Rifampin

– New Data from PURPOSE Trials Further Demonstrate that Lenacapavir (Yeztugo ® ) was Effective and Well Tolerated Across a Broad Range of Populations, Including Pregnant and Lactating Women, Adolescents and Young People – – Data Also Showed Twice-Yearly Injectable PrEP was Preferred vs. Daily Oral Medication Among PURPOSE Trial Participants – – Gilead’s Research Presentations and Community Events at IAS Reflect Commitment to Partnerships in Developing Person-Centered Options for a Diverse Range of Populations – FOSTER CITY, CA, USA I July 14, 2025 I Gilead Sciences, Inc. (Nasdaq: GILD) today announced that Gilead researchers and collaborators will present new Phase 3 PURPOSE trial data at IAS 2025 showing that twice-yearly lenacapavir (Yeztugo ® ) was effective and well tolerated among a broad range of populations who need or want pre-exposure prophylaxis (PrEP) for HIV prevention, including pregnant and lactating women, adolescents and young people, and supports lenacapavir dosing recommendations for people in special situations, such as those taking medication to treat tuberculosis (TB) and other conditions. Researchers will also present new quantitative and qualitative data showing that participants in both Phase 3 PURPOSE trials indicated a preference for twice-yearly PrEP injections over daily oral medication. The new data, from the company’s pivotal Phase 3 PURPOSE 1 ( NCT04994509 ) and PURPOSE 2 ( NCT04925752 ) trials that assessed the efficacy and safety of twice-yearly Yeztugo for PrEP, will be presented via poster sessions and during a Yeztugo-dedicated oral session at the International AIDS Society (IAS) 2025, the 13 th IAS Conference on HIV Science in Kigali, Rwanda on Thursday, July 17. The data presentations come less than a month after the U.S. Food and Drug Administration (FDA) approved Yeztugo as the first and only twice-yearly HIV prevention option. The data underscore Gilead’s focus on intentional inclusion in the PURPOSE program to ensure broad and robust population data at the trials’ primary analyses, as well as spotlight the community and organizational collaborations that guided the trial design and implementation process. “It’s a thrill to be back in Kigali with so many of the community, advocacy and research partners who helped make PURPOSE the most intentionally inclusive HIV prevention trial program ever conducted,” said Moupali Das, Vice President of Clinical Development, HIV Prevention & Pediatrics at Gilead Sciences. “As the first and only twice-yearly PrEP option, Yeztugo continues to demonstrate efficacy and tolerability among diverse populations, and we’re excited to highlight new data on this breakthrough HIV prevention option here at IAS 2025.” Yeztugo was Efficacious and Well Tolerated in Trials Among Pregnant and Lactating Women, Adolescents and Young People, and Can Be Administered in People Receiving Treatment for TB and Other Conditions Pregnant and lactating women—who face a heightened likelihood of acquiring HIV—have historically been excluded from HIV prevention trials. Based on input from community meetings in locations including Kigali, Gilead ensured that pregnant and lactating women were included in the Phase 3 PURPOSE 1 trial, which evaluated twice-yearly Yeztugo in cisgender women and adolescent girls in Sub-Saharan Africa. PURPOSE data presented at IAS 2025 show that Yeztugo was efficacious in pregnant and breastfeeding or lactating women, with no new cases of HIV reported among 184 participants in the Yeztugo group (there were a total of 509 pregnancies among 487 participants in PURPOSE 1). Data also show that Yeztugo was well tolerated by these women, that there were similar safety profiles between pregnant and non-pregnant women, and that there were no clinically significant differences in predicted Yeztugo exposure by pregnancy trimester or postpartum status. Additionally, exposure in breastfed infants was minimal. Young people aged 16-25 years are also at an increased likelihood of experiencing HIV acquisition globally, but, like pregnant women, are often not proactively included in Phase 3 HIV prevention trials. Gilead intentionally included this population in the PURPOSE 1 trial and the PURPOSE 2 trial, which evaluated twice-yearly Yeztugo among a broad and geographically diverse range of cisgender men and gender-diverse people. Data presented at IAS 2025 show that Yeztugo was efficacious in people aged 16-25 years, with zero reported HIV infections in young people receiving Yeztugo in PURPOSE 1 and two HIV infections among young people in PURPOSE 2. Additionally, there were no clinically significant pharmacokinetic differences between the 16-25-year-old group and adults aged over 25 years. Yeztugo was well tolerated across both trials among participants of all ages, with no new safety concerns identified. Globally, those at higher likelihood of HIV acquisition may also be vulnerable to TB, which can be treated by rifamycin-class drugs including rifampin and rifabutin. Yeztugo is a substrate of CYP3A, and strong CYP3A inducers such as rifampin, or moderate inducers such as rifabutin, may potentially lower Yeztugo plasma concentrations. Gilead will present modeling data showing supplemental Yeztugo dosing for strong and moderate CYP3A inducers to allow people receiving Yeztugo to receive rifamycin-containing TB treatment, if necessary. Yeztugo is also a moderate inhibitor of CYP3A and could theoretically increase levels of drugs such as statins for lowering cholesterol or PDE5 inhibitors for treating erectile dysfunction; dosing recommendations for these special situations will also be reviewed. Preference for Twice-Yearly Prevention Option Over Daily Oral PrEP New qualitative and quantitative self-reported data from PURPOSE 1 and PURPOSE 2 show significant preference for twice-yearly injectable PrEP compared with daily oral PrEP among study participants. More than 75% of study participants who were surveyed preferred twice-yearly injectable administration; of these, more than 50% reported a strong preference. Reasons given for favoring twice-yearly injectable PrEP versus daily oral PrEP include feeling more protected from HIV (69%) and feeling more confident about not missing a dose (77%). “Certain groups—including pregnant and lactating women, adolescents and young people—are disproportionately affected by HIV, yet have long been underrepresented in HIV clinical trials,” said Linda-Gail Bekker, MBChB, DTM&H, DCH, FCP(SA), PhD, Director of the Desmond Tutu HIV Center at the University of Cape Town, South Africa, and former President of the International AIDS Society. “The PURPOSE program set a new standard for innovative, intentional inclusion by ensuring we would have safety and efficacy data in these populations from the outset. The results not only show that Yeztugo provides strong protection against HIV and was well tolerated in these groups, but also highlight the critical need for PrEP options that reflect people’s preferences—reducing barriers to uptake and helping close persistent gaps in prevention.” Continued Global Regulatory Filings for Lenacapavir for PrEP, as Well as Milestone Partnerships On June 18, 2025, Gilead received FDA approval for Yeztugo as PrEP to reduce the risk of sexually acquired HIV in adults and adolescents weighing at least 35kg. Gilead has also submitted a marketing authorization application (MAA) and EU-Medicines for all (EU-M4all) application with the European Medicines Agency (EMA), both of which the EMA has validated and will review under an accelerated assessment timeline. Gilead has also filed for regulatory approval for twice-yearly lenacapavir for PrEP with authorities in Australia, Brazil , Canada, South Africa and Switzerland. Additionally, now that lenacapavir has received FDA approval for PrEP, Gilead is preparing additional filings in countries that rely on stringent regulatory authority approvals for regulatory submission, including Argentina, Mexico and Peru. Gilead will continue to share updates on additional regulatory filings. Lenacapavir for HIV prevention is not approved by any regulatory authority outside of the United States. Last week, Gilead announced a strategic partnership agreement with The Global Fund to Fight AIDS, Tuberculosis and Malaria to supply enough doses of lenacapavir, at no profit to Gilead, to reach up to two million people over three years in countries supported by the Global Fund and that are included in Gilead’s voluntary licensing agreements for lenacapavir . There is currently no cure for HIV or AIDS. Please see below for U.S. Indication and Important Safety Information, including Boxed Warning , for Yeztugo. 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 the, 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 . About Lenacapavir Lenacapavir is approved in multiple countries for the treatment of multi-drug-resistant HIV in adults, in combination with other antiretrovirals. Lenacapavir is also approved in the United States to reduce the risk of sexually acquired HIV in adults and adolescents weighing at least 35kg who are at risk of HIV acquisition. 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. The journal Science named lenacapavir its 2024 “Breakthrough of the Year.” U.S. Indication for Yeztugo Yeztugo (lenacapavir) injection, 463.5 mg/1.5 mL, is indicated for pre‑exposure prophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1 in adults and adolescents (>35kg) who are at risk for HIV-1 acquisition. Individuals must have a negative HIV-1 test prior to initiating Yeztugo. 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 13 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 has been recognized as one of the leading philanthropic funders of HIV-related programs in a report released by Funders Concerned About AIDS. About Gilead Sciences Gilead Sciences, Inc. is a biopharmaceutical company that has pursued and achieved breakthroughs in medicine for more than three decades, with the goal of creating a healthier world for all people. The company is committed to advancing innovative medicines to prevent and treat life-threatening diseases, including HIV, viral hepatitis, COVID-19, cancer and inflammation. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California. SOURCE: Gilead Sciences

小分子化学创新药是指分子量通常小于1000道尔顿的化学合成药物，具有明确的化学结构和作用机制，作用靶点广泛，可以针对细胞内的蛋白质、酶、受体等多种生物分子进行调节。近年来，国产小分子化学创新药研发和临床领域取得了显著进展，但也面临着诸多挑战。本文将从研发现状、技术突破、临床现状、面临的挑战及未来发展趋势等方面进行详细阐述，以期为相关研究和产业发展提供参考。(一)研发现状自20世纪50年代至世纪末，我国药物研发处于跟踪模仿阶段，市场上的药物以成本低廉的仿制药、普药为主，小分子化学药的研发也主要集中在对国外已上市药物的仿制和改良上，缺乏自主创新能力。进入21世纪，随着研发能力和工业化水平的不断提高，我国的药物研发进入模仿创新阶段，开始针对已知靶点设计与已存在药物结构不同的新药，如一些小分子靶向药物的开发，但本质上仍属于仿制思路。1.1 政策支持推动研发加速自2015年国务院发布《关于改革药品医疗器械审评审批制度的意见》以来，中国药品审评审批制度改革不断深化。随着一系列鼓励新药创制、提升药品质量、促进产业升级的政策出台，我国药物研究开始迈向原始创新阶段，国产小分子化学创新药研发逐渐向真正意义上的原研和创新方向靠拢，开始对标同类最优或同类首创品种，向“全球新”方向迈进。2024年11月15日，国家药监局正式批准了首个优化创新药临床试验审评审批试点项目，大大缩短了创新药的研发和上市周期，为国产小分子化学创新药研发创造了有利条件。1.2 研发管线数量增长2023年，中国治疗用创新生物制品新药临床试验申请（IND）注册申请受理数量达到1070件（包括创新治疗用生物制品833件），为统计时间段内的峰值；预防用创新生物制品IND注册申请受理也呈逐年增长的趋势，2023年共有74件受理事件。这表明中国创新药研发正步入高质量发展阶段，其中小分子化学创新药的研发也呈现出活跃态势。1.3 研发实力逐步提升过去十年，中国创新药企业自研创新药数量位居全球首位，且从模仿逐渐走向源头创新，首创新药（FIC）数量占比不断提升。在小分子化学创新药领域，也取得了一些重大突破，如必贝特开发的盐酸伊吡诺司他，是全球首创的双靶点血癌新药。(二)技术突破2.1 靶向技术小分子靶向药物是目前小分子化学创新药研发的热点方向，通过针对特定的疾病靶点，如激酶、受体等，设计出具有高亲和力和选择性的小分子化合物，实现对疾病的精准治疗。例如，恒瑞医药的马来酸盐吡咯替尼，主要用于乳腺癌治疗，通过靶向特定的激酶，抑制肿瘤细胞的生长和增殖。2.2 PROTAC技术蛋白水解靶向嵌合体（PROTAC）技术是一种新兴的小分子药物研发技术，通过将小分子化合物与泛素-蛋白酶体系统相结合，实现对特定蛋白质的降解，从而达到治疗疾病的目的。该技术为小分子化学创新药的研发提供了新的思路和方向，有望在未来开发出更多具有创新性的药物。2.3 人工智能辅助随着信息技术与生物技术的融合发展，人工智能在小分子化学创新药研发中的应用越来越广泛。通过机器学习、深度学习等技术，可以对大量的药物数据进行分析和挖掘，预测药物的活性、毒性、代谢等性质，加速药物研发的进程。例如，一些企业利用人工智能技术进行药物分子的设计和优化，提高了研发效率和成功率。(三)临床现状3.1 临床试验数量增加随着研发管线的丰富，国产小分子化学创新药进入临床试验的数量也在不断增加。2023年，中国CDE受理注册申请受理号16812个（11455个品种），同比增长37.32%。其中，化药申请受理号11825个（7645个品种），同比增长34.33%，占全年受理量的70.34%；生物制品受理号2214个（1320个品种），同比增长17.58%。3.2 临床试验设计优化在临床试验设计方面，国产小分子化学创新药逐渐向国际先进水平靠拢。例如，一些企业在开展临床试验时，会采用更科学的随机、双盲、对照试验设计，以确保试验结果的准确性和可靠性。同时，也会根据药物的特点和患者的需求，制定个性化的临床试验方案。3.3 临床试验质量提高为了保证临床试验的质量，中国药监部门对临床试验的监管日益严格。临床试验机构需要具备相应的资质和条件，研究人员需要经过专业培训，试验过程需要遵循相关的规范和标准。此外，一些企业还会引入第三方监查机构，对临床试验进行全程监查，确保试验的合规性和数据的可靠性。(四)企业创新4.1 大型药企转型一些老牌大型仿制药企业，如恒瑞医药、正大天晴等，通过加大研发投入、引进高端人才、与国内外科研机构合作等方式，实现了从仿制药向创新药的转型。这些企业在小分子化学创新药研发方面具有强大的研发实力和丰富的经验，不断推出具有自主知识产权的创新药物。4.2 创新药企崛起以贝达药业、百济神州、艾力斯等为代表的创新药企，专注于小分子化学创新药的研发，通过自主创新和国际合作，开发出了一系列具有国际竞争力的创新药物。例如，贝达药业的埃克替尼，是我国首个自主研发的小分子靶向抗肿瘤药，打破了国外药企在该领域的垄断。4.3 初创企业涌现近年来，大量的临床期初创药企涌现，这些企业通常专注于特定的治疗领域或技术平台，凭借灵活的运营模式和创新的研发思路，为小分子化学创新药的研发注入了新的活力。例如，凌科药业专注于第二代高选择性和第三代组织特异性jak抑制剂的研发，已建立起包含4款临床产品在内的研发管线。(五)面临的挑战5.1 同质化竞争严重大量企业集中在同一治疗领域和适应症上，导致资源浪费和恶性内耗，制约了产业的健康发展。这种同质化竞争不仅降低了创新药的研发效率，也增加了企业的经营风险，不利于产业的长期发展。5.2 支付体系单一目前，中国创新药主要依赖医保支付，支付渠道相对单一，难以满足创新药的多元化支付需求。医保定价难，创新药面临进医保回报不足、不进医保缺乏市场的困境。这不仅影响了企业的创新积极性，也限制了创新药的市场发展。5.3 国际化布局困难在全球注册方面，不同国家和地区的法规和标准差异较大，增加了中国创新药企业进入国际市场的难度。此外，国际注册的时间和成本也较高，对企业的资金实力和国际化经验提出了较高要求。临床试验设计是国际化过程中面临的另一个难题，国际临床试验的设计需要考虑不同人群的差异，这增加了试验的复杂性和成本。与此同时，随着全球医药市场的竞争日益激烈，国产小分子化学创新药需要走向国际市场，与国际先进药企竞争。然而，我国在药物研发的国际化方面还存在一定的不足，如对国际法规和标准的了解不够深入、国际临床试验经验不足等，限制了国产创新药的国际化进程。5.4 创新力有待加强尽管国产小分子化学创新药研发取得了显著进展，但在一些关键领域和核心技术上，与国际先进水平仍存在差距。部分企业仍存在跟风创新、伪创新等问题，缺乏真正具有原创性的创新成果。5.5 研发投入有差距小分子化学创新药研发是一个高投入、高风险的过程，需要大量的资金支持。虽然近年来我国医药企业的研发投入有所增加，但仍与国际大型药企相比存在较大差距，限制了研发的深度和广度。5.6 临床试验能力不足临床试验是小分子化学创新药研发的关键环节，需要专业的临床试验团队、完善的临床试验设施和规范的临床试验管理。目前，我国在临床试验能力方面还存在一定的短板，影响了药物研发的进度和质量。(六)总结总的来说，国产小分子化学创新药研发正处于快速发展阶段，虽然面临着诸多挑战，但也有着广阔的发展前景。未来，随着政策支持力度的加大、研发投入的增加、技术创新的不断涌现以及国际化的推进，国产小分子化学创新药有望在全球医药市场中占据更重要的地位，为全球患者提供更多的治疗选择。参考文献：[1] 《2023年度药品审评报告》[2] Mullins ME,Horowitz BZ,Linden DH,et al.Life-threatening interaction of mibefradil and beta-blockers with dihydropyridine calcium channel blockers [J].JAMA,1998,280(2):157-158.[3] Mu S,Tang Z,Novotny W,et al.Effect of rifampin and itraconazole on the pharmacokinetics of zanubrutinib (a Bruton's tyrosine kinase inhibitor) in Asian and non-Asian healthy subjects [J].Cancer Chemother Pharmacol,2020,85(2):391-399.[4] Po AL,Zhang WY.What lessons can be learnt from withdrawal of mibefradil from the market [J]?Lancet,1998,351(9119):1829-1830.作者介绍：Ketty，主要从事药物研发和科普，制药行业政策和发展研究工作。药事纵横投稿须知：稿费已上调，欢迎投稿