Elbasvir/Grazoprevir

点评 | 王平（同济大学）、胡荣贵（中科院上海生命科学研究院）在生物化学研究和现代药物开发领域，靶向蛋白质降解（Targeted Protein Degradation, TPD）技术不仅为调控生物体内特定蛋白质的活性和丰度提供全新的研究手段，而且通过利用细胞自身的蛋白质降解机制来识别并降解疾病相关的靶蛋白，为癌症和神经退行性疾病等多种疾病治疗提供了新的治疗策略【1,2】。目前，TPD技术主要以小分子降解剂（PROTACs）或降解子系统（Degron）为主，这些技术虽然能够有效降解靶蛋白，但它们也面临一些挑战：例如PROTACs技术面临药物筛选流程的复杂性、构建可控PROTACs必须进行的化学基团修饰引起分子量增加，以及潜在的药物毒性问题。另外，Degron系统需要对靶蛋白进行特定的预先修饰，这极大地限制了靶向内源蛋白质降解技术在生物医学领域的广泛应用。针对上述问题，2024年3月12日，华东师范大学生命科学学院、上海市调控生物学重点实验室、医学合成生物学研究中心研究员叶海峰团队在Molecular Cell杂志上发表题目为 A programmable targeted protein degradation platform for versatile applications in mammalian cells and mice的研究论文。文中，他们报道了一种精准可控的模块化靶向蛋白降解系统(ΔTrim-TPD)。基于Trim-Away技术，该团队首先通过筛选获得了一种降解效率高达80%-90%的E3泛素连接酶Trim21截断变体(ΔTrim21)，随后开发了一系列基于ΔTrim21的可控靶向蛋白降解系统，实现化学小分子、光调控细胞和小鼠体内的靶向蛋白质降解。ΔTrim-TPD系统的设计灵感来自于Trim-Away技术。Trim-Away 技术通过E3泛素连接酶TRIM21识别并与与抗体的 Fc 区域相结合，随后将与抗体结合的蛋白质传递到了蛋白酶体进行降解【3】。此技术的优势在于只需引入外源抗体和E3效应蛋白（Trim21），无需对目标蛋白进行任何修饰。特异性的抗原-抗体结合降低了非目标效应的风险。另外，Trim-Away技术可以借助已有的抗体库来实现针对多种目标蛋白的快速降解。基于Trim-Away技术原理，叶海峰团队通过筛选获得了一种缺乏B-box结构域的Trim21截断体 (ΔTrim21)，与野生型Trim21 (wtTrim21) 相比，其降解效率从20-30%提高至80-90%。在ΔTrim21的基础上，团队进一步开发出三种精准可控的靶向蛋白降解系统，包括红光调控的靶向蛋白降解系统（RedΔTrim-TPD），化学小分子调控的靶向蛋白降解系统（ChemΔ2Trim-TPD）和蓝光调控的靶向蛋白降解系统（OptoΔ2Trim-TPD）。经实验证明，这些系统能够在细胞和小鼠体内通过无毒性的光或临床药物小分子诱导触发靶蛋白质的降解 (图1)。图1 ΔTrim-TPD系统的设计及其应用研究团队利用课题组前期开发的红光诱导REDMAP系统【4】调控ΔTrim21的表达，进而开发了红光调控的靶向蛋白降解系统—RedΔTrim-TPD。通过将RedΔTrim-TPD转染到已感染HSV-1-GFP病毒的HEK-293T细胞中，研究表明红光触发降解系统在12 h内降解病毒包装蛋白gD以抑制HSV-1病毒增殖。接着，为了实现对靶蛋白进行分钟级别的快速降解，研究人员开发了化学诱导的蛋白降解系统 (ChemΔ2Trim-TPD)。通过对抗体和ΔTrim21蛋白的结构进行优化，研究人员将去除Fc片段的抗体（ΔAb）和删除PRYSPRY结构域的ΔTrim21蛋白（Δ2Trim21）与小分子诱导的二聚化蛋白进行融合表达。选用的小分子诱导二聚化蛋白包括(1)ABI/PYL1，可由一种无毒且低成本的植物激素ABA诱导; (2) NS3a/GNCR1，由临床批准的抗病毒药物grazoprevir (GZV)诱导; (3) NS3a/DNCR2，由临床批准的抗病毒药物danoprevir (DNV) 诱导。当ABA、GZV或DNV存在时，ChemΔ2Trim-TPD便可组装成ΔAb-Δ2Trim21复合体在30分钟内实现靶蛋白的降解。在验证ChemΔ2Trim-TPD系统的概念之后，研究人员下一步将其应用于基因编辑的精准控制。他们设计构建了三种ChemΔ2Trim-TPD介导的CRISPR-（d）Cas9系统，分别为：GZV依赖的转录抑制(ChemΔ2Trim-TPDi)、转录去抑制(ChemΔ2Trim-TPDdisi)以及基因删除(ChemΔ2Trim-TPDdel)系统。通过对CRISPR-(d)Cas9系统相关蛋白的可控式降解，研究人员实现了临床级小分子药物调控的基因表观修饰和基因编辑。然后，研究人员利用Magnets 系统设计构建了蓝光调控的靶蛋白降解系统（OptoΔ2Trim-TPD），该系统可以在30分钟内实现对于不同半衰期（从10分钟到5天）、不同分子量（从21 kDa到185 kDa）靶蛋白的快速降解。OptoΔ2Trim-TPD通过蓝光控制实现了对肿瘤相关蛋白的降解，并呈现出光照时间、光照强度依赖性的靶蛋白降解动力学特征。最后，研究人员通过慢病毒递送OptoΔ2Trim-TPD系统至小鼠黑色素瘤，实现了小鼠只需每天照30分钟蓝光，即可在肿瘤细胞中诱导靶蛋白(膜蛋白PD-L1和致癌转录因子c-Myc)的降解，有效抑制肿瘤生长，显著延长小鼠生存期。综上，研究人员开发的基于ΔTrim21的可控靶向蛋白质降解系统进一步拓展了蛋白质降解领域的研究，提供了一种快速、高效、可控的胞内蛋白和跨膜蛋白靶向降解手段，为细胞生物学基础研究提供了强大的工具，并有望推进基因和细胞的精准治疗。封面图展示了蛋白降解三聚体的形成，包括E3泛素连接酶ΔTRIM21模块，纳米抗体模块和靶蛋白。当受外部光照射时，ΔTRIM21模块与纳米体模块相互作用，促进与目标蛋白质的结合，然后复合物进入蛋白酶体进行目标蛋白降解。该论文的通讯作者为华东师范大学生命科学学院叶海峰研究员。博士研究生马小丁和博士后尹剑丽为该论文的共同第一作者。专家点评王平（同济大学医学院，教授）在现代生物医药研究领域，靶向蛋白质降解（TPD）技术作为一种创新的药物开发策略，旨在通过操控细胞内固有的降解路径，精确调节特定蛋白质的活性及其在生物体内的丰度。TPD技术因其在治疗多种疾病，包括恶性肿瘤和神经退行性疾病等方面显示出的巨大潜力而受到关注。然而，目前广泛使用的蛋白降解系统，如PROTACs，存在着一系列挑战，包括药物筛选流程的复杂性、构建可控PROTACs进行必要的化学基团修饰导致的分子量增加和潜在的药物毒性问题，以及基于降解子（Degron）的蛋白降解系统需要对靶标蛋白进行预先修饰，这些都限制了TPD技术的广泛应用。为了克服这些挑战，叶海峰团队开发了一种基于Trim-Away技术的新型靶蛋白降解系统，称为ΔTrim-TPD。与原始的Trim-Away技术相比，ΔTrim-TPD可使靶蛋白降解效率从~30%提升至80%-90%，并且该系统展现了在不同类型细胞、对不同种类蛋白（也包括不同半衰期蛋白）都具有良好的降解效果。其次，ΔTrim-TPD系统通过使用特异性抗体直接识别并降解目标蛋白，避免了对靶蛋白的直接修饰，显著降低了非特异性降解（即脱靶效应）的风险。该团队还开发了多个可控式靶蛋白降解系统，包括RedΔTrim-TPD、ChemΔ2Trim-TPD和OptoΔ2Trim-TPD，这些系统通过不同的信号（如化学小分子、红光、蓝光）触发靶蛋白降解，展示了TPD技术的高度可控性和灵活性。特别值得一提的是，OptoΔ2Trim-TPD在小鼠肿瘤模型中的应用，通过局部光照激活肿瘤相关靶蛋白的高效、快速（只需每天光照15分钟）降解，验证了其系统在抑制肿瘤生长方面的潜力。综上，这些系统的开发不仅为研究蛋白质功能和疾病机制提供了强大的新工具，而且为基于TPD的精准治疗策略的实现奠定了基础。专家点评胡荣贵（中科院上海生命科学研究院，研究员）靶向蛋白质降解（TPD）技术在现代药物开发和生物化学研究中已显露其革命性的潜力，特别是在治疗癌症和神经退行性疾病方面。然而，这一领域还面临着一系列挑战，包括确保靶向性和减少不良反应等挑战。最近，华东师范大学生命科学学院叶海峰团队在Molecular Cell杂志上发表的研究论文，提出了一种名为ΔTrim-TPD的新型靶向蛋白质降解系统。该系统基于Trim-Away技术，通过筛选E3泛素酶Trim21的截断变体（ΔTrim21）来实现对靶蛋白的精准可控高效降解。研究团队还开发了多个基于ΔTrim21的靶向蛋白质降解系统，实现了化学和光触发的可编程蛋白降解，在细胞和动物模型中都显示出了高效的降解效率。该研究不仅展示了ΔTrim-TPD系统的高效性和可控性，还突破了传统TPD技术在选择性，精确性和靶蛋白修饰上的限制。通过开发基于化学小分子、红光和蓝光的三种不同的调控方式，他们为靶向蛋白降解技术提供了更多的应用可能性。首先，他们开发的红光触发降解系统在12 h内降解病毒包装蛋白，成功抑制了HSV-1病毒增殖。接着，他们开发了小分子、蓝光触发的模块化蛋白降解系统，实现了分钟诱导蛋白降解的启动：30分钟的诱导就可以实现靶蛋白的最大降解效果（80%-90%）。此外，他们的降解系统可以降解不同半衰期（从10分钟到5天）以及不同蛋白大小（从21 kDa到185 kDa）的各种蛋白，并具有诱导时间、强度依赖性。这些数据展示了这项技术的可控性和灵活性。这些技术的应用不仅在控制基因编辑和减少脱靶效应方面展示了潜力，在小鼠肿瘤模型的实验中，通过对肿瘤区域进行短暂的日常光照，还实现了肿瘤相关蛋白（PDL-1, c-Myc）的迅速且高效降解，从而证实了该系统在抑制肿瘤方面的有效性。这些创新不仅提高了TPD技术的实用性，也为药物开发和疾病治疗提供了新的策略。叶海峰团队的研究拓宽了TPD技术在精准靶向治疗方面的应用，为生物医学研究及治疗策略的未来发展提供了新的思路。然而，尽管这项技术带来希望，其在实际应用中的成本、组织靶向性及长期安全性等挑战仍需进一步研究和克服。原文链接：https://www-cell-com.libproxy1.nus.edu.sg/molecular-cell/abstract/S1097-2765(24)00138-2制版人：十一参考文献1 Dale, B. et al. Advancing targeted protein degradation for cancer therapy. Nat Rev Cancer 21, 638-654, doi:10.1038/s41568-021-00365-x (2021).2 Schapira, M., Calabrese, M. F., Bullock, A. N. & Crews, C. M. Targeted protein degradation: expanding the toolbox. Nat Rev Drug Discov 18, 949-963, doi:10.1038/s41573-019-0047-y (2019).3 Clift, D. et al. A Method for the Acute and Rapid Degradation of Endogenous Proteins. Cell 171, 1692-1706 e1618, doi:10.1016/j.cell.2017.10.033 (2017).4 Zhou, Y. et al. A small and highly sensitive red/far-red optogenetic switch for applications in mammals. Nat Biotechnol 40, 262-272, doi:10.1038/s41587-021-01036-w (2022).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↓

Other key data to be presented from ViiV Healthcare’s innovative pipeline and portfolio include the exploration of different mechanisms of action through broadly neutralising antibodies as well as real-world insights from established long-acting and 2-drug regimens LONDON--(BUSINESS WIRE)-- ViiV Healthcare, the global specialist HIV company majority owned by GSK, with Pfizer and Shionogi as shareholders, today announced the presentation of 64 abstracts that includes highlights of the company’s next-generation pipeline advancements, alongside data from its diverse portfolio of marketed HIV treatment and prevention options at the Conference on Retroviruses and Opportunistic Infections (CROI 2024) being held in Denver, Colorado, from 3 – 6 March 2024. Kimberly Smith, M.D., MPH, Head of Research & Development at ViiV Healthcare, said: “As leaders in developing long-acting injectables for the treatment of HIV, we’re excited to present new data setting the stage for ViiV’s next generation of medicines and demonstrating how key pipeline assets will target HIV in different ways. These findings, as well as the breadth of data we’ll present on our marketed products, including new interim results from the LATITUDE study, reflect a portfolio and future-looking pipeline focused on ending the HIV epidemic. We look forward to sharing them with the scientific and HIV communities at CROI 2024.” Key abstracts to be presented at CROI 2024 by ViiV Healthcare and its study partners will include: Data introducing our next generation of potential ultra long-acting medicines for HIV: ViiV Healthcare will share findings from a phase I study evaluating different formulations of cabotegravir and their potential for dosing every four months. The ongoing, open-label, single-dose, dose-escalation phase I study in 70 healthy adults assessed both the 200 mg/mL formulation of cabotegravir in combination with recombinant human hyaluronidase PH20 (rHuPH20), as well as a new formulation of cabotegravir (CAB ULA) administered by itself.1 Researchers will share safety and pharmacokinetic findings from both ultra long-acting approaches and their potential for future clinical development. Findings advancing different mechanisms of action in HIV research: New phase IIa findings from the BANNER study of VH3810109 (N6LS), an investigational, broadly neutralising antibody (bNAb), will be presented. Researchers will share findings of the bNAb administered intravenously and the first efficacy findings of its subcutaneous administration.2 Findings from the SPAN study of N6LS, examining the safety and tolerability of the highest subcutaneous and intravenous N6LS doses administered to date, with and without PH20, will also be presented.3 Additionally, efficacy and safety data from a non-ViiV owned bNAb asset, VRC07-523LS, in a phase II, open-label clinical trial used in combination with long-acting CAB for maintenance antiretroviral therapy (ART) will be presented.4 New data on long-acting therapy vs daily oral standard of care, in traditionally non-adherent populations: Interim analysis of the LATITUDE phase III trial will be presented showing that, the injectable antiretroviral treatment for HIV, Cabenuva (cabotegravir and rilpivirine [CAB+RPV LA]), demonstrates superior efficacy compared to daily oral standard of care (SOC) in individuals with a history of antiretroviral adherence challenges. The NIAID/ACTG also announced a modification to the study, where further randomisation has been stopped and participants in the SOC arm are being given the option to switch to the long-acting therapy arm.5 Real-world evidence from across our treatment and prevention portfolios: New findings from SEARCH, a randomised study evaluating the real-world impact of the inclusion of long-acting cabotegravir for PrEP in an HIV prevention coverage package compared to the standard-of-care of oral PrEP and PEP alone in rural Uganda and Kenya, will also be presented.6 Real-world evidence findings for the complete long-acting HIV treatment regimen Cabenuva will be presented from the OPERA cohort examining ART-experienced, virally suppressed adults living with HIV who switched to CAB+RPV LA or to an oral regimen.7 Findings for the 2-drug regimen, Dovato (dolutegravir, lamivudine [DTG/3TC]), will include the InfCare HIV study, which presents three-year switch data, from 3-drug regimen to Dovato, in a long-term real-world Swedish cohort.8 This study adds to the body of real-world evidence to date that includes more than 40,000 people living with HIV.9 Here is a list of ViiV Healthcare-sponsored or supported studies to be presented at CROI 2024: Title First Author Presentation Number Presentation Dolutegravir A single once-daily ABC/DTG/3TC tablet predicts safe and effective exposures in children 3 to <6kg H. Chandasana 02770 Poster Tuesday, March 5 2:30-4:00pm MST Population pharmacokinetics of ABC/DTG/3TC FDC to support dosing in peds with HIV-1 (IMPAACT 2019) H. Chandasana 03110 Poster Tuesday, March 5:30-4:00pm MST Dolutegravir and growth in pediatric populations with HIV-1: IMPAACT P1093 and IMPAACT 2019 M. McKenna 01783 Poster Tuesday, March 5 2:30-4:00pm MST Switching to DTG+3TC vs 3-drug regimens in routine clinical care: long-term Swedish data E. Sörstedt 01838 Poster Tuesday, March 5 2:30-4:00pm MST Temporal trends of cardiovascular disease incidence in people with HIV from 2001-2021 N. Jaschinski 02263 Poster Tuesday, March 5 2:30-4:00pm MST Increased cancer risk with low CD4 counts persists despite over 2 years of virological suppression J. Hoy 01462 Poster Wednesday, March 6 2:30-4:00pm MST Cabotegravir for Treatment Long-acting Injectable CAB/RPV is Superior to Oral ART in PWH with adherence challenges: ACTG A5359 A. Rana 03579 Oral Wednesday, March 6 12:51-1:00pm MST Real-world utilization of cabotegravir + rilpivirine in the US: data from Trio Health cohort J. J. Eron 01374 Poster Monday, March 4 2:30-4:00pm MST Real-world effectiveness of cabotegravir + rilpivirine vs. standard of care oral regimens in the US R. K. Hsu 01952 Poster Monday, March 4 2:30-4:00pm MST HIV-1 RNA blips and low-level viral replication: SOLAR (CAB+RPV LA vs. BIC/FTC/TAF) C. Latham 00138 Poster Monday, March 4 2:30-4:00pm MST Model based comparison of cabotegravir pharmacokinetics following thigh and gluteal injections K. Han 03157 Poster Wednesday, March 6 2:30-4:00pm MST Cabotegravir for PrEP SEARCH Randomized trial of Dynamic Choice HIV Prevention including injectable cabotegravir (CAB-LA) J. Kabami 03405 Late-Breaker Oral Tuesday, March 5 10:00-12:00pm MST Pre-exposure prophylaxis with cabotegravir long-acting injectable in the OPERA cohort A. Mills 01400 Poster Monday, March 4 2:30-4:00pm MST Real-world use of cabotegravir long acting for pre-exposure prophylaxis: TRIO cohort K. Mayer 01907 Poster Monday, March 4 2:30-4:00pm MST Cabotegravir PopPK analysis of adults and adolescents living with HIV or at risk for HIV receiving PrEP Y. Lin 03038 Poster Tuesday, March 5 2:30-4:00pm MST Interest in long-acting injectable PrEP among transgender women in the United States E. E. Cooney 00621 Poster Wednesday, March 6 2:30-4:00pm MST Healthcare staff acceptability and feasibility of telehealth delivery of cabotegravir for PrEP A. Liu 03080 Poster Wednesday, March 6 2:30-4:00pm MST Fostemsavir Temsavir treatment enhances bNAb recognition and subsequent clearance of HIV-1 infected cells R. Ferris 02971 Poster Monday, March 4 2:30-4:00pm MST Pipeline: Ultra Long-Acting Cabotegravir Phase I study of cabotegravir long-acting injectable formulations supports ≥4-monthly dose interval K. Han 00251 Oral Monday, March 4 10:00-12:00pm MST Pipeline: Broadly Neutralising Antibodies VH3810109 (N6LS) in antiretroviral therapy–naive adults with HIV-1: phase IIa BANNER efficacy data P. Leone 01911 Oral Monday, March 4 10:00-12:00pm MST Safety and efficacy of VRC07-523LS plus long-acting cabotegravir in the phase 2 ACTG A5357 Trial B. Taiwo 02254 Oral Monday, March 4 10:00-12:00pm MST High-dose VH3810109 (N6LS) ± recombinant human hyaluronidase PH20: phase I SPAN study safety results B. Win 01988 Poster Wednesday, March 6 2:30-4:00pm MST Pipeline: Maturation Inhibitors Next-generation maturation inhibitor GSK3640254 showed broad spectrum potency without MI resistance B. McAuliffe 03095 Poster Wednesday, March 6 2:30-4:00pm MST The preclinical pro maturation inhibitor VH3739937 J. Jeffrey 02819 Poster Wednesday, March 6 2:30-4:00pm MST General HIV Resistance in young children newly diagnosed with HIV in Western Cape, South Africa K. Anderson 01012 Poster Tuesday, March 5 2:30-4:00pm MST DOVATO (dolutegravir and lamivudine) tablets INDICATION Dovato is indicated as a complete regimen to treat HIV-1 infection in adults with no antiretroviral (ARV) treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable ARV regimen with no history of treatment failure and no known resistance to any component of Dovato. IMPORTANT SAFETY INFORMATION BOXED WARNING: PATIENTS CO-INFECTED WITH HEPATITIS B VIRUS (HBV) AND HIV-1: EMERGENCE OF LAMIVUDINE-RESISTANT HBV AND EXACERBATIONS OF HBV All patients with HIV-1 should be tested for the presence of HBV prior to or when initiating Dovato. Emergence of lamivudine-resistant HBV variants associated with lamivudine-containing antiretroviral regimens has been reported. If Dovato is used in patients co-infected with HIV-1 and HBV, additional treatment should be considered for appropriate treatment of chronic HBV; otherwise, consider an alternative regimen. Severe acute exacerbations of HBV have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued lamivudine, a component of Dovato. Closely monitor hepatic function in these patients and, if appropriate, initiate anti-HBV treatment. CONTRAINDICATIONS Do not use Dovato in patients with previous hypersensitivity reaction to dolutegravir or lamivudine Do not use Dovato in patients receiving dofetilide WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Hypersensitivity reactions have been reported with dolutegravir and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury Discontinue Dovato immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, as a delay in stopping treatment may result in a life-threatening reaction. Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated Hepatotoxicity: Hepatic adverse events have been reported, including cases of hepatic toxicity (elevated serum liver biochemistries, hepatitis, and acute liver failure), in patients receiving a dolutegravir-containing regimen without pre-existing hepatic disease or other identifiable risk factors Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations with use of Dovato. In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation, particularly in the setting where anti-hepatitis therapy was withdrawn Monitoring for hepatotoxicity is recommended Embryo Fetal Toxicity: Assess the risks and benefits of Dovato and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy due to the risk of neural tube defects Pregnancy testing is recommended before initiation of Dovato. Individuals of childbearing potential should be counseled on the consistent use of effective contraception Lactic Acidosis and Severe Hepatomegaly With Steatosis: Fatal cases have been reported with the use of nucleoside analogs, including lamivudine. Discontinue Dovato if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity develop, including hepatomegaly and steatosis in the absence of marked transaminase elevations. Adverse Reactions or Loss of Virologic Response Due to Drug Interactions with concomitant use of Dovato and other drugs may occur (see Contraindications and Drug interactions). Immune Reconstitution Syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported with the use of Dovato. Adverse reactions The most common adverse reactions (incidence ≥2%, all grades) with Dovato were headache (3%), nausea (2%), diarrhea (2%), insomnia (2%), fatigue (2%), and anxiety (2%). Drug interactions Consult full Prescribing Information for Dovato for more information on potentially significant drug interactions Dovato is a complete regimen. Coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended Drugs that induce or inhibit CYP3A or UGT1A1 may affect the plasma concentrations of dolutegravir Administer Dovato 2 hours before or 6 hours after taking polyvalent cation-containing antacids or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications. Alternatively, Dovato and supplements containing calcium or iron can be taken with food Use in specific populations Pregnancy: There are insufficient human data on the use of Dovato during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. An Antiretroviral Pregnancy Registry has been established. Advise individuals of childbearing potential of the potential risk of neural tube defects. Assess the risks and benefits of Dovato and discuss with the patient to determine if an alternative treatment should be considered at the time of conception through the first trimester of pregnancy or if pregnancy is confirmed in the first trimester Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission, developing viral resistance in HIV-positive infants, and adverse reactions in a breastfed infant Females and Males of Reproductive Potential: Pregnancy testing is recommended before initiation of Dovato. Counsel individuals of childbearing potential taking Dovato on the consistent use of effective contraception Renal Impairment: Dovato is not recommended for patients with creatinine clearance <30 mL/min. Patients with a sustained creatinine clearance between 30 and 49 mL/min should be monitored for hematologic toxicities, which may require a dosage adjustment of lamivudine as an individual component Hepatic Impairment: Dovato is not recommended in patients with severe hepatic impairment (Child-Pugh Score C) For more information, please see full US Prescribing Information for Dovato: https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Dovato/pdf/DOVATO-PI-PIL.PDF CABENUVA (cabotegravir; rilpivirine) extended-release injectable suspensions INDICATION CABENUVA is indicated as a complete regimen for the treatment of HIV-1 infection in adults and adolescents 12 years of age and older and weighing at least 35 kg to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Do not use CABENUVA in patients with previous hypersensitivity reaction to cabotegravir or rilpivirine Do not use CABENUVA in patients receiving carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, systemic dexamethasone (>1 dose), and St John’s wort WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Serious or severe hypersensitivity reactions have been reported in association with other integrase inhibitors and could occur with CABENUVA Hypersensitivity reactions, including cases of drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported during postmarketing experience with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries Discontinue CABENUVA immediately if signs or symptoms of hypersensitivity reactions develop. Clinical status, including liver transaminases, should be monitored and appropriate therapy initiated. Cabotegravir and rilpivirine oral lead-in may be used to help identify patients who may be at risk of a hypersensitivity reaction Post-Injection Reactions: Serious post-injection reactions (reported in less than 1% of subjects) were reported within minutes after the injection of rilpivirine, including dyspnea, bronchospasm, agitation, abdominal cramping, rash/urticaria, dizziness, flushing, sweating, oral numbness, changes in blood pressure, and pain (e.g., back and chest). These events may have been associated with accidental intravenous administration and began to resolve within a few minutes after the injection Carefully follow the Instructions for Use when preparing and administering CABENUVA. The suspensions should be injected slowly via intramuscular injection and avoid accidental intravenous administration. Observe patients briefly (approximately 10 minutes) after the injection. If a post-injection reaction occurs, monitor and treat as clinically indicated Hepatotoxicity: Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine with or without known pre-existing hepatic disease or identifiable risk factors Patients with underlying liver disease or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations Monitoring of liver chemistries is recommended and treatment with CABENUVA should be discontinued if hepatotoxicity is suspected Depressive Disorders: Depressive disorders (including depressed mood, depression, major depression, mood altered, mood swings, dysphoria, negative thoughts, suicidal ideation, suicide attempt) have been reported with CABENUVA or the individual products Promptly evaluate patients with depressive symptoms Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: The concomitant use of CABENUVA and other drugs may result in known or potentially significant drug interactions (see Contraindications and Drug Interactions) Rilpivirine doses 3 and 12 times higher than the recommended oral dosage can prolong the QTc interval CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes Long-Acting Properties and Potential Associated Risks with CABENUVA: Residual concentrations of cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). Select appropriate patients who agree to the required monthly or every-2-month injection dosing schedule because non-adherence could lead to loss of virologic response and development of resistance To minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive antiretroviral regimen no later than 1 month after the final injection doses of CABENUVA when dosed monthly and no later than 2 months after the final injections of CABENUVA when dosed every 2 months. If virologic failure is suspected, switch the patient to an alternative regimen as soon as possible ADVERSE REACTIONS The most common adverse reactions in adults (incidence ≥2%, all grades) treated with CABENUVA were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash The safety of CABENUVA in adolescents is expected to be similar to adults DRUG INTERACTIONS Refer to the applicable full Prescribing Information for important drug interactions with CABENUVA, VOCABRIA (cabotegravir), or EDURANT (rilpivirine) Because CABENUVA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended Drugs that are strong inducers of UGT1A1 or UGT1A9 are expected to decrease the plasma concentrations of cabotegravir. Drugs that induce or inhibit CYP3A may affect the plasma concentrations of rilpivirine CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes USE IN SPECIFIC POPULATIONS Pregnancy: There are insufficient human data on the use of CABENUVA during pregnancy to adequately assess a drug-associated risk for birth defects and miscarriage. Discuss the benefit-risk of using CABENUVA during pregnancy and conception and consider that cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA. An Antiretroviral Pregnancy Registry has been established Lactation: Potential risks of breastfeeding include HIV-1 transmission, developing viral resistance in HIV-positive infants, and adverse reactions in a breastfed infant For more information, please see full US Prescribing Information for Cabenuva: APRETUDE (cabotegravir) extended-release injectable suspensions INDICATION APRETUDE is indicated in at-risk adults and adolescents weighing at least 35 kg for pre-exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 infection. Individuals must have a negative HIV-1 test prior to initiating APRETUDE (with or without an oral lead-in with oral cabotegravir) for HIV-1 PrEP. IMPORTANT SAFETY INFORMATION BOXED WARNING: RISK OF DRUG RESISTANCE WITH USE OF APRETUDE FOR HIV-1 PRE-EXPOSURE PROPHYLAXIS (PrEP) IN UNDIAGNOSED HIV-1 INFECTION Individuals must be tested for HIV-1 infection prior to initiating APRETUDE or oral cabotegravir, and with each subsequent injection of APRETUDE, using a test approved or cleared by the FDA for the diagnosis of acute or primary HIV-1 infection. Drug-resistant HIV-1 variants have been identified with use of APRETUDE by individuals with undiagnosed HIV-1 infection. Do not initiate APRETUDE for HIV-1 PrEP unless negative infection status is confirmed. Individuals who become infected with HIV-1 while receiving APRETUDE for PrEP must transition to a complete HIV-1 treatment regimen. CONTRAINDICATIONS Do not use APRETUDE in individuals: with unknown or positive HIV-1 status with previous hypersensitivity reaction to cabotegravir receiving carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, and rifapentine WARNINGS AND PRECAUTIONS Comprehensive Management to Reduce the Risk of HIV-1 Infection: Use APRETUDE as part of a comprehensive prevention strategy, including adherence to the administration schedule and safer sex practices, including condoms, to reduce the risk of sexually transmitted infections (STIs). APRETUDE is not always effective in preventing HIV-1 acquisition. Risk for HIV-1 acquisition includes, but is not limited to, condomless sex, past or current STIs, self-identified HIV risk, having sexual partners of unknown HIV-1 viremic status, or sexual activity in a high prevalence area or network. Inform, counsel, and support individuals on the use of other prevention measures (e.g., consistent and correct condom use; knowledge of partner[s] HIV-1 status, including viral suppression status; regular testing for STIs) Use APRETUDE only in individuals confirmed to be HIV-1 negative. HIV-1 resistance substitutions may emerge in individuals with undiagnosed HIV-1 infection who are taking only APRETUDE, because APRETUDE alone does not constitute a complete regimen for HIV-1 treatment. Prior to initiating APRETUDE, ask seronegative individuals about recent (in past month) potential exposure events and evaluate for current or recent signs or symptoms consistent with acute HIV-1 infection (e.g., fever, fatigue, myalgia, skin rash). If recent (<1 month) exposures to HIV-1 are suspected or clinical symptoms consistent with acute HIV-1 infection are present, use a test approved or cleared by the FDA as an aid in the diagnosis of acute HIV-1 infection When using APRETUDE, HIV-1 testing should be repeated prior to each injection and upon diagnosis of any other STIs Additional HIV testing to determine HIV status is needed if an HIV-1 test indicates possible HIV-1 infection or if symptoms consistent with acute HIV-1 infection develop following an exposure event. If HIV-1 infection is confirmed, then transition the individual to a complete HIV-1 treatment Counsel HIV-1 uninfected individuals to strictly adhere to the recommended dosing and testing schedule for APRETUDE Potential Risk of Resistance with APRETUDE: There is a potential risk of developing resistance to APRETUDE if an individual acquires HIV-1 either before, while taking, or following discontinuation of APRETUDE. To minimize this risk, it is essential to clinically reassess individuals for risk of HIV-1 acquisition and to test before each injection to confirm HIV-1–negative status. Individuals who are confirmed to have HIV-1 infection must transition to a complete HIV-1 treatment. If individuals at continuing risk of HIV-1 acquisition discontinue APRETUDE, alternative forms of PrEP should be considered and initiated within 2 months of the final injection of APRETUDE Long-Acting Properties and Potential Associated Risks with APRETUDE: Residual concentrations of cabotegravir may remain in the systemic circulation of individuals for prolonged periods (up to 12 months or longer). Take the prolonged-release characteristics of cabotegravir into consideration and carefully select individuals who agree to the required every-2-month injection dosing schedule because non-adherence or missed doses could lead to HIV-1 acquisition and development of resistance Hypersensitivity Reactions: Serious or severe hypersensitivity reactions have been reported in association with other integrase inhibitors and could occur with APRETUDE Discontinue APRETUDE immediately if signs or symptoms of hypersensitivity reactions develop. Clinical status, including liver transaminases, should be monitored and appropriate therapy initiated Hepatotoxicity: Hepatotoxicity has been reported in a limited number of individuals receiving cabotegravir with or without known pre-existing hepatic disease or identifiable risk factors Clinical and laboratory monitoring should be considered and APRETUDE should be discontinued if hepatotoxicity is suspected and individuals managed as clinically indicated Depressive Disorders: Depressive disorders (including depression, depressed mood, major depression, persistent depressive disorder, suicidal ideation or attempt) have been reported with APRETUDE Promptly evaluate patients with depressive symptoms Risk of Reduced Drug Concentration of APRETUDE Due to Drug Interactions: The concomitant use of APRETUDE and other drugs may result in reduced drug concentration of APRETUDE Refer to the full Prescribing Information for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during use of, and after discontinuation of APRETUDE; review concomitant medications during use of APRETUDE ADVERSE REACTIONS The most common adverse reactions (incidence ≥1%, all grades) with APRETUDE were injection site reactions, diarrhea, headache, pyrexia, fatigue, sleep disorders, nausea, dizziness, flatulence, abdominal pain, vomiting, myalgia, rash, decreased appetite, somnolence, back pain, and upper respiratory tract infection. DRUG INTERACTIONS Refer to the full Prescribing Information for important drug interactions with APRETUDE Drugs that induce UGT1A1 may significantly decrease the plasma concentrations of cabotegravir USE IN SPECIFIC POPULATIONS Lactation: Assess the benefit-risk of using APRETUDE to the infant while breastfeeding due to the potential for adverse reactions and residual concentrations in the systemic circulation for up to 12 months or longer after discontinuation Pediatrics: Not recommended in individuals weighing less than 35 kg For more information, please see full US Prescribing Information for APRETUDE: RUKOBIA (fostemsavir) extended-release tablets INDICATION RUKOBIA, in combination with other antiretrovirals (ARVs), is indicated to treat HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current ARV regimen due to resistance, intolerance, or safety considerations. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Do not use in patients with previous hypersensitivity to fostemsavir or any of the components of RUKOBIA. Do not use RUKOBIA in patients receiving strong cytochrome P450 (CYP)3A inducers, including but not limited to enzalutamide, carbamazepine, phenytoin, rifampin, mitotane, and St John’s wort (Hypericum perforatum). WARNINGS AND PRECAUTIONS Immune Reconstitution Syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported with the use of RUKOBIA. QTc Prolongation with Higher than Recommended Dosages: RUKOBIA at 2,400 mg twice daily has been shown to significantly prolong the QTc interval of the electrocardiogram. Use RUKOBIA with caution in patients with a history of QTc interval prolongation or in patients with relevant pre-existing cardiac disease or who are taking drugs with a known risk of Torsade de Pointes. Elderly patients may be more susceptible to drug-induced QT interval prolongation. Elevations in Hepatic Transaminases in Patients with Hepatitis B or C Virus Co-infection: Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection. Diligence should be applied in initiating or maintaining effective hepatitis B therapy when starting RUKOBIA in patients co-infected with hepatitis B. Adverse Reactions or Loss of Virologic Response Due to Drug Interactions with concomitant use of RUKOBIA and other drugs may occur (see Contraindications and Drug Interactions). Adverse reactions The most common adverse reaction (all grades, randomized cohort) observed in ≥5% of subjects was nausea (10%). 81% of adverse reactions reported with RUKOBIA were mild or moderate in severity. Drug interactions See the full Prescribing Information for RUKOBIA for a complete list of significant drug interactions. Temsavir may increase plasma concentrations of grazoprevir and voxilaprevir. Use an alternative hepatitis C virus regimen if possible. Use the lowest possible starting dose for statins and monitor for statin-associated adverse events. Patients receiving RUKOBIA should not take doses of estrogen-based therapies, including oral contraceptives, that contain more than 30 mcg/day of ethinyl estradiol. Caution is advised particularly in patients with additional risk factors for thromboembolic events. Use in specific populations Pregnancy: There are insufficient human data on the use of RUKOBIA during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. An Antiretroviral Pregnancy Registry has been established. Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission, developing viral resistance, and adverse reactions in a breastfed infant. For more information, please see full US Prescribing Information for RUKOBIA: About ViiV Healthcare ViiV Healthcare is a global specialist HIV company established in November 2009 by GSK (LSE: GSK) and Pfizer (NYSE: PFE) dedicated to delivering advances in treatment and care for people living with HIV and for people who are at risk of acquiring HIV. Shionogi became a ViiV shareholder in October 2012. The company’s aims are to take a deeper and broader interest in HIV and AIDS than any company has done before and take a new approach to deliver effective and innovative medicines for HIV treatment and prevention, as well as support communities affected by HIV. For more information on the company, its management, portfolio, pipeline, and commitment, please visit viivhealthcare.com. 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. Cautionary statement regarding forward-looking statements GSK cautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Such factors include, but are not limited to, those described under Item 3.D “Risk factors” in the company's Annual Report on Form 20-F for 2022, and Q4 Results for 2023. Registered in England & Wales: GSK plc ViiV No. 3888792 Healthcare Limited No. 06876960 Registered Office: GSK plc 980 Great West Road Brentford, Middlesex United Kingdom TW8 9GS ViiV Healthcare Limited GSK Medicines Research Centre Gunnels Wood Road, Stevenage United Kingdom SG1 2NY References 1 Han, et al. Phase I Study of Cabotegravir Long-Acting Injectable Formulations Supports ≥4-Monthly Dose Interval. Presented at 31st Conference on Retroviruses and Opportunistic Infections (CROI). March 2024. 2 Leone, et al. VH3810109 (N6LS) in Antiretroviral Therapy–Naive Adults With HIV-1: Phase IIa BANNER Efficacy Data. Presented at 31st Conference on Retroviruses and Opportunistic Infections (CROI). March 2024. 3 Win, et al. High-Dose VH3810109 (N6LS) ± Recombinant Human Hyaluronidase PH20: Phase I SPAN Study Safety Results. Presented at 31st Conference on Retroviruses and Opportunistic Infections (CROI). March 2024. 4 Taiwo, et al. Safety and Efficacy of VRC07-523LS plus Long-Acting Cabotegravir in the Phase 2 ACTG A5357 Trial. Presented at 31st Conference on Retroviruses and Opportunistic Infections (CROI). March 2024. 5 Rana, et al. Long-acting Injectable CAB/RPV is Superior to Oral ART in PWH with adherence challenges: ACTG A5359. Presented at 31st Conference on Retroviruses and Opportunistic Infections (CROI). March 2024. 6 Kamya, et al. SEARCH Randomized trial of Dynamic Choice HIV Prevention including injectable cabotegravir (CAB-LA). Presented at 31st Conference on Retroviruses and Opportunistic Infections (CROI). March 2024. 7 Hsu, et al. Real-World Effectiveness of Cabotegravir + Rilpivirine vs. Standard of Care Oral Regimens in the US. Presented at 31 Conference on Retroviruses and Opportunistic Infections (CROI). March 2024. 8 Sörstedt, et al. Switching to DTG+3TC vs 3-drug regimens in routine clinical care: long-term Swedish data. Presented at 31st Conference on Retroviruses and Opportunistic Infections (CROI). March 2024. 9 Data on File