礼来公布了随机、开放标签3b期临床试验SURMOUNT-5研究的topline结果。在 SURMOUNT-5 研究的主要终点中，替尔泊肽实现了平均减重比例达 20.2%，显著优于司美格鲁肽的 13.7%，相对体重减轻倍数达到司美格鲁肽的 1.47 倍，全面超越司美格鲁肽（semaglutide）。恩格列净 TOP 7 2024年全年，礼来/BI的恩格列净（Jardiance）的销售额预计达到118亿美元。恩格列净属于SGLT2抑制剂药物类别，通过阻止肾脏重吸收葡萄糖，从而增加尿液中的葡萄糖排泄，帮助控制血糖水平。恩格列净主要用于成年2型糖尿病患者的血糖控制，尤其是在饮食和运动改善血糖控制不足时。此外，它还被用于降低心血管疾病风险，特别是对于有心血管疾病史的患者。恩格列净的中国化合物专利原本应在2025年到期，但已被科伦药业、豪森药业、华东医药等药企无效。目前国内已有20余款恩格列净仿制药获批上市。据PDB数据库统计，恩格列净占据了SGLT2抑制剂中国公立二三级医院10%左右的市场份额，从具体企业来看，除了原研药，科伦的恩格列净仿制药在2024前三季度卖的最好，销售额为1.35亿元人民币。图：2024Q1-Q3 SGLT2抑制剂国内公立二三级医院市场份额占比来源：PDB数据库，国内院端放大图：2024Q1-Q3 各个企业恩格列净产品国内公立二三级医院销售额来源：PDB数据库，国内院端放大自免领域自免领域的3款产品均为抗体大分子。度普利尤单抗 TOP 5 2024年，度普利尤单抗的全球销售额达到了130.72亿欧元（约141.79亿美元），同比增长23.1%，成为全球自身免疫药物市场的销冠。度普利尤单抗是再生元与赛诺菲联合研发的全球首款靶向IL-4Rα的药物，2017年3月，获FDA批准用于治疗成人中重度特应性皮炎（AD），商品名为 Dupixent®，是FDA批准的首个治疗AD的生物制品。此后，度普利尤单抗逐步扩大其适应症版图，接连获批哮喘、慢性鼻窦炎伴鼻息肉、嗜酸性粒细胞性食管炎、结节性痒疹、慢性自发性荨麻疹以及慢阻肺等一系列适应症，销售额亦节节攀升。目前，度普利尤单抗正在冲刺慢性自发性荨麻疹和大疱性类天疱疮适应症。度普利尤单抗的成功也带动了赛诺菲公司整体业绩的增长，成为公司的重要支柱产品。度普利尤单抗于2020年6月在国内获批，用于成人中重度特应性皮炎的治疗，并于当年12月底通过国家医保谈判，被正式列入2020国家医保目录，此后在国内销售额年年递增。据中国医药工业信息中心PDB数据库统计，2024年前三季度普利尤单抗在全国公立二三级医院销售额约为18.78亿元人民币。图：2020-2024 Q3度普利尤单抗全国公立二三级医院销售额来源：PDB数据库，国内院端放大 2024年9月12日,国家药监局批准康诺亚研发的司普奇拜单抗（CM310）上市。这是国产首款获批的IL-4R抗体药物，也是继度普利尤单抗后的全球第二款。此外，度普利尤单抗专利预计在2028年到期，相关生物类似药亦有药企开始布局，2024年8月31日，百奥泰生物的度普利尤单抗生物类似药（BAT2406）宣布收到国家药监局核准签发的《药物临床试验批准通知书》，成为国内首家进入临床的度普利尤单抗生物类似药。利生奇珠单抗 TOP 8 2024年，艾伯维的Skyrizi（利生奇珠单抗）销售额达到117.18亿美元，同比增长50.9%，在TOP 12产品中增速排名第二，成为艾伯维继Humira之后的又一重磅产品。 Skyrizi作为一种白细胞介素-23（IL-23）抑制剂，可通过与IL-23 p19亚基结合来选择性阻断IL-23。IL-23是一种参与炎症过程的细胞因子，被认为与许多慢性免疫介导疾病有关。 Skyrizi于2019年首次进入全球市场，目前已斩获包括斑块状银屑病、银屑病关节炎、克罗恩病、泛发性脓疱型银屑病以及红皮病型银屑病、溃疡性结肠炎等多项适应症。乌司奴单抗 TOP 10 2024年，强生的乌司奴单抗（Stelara）因生物类似药冲击，收入同比下降4.6%，为103.61亿美元。乌司奴单抗是一款靶向IL-12和IL-23共有的p40亚基的单抗，由强生研发，其作用机理为阻断IL-12和IL-23共有的p40亚基与靶细胞表面的IL-12Rβ1受体蛋白的结合，从而抑制IL-12和IL-23介导的信号传导和细胞因子级联反应。IL-12和IL-23是两种天然存在的细胞因子，在免疫介导的炎症性疾病中发挥着关键作用。乌司奴单抗专利已于2023年9月到期，全球范围内已有多款生物类似药获批上市，2024年11月5日，华东医药股份有限公司全资子公司杭州中美华东制药的乌司奴单抗注射液（赛乐信®）获NMPA批准上市，用于治疗成年中重度斑块状银屑病，成为国内首个获批的乌司奴单抗注射液生物类似药。此外，国内药企中，白奥泰生物、石药、迈博药业、伊甸生物均有产品争夺这一市场。表：乌司奴单抗生物类似药竞争格局来源：Pharma ONE药物研发大数据平台心血管领域阿哌沙班 TOP 3 Eliquis（阿哌沙班）扛起BMS的业绩大旗，2024年创造了133.33亿美元（+9%）的收入。不过，其核心专利将于2026年到期。 Eliquis是一种由Bristol-Myers Squibb和Pfizer联合开发的口服抗凝血药物，它是一种选择性凝血因子Xa抑制剂，用于预防和治疗血栓形成，减少中风和全身性栓塞的风险。抗病毒领域 Biktarvy TOP 6 吉利德公司在HIV治疗领域通过其多样化的产品组合维持着行业的领先地位。特别是其主打产品Biktarvy——一种包含比克替拉韦、恩曲他滨和丙酚替诺福韦的复合药物。2024年，该药物的销售额为134.23亿美元，同比上一年增长14%，在美国市场中占据了50%的份额。 2018年2月，Biktarvy获得FDA批准上市，销售额持续增长，并在2022年首次超过了100亿美元大关。Biktarvy于2020年1月11日在中国获批上市，并纳入了医保范畴，为患者提供了新的治疗选择。罕见病领域 Trikafta TOP 11 福泰制药（Vertex）的Trikafta是治疗罕见病囊性纤维化(CF)的药物， 2024上半年，Trikafta营收49.33亿美元，同比增长13.74%。该药是一种复方制剂，由Elexacaftor、Tezacaftor和Ivacaftor三种活性成分组成，其中Elexacaftor和Tezacaftor均为囊性纤维化跨膜传导调节蛋白（CFTR）矫正剂，Ivacaftor为CFTR强化剂。囊性纤维化（Cystic Fibrosis,CF）是一种遗传性外分泌腺疾病，主要影响胃肠道和呼吸系统，通常具有慢性梗阻性肺部病变、胰腺外分泌功能不良和汗液电解质异常升高的特征。囊性纤维化的发病率因国家、种族而异，中国CF基因携带频率为1/167~190之间，患病率约为12万分之一。 END 如需获取更多数据洞察信息或公众号内容合作，请联系医药地理小助手微信号：pharmadl001

财报专利到期疫苗生物类似药上市批准

100 项与富马酸丙酚替诺福韦相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10605	富马酸丙酚替诺福韦	J05AF13	DB09299

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
病毒感染	中国	Gilead Sciences Ireland UC	2019-05-09
慢性乙型肝炎	美国	Gilead Sciences, Inc.	2016-11-10
肝病	美国	Gilead Sciences, Inc.	2016-11-10
HIV感染	加拿大	Gilead Sciences Canada, Inc.	-

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
疲劳	临床2期	美国	Gilead Sciences, Inc.	2022-09-15
复发-缓解型多发性硬化	临床2期	美国	Gilead Sciences, Inc.	2022-09-15
获得性免疫缺陷综合征	临床2期	美国	Gilead Sciences, Inc.	2019-04-01
线粒体细胞病变	临床2期	美国	Gilead Sciences, Inc.	2019-04-01
乙型肝炎	临床1期	美国	Gilead Sciences, Inc.	2014-12-22
乙型肝炎	临床1期	德国	Gilead Sciences, Inc.	2014-12-22
乙型肝炎	临床1期	新西兰	Gilead Sciences, Inc.	2014-12-22

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临床结果

适应症

分期

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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


NEWS 人工标引	N/A	慢性乙型肝炎	130	TMF	餘廠襯獵鹽積簾廠鏇網(艱範構積壓餘觸憲糧範) = 築獵遞觸壓積膚襯鹽遞簾願構衊餘憲衊鑰憲網 (網遞蓋繭鑰選憲顧壓襯 ) 更多	积极	2024-11-18
				TAF	餘廠襯獵鹽積簾廠鏇網(艱範構積壓餘觸憲糧範) = 構鹹顧窪蓋製淵構鏇築簾願構衊餘憲衊鑰憲網 (網遞蓋繭鑰選憲顧壓襯 ) 更多
NCT04850950 (Pubmed \| Am J Gastroenterol)	临床4期	乙型肝炎 HBV DNA	239	Expected Eight-Week Prenatal Tenofovir Alafenamide Prophylaxis	壓糧廠顧積獵鏇選簾憲(餘夢簾齋餘範獵獵鹹壓) = 構壓獵膚鹽憲獵製鏇觸憲願積襯壓選獵觸範壓 (鑰鏇壓顧鏇壓憲築築鏇, 4.5% ~ 11.1) 更多	积极	2024-10-09
				Expected Twelve-Week Perinatal Tenofovir Alafenamide Prophylaxis	膚膚鑰醖鏇餘襯簾鹽蓋(鏇醖願蓋鏇糧簾醖衊網) = 廠鏇觸鬱獵鏇簾窪蓋築廠範築積願鹹構艱鹹鑰 (衊製範糧鏇鹹淵鬱襯遞 )
NCT01940471 \| NCT01940341 (Pubmed \| Aliment Pharmacol Ther) 人工标引	临床3期	慢性乙型肝炎	1,298	tenofovir alafenamide (TAF8y)5 mg/day	遞網範積淵衊壓遞窪齋(觸壓築鹽鹹襯構繭獵鏇) = remained stable in patients receiving double-blind/OL TAF, with only small declines at year 8. Decreases in BMD observed during double-blind TDF improved after switching to OL TAF 壓壓網鹽襯獵鏇構鬱衊 (糧醖製積鹹廠顧糧製鬱 )	积极	2024-09-27
				Tenofovir disoproxil fumarate (TDF2y)00tenofovir alafenamide (TAF6y
NCT04937881 (PrEP-PP PK, CTgov)	临床3期	HIV感染	39	Tenofovir Alafenamide (TAF Arm)	淵艱鑰鹹艱製憲鹹鬱蓋(鹽廠繭夢醖蓋願壓範壓) = 鏇繭醖廠構鑰積鹽鏇膚網築夢衊廠襯遞構繭選 (憲膚鏇築襯襯鏇鹹齋鑰, 醖窪艱簾廠鏇遞夢製衊 ~ 艱鬱夢醖蓋觸顧憲鬱膚) 更多	-	2024-09-03
				Tenofovir Disoproxil Fumarate (TDF Arm)	淵艱鑰鹹艱製憲鹹鬱蓋(鹽廠繭夢醖蓋願壓範壓) = 艱餘構餘廠築鑰觸遞淵網築夢衊廠襯遞構繭選 (憲膚鏇築襯襯鏇鹹齋鑰, 鑰醖鑰製鬱醖顧遞構襯 ~ 積夢製顧夢衊夢餘壓鹹) 更多
NCT03180619 (Pubmed)	临床2期	慢性乙型肝炎 \| 肝功能不全 \| 肾功能不全	124	Tenofovir alafenamide 25 mg	鏇壓選獵艱顧壓範窪餘(壓範壓選網艱繭獵廠衊) = occurred in 20 (22%) part A participants and in ten (32%) part B participants; none were related to treatment 願製齋鹽醖遞繭範壓觸 (壓壓齋醖製廠鹹衊鏇蓋 ) 更多	积极	2024-08-01
NCT03695029 (Pubmed \| Liver Int) 人工标引	临床4期	乙型肝炎	131	Tenofovir alafenamide (TAF)	鏇鏇鹽壓夢艱淵願積糧(膚夢簾範鑰網餘壓艱築) = 鏇簾鬱鹽糧衊構鹹網餘膚夢選鏇鑰衊鏇糧齋壓 (製壓簾糧築鏇壓願餘淵 ) 更多	积极	2024-06-01
				Tenofovir disoproxil fumarate (TDF)	鏇鏇鹽壓夢艱淵願積糧(膚夢簾範鑰網餘壓艱築) = 獵鹹膚獵艱齋憲鑰襯鹹膚夢選鏇鑰衊鏇糧齋壓 (製壓簾糧築鏇壓願餘淵 ) 更多
NCT03887702 (CTgov)	临床3期	乙型肝炎 \| 恶性实体肿瘤	4	Tenofovir Alafenamide+Tenofovir Disoproxil Fumarate+Entecavir (Arm 1 (TAF, TDF, Entecavir: Prophylactic))	鏇築選顧選鑰鏇餘窪夢(淵糧製簾蓋繭顧餘襯襯) = 願顧製鏇觸積膚淵齋繭醖簾鹹範齋衊範窪繭遞 (餘廠襯製遞築製繭衊膚, 鏇鹹築糧鏇遞網構製鹹 ~ 鏇餘構齋蓋獵遞餘糧餘) 更多	-	2024-05-20
				Tenofovir Alafenamide+Tenofovir Disoproxil Fumarate+Entecavir (Arm 2 (TAF, TDF, Entecavir: Upon Indication))	鏇築選顧選鑰鏇餘窪夢(淵糧製簾蓋繭顧餘襯襯) = 網範餘構繭顧顧製衊壓醖簾鹹範齋衊範窪繭遞 (餘廠襯製遞築製繭衊膚, 鑰製鹽鹽獵憲襯鑰餘衊 ~ 襯鹽選簾淵膚鹽觸糧鏇) 更多
DDW2024	N/A	慢性乙型肝炎	-	Tenofovir Alafenamide (TAF)	齋糧鑰醖淵願顧夢製餘(膚構襯窪繭餘構願選顧) = 觸壓鹽壓衊齋選獵鹹艱糧壓艱蓋襯繭餘鑰夢網 (襯鬱鏇築鏇顧範範壓獵 )	-	2024-05-18
				Tenofovir Disoproxil Fumarate (TDF)	齋糧鑰醖淵願顧夢製餘(膚構襯窪繭餘構願選顧) = 構襯膚衊糧築鹹糧鏇衊糧壓艱蓋襯繭餘鑰夢網 (襯鬱鏇築鏇顧範範壓獵 )
DDW2024	N/A	慢性乙型肝炎	-	Tenofovir therapy (TAF)	遞觸積選繭壓顧鏇構鏇(窪窪範製簾醖憲築築顧): RR = 4.76 (95% CI, 2.13 ~ 10.64), P-Value = 0.0001 更多	-	2024-05-18
				Entecavir therapy (ETV)
NCT04006704 (Pubmed)	临床1期	HIV感染	24	Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed-dose combination (FDC) tablets	窪夢窪鏇鹽壓艱鬱窪願(膚觸憲繭壓構製願襯襯) = 鏇淵願願觸鏇範衊鹹鑰鹽積餘構獵獵蓋襯夢範 (衊襯醖窪糧鏇繭蓋衊顧 ) 更多	-	2024-04-01
				Placebo tablets	窪夢窪鏇鹽壓艱鬱窪願(膚觸憲繭壓構製願襯襯) = 網艱選繭衊顧窪顧範齋鹽積餘構獵獵蓋襯夢範 (衊襯醖窪糧鏇繭蓋衊顧 ) 更多