Emtricitabine/Tenofovir Disoproxil Fumarate

▎药明康德内容团队编辑 吉利德科学（Gilead Sciences）今日公布其每半年注射一次的艾滋病毒衣壳抑制剂lenacapavir用于预防艾滋病毒（HIV）感染的第二项关键3期试验PURPOSE 2的全部结果。分析显示，接受lenacapavir的受试者中，高达99.9%未感染艾滋病毒，且其预防艾滋病毒感染的效果，优于现有每日一次口服疗法。详细数据公布于艾滋病毒感染药物治疗国际大会，并将发表在《新英格兰医学杂志》上。上个月，美国FDA授予lenacapavir用于艾滋病毒感染暴露前预防（PrEP）的突破性疗法认定。该公司预计在今年年底前开始lenacapavir用于PrEP的一系列全球监管申请。 全球每年新增约130万艾滋病毒感染病例。近年来研究发现，在未受到感染时服用抗病毒药物，可以降低艾滋病毒感染的风险。这种预防艾滋病毒感染的疗法称为PrEP疗法。首款获批的艾滋病PrEP药物是由吉利德所开发的每日口服的Truvada，如果按指示服用，预防艾滋病的效果显著。虽然每日口服的PrEP疗法几乎可100%避免艾滋病毒感染，但由于药物成本以及服用与艾滋病相关药物所面临的污名等因素限制，许多人难以坚持每日服药，口服PrEP疗法的实际效果远低于理论值。因此开发一种能够增加服药依从性的长效PrEP疗法具有显著需求。 PURPOSE 2是一项随机、双盲、多中心的3期研究，旨在评估在3271名受试者中，与背景艾滋病毒发病率（bHIV）和每日一次口服疗法Truvada相比，每年两次皮下注射lenacapavir作为PrEP疗法的安全性和有效性。此次公布的完整试验结果如下： 图片来源：123RF 受试者对lenacapavir注射剂表现出高依从性 受试者接受安慰剂与lenacapavir注射的依从性很高：在第26周时，91.0%的受试者按时注射；在试验一年时，92.8%的受试者按时注射。无论是接受lenacapavir还是安慰剂注射，两个队列的按时注射率（前次注射后28周内）都相似。 与背景艾滋病毒发病率相比，lenacapavir使艾滋病毒感染率降低了96% Lenacapavir能够有效降低受试者的艾滋病毒感染率：99.9%的lenacapavir组受试者没有感染艾滋病毒。尽管PURPOSE 2受试者报告的性行为、化学性行为（chemsex）和性传播感染水平较高，在2179名受试者中仅有2例新发病例（0.10/100人年，95% CI：0.01至0.37）。分析显示，试验达主要终点，每年两次的lenacapavir在预防艾滋病毒感染上优于bHIV（2.37/100人年，95% CI：1.65至3.42），相对风险降低96%（感染率比[IRR]：0.04；95% CI：0.01至0.18；p<0.0001）。此外，与每日一次服用Truvada相较，lenacapavir减少艾滋病毒感染风险的效果高出89%（IRR：0.11；95% CI：0.02至0.51；p=0.00245）。 两名感染艾滋病毒受试者的lenacapavir血浆浓度在预定、经血浆水平测试的代表性受试者亚群的总体药物浓度范围内。试验数据证实，两名受试者都是在第一次注射lenacapavir后、第二次注射之前感染了艾滋病毒，并且两名受试者都是使用标准艾滋病毒检测进行诊断。重要的是，根据对先前随访样本的回溯性HIV-1 RNA病毒载量检测，这两人的艾滋病感染诊断并未延误。艾滋病PrEP领域尤其关注长效PrEP使用者感染艾滋病毒时诊断延迟的可能性。 Truvada的依从性最初很高，但随着时间的推移而下降 试验通过随机检测受试者血液样本中的tenofovir diphosphate来衡量Truvada的依从性，结果发现受试者的依从性最初很高，但随着时间的推移而下降：第8周时82%的受试者的tenofovir diphosphate水平达到与高依从性（每周四片或以上）相符的水平，此数值在第26周时为67%，一年时为62%。 Truvada组发生9起艾滋病毒感染事件，所有受试者的依从性都很低或没有依从性 Truvada组中的1086人中发生9例（0.93/100人年，95% CI：0.43至1.77）。数据表明，这9名受试者服用Truvada的依从性很低或没有依从性，或者在确诊前10多天就已停止服药。在这9名受试者中，有2人的tenofovir diphosphate水平较低，6人的水平低于侦测下限，1人停止服用Truvada。 PURPOSE 2是lenacapavir第二项关键的3期试验。2024年6月时所公布的PURPOSE 1关键3期试验结果显示，lenacapavir在女性中的艾滋病毒感染预防用途上显示出100%的有效性，该试验也因达到关键疗效终点而提前揭盲。吉利德预计PURPOSE 1和PURPOSE 2试验的数据将支持其即将进行的监管申请。 Lenacapavir（商品名Sunlenca）是一种“first-in-class”长效艾滋病毒衣壳抑制剂，可以干扰艾滋病毒衣壳蛋白的组装和拆卸，在病毒生命周期的多个阶段发挥作用。Lenacapavir在2019年5月获得美国FDA授予的突破性疗法认定，用于联合其他抗逆转录病毒药物治疗多重耐药的重度经治艾滋病毒感染者。之前一项2/3期试验表明，lenacapavir让患者有望只需每隔6个月接受一次注射，就可以维持它的效力。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放 参考资料： [1] Gilead Presents Full PURPOSE 2 Data Results for Twice-Yearly Lenacapavir for HIV Prevention at HIV Glasgow. Retrieved November 13, 2024 from https://www.businesswire.com/news/home/20241112740576/en 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新

FOSTER CITY, Calif.--( BUSINESS WIRE )--Gilead Sciences, Inc. (Nasdaq: GILD) today presented the first in-depth look at full results from its pivotal Phase 3 PURPOSE 2 trial ( NCT04925752 ), which is studying twice-yearly lenacapavir, the company’s injectable HIV-1 capsid inhibitor, for the investigational use of HIV prevention among a broad and geographically diverse range of cisgender men and gender-diverse people. Newly presented results include data on adherence to and pharmacokinetics of lenacapavir among trial participants. The data were presented during an oral abstract session at the International Congress on Drug Therapy in HIV Infection (HIV Glasgow) and will be published in The New England Journal of Medicine . The release of the full PURPOSE 2 data follows the unblinding of the trial at interim analysis in September and a presentation of additional efficacy and safety data last month at the HIV Research for Prevention Conference in Lima, Peru. Those previously reported data showed that lenacapavir reduced HIV infections by 96% compared to background HIV incidence (bHIV), with two incident cases among 2,179 participants, corresponding to 99.9% of participants not acquiring HIV infection in the lenacapavir group. Twice-yearly lenacapavir also demonstrated superiority to once-daily Truvada ® (emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg; F/TDF) for pre-exposure prophylaxis (PrEP) and was generally well-tolerated, with no significant or new safety concerns identified. “ We’re at a crossroads in the HIV epidemic, and a twice-yearly choice for HIV prevention, if approved, could be transformative as we work toward achieving the UNAIDS 2030 targets around the world,” said PURPOSE 2 Principal Investigator Onyema Ogbuagu, MBBCh, FACP, FIDSA, Associate Professor of Medicine and Pharmacology at Yale School of Medicine and Director of the Yale Antivirals and Vaccines Research Program. “ Lenacapavir for PrEP could provide an important alternative to existing preventative medications that require more frequent dosing, and could help transform the HIV prevention landscape by addressing a range of unmet needs for individuals who need or want PrEP globally.” Participants demonstrated high adherence to lenacapavir and injections Adherence to lenacapavir and to the placebo injections that were part of the oral PrEP study group was high: 91.0% of all trial participants received on-time injections at week 26, and 92.8% of participants received on-time injections at one year. On-time injection rates (within 28 weeks of prior injection) were similar across both study groups, whether receiving lenacapavir or placebo injections. Lenacapavir reduced HIV infections by 96% compared to background HIV incidence (bHIV) Lenacapavir was highly effective at reducing HIV infections among trial participants: 99.9% of participants did not acquire HIV in the lenacapavir group, with two incident cases among 2,179 participants (0.10/100 person-years, 95% CI, 0.01 to 0.37), despite reported high levels of sexual behavior, chemsex and sexually transmitted infections observed among PURPOSE 2 participants. The results demonstrated superiority of twice-yearly lenacapavir over bHIV (2.37/100 person-years, 95% CI, 1.65 to 3.42; primary endpoint), with 96% relative risk reduction (IRR 0.04; 95% CI, 0.01 to 0.18; p<0.0001). Additionally, twice-yearly lenacapavir was 89% more effective at reducing HIV infections than once-daily Truvada (IRR 0.11; 95% CI, 0.02 to 0.51; p=0.00245). Lenacapavir plasma concentrations for the two participants who acquired HIV in this group were within the range of the overall lenacapavir concentrations in the pre-selected, representative subset of participants whose blood plasma levels were tested. Lenacapavir plasma concentrations were also similar to those in prior studies that included lenacapavir. Trial data confirm that both participants acquired HIV after receiving their first injections of lenacapavir but prior to their second injections, and both participants were diagnosed using standard HIV tests. Importantly, based on retrospective standard HIV-1 RNA viral load testing of prior visit samples, there was no delayed HIV diagnosis for either person. The HIV PrEP field has paid particular attention to the potential for delayed diagnosis for individuals who acquire HIV when using long-acting PrEP. Cases of HIV infection despite high adherence to other forms of PrEP, including Truvada, have been reported, often in the context of high exposures to HIV and repeated mucosal injury. Gilead has offered open-label lenacapavir to all trial participants in PURPOSE 1 (evaluating lenacapavir for PrEP among cisgender women) and is offering open-label lenacapavir to all participants in PURPOSE 2, and will continue to follow participants and test for incident HIV infection. Truvada adherence was initially high but declined over time Adherence to Truvada, measured through detection of tenofovir diphosphate in blood samples from a subset of random participants, was initially high but declined over time: tenofovir diphosphate levels consistent with high adherence (four or more tablets per week) were seen in 82% of participants at week 8, 67% at week 26 and 62% at one year. In the Truvada group, nine incident HIV infections occurred, all in participants with low or no adherence There were nine incident cases among 1,086 individuals in the Truvada group (0.93/100 person-years; 95% CI, 0.43 to 1.77; secondary endpoint). These nine participants had evidence of low or no adherence to Truvada, or had discontinued taking it more than 10 days prior to diagnosis. Among the nine participants, two had low levels of tenofovir diphosphate, six had levels below the quantification limit, and one person who was missing a dried blood spot sample had discontinued Truvada. PURPOSE 2 trial background PURPOSE 2 is a Phase 3, double-blind, multicenter, randomized study evaluating the safety and efficacy of twice-yearly subcutaneous lenacapavir for PrEP versus bHIV and once-daily oral Truvada in 3,271 cisgender gay, bisexual, and other men, transgender women, transgender men, and gender non-binary individuals aged 16 years or older who have sex with partners assigned male at birth. The trial spanned 88 sites in Argentina, Brazil, Mexico, Peru, South Africa, Thailand and the United States, and participants were randomized in a 2:1 ratio to lenacapavir and Truvada, respectively. Because effective PrEP options already exist, there is broad consensus in the PrEP field that a placebo group would be unethical; thus, the trial used bHIV as the primary comparator and Truvada as a secondary comparator. PURPOSE 2 is the second pivotal Phase 3 trial to demonstrate superior efficacy for twice-yearly lenacapavir for the investigational use of HIV prevention as PrEP, and to be unblinded early because it met its key efficacy endpoints. In June 2024, the PURPOSE 1 trial ( NCT04994509 ), studying lenacapavir for PrEP among cisgender women in sub-Saharan Africa, was also unblinded early because it met its key efficacy endpoints. Gilead continues to focus on global access strategies, including for low-, middle- and high-income countries Data from both PURPOSE 1 and PURPOSE 2 will support a series of global regulatory filings for lenacapavir for PrEP that will begin by the end of 2024. Last month, the FDA granted lenacapavir for PrEP Breakthrough Therapy Designation, which is intended to expedite the development and review of new drugs that may demonstrate substantial improvement over available therapy. Also last month, the FDA granted a rolling review for lenacapavir for PrEP, a process that allows the FDA to expedite the review of a drug application by allowing a company to submit sections of the application for review as they are completed. Gilead is executing an access strategy, informed by more than 100 global health advocates and organizations, that prioritizes speed and enables the most efficient paths for the regulatory review and approval of lenacapavir for PrEP in regions around the world. Last month, Gilead announced that it had signed non-exclusive, royalty-free voluntary licensing agreements with six pharmaceutical companies to manufacture and supply high-quality, low-cost versions of lenacapavir for 120 high-incidence, resource-limited countries, which are primarily low- and lower-middle income countries. Additionally, Gilead is actively working on additional ways to support access in upper-middle and high-income countries to establish fast, efficient pathways to help reach people who need or want PrEP, including expediting regulatory filings, engagement with partners and governments, and manufacturing infrastructure planning. Additionally, in countries with PURPOSE 2 trial sites, including Argentina, Brazil, Mexico, Peru and the United States, trial participants are being offered and will be able to stay on open-label lenacapavir until it is available in their country. “ Gilead recognizes the importance of prevention in ending the HIV epidemic and is deeply committed to ensuring broad, sustainable global access to lenacapavir for PrEP, if approved,” said Jared Baeten, MD, PhD, Senior Vice President, Clinical Development and Virology Therapeutic Area Head, Gilead Sciences. Updates on regulatory filings for lenacapavir for PrEP will be shared as discussions with regulatory bodies progress. The use of lenacapavir for the prevention of HIV is investigational and has not been determined to be safe or efficacious and is not approved anywhere globally. There is currently no cure for HIV or AIDS. About the PURPOSE Program Gilead’s landmark PURPOSE program is the most comprehensive and diverse HIV prevention trial program ever conducted. The program comprises five HIV prevention trials around the world that are focused on innovation in science, trial design, community engagement and health equity. The PURPOSE trials are evaluating the safety and efficacy of an investigational, twice-yearly injectable medicine, lenacapavir, to reduce the chance of getting HIV. The Phase 2 and 3 program, consisting of PURPOSE 1-5, is assessing the potential of lenacapavir to help a diverse range of people around the world who could benefit from PrEP. More information about the PURPOSE program, including individual trial descriptions, populations and locations, can be found at www.purposestudies.com . A bout Lenacapavir Lenacapavir is approved in multiple countries for the treatment of adults with multi-drug resistant HIV in combination with other antiretrovirals. The use of lenacapavir for HIV prevention is investigational and the safety and efficacy of lenacapavir for this use have not been established. The multi-stage mechanism of action of lenacapavir is distinguishable from other currently approved classes of antiviral agents. While most antivirals act on just one stage of viral replication, lenacapavir is designed to inhibit HIV at multiple stages of its lifecycle and has no known cross resistance exhibited in vitro to other existing drug classes. Lenacapavir is being evaluated as a long-acting option in multiple ongoing and planned early and late-stage clinical studies in Gilead’s HIV prevention and treatment research program. Lenacapavir is being developed as a foundation for potential future HIV therapies with the goal of offering both long-acting oral and injectable options with several dosing frequencies, in combination or as a mono agent, that help address individual needs and preferences of people and communities affected by HIV. About Gilead HIV For more than 35 years, Gilead has been a leading innovator in the field of HIV, driving advances in treatment, prevention and cure research. Gilead researchers have developed 12 HIV medications , including the first single-tablet regimen to treat HIV, the first antiretroviral for pre-exposure prophylaxis (PrEP) to help reduce new HIV infections, and the first long-acting injectable HIV treatment medication administered twice-yearly. Our advances in medical research have helped to transform HIV into a treatable, preventable, chronic condition for millions of people. Gilead is committed to continued scientific innovation to provide solutions for the evolving needs of people affected by HIV around the world. Through partnerships , collaborations and charitable giving, the company also aims to improve education, expand access and address barriers to care, with the goal of ending the HIV epidemic for everyone, everywhere. Gilead was recognized as one of the leading philanthropic funders of HIV-related programs in a report released by Funders Concerned About AIDS. Forward-Looking Statements This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including Gilead’s ability to initiate, progress and complete clinical trials in the anticipated timelines or at all, and the possibility of unfavorable results from ongoing and additional clinical trials, including those involving lenacapavir (such as PURPOSE 1 and PURPOSE 2); uncertainties relating to regulatory applications and related filing and approval timelines, including regulatory applications for lenacapavir for PrEP, and the risk that any regulatory approvals, if granted, may be subject to significant limitations on use or subject to withdrawal or other adverse actions by the applicable regulatory authority; the possibility that Gilead may make a strategic decision to discontinue development of lenacapavir for indications currently under evaluation and, as a result, lenacapavir may never be successfully commercialized for such indications; Gilead’s ability to effectively manage the supply and distribution of lenacapavir, including through direct supply as well as indirect supply through the voluntary licensing agreements, and the ability of the parties to meet potential demand for lenacapavir, in each case, subject to necessary regulatory approvals; and any assumptions underlying any of the foregoing. These and other risks, uncertainties and factors are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2024, as filed with the U.S. Securities and Exchange Commission. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. The reader is cautioned that any such forward-looking statements are not guarantees of future performance and involve risks and uncertainties, and is cautioned not to place undue reliance on these forward-looking statements. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation and disclaims any intent to update any such forward-looking statements. U.S. full Prescribing Information for Truvada, including Boxed Warning, and lenacapavir are available at www.gilead.com . Gilead and the Gilead logo, Truvada, and Truvada for PrEP are registered trademarks of Gilead Sciences, Inc., or its related companies. For more information about Gilead, please visit the company’s website at www.gilead.com , follow Gilead on X/Twitter (@Gilead Sciences) and LinkedIn (@Gilead-Sciences).