更新于：2024-12-24
Filgotinib Maleate
非戈替尼
更新于：2024-12-24
概要
基本信息
原研机构 |
非在研机构- |
最高研发阶段批准上市 |
首次获批日期 欧盟 (2020-09-24), |
最高研发阶段(中国)- |
特殊审评孤儿药 (美国) |
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结构
分子式C25H27N5O7S |
InChIKeyBFENHEAPFWQJFL-BTJKTKAUSA-N |
CAS号1802998-75-9 |
关联
78
项与 非戈替尼 相关的临床试验JAK Inhibitor Dose TAPering Strategy Study in Low Disease Activity Rheumatoid Arthritis Patients
This study aims to assess the feasibility of tapering JAK inhibitors in rheumatoid arthritis patients in low disease activity by comparing a group of patients tapering the JAK inhibitor dosage to a group of patients continuing the full-dose.
Participants will:
* Either take
1. JAK inhibitor dose-tapering strategy.
2. JAK inhibitor continuous therapy strategy.
* Visit the clinic once every 3 months for checkups and tests
* Keep a diary of their treatment intake and symptoms
Participants will:
* Either take
1. JAK inhibitor dose-tapering strategy.
2. JAK inhibitor continuous therapy strategy.
* Visit the clinic once every 3 months for checkups and tests
* Keep a diary of their treatment intake and symptoms
开始日期2025-01-01 |
申办/合作机构 |
A Multicenter, Open-label, Single-arm, Phase 4 Study to Evaluate the Efficacy and Safety of Filgotinib in Korean Patients With Rheumatoid Arthritis
The primary purpose of this study is to assess the percentage of participants achieving an American College of Rheumatology (ACR) 20 percent (%) Improvement (ACR20) response at Week 12 of the administration of the investigational product.
开始日期2024-10-22 |
申办/合作机构 |
Exploring the Effects of Filgotinib, an Oral JAK-1 Selective Inhibitor, Proteomic Profile and Micro-RNA Expression in Peripheral Blood Mononuclear Cell (PBMC) of Patients With Active Rheumatoid Arthritis (RA)
Purpose:
The study aims to investigate how Filgotinib affects proteins and micro-RNA in the blood of patients with rheumatoid arthritis. This could help understand its impact on inflammation and bone health in these patients.
Study Design:
This is a single-center, prospective randomized study.
The study aims to investigate how Filgotinib affects proteins and micro-RNA in the blood of patients with rheumatoid arthritis. This could help understand its impact on inflammation and bone health in these patients.
Study Design:
This is a single-center, prospective randomized study.
开始日期2024-07-15 |
申办/合作机构 |
100 项与 非戈替尼 相关的临床结果
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100 项与 非戈替尼 相关的转化医学
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100 项与 非戈替尼 相关的专利（医药）
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312
项与 非戈替尼 相关的文献（医药）2024-12-31·Virulence
Immunosuppressants exert antiviral effects against influenza A(H1N1)pdm09 virus via inhibition of nucleic acid synthesis, mRNA splicing, and protein stability
Article
作者: Pu, Feiyang ; Wang, Xin ; Feng, Xili ; Yang, Xuanye ; Duan, Kai ; Ma, Zhongren ; Nian, Xuanxuan ; Yang, Xiao-Ming ; Zhang, Jiayou ; Ma, Xiao-Xia
Influenza A virus (IAV) poses a threat to patients receiving immunosuppressive medications since they are more susceptible to infection with severe symptoms, and even death. Understanding the direct effects of immunosuppressants on IAV infection is critical for optimizing immunosuppression in these patients who are infected or at risk of influenza virus infection. We profiled the effects of 10 immunosuppressants, explored the antiviral mechanisms of immunosuppressants, and demonstrated the combined effects of immunosuppressants with the antiviral drug oseltamivir in IAV-infected cell models. We found that mycophenolic acid (MPA) strongly inhibits viral RNA replication via depleting cellular guanosine pool. Treatment with 6-Thioguanine (6-TG) promoted viral protein degradation through a proteasomal pathway. Filgotinib blocked mRNA splicing of matrix protein 2, resulting in decreased viral particle assembly. Furthermore, combined treatment with immunosuppressants and oseltamivir inhibits IAV viral particle production in an additive or synergic manner. Our results suggest that MPA, 6-TG, and filgotinib could be the preferential choices for patients who must take immunosuppressants but are at risk of influenza virus infection.
2024-12-01·GASTROENTEROLOGY
AGA Living Clinical Practice Guideline on Pharmacological Management of Moderate-to-Severe Ulcerative Colitis
Review
作者: Haydek, John P ; Limketkai, Berkeley N ; Loftus, Edward V ; Haydek, John P. ; Loftus, Edward V. ; Singh, Siddharth ; Limketkai, Berkeley N. ; Scott, Frank I. ; Agrawal, Manasi ; Scott, Frank I ; Ananthakrishnan, Ashwin N ; Ananthakrishnan, Ashwin N.
BACKGROUND & AIMS:
This American Gastroenterological Association (AGA) living guideline is intended to support practitioners in the pharmacological management of moderate-to-severe ulcerative colitis (UC).
METHODS:
A multidisciplinary panel of content experts and guideline methodologists used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework to prioritize clinical questions, identify patient-centered outcomes, conduct an evidence synthesis, and develop recommendations on the pharmacological management of moderate-to-severe UC.
RESULTS:
The AGA guideline panel made 14 recommendations. In adult outpatients with moderate-to-severe UC, the AGA recommends the use of infliximab, golimumab, vedolizumab, tofacitinib, upadacitinib, ustekinumab, ozanimod, etrasimod, risankizumab, and guselkumab, and suggests the use of adalimumab, filgotinib, and mirikizumab over no treatment. In patients who are naïve to advanced therapies, the AGA suggests using a higher-efficacy medication (eg, infliximab, vedolizumab, ozanimod, etrasimod, upadacitinib, risankizumab, and guselkumab) or an intermediate-efficacy medication (eg, golimumab, ustekinumab, tofacitinib, filgotinib, and mirikizumab) rather than a lower-efficacy medication (eg, adalimumab). In patients who have previously been exposed to 1 or more advanced therapies, particularly tumor necrosis factor (TNF)-α antagonists, the AGA suggests using a higher-efficacy medication (eg, tofacitinib, upadacitinib, and ustekinumab) or an intermediate-efficacy medication (eg, filgotinib, mirikizumab, risankizumab, and guselkumab) rather than a lower-efficacy medication (eg, adalimumab, vedolizumab, ozanimod, and etrasimod). In adult outpatients with moderate-to-severe UC, the AGA suggests against using thiopurine monotherapy for induction of remission, but suggests using thiopurine monotherapy over no treatment for maintenance of (typically corticosteroid-induced) remission. The AGA suggests against using methotrexate monotherapy, for induction or maintenance of remission. In adult outpatients with moderate-to-severe UC, the AGA suggests the use of infliximab, adalimumab, and golimumab in combination with an immunomodulator over corresponding monotherapy. However, the AGA makes no recommendation in favor of, or against, the use of non-TNF antagonist biologics in combination with an immunomodulator over non-TNF biologic alone. In patients with UC who are in corticosteroid-free clinical remission for at least 6 months on combination therapy of TNF antagonists and an immunomodulator, the AGA suggests against withdrawal of TNF antagonists, but makes no recommendation in favor of, or against, withdrawing immunomodulators. In adult outpatients with moderate-to-severe UC, who have failed 5-aminosalicylates, and have escalated to therapy with immunomodulators or advanced therapies, the AGA suggests stopping 5-aminosalicylates. Finally, in adult outpatients with moderate-severe UC, the AGA suggests early use of advanced therapies and/or immunomodulator therapy, rather than gradual step-up after failure of 5-aminosalicylates. The panel also proposed key implementation considerations for optimal use of these medications and identified several knowledge gaps and areas for future research.
CONCLUSIONS:
This guideline provides a comprehensive, patient-centered approach to the pharmacological management of patients with moderate-to-severe UC.
2024-12-01·Lancet Gastroenterology & Hepatology
Does filgotinib work for Crohn's disease?
Article
作者: Ainsworth, Mark Andrew
125
项与 非戈替尼 相关的新闻（医药）2024-12-15
·精准药物
自2001年imatinib（伊马替尼，商品名：格列卫）获批以来，小分子激酶抑制剂（SMKI）已发展成为癌症治疗的一类主要靶向疗法。公开资料显示，过去的二十年里，已超过100个SMKI获得了美国食品药品监督管理局(FDA)（约80个）和中国国家药品监督管理局(NMPA)（22个）的批准，为人类健康带来了显著效益。
然而，SMKI存在一个不可忽视的“短板”：即患者会发展出耐药性。这种情况通常在临床治疗大约1-2年后出现，导致需要更换治疗方案，不得不采用其他替代治疗策略或使用更新一代的激酶抑制剂。
本文以Nature Reviews Drug Discovery（2024年影响因子122.7）的一篇综述为蓝本，讨论激酶抑制剂的定义（划分标准）及设计趋势，包括变构和共价抑制剂、双功能抑制剂和化学降解剂的开发。
文末链接可跳转原文
2021年8月5日Uppsala University（瑞典乌普萨拉大学）的Helgi B. Schiöth课题组在Nat. Rev. Drug Discov.以“Trends in kinase drug discovery: targets, indications and inhibitor design”为题发表综述。
全文内容两万余字，详尽阐述了激酶类药物的各方面信息，仅供学术交流。
目 录
1
Introduction
/
2
已上市的激酶抑制剂
2.1 激酶家族和靶标中已批准的药物
2.2 肿瘤适应症的激酶抑制剂
2.3 肿瘤适应症之外的激酶抑制剂
2.4 药物分类
3
激酶抑制剂设计的趋势
3.1 激酶催化结构域的结构特征
3.2 理性设计抑制剂的策略
3.3 激酶抑制剂的化学结构趋势
3.4 变构抑制剂
3.5 共价抑制剂
3.6 大环化合物
3.7 双功能抑制剂
4
研究性药物的发展趋势
4.1 激酶抑制剂临床试验的成功率
4.2 激酶家族的在研药物靶标
4.3 新型靶点肿瘤学的激酶抑制剂
4.4 新型靶点肿瘤学以外的激酶抑制剂
4.5 已停止开发抑制剂的激酶
5
展望
/
1. Introduction
由激酶和磷酸酶介导的可逆蛋白质磷酸化在调节细胞功能（例如细胞增殖、凋亡、亚细胞易位、炎症和代谢）方面具有关键作用。人类激酶组由约560种蛋白激酶组成，其中包括约500种真核蛋白激酶(ePK)，分为八个主要组，例如酪氨酸激酶，以及约60种非典型蛋白激酶，例如具有保守激酶的脂质激酶与ePK类似，但与ePK的其他高度保守的序列基序不同。
自20世纪80年代以来，蛋白激酶已被认为是潜在的药物靶点，特别是基于对癌症的分子理解的进展，包括SRC等癌基因的发现。然而，由于细胞中ATP浓度高、对激酶活性调节和保守的ATP结合口袋了解甚少，开发与ATP位点结合的蛋白激酶抑制剂最初被视为难以克服的挑战。尽管如此，天然化合物staurosporine因其强大的激酶抑制活性而受到人们追捧，尽管选择性较差。到20世纪80年代末，这为识别并优化针对ATP结合位点、具有合适药物性质、选择性和效力的合成小分子激酶抑制剂（SMKIs）铺平了道路。
在上世纪90年代此类努力下，两种激酶抑制剂获得了监管部门的批准。Fasudil（法舒地尔）是一种Rho相关卷曲螺旋蛋白激酶（ROCK1和ROCK2）抑制剂，于1995年在日本被批准用于治疗脑血管痉挛，但Fasudil的ROCK抑制活性直到1997年才被描述。Sirolimus（西罗莫司）是一种天然产物，在雷帕霉素机制靶点(mTOR)的发现中发挥了关键作用，于1999年成为第一个在美国上市的激酶抑制剂。FDA批准用于预防器官排斥，现在回想起来，它也是第一个变构激酶抑制剂。鉴于这两种药物的开发经验，伊马替尼（CGP 57148、STI571）于1992年在Ciba-Geigy实验室发现，并于2001年获得FDA批准，被视作激酶抑制剂开发中的一项关键里程碑。伊马替尼可有效抑制多种酪氨酸激酶，包括BCR-ABL和血小板衍生生长因子受体(PDGFR)，最初被批准用于治疗BCR-ABL驱动的慢性粒细胞性白血病(CML)，随后用于其他适应症，例如治疗KIT驱动的胃肠道肿瘤(GIST)。其显著的临床效果成为肿瘤学领域分子靶向治疗活动激增的催化剂，过去的二十年里，激酶抑制剂在这一领域一直占据着重要地位。
近期对激酶抑制剂的综述描述了激酶药物发现的重要方面，包括靶向途径和蛋白质家族，仅FDA批准的SMKI，相关疾病适应症或结构方面。然而，据我们所知，还没有发表过关于临床试验中激酶抑制剂和激酶靶点的综合分析，由此我们单独撰文（有关数据集和分析的来源的详细信息，参阅正文Box 1）。我们介绍了FDA批准的激酶抑制剂和药物在临床试验中的趋势，这些趋势可以扩大治疗靶向的激酶组的比例。考虑到这些机会，我们还讨论了激酶抑制剂设计的趋势和策略。2. 已上市的激酶抑制剂
自1995年Fasudil获批以来，全球获批的激酶抑制剂数量已增至98种药物[该文发表于2021年，故与笔者在推文开始时的数据有出入]，其中71种为已获得FDA批准的SMKI（截至2021年5月）。值得注意的是，过去5年批准的SMKI数量增加了一倍以上，FDA批准了37个药物，SMKI约占2016-2021年FDA批准的所有新药的15%。FDA还批准了10种靶向受体酪氨酸激酶(RTKs)的单克隆抗体(mAbs)。另外16种SMKI和一种mAb已获得其他监管机构的批准（详见下表）。
2.1 激酶家族和靶标中已批准的药物
FDA批准的71个SMKI靶向21个激酶家族，约占激酶组的20%，这与之前对蛋白激酶靶点覆盖范围的估计相对应。已获得FDA批准的药物靶向的激酶（通常被认为是通过行业标准进行临床验证的）包括八个主要ePK组中五个家族的成员（TK、TKL、STE、CMGC和AGC），其中一个家族属于非典型蛋白激酶组(PIKK)和脂质激酶中的一个家族（PI3K；磷脂酰肌醇-4,5-二磷酸-3-激酶）。具体来说，这71个SMKI主要抑制这些组中的大约42个蛋白质，其中大多数（49个SMKI）主要针对TK组中15个家族成员的30个蛋白质（图2）。尽管TK组是利用最多的激酶组，但只有大约30%是有针对性的，这表明仍有很大的进一步探索空间。
RTK的HER家族(HER1-4)成员是最具针对性的，有8种FDA批准的SMKI和8种FDA批准的mAb专门针对这些蛋白质。RTK的血管内皮生长因子受体(VEGFR)家族也受到了广泛的研究，其中有7种SMKI和一种mAb已获得FDA批准，尽管所有SMKI都是非选择性抑制剂，也与其他RTK相互作用。Janus激酶(JAK)的抑制是另一种流行的治疗策略，迄今为止，针对该家族的五种SMKI已获得FDA批准。
2.2 肿瘤适应症的激酶抑制剂
有大量临床证据支持激酶在癌症中的驱动作用，因为它们通过易位或激活突变而异常激活。染色体易位产生定位异常的融合蛋白，可能具有潜在致癌性。这些疾病驱动因素的识别和表征促进了分子引导癌症疗法的设计和批准，首先是伊马替尼治疗由BCR-ABL易位驱动的慢性粒细胞白血病（CML）的开创性例子，这种易位导致蛋白的酪氨酸激酶活性升高。
大多数FDA批准的SMKI（61个；89%）和所有FDA批准的靶向激酶的mAb（10种mAb）均具有肿瘤学适应症。继伊马替尼之后，迄今为止还有四种针对ABL的SMKI已获得批准：尼洛替尼、达沙替尼、博舒替尼和帕纳替尼（有关ABL抑制剂开发的详细信息，参见Box 2）。值得注意的是，SMKI治疗CML已被证明是持久的，并且相当大比例的慢性期CML患者(高达40%)在停止治疗后没有复发。
在我们集中处理已批准药物数据中，超过20%（19种SMKI和2种mAb）被批准用于非小细胞肺癌（NSCLC）的治疗。考虑到肺癌是男性和女性中最主要的癌症死亡原因，并且80-85%的肺癌病例是非小细胞肺癌，这一点非常重要。对于NSCLC的批准药物说明了激酶抑制剂在肿瘤学领域的总体发展趋势：识别肿瘤的分子特征能够促进第一代SMKI的研发及应用，并指导进一步的药物研发以克服耐药性的出现。事实上，针对获得性耐药的下一代抑制剂占到了针对七个主要激酶基因家族（NTRK、ABL、ALK、BTK、FLT3、KIT和MET）的药物的70%。新一代测序（Next-generation sequencing）已经成为非小细胞肺癌中肿瘤测序的金标准，用以检测驱动突变并促进在一个单一检测中全面测试多个基因靶标。这有助于识别EGFR、ALK、ROS1、NTRK和MET等基因中的驱动变异，这些变异现在已成为FDA批准的药物的目标。
在2000年代初期首批被批准用于NSCLC治疗的SMKI是吉非替尼和厄洛替尼，其基于表皮生长因子受体（EGFR）在肿瘤生长和进展中的重要作用而设计的。然而，针对EGFR的SMKI常常会遇到由突变引起的药物耐药性问题。特别是，T790M看门人突变会在接受EGFR抑制剂治疗的患者中高达50%的比例出现。外显子21中的单点替换突变（L858R）和外显子19的缺失，通常被称为“经典”的EGFR激活突变，因为它们占EGFR激酶域突变的85-90%，这些突变被认为是与不同临床病理特征相关的敏化突变。外显子20的插入也是激活突变；然而，它们本身对EGFR抑制剂并不敏感，并且与较差的患者预后相关联。包括阿法替尼和达可替尼在内的下一代共价SMKI已被FDA批准，这些药物对诸如T790M之类的突变有效。此外，第三代抑制剂奥希替尼也被批准，它能特异性地靶向激活突变以及T790M耐药突变。
ALK（间变性淋巴瘤激酶）的重排会产生异常的ALK蛋白，促进细胞增殖和迁移，在大约5%的非小细胞肺癌（NSCLC）病例中被识别。首个ALK抑制剂克唑替尼于2011年获得批准。与ALK密切相关的是ROS1，它同样可以被ALK抑制剂靶向。ROS1的重排在NSCLC中的发生率约为1-2%。此外，在克唑替尼耐药的患者中，获得性ROS1耐药突变的发生率可达60%。为了改进克唑替尼的治疗特性并克服耐药突变，已经开发出了第二代和第三代化合物。自从克唑替尼之后，又有四种额外的SMKI被FDA批准用于ALK或ROS1易位的治疗：色瑞替尼、艾乐替尼、布加替尼和劳拉替尼。最近，又有四种额外的SMKI被批准用于治疗与特定激酶相关的突变引起的NSCLC：塞培利替尼和普拉塞替尼用于RET融合阳性的NSCLC治疗；卡马替尼和特泊替尼用于MET突变阳性的NSCLC治疗。
针对肿瘤血管生成是重要的抗癌策略之一，许多已获批准的激酶抑制剂成功地针对了由VEGFR（血管内皮生长因子受体）、PDGFR（血小板衍生生长因子受体）、KIT、成纤维细胞生长因子受体（FGFRs）和MET驱动的血管生成途径。例如，有五种被FDA批准的SMKI用于肾细胞癌的治疗，这些药物可以抑制VEGFR以及其他受体酪氨酸激酶（RTKs），还有两种获批的雷帕霉素类似物抑制剂，即替西罗莫司和依维莫司，它们靶向mTOR（哺乳动物雷帕霉素靶蛋白），这是VEGFR信号传导途径下游的一个关键分子。转移性结直肠癌（CRC）也通过使用FDA批准的mAb雷莫芦单抗和在中国获批的SMKI呋喹替尼来抑制VEGFR。髓样甲状腺癌则通过VEGFR抑制剂vandetanib、cabozantinib和lenvantinib以及上述提到的RET抑制剂pralsetinib和selpercatinib来进行治疗。
PDGFR和KIT由伊马替尼抑制，并且这种活性促成了其在2002年获得FDA批准用于治疗胃肠道间质瘤（GISTs）。与其他癌症一样，为了提高疗效和/或解决对第一代药物的耐药性问题，进一步开发了更多的SMKI。其中两种药物avapritinib和ripretinib在2020年获得批准，它们靶向特定的PDGFR和KIT激活环突变，这些突变导致高达85%-90%的GISTs患者复发。最近，FGFR途径的血管生成抑制已被证实是一种有效的治疗策略，这体现在2019年erdafitinib获得FDA批准用于治疗携带FGFR改变的晚期尿路上皮癌，以及2020年pemigatinib获得FDA批准，这是首个针对胆管癌的靶向治疗药物，胆管癌是一种以FGFR驱动突变为特征的侵袭性肿瘤。
其他RTK蛋白家族已被批准的激酶抑制剂用于多种癌症适应症。其中最突出的是针对HER2治疗乳腺癌的药物，这些药物包括已批准的9种激酶靶向药物。1998年批准的针对HER2的单克隆抗体trastuzumab，这是使用RTK靶向药物由伴生诊断指导的先驱案例，以及最近批准的针对HER2的单克隆抗体margetuximab，以及四种SMKIs：lapatinib、neratinib、tucatinib和pyrotinib（在中国批准），这些药物也用于治疗HER2+乳腺癌患者。我们的数据也包含了两种靶向HER2的抗体药物偶联物：曲妥珠单抗-艾美汀辛（trastuzumab-emtansine）和曲妥珠单抗-德鲁克斯替坎（trastuzumab-deruxtecan）。尽管细胞毒性载荷是这些抗体-药物偶联物抗癌活性的关键驱动因素，而不是仅抑制HER2的活性，但我们将其包含在内以完整说明。
各种细胞内激酶也已被批准的SMKIs所靶向。针对在细胞分裂中起重要作用的CDK4和CDK6的靶向治疗非常成功，现在有三种SMKIs：palbociclib、ribociclib和abemaciclib，已成为特定乳腺癌治疗的标准方案。2021年批准的一种CDK4/CDK6抑制剂trilaciclib用于小细胞肺癌的髓细胞保存疗法。转移性黑色素瘤是一种难以治疗的疾病，常见的BRAF突变使其特别具有侵略性。六种SMKIs已被批准用于此适应症：三种是BRAF抑制剂（vemurafenib、dabrafenib和encorafenib），三种是MEK抑制剂（trametinib、cobimetinib和binimetinib）。此外，2018年FDA批准了dabrafenib联合trametinib的MEK/BRAF组合疗法。此外，此外，证据表明，将SMKIs（特别是MEK和BRAF抑制剂）与免疫疗法联合使用，可以实现持久响应，并且具有更好的治疗效果
PI3K-AKT-mTOR途径涉及细胞存活、代谢和细胞生长的调节。在许多癌症中，该途径的失调导致了对它的组分进行靶向的广泛研究。这些研究导致了仅有的批准的激酶抑制剂，这些抑制剂靶向脂质激酶，始于2014年FDA批准idelalisib（针对PI3K δ的第一类SMKI），用于治疗各种淋巴瘤。此后，2017年批准了PI3K α/β双重抑制剂copanlisib用于滤泡性淋巴瘤，2018年批准了PI3K δ/γ双重抑制剂duvelisib用于多种淋巴瘤适应症，以及2019年批准了PI3K α选择性抑制剂alpelisib用于治疗乳腺癌。已经批准了三种靶向mTOR的SMKIs（见上文），包括sirolimus（最早期的激酶抑制剂之一），已被批准用于多种适应症，包括肿瘤性和非肿瘤性适应症。
通过靶向激酶治疗其他血液恶性肿瘤已经取得了实质性进展。值得注意的是，套细胞淋巴瘤和慢性淋巴细胞白血病正在通过FDA批准的三种布鲁顿酪氨酸激酶(BTK)抑制剂来治疗：ibrutinib、acalabrutinib和zanubrutinib。值得注意的是，这三种药物均通过共价作用机制发挥作用，而ibrutinib（伊布替尼）的成功在很大程度上催化了重新评估共价抑制作为药物设计策略的重要性（见下文），与阿法替尼（见上文）一起推动了这一领域的进展。
最后，激酶抑制剂也在引领利用肿瘤的分子特征而非组织来源来开发抗癌药物的先驱努力。在发现NTRK1作为结直肠癌（CRC）中致癌融合基因产物的一部分后的三十年，以及随后发现了NTRK2和NTRK3之后，泛TRK抑制剂larotrectinib成为了仅有的第二种组织无关型疗法进入市场（继pembrolizumab之后），在2018年获得FDA批准用于治疗携带NTRK基因融合的实体瘤患者。自此以后，多激酶抑制剂entrectinib也加入进来，它同样被批准用于携带NTRK基因融合的实体瘤患者的治疗。其他激酶抑制剂也在无组织特异性的开发项目中进行研究，其中包括已获批的RET抑制剂pralsetinib和selpercatinib。
[Box 2的部分内容*] BCR-ABL激酶抑制剂的发展揭示了一些激酶药物发现的一般性教训。首先，别构激酶抑制剂可以非常具有选择性；asciminib是合成选择性激酶抑制剂（SMKIs）中最具选择性的抑制剂之一。其次，寻找激酶抑制剂的生化筛选实验最好使用天然且全长的蛋白质进行，如果可能的话，这样可以获得多样化的调控相互作用的信息。第三，理解激酶抑制剂的作用机制需要投入大量的时间和劳动密集型工作至药物化学、药理学、生物化学、生物物理学、细胞生物学和结构生物学等领域。从伊马替尼获得批准到asciminib进入一期临床试验，历经了13年的时间。最后，了解激酶抑制剂所治疗的疾病是非常重要的。伊马替尼和其他靶向ABL治疗慢性粒细胞白血病（CML）的抑制剂，在疗效方面仍然非常突出，相比过去二十年为其他癌症开发的许多激酶抑制剂而言，它们的疗效前所未有。这可能反映出伊马替尼和其他BCR-ABL抑制剂在概念上更接近预防癌症，即防止CML的急性期（爆裂危象）而非仅仅治疗癌症，后者往往在较晚阶段才被诊断。实际上，慢性粒细胞白血病的慢性期，尤其是在早期阶段，更像是一种骨髓增生性疾病而非癌症。许多骨髓增生性疾病是由酪氨酸激酶驱动的，例如真性红细胞增多症（JAK2）、慢性粒单核细胞白血病（PDGFR）和嗜酸性粒细胞增多综合征（PDGFR），尽管它们很少转变为癌症，与CML不同。
2.3 肿瘤适应症之外的激酶抑制剂
许多激酶参与免疫反应的调节。例如，JAK是辅助性T细胞（TH1、TH2和TH17）免疫反应的关键成分，因为它们是许多细胞因子（包括干扰素和白细胞介素）的辅助信使。11种SMKI（占已获批SMKI的13%以上）已被批准用于免疫系统相关适应症，主要是自身免疫性疾病和炎症性疾病。
第一个在肿瘤学之外获得批准的激酶抑制剂是ruxolitinib，这是一种JAK1和JAK2抑制剂，在认识到JAK2中的激活突变导致一组骨髓增生性肿瘤后，于2011年被FDA批准用于治疗中度或高危骨髓纤维化患者。JAK2抑制剂fedratinib也于2019年被批准用于此类疾病。
类风湿性关节炎是获批SMKI最多的自身免疫性疾病（总共5种，FDA批准了3种）。所有五种SMKI都选择性地靶向JAK的亚型，包括第一个被批准用于类风湿性关节炎的SMKI：2012年的托法替布（其次是baricitinib、upadacitinib、peficitinib和filgotinib）。Peficitinib主要抑制JAK3，并于2019年获得日本药品和医疗器械管理局（PMDA）的批准。Filgotinib是一种选择性JAK1抑制剂，已获得EMA和PMDA的批准；但是，出于安全原因，FDA推迟了对其新药申请的决定。JAK激酶抑制剂也正在研究其他免疫疾病，而delgocitinib是一种泛JAK 抑制剂，于2020年获得PMDA批准，是第一个被批准用于皮肤病特应性皮炎的激酶抑制剂。
激酶SYK参与先天性和适应性免疫反应，与过敏和自身免疫性疾病以及血液系统恶性肿瘤的发展有关。Fostamitinib是一种一流的SYK抑制剂，由于其能够减少抗体介导的血小板破坏，于2018年被FDA批准用于治疗慢性免疫性血小板减少症。器官移植的排斥反应预防和移植物抗宿主病也是适合激酶抑制的免疫相关问题。两种药物已被批准用于这些疾病中的每一种：依鲁替尼和芦可替尼。
另外，几种SMKI已被批准用于肿瘤学和免疫学以外的疾病。其中包括用于脑血管痉挛的 ROCK1和ROCK2抑制剂法舒地尔（如上所述）、用于结节性硬化症复合物相关部分性癫痫发作的mTOR抑制剂依维莫司、用于特发性肺纤维化的VEGFR抑制剂尼达尼布、用于晚期系统性肥大细胞增多症的FLT3抑制剂米哚妥林和另一种ROCK1/ROCK2抑制剂奈他舒地尔，用于青光眼和高眼压症。
2.4 药物分类
几乎所有FDA批准的SMKI都针对激酶ATP结合位点（63个SMKI），除了3种雷帕霉素类、4种MEK抑制剂和靶向肽底物位点的双重SRC和微管蛋白聚合抑制剂tirbanibulin（结合模式的进一步讨论见下文）。ATP结合位点在人类激酶组中的保守性意味着“ATP模拟物”经常与许多其他不同的激酶发生交叉反应，从而产生具有混杂特征的化合物。达沙替尼或舒尼替尼等混杂化合物被称为多激酶抑制剂，可能具有一些毒理学问题。然而，这种交叉反应也可能是潜在的优势。例如，伊马替尼对多种激酶的活性使其能够应用于多种适应症，例如BCR-ABL易位驱动的CML、KIT驱动的GIST和PDGFR α失调驱动的嗜酸性粒细胞增多综合征。通过阻断两种或多种激酶来抑制细胞网络中的多个节点也可以产生可能具有临床有用的协同作用；例如，用前面提到的达拉非尼加曲美替尼的组合靶向BRAF和MEK通路。
RTK的细胞表面位置已被10种FDA批准的mAb成功用于治疗乳腺癌、CRC、NSCLC、软组织肉瘤和肝细胞癌。此类药物的作用机制比SMKI抑制激酶活性更复杂，可能包括阻断配体结合（从而阻止激酶激活）、促进受体内化和抗体依赖性细胞毒性3. 激酶抑制剂设计的趋势
通过了解其结合位点的结构，SMKI的鉴定已大大推进。迄今为止已发表5500多种催化结构域结构，涵盖104个家族的约300种激酶。在本节中，我们概述了与基于结构的药物设计相关的主要特征以及不同类型SMKI开发的趋势。
3.1激酶催化结构域的结构特征
蛋白激酶折叠结构的架构最早是由Knighton等人在1991年描述的，他们报道了蛋白激酶A(PKA)与ATP-Mg2+及抑制性肽结合的结构。这一结构揭示了一个双叶状的排列，包括一个较小的N端叶，其中含有一个五条链组成的反平行β-层状结构(β1至β5)、保守的调控α-C螺旋、两个额外的螺旋片段，以及一个主要由α螺旋构成的较大的C端叶（下图a）。
ATP辅助因子夹在两个叶之间，并在腺嘌呤环和铰链区之间形成氢键，从而建立了连接叶的骨架。这些氢键代表了ATP模拟抑制剂设计的重要锚点，并定义了碱性激酶抑制剂支架。ATP也由富含甘氨酸的环 [G-loop，也称为磷酸盐结合环(P-loop)]协调。这是一个高度灵活的区域，存在于β折叠结构β1和β2中，共有序列基序GXGXφG，其中φ代表疏水残基。第二个关键序列基序（V）AxK位于β3中。
活跃态激酶的一个标志性结构特征是，在(V)AxK基序中的赖氨酸残基与位于α-C螺旋中的保守谷氨酸之间形成的一个保守盐桥，该盐桥将α-C螺旋定位（“α C-in”构象）。α-C螺旋具有重要的调控作用，因为(V)AxK盐桥有助于ATP磷酸基团的配位。在非活跃态激酶中，α-C螺旋从其在活跃状态下的位置向外移动（“α C-out”构象），并且通常还会使中心的保守谷氨酸旋转远离ATP结合位点。
在α C-in状态下，α C螺旋的C末端通过与保守的三肽Asp-Phe-Gly (DFG)基序相互作用而得到进一步稳定，后者还锚定了激活段的N末端。在其活跃的“DFG-in”构象中，DFG天冬氨酸残基指向ATP的磷酸基团，协调一个对催化非常重要的Mg2+。在非活跃态激酶中，DFG处于可动状态，使苯丙氨酸残基移位。这种所谓的“DFG-out”构象开启了一个深且主要是疏水性的结合口袋（见下文）。DFG-out运动也会导致激活段的无序化，这是一个长度和序列可变的可动结构元件，包含DFG基序、激活环（A-loop）并在末端以螺旋状的APE (Ala-Pro-Glu)基序结束。A-loop还包含调控激酶活化的磷酸化位点，对于非组成性活跃的激酶来说，可通过自身磷酸化或跨磷酸化来进行调控。最后，催化环包含一个高度保守的Y/HRD (Tyr/His-Arg-Asp)基序，其中严格保守的天冬氨酸是催化所必需的。
ePKs (可被调节的蛋白激酶) 的三维结构高度保守，包括一组结构上重要的疏水性残基。这些残基形成了两条脊柱，在活跃状态下连接并正确对齐两个激酶叶，并定位关键的序列基序以利于催化过程。一条脊柱被称为催化脊柱(C-spine)，它由辅因子ATP的腺嘌呤环系统补充，并连接激酶域铰链侧的结构元件。另一条疏水性脊柱被称为调控脊柱(R-spine)，在活跃状态下感知β4片层、α C螺旋、DFG基序和下叶α E螺旋的正确排列（上图b）。在非活跃状态下，R-spine残基的移位会导致R-spine断裂。通过突变研究实验验证了脊柱残基的功能重要性，这些研究表明脊柱残基的疏水接触对于适当的催化功能是必需的。由于它们靠近ATP结合位点，许多激酶抑制剂会与脊柱残基相互作用，甚至插入或改变脊柱的相互作用。
称为“守门人”残基（gatekeeper，也可译为门控残基）连接着C-spine和R-spine（在PKA中为M120），位于铰链区域的N末端。守门人残基对于药物开发的重要性很早就被认识到。虽然不常见，但如果存在像苏氨酸这样的小型守门人残基，则能够设计出针对其他激酶具有选择性的抑制剂，因为它使得后口袋对小分子开放；这意味着与该口袋结合的抑制剂无法与其他在守门人位置拥有大型疏水性残基的激酶结合。人类激酶中守门人位置不存在甘氨酸残基，这促使人们设计出了特异性靶向激酶守门人突变体的大体积ATP类似物。然而，转变为体积更大的残基从而在空间上排除抑制剂的守门人突变是激酶药物耐药性的常见原因。[译者注：这句话比较拗口，推测作者的意思是：守门人残基（gatekeeper）通常不会出现甘氨酸这样的小体积残基。因为甘氨酸作为最小的氨基酸，它的侧链仅有一个氢原子，这使得它能够适应各种空间环境；当它缺少时能为设计特异性更强的抑制剂提供了一种契机。然而，当守门人位置发生突变，变成了体积更大的残基时，这些突变可能会阻止原本有效的抑制剂与激酶结合，从而导致药物耐药性。强调守门人残基的特性对于激酶抑制剂设计的重要性。]
3.2 理性设计抑制剂的策略
蛋白激酶结构的高度动态特性允许设计识别活性或多种非活性构象的抑制剂。激酶的失活状态在结构上特别多样化，并在药物开发中得到了广泛的探索。已对激酶催化结构域中存在的80多个可能的配体结合位点进行了编目和描述。对该领域的详细描述超出了本综述的范围，因此我们的描述仅限于现代激酶药物发现中已经确立的主要结合模式。
1型抑制剂（Type 1）针对激酶的活跃状态。抑制剂中的中心嘌呤部分模仿了ATP在铰链区形成的氢键结合，同时α C螺旋和DFG基序均处于它们的活跃“in”位置。然而，在这一结构中，G-loop并未形成活跃构象与嘌呤环和Y253形成芳香性堆积相互作用。芳香族氨基酸经常出现在G-loop的末端。在ATP结合的活跃状态下，这些残基朝向远离ATP结合位点的方向排列。有趣的是，在许多激酶抑制剂复合物中观察到了所谓的“折叠P-loop构象”，并且这种构象被认为与有利的抑制剂选择性相关联。
2型抑制剂（Type 2）结合到非活跃态的激酶，其特征是DFG-out构象。DFG基序向外移动形成了一个大的疏水性口袋，这一口袋被该抑制剂中的三氟甲基苯基部分靶向。α C螺旋保持其活跃状态下的α C-in位置，这一点通过(V)AxK K271与保守的α C谷氨酸E286之间形成的经典盐桥得以体现，而G-loop则维持其折叠构象。
在经典的Type 1和Type 2之间的结合模式之间存在许多中间状态，一些作者引入了类型1.5（Type 1.5）的结合模式。然而，在激酶文献中，类型1.5抑制剂的定义并不明确。严格来说，类型1.5抑制剂可以定义为破坏R-spine的抑制剂，但这个词也被用来描述那些结合后导致任何偏离理想活跃构象的结构偏差的抑制剂，包括异常的G-loop构象和激活段的自我抑制构象。由于这些结构元素高度可动，并且它们的构象可能取决于晶体堆积，我们认为将这种结合模式限定为破坏R-spine而不靶向经典Type 2特有的DFG-out口袋的抑制剂更为有用。在BRAF-dabrafenib复合物中，α C螺旋向外移动，导致R-spine断裂和(V)AxK (K483)与α C谷氨酸(E591)之间的盐桥断裂，而DFG基序仍保持在DFG-in位置。
上图为3型抑制剂（Type 3）结合模式在激酶MEK1中的示例。抑制剂占据了一个由α C-out移动和激活段的非活跃螺旋构象共同形成的口袋（虚线圈）。辅因子ATP-Mg2+以球棍模型表示，结合到ATP结合位点，而DFG基序处于DFG-in构象。
非经典结合模式代表了吸引人的设计策略，因为这类化合物通常比经典的Type 1和Type 2抑制剂具有更高的选择性和更长的目标驻留时间。例如，EGFR抑制剂拉帕替尼结合到DFG-in构象，但它诱导了显著的结构重排，这解释了它对EGFR的高度选择性。同样，蛋白激酶R (PKR)-样内质网激酶(PERK)抑制剂GSK2606414和MET抑制剂SGX523靶向激活段的一种非活跃构象。ERK1/ERK2抑制剂SCH772984特异性地与由α C-out和折叠P-loop构象共同形成的独特结合口袋相互作用。Kinase-Ligand Interaction Fingerprints and Structures (KLIFS)数据库为研究配体相互作用和整个激酶组中不同结合模式的分布提供了一个宝贵的资源。
近期的研究也探讨了水在配体设计中的作用。早期的模型仅从简单的熵增观点考虑了配体置换结合位点水分子的情况。现在，更加精细的计算工具能够详细分析结构模型中观察到的每个水分子，以评估水在配体效力、构象变化和配体解离速率中的作用。
3.3 激酶抑制剂的化学结构趋势
ATP结合位点是已批准的SMKI靶向的主要位点，占FDA批准的71种药物中的63种。与ATP腺嘌呤环类似，ATP模拟物抑制剂通过氢键锚定到激酶铰链骨架上。已经开发了几种充当铰链粘合剂的支架。融合的六元环体系（Fused six-membered ring systems）：如（异）喹啉和喹唑啉，首先在法舒地尔的开发中建立，随后是吉非替尼和厄洛替尼，是最常用的ATP模拟物，有18个获批SMKI。用于伊马替尼的氨基嘧啶和密切相关的氨基吡啶部分也仍然是经常使用的铰链结合剂，有17种SMKI获得批准（下图，氢键供体和受体用红色箭头表示）。
译者注：在药物小分子的开发中，由于Lipinski等类药经验规则的因素，常需要考量一个化学结构中的“氢键供体”、“氢键受体”数量，以便更好的成药。
这里的供体很好找，但氢键受体不能简单的将N、O原子加和。氢键通常发生在含孤对电子的原子与氢原子之间，因此，即使在一个化学结构中有多个杂原子，也不一定所有这些杂原子都能充当有效的氢键受体。例如，在某些杂环化合物中，氮原子如果参与了环的共轭体系，可能就不太容易作为氢键受体，因为其孤对电子参与了π电子体系，没有多余的孤对电子去形成氢键。所以上图中红色箭头只标注了特定的一些杂原子。
图源：《Drug-Like Properties》 Li Di, Edward H. Kerns.
第三类铰链结合基团是融合的五元和六元环系统，例如吡咯并嘧啶、吡咯并吡啶、嘌呤、氧吲哚和吡咯或咪唑三嗪。从结构上看，吡唑并氨基嘧啶和咪唑并氨基吡嗪也与这一类铰链结合基团相关，但根据它们的铰链结合模式，应将其视为氨基嘧啶的衍生物。非芳香性铰链结合基团由酰胺代表。共有17种SMKIs含有多种铰链结合支架，但在开发三分之二已批准的SMKIs的过程中探索的化学空间之狭窄令人惊讶。
3.4 变构抑制剂
大多数信号激酶以非活性状态表达，该状态被许多不同的机制激活，例如由翻译后修饰或通过与支架蛋白或侧翼调节结构域的相互作用诱导的结构变化。因此，激酶调节细胞信号传导的关键作用需要高度的催化结构域可塑性。通过开发阻止激酶激活的变构抑制剂，这一特性得到了广泛的探索。
变构激酶抑制剂在它们阻止的激活机制上有所不同，因此仅根据其结合位置对它们进行分类。3型抑制剂（Type 3）在α C-out构象诱导的口袋中与ATP结合位点附近结合，在某些情况下由A-loop的非活性构象诱导。所有四种临床批准的MEK1/MEK2抑制剂都是与变构后口袋结合的3型抑制剂的例子。DFG处于活性的“in”构象中，允许3型抑制剂和ATP同时结合。一些3型抑制剂还与ATP的磷酸骨架形成极性相互作用，导致ATP非竞争性作用模式。然而，越来越多的3型抑制剂与经典后袋结合，但稳定了DFG-out构象。示例包括靶向FAK、TRKA、PAK1和IGF1R的变构抑制剂。值得注意的是，这些抑制剂对密切相关的家族成员显示出亚型选择性。
4型抑制剂（Type 4）结合到远离ATP结合位点的别构位点（下图中展示了不同结合类型的示意表示）。4型抑制剂的例子是ABL抑制剂GNF-2，它结合到C末端激酶叶上的一个诱导性口袋，这个口袋也是诸如肉豆蔻酸酯等脂质的结合位点。这种4型抑制剂利用了ABL激酶独特的激活机制：在非活跃态的ABL激酶中，ABL N末端的一个肉豆蔻酰化残基结合到C叶的结合口袋，这导致了一个闭合的非活跃构象的稳定。在致癌融合蛋白BCR-ABL中，由于存在N末端融合伙伴BCR，这种失活机制丧失，导致ABL持续活跃。GNF-2和正在研究中的4型抑制剂asciminib (ABL001)模仿了肉豆蔻酸的结合，并诱导了一个类似于非活跃野生型蛋白的非活跃状态。有趣的是，将肉豆蔻酸模拟的ABL类型4抑制剂与传统的ATP竞争性药物联合使用可以降低产生药物耐药性突变的风险。
其他几种4型抑制剂已进入临床试验，包括变构AKT1抑制剂MK-2206，它在AKT催化结构域和普列克底物蛋白同源性（PH）结构域之间的界面结合。当激酶被MK-2206靶向和结合时，激酶被锁定在无活性构象中。这也阻止了AKT1募集到质膜，质膜是AKT1激活所需的重新定位事件。现已报道了多种靶向不同结合位点的临床前变构抑制剂，例如PDK1相互作用片段（PIF）口袋。变构抑制剂还允许选择性靶向突变，如EAI045所示，它靶向EGFR耐药突变体EGFR-L858R/T790M和EGFR-L858R/T790M/C797S，同时在很大程度上保留野生型EGFR。
蛋白激酶的变构靶向提供了以高度特异性方式模拟自然调节机制的机会。这些激酶活性调节剂的治疗潜力是巨大的，激酶领域才刚刚开始在临床环境中探索这种靶向策略。
译者注：
类型
结合特征
结合模型
Type 1
结合到激酶的活跃状态，以DFG-in构象为标志
Type 1.5
介于Type 1和Type 2之间，定义不清晰。通常指破坏R-spine但不针对DFG-out口袋
Type 2
结合到激酶的非活跃状态，以DFG-out构象为标志
Type 3
结合到靠近ATP位点的变构位点。由α C-out构象和激活段的非活跃构象共形成口袋
Type 4
结合到远离ATP位点的变构位点
3.5 共价抑制剂
自2013年共价EGFR抑制剂阿法替尼和BTK抑制剂伊布替尼被FDA率先批准以来，几种共价激酶抑制剂陆续被批准（见上文）。最近又批准了7种靶向EGFR突变体或BTK的SMKI（补充表1）。除acalabrutinib外，所有目前批准的共价激酶抑制剂都使用丙烯酰胺基团作为共价键形成的亲电试剂。用吸电子基团（如氰基）取代丙烯酰胺中的α位置，允许设计可逆的共价抑制剂。这已在几种具有延长靶标停留时间的高选择性工具分子的开发中进行了探索。使用共价靶向设计高选择性激酶抑制剂的潜力是巨大的，但这种设计策略仍未得到广泛探索。
3.6 大环化合物
大环类结构已成为提高抑制剂效力和选择性以及药代动力学特性的最新策略。例如，劳拉替尼就是基于其非环化模板克唑替尼开发的。大环化锁定了克唑替尼的生物活性构象，从而显著提高了对ALK和ROS的效力，以及出色的中枢神经系统渗透性。此外，劳拉替尼对第一代和第二代ALK抑制剂的耐药突变有效，并且与其母体化合物相比，它具有更好的药理学特性。另一个成功的大环化的有趣例子是EGFR抑制剂BI-4020，它被设计为靶向三代EGFR耐药突变，例如在NSCLC152中出现的EGFR-L858R、EGFR-T790M和EGFR-C797S。
3.7 双功能抑制剂
最近出现了大量其他类别的抑制剂，包括双底物和二价抑制剂，以及通过与蛋白质界面结合诱导新蛋白质相互作用的分子胶。这些药物连接与不同结合位点相互作用的抑制剂；例如，具有SH2结构域配体或底物竞争性抑制剂的ATP模拟抑制剂。这种抑制剂在一些出版物中被称为5型抑制剂（Type 5）。然而，由于这些抑制剂是通过化学接头将1型抑制剂与靶向远程二级结合位点的化合物结合的复合抑制剂，因此我们认为这类不同的抑制剂引入新名称在概念上没有优势。它们的大分子量使得在临床上开发这些抑制剂具有挑战性，但通常观察到的这些双重抑制剂选择性的增加可能为靶点验证和功能研究提供有趣的化学工具。
化学降解剂，如蛋白降解靶向嵌合体(PROTACs)也属于双功能抑制剂类别。由于PROTACs能够催化性地降解目标分子，并且通常具有增强的亚型和突变体选择性，因此近年来受到了广泛关注。这是通过将传统激酶抑制剂与结合E3泛素连接酶的配体相连实现的。蛋白激酶似乎非常适合于降解。最近的一项研究报道了使用泛激酶抑制剂为大约200种ePKs开发的PROTAC先导化合物。已经为重要的激酶药物靶标开发了选择性的PROTACs，包括BRAF、EGFR-L858R/T790M致癌突变体、JAK、BTK、ALK、AKT、CDK6、CDK9、TBK1、Aurora激酶A、TRKA、FAK等。与一般的双功能抑制剂一样，将这些分子开发用于临床应用的药理学挑战比传统的小分子更大，但首批化合物现在已经进入了临床试验阶段。在不久的将来，预计会有更多的PROTACs进入临床开发阶段，令人期待的是，与传统抑制剂相比，PROTACs在临床研究中的表现将会如何。
PROTAC的一个有吸引力的变体是分子胶，它与两种蛋白质的界面结合，从而形成复合物。在激酶领域，很早就发现了调节激酶功能的分子胶。大环内酯类雷帕霉素及其相关雷帕洛酯通过诱导FKBP12（FK506（他克莫司）结合蛋白）、雷帕霉素和mTOR174之间形成三元复合物来变构抑制mTOR。分子胶可以通过将新型底物募集到E3泛素连接酶，在泛素系统中用作选择性降解剂。自从将E3连接酶cereblon鉴定为沙利度胺的靶标以来，已将几种转录因子鉴定为新底物，包括C2H2锌指蛋白 SALL4，这是沙利度胺致畸性的关键因子。这解释了沙利度胺的致畸机制以及它通过降解机制的免疫调节功能。激酶CK1α也被鉴定为新底物，有助于沙利度胺衍生物来那度胺治疗多发性骨髓瘤和5q-缺失相关骨髓增生异常综合征的临床疗效。含有表面暴露部分的常规激酶抑制剂也可诱导选择性降解。最近，CDK抑制剂CR8-a已被证明可将cullin 4衔接蛋白 DDB1（DNA损伤结合蛋白1）募集到CDK12-细胞周期蛋白K复合物中，在那里它充当该激酶的分子胶和选择性降解剂。由于其低分子量，分子胶可以成为具有非常特定作用方式的药物开发的有吸引力的先导化合物。然而，大多数分子胶是偶然发现的，或者是基于天然产物开发的，目前缺乏合理的鉴定策略。 4. 研究性药物的发展趋势
我们对ClinicalTrials.gov网站的分析确定了近600种在临床试验中注册的激酶靶向药物，其中包括475个新型SMKI（包括其他监管机构批准并可能寻求FDA批准的药物，但不包括71个已经获得FDA批准的SMKI）和124个生物制剂。与之前的类似分析相比，在过去5年中，进入临床开发的SMKI数量增加了200%以上，2014年有177家SMKI达到这一阶段，2010年有149家达到这一阶段。
在临床试验中注册的475种SMKI中，其中近一半（253个）目前正在开发中，要么正在进行试验，要么正在开始新的试验，而222种被确定为没有积极开发。临床试验中大约40%（194个）的激酶抑制剂靶向45个新型激酶家族，这些激酶家族包含215种蛋白质（占激酶组的40%），尽管我们确定其中大约110种是激酶抑制剂的主要靶点，因此更准确的估计是，除了已批准药物验证的靶点之外，20%的激酶组正在使用临床开发中的药物进行研究。这表明与其它主要靶标家族相比，新型激酶领域的探索十分稳健；例如，在一项类似的近期分析中，使用临床试验中的药物对新型G蛋白偶联受体(GPCR)进行研究的比例仅为16%。
4.1 激酶抑制剂临床试验的成功率
使用来自3700多项临床试验中475种研究药物的数据并推断71种已批准药物的试验完成信息，我们估计激酶抑制剂从I期到II期的过渡概率为72%，从II期到III期的66%，从III期到批准和上市的86%。通过概率是使用Hay等人的描述计算的，这些描述基于DiMasi和Grabowski研究。通过成功率的分析在方法和数据上是异质的，直接比较可能很困难；然而，调查药物先导适应症成功率的里程碑式研究通常引用了与我们相当的比率，例如I至II期为67-71%，II期至III期为40-45%，III期为64-68%到新药申请（NDA）/生物许可申请（BLA）。我们的估计远高于FDA对一般药物临床研究阶段成功率的估计，I期至II期约为70%，II期至III期约为33%，III期至下一阶段高达30%。有趣的是，我们的结果与Walker和Newell十多年前对激酶抑制剂的估计相当，后者分别计算了80%、69%和85%，并表明激酶抑制剂继续降低了总体损耗率，并在从II期到III期的高风险过渡中继续取得成功。
在II期临床试验期间，无论是小分子还是大分子疗法，对于各种适应症而言，候选药物的阶段过渡概率下降是普遍存在的现象，并且之前已经进行了分析。Morgan等人的重要发现指出缺乏临床疗效是主要原因，这可以通过解决候选药物生存的三个药理支柱来缓解：在靶点部位的暴露、靶点结合以及药理活性的表达。既往对激酶抑制剂的分析以及我们的研究都表明，在后期发展阶段，候选药物的淘汰率低于FDA对一般药物的整体估计。这可能是由于反复针对已经充分理解的激酶信号传导途径以及开发出更具有选择性的抑制剂，这些抑制剂能够在疾病中有效地抑制激酶信号传导。我们还注意到激酶抑制剂从I期到获得批准的整体成功率相似，我们估计目前约为41%。这略低于之前对激酶抑制剂的评估，该评估整体成功率为约47%。然而，我们的研究包含了额外十年的数据以及大约三倍多的药物（546种相比于137种）。此外，确定不再活跃的候选药物的方法差异可能会影响分析结果。
4.2 激酶家族的在研药物靶标
已建立的激酶家族和靶标继续通过新型候选药物在临床试验中进行积极研究。大约12%（599种中的73种）的临床试验候选药物针对HER家族中的激酶以治疗各种癌症，其中包括26种新型SMKIs和47种新型生物制剂。VEGFRs也继续作为抗癌靶标进行研究，有30种新型SMKIs和9种新型生物制剂针对这些RTKs在临床试验中。此外，有54种PI3K或PI3K-mTOR途径抑制剂在临床试验中，其中有6种在III期临床试验中用于治疗一系列适应症，如淋巴瘤（buparlisib）、激活的PI3K δ综合征（leniolisib）和骨髓纤维化（parsaclisib）。PI3K和mTOR抑制剂也可能具有治疗罕见遗传性过度生长综合症的潜力，如PTEN错构瘤、结节性硬化症和PIK3CA相关的过度生长谱系。
在肿瘤学之外，目前有12种靶向JAK的SMKI处于各种免疫炎症性疾病的临床试验中，其中7种处于III期试验中。特别令人感兴趣的是III期JAK3抑制剂ritlecitinib（PF-06651600），它在II期试验中显示出前景后，于2018年获得了脱发的突破性疗法认定，以及一种肠道选择性pan-JAK抑制剂（TD-1473），在早期临床试验中显示出有希望的结果，目前正在进行多项II/III期试验。
BTK抑制剂在治疗B细胞相关血癌方面非常成功（见上文），B细胞在自身免疫性疾病中的作用也导致BTK抑制剂被研究用于治疗此类疾病。7种BTK抑制剂正在系统性红斑狼疮的II期试验中进行研究，两种BTK抑制剂（evobrutinib和SAR442168）正在进行多发性硬化症的II期和III期试验，evobrutinib在之前的一项试验中显示出边际疗效且毒性有限
如上所述，临床试验中至少有45种不同的新型激酶家族成为靶标，其中包括110多种被确定为主要靶标的不同激酶。在临床开发中，几个家族已成为大量药物的目标，抑制剂的化学类型和目标适应症发生了变化。有趣的是，与其他主要激酶组相比，TK组中的新家族的靶向性较低。在CMGC（CDK、MAPK、GSK3和CLK家族）组中，近50种药物进入了针对已在临床试验中长期研究的成员的试验，例如丝裂原活化蛋白激酶（MAPK）p38家族、ERK家族和细胞周期蛋白依赖性激酶（CDK）家族的成员。超过20种药物靶向Aurora激酶家族，而在AGC组中，17种抑制剂靶向AKT（蛋白激酶 B，PKB）家族。所有目标家族的更多详细信息见补充图1。下面讨论新家族的选定示例，细分为正在研究肿瘤适应症的家族和正在研究肿瘤学以外的适应症的家族。下图总结了临床试验中激酶靶向药物的疾病适应症。
临床试验中激酶靶向剂的疾病适应症
4.3 新型靶点肿瘤学的激酶抑制剂
Aurora激酶家族（Aurora kinase A、Aurora kinase B 和 Aurora kinase C）是尚未批准药物的最具针对性的激酶家族，已有22种药物进入临床试验。长期以来，这些激酶在细胞分裂中的作用及其在广泛的人类肿瘤中的过表达激发了人们对其作为治疗靶点的潜力的兴趣，但超过80%已进入临床试验的Aurora激酶抑制剂的开发已停止。第一代Aurora激酶抑制剂在实体瘤中进行了测试，但试验结果表明疗效有限且毒性高，这可能是因为实体瘤中的细胞增殖相对较慢，并且需要通过多个细胞周期的药物暴露才能诱导最大的肿瘤抗增殖作用。这些临床失望带来了策略的变化，正在研究第二代亚型选择性Aurora激酶抑制剂用于血液系统恶性肿瘤，其基本原理是它们相对于实体瘤具有更高的同质性和更高的增殖率。目前，四种Aurora激酶抑制剂正在作为单一疗法或联合疗法在白血病（如急性髓性白血病和慢性淋巴细胞白血病）以及实体瘤中进行试验。
CDK家族包括20个成员，在功能上可分为控制细胞周期转换（包括CDK1、CDK2、CDK4、CDK5和CDK6）和调节转录（包括CDK8、CDK9、CDK11和CDK20）的家族，尽管这两种活性都存在于CDK7等多个家族成员中。基于它们在控制细胞分裂中的作用以及癌症表现出细胞周期失调，CDK已成为20年的治疗靶点。第一代CDK抑制剂，例如针对大多数CDK的广泛研究的黄酮吡啶醇（alvocidib），显示出疗效不足和显著毒性。新一代抑制剂的开发于2015年成功验证了选择性靶向CDK4和CDK6治疗乳腺癌的验证，FDA批准了palbociclib，随后于2017年批准了abemaciclib和ribociclib（见上文）。CDK家族成员继续在临床试验中接受深入研究，其中5种新型SMKI在临床试验中靶向CDK4家族，另外12种靶向 CDK7、CDK8/CDK19以及CDK2和CDK9的SMKI选择性或与目前处于I期和II期试验中的其他药物联合使用。
已知肿瘤细胞通过DNA损伤反应（DDR）对许多癌症疗法产生耐药性，DDR支持DNA修复。几种专门开发的SMKI通过靶向参与DDR的激酶来对抗这种耐药机制，包括共济失调-毛细血管扩张症和Rad3相关（ATR）、DNA依赖性蛋白激酶催化亚基（DNA-PK）和检查点激酶1（CHK1）。目前，四种靶向ATR、DNA-PK或CHK1的SMKI正在进行20项针对不同类型恶性肿瘤的II期试验。
4.4 新型靶点肿瘤学以外的激酶抑制剂
目前，有40多种激酶抑制剂正在进行针对类风湿性关节炎、银屑病、系统性红斑狼疮、炎症性肠病、多发性硬化症和斑秃等免疫系统疾病的临床试验，其中12种药物处于III期试验中。如上所述，其中一些药物抑制已建立的靶点，例如JAK，但也有一些针对炎症性疾病的新型激酶靶点，包括IL-1受体相关激酶4（IRAK4）、受体相互作用丝氨酸/苏氨酸蛋白激酶1（RIPK1）、肿瘤进展位点2（TPL2）和酪氨酸激酶2（TYK2）。
目前有16种SMKI正在进行类风湿性关节炎的临床试验。III期试验中的所有三种药物都已确定靶点，但II期试验中的一种SMKI具有一种新的作用方式：PF-06650833靶向IRAK4，从而抑制IL-1的信号传导，IL-1是一种有效的促炎细胞因子，参与各种自身免疫性疾病的发病机制。
RIPK1在另一种有效的促炎细胞因子肿瘤坏死因子（TNF）介导炎症中很重要，RIPK1活性增加与神经炎症和细胞坏死性凋亡有关。第一个靶向RIPK1的药物于2015年进入临床试验，现在有三个RIPK1 SMKI在临床试验中。其中进度最快的是GSK2982772，它已经完成了治疗各种自身免疫性疾病的八项I期和II期临床试验，并且正在进行中度至重度银屑病的I期试验。
越来越多的证据描述了TPL2参与炎症的多方面方式，包括MEK1/MEK2的正调节激活ERK1/ERK2信号传导和中性粒细胞中p38α和p38δ的正调节。因此，据推测，抑制其活性可能有益于治疗类风湿性关节炎和银屑病等炎症性疾病以及多发性硬化症。一种TPL2抑制剂GS-4875已进入临床试验，目前正在进行治疗溃疡性结肠炎的II期研究。
总体而言，有15种药物正在进行临床试验，通过抑制除RIPK1之外的几种激酶（包括JAK1、TYK2、IRAK4和ROCK2）来治疗银屑病。有趣的是，JAK激酶（JAK1-3和TYK2）包含两个激酶结构域：一个具有催化活性的JH1结构域和假激酶结构域JH2，后者在TYK2激活中起重要作用。所有临床批准的JAK抑制剂都是JH1抑制剂，在JH1结构域内显示出中等选择性，这一特性与严重的副作用有关。然而，TYK2的假激酶结构域显示出一些已探索用于抑制剂开发的结构特征。该领域的主要药物是两种TYK2 JH2抑制剂deucravacitinib（BMS-986165）和BMS-986202。这些药物都已被证明可以有效阻止TYK2激活，对其他JAK家族成员和激酶组具有显著的选择性，目前正在进行III期试验。deucravacitinib的不良事件已报道，包括意外眼损伤、头晕和原位恶性黑色素瘤，但如果这些药物在当前的III期试验中被证明足够安全并保持相同的疗效，它们很可能在不久的将来获得批准，从而成为第一个靶向失活假激酶结构域的抑制剂。
CDC样激酶2（CLK2）和双特异性酪氨酸磷酸化调节激酶1A（DYRK1A）是Wnt信号传导、软骨形成和炎症的调节因子，抑制这些激酶已证明对骨关节炎具有潜在的疾病缓解作用。小分子双激酶抑制剂lorecivivint通过诱导软骨细胞分化、软骨再生和保护以及提高关节健康评分显示出有希望的骨关节炎治疗效果。它目前正在进行三项治疗膝骨关节炎的III期试验，II期试验的结果证明了lorecivivint的疾病缓解能力及其作为同类首创药物的潜力。
p38 MAP激酶最初在1990年代被发现为炎性细胞因子生物合成的关键调节因子，此后它们被广泛用于治疗类风湿性关节炎等炎症性疾病，迄今为止尚未批准任何针对这些激酶的抑制剂。至少有20种此类药物已进入临床试验，但其中16种（80%）药物的开发似乎已停止。第一代SMKI靶向p38α和p38β，但脱靶效应、效力问题、代偿途径和毒性限制了其临床开发。开发了第二代抑制剂，例如慢关断速率抑制剂BIRB 796，但也没有成功。然而，最近的一篇综述指出，p38研究转向关注更急性的炎症性疾病，包括慢性阻塞性肺病或哮喘。此外，p38激酶功能与多种神经和精神疾病有关，尤其是与神经炎症反应相关。neflamapimod（VX-745）是最近进入临床试验的P38 SMKI之一，属于一类新型p38抑制剂，其中包含双环杂环核心，对p38α的选择性高于p38β。Neflamapimod在II期试验中显示出阿尔茨海默病患者的认知改善具有统计学意义，目前正在进行三项II期试验，用于治疗亨廷顿病（NCT03980938）、阿尔茨海默病（NCT03435861）和路易体痴呆（NCT04001517）。
激酶抑制剂在神经系统疾病中的探索尚处于早期阶段，尚无获批的抑制剂，大多数药物仍处于I期或II期试验中。除neflamapimod 外，几种药物正在进行临床试验，针对促炎细胞因子产生和免疫反应的各个方面，基于炎症在阿尔茨海默病等疾病中的重要性的证据。DNL747抑制RIPK1，依迪克替尼（JNJ-40346527）靶向集落刺激因子1受体（CSF1R），马赛替尼与KIT和其他RTK结合。2020年12月，据报道，在一项II/III期试验中，与安慰剂相比，马赛替尼作为胆碱酯酶抑制剂的附加疗法可提供临床益处，验证性试验应很快启动。另一种有趣的药物是saracatinib（AZD0530），它抑制Src家族的成员Fyn激酶。这可能是阿尔茨海默病治疗的一个有前途的策略，因为其下游途径被认为是β淀粉样蛋白毒性的基础，淀粉样蛋白是该疾病的一个标志。有趣的是，在II期试验（NCT02955186）中，萨拉卡替尼也被分析为酒精使用障碍的潜在治疗候选者，因为Fyn信号与饮酒行为有关。
神经系统疾病的另一个有趣的激酶靶点是富含亮氨酸的重复激酶2（LRRK2），因为LRRK2中的激活突变是遗传性帕金森病最常见的常染色体显性遗传原因。三种LRRK2抑制剂现已进入治疗帕金森病的I期试验：两种SMKI（DNL201 和 DNL151）和一种反义寡核苷酸（ION-859）。到目前为止，DNL201的结果表明，它的耐受性良好，DNL151计划在临床试验中取得进展。ION-859的试验目前正在招募患者。
衔接蛋白相关激酶1（AAK1）作为治疗神经性疼痛的靶点而受到广泛关注，这可能为一类新型镇痛药提供基础。动物模型研究表明，AAK1的抑制在机制上与α2肾上腺素能信号有关，而不是与阿片受体有关，以减轻疼痛反应。一种新型AAK1抑制剂已进入试验阶段;小分子LX9211目前正处于神经痛和糖尿病性神经病变的两项II期试验中，最近获得了FDA的快速通道资格。
4.5 已停止开发抑制剂的激酶
至少有11个激酶家族和大约20个激酶靶标的抑制剂开发似乎已经停滞或被放弃，因为没有药物在积极试验中，并且这些药物的许多最新状态报告来自5年多前。补充表4提供了我们数据集中已停用的药物和激酶靶标，我们在此处简要讨论了选定的示例。
一个重要的家族是Jun N末端激酶（JNK）家族，它们是MAP激酶，参与调节细胞存活和增殖，以响应与癌症、免疫疾病和神经退行性疾病等一系列疾病有关的细胞因子和生长因子。四种JNK抑制剂于2005年进入临床试验，用于治疗髓系白血病（CC-401；I期）、2011年纤维化疾病（CC-930；II期）、2012年（PGL5001；II期）子宫内膜异位症和2008年（AM-111；2017年完成的III期试验），但尚未取得进一步进展。激酶抑制剂的常见局限性，包括毒性和缺乏激酶特异性，已被列为可能的原因。
临床试验中药物开发似乎暂停的新型激酶靶标的最新例子是单极纺锤体1（MPS1）激酶，它在细胞分裂中起重要作用。两种ATP竞争性激酶抑制剂BAY1161909和BAY1217389在临床前模型中作为单一药物显示出中等疗效，但与紫杉醇联合使用并进入I期试验与紫杉醇联合使用时具有协同效应。虽然作为战略决策终止了BAY1161909的开发，但BAY1217389 完成了试验并显示出良好的耐受性、可控的不良反应和疗效的初步证据，但其开发似乎最近已停止。5. 展望
尽管激酶药物发现领域已经取得了重大进展，但仍有许多挑战和机遇。在肿瘤学领域，激酶抑制剂已成为过去二十年来癌症治疗的基石之一，自从伊马替尼获批以来。为了长期有效性，对抗药物耐药性是迫切需要的，为此正在开发几种策略。设计针对常见的和罕见的激酶驱动突变的药物是其中之一，正如上述NSCLC中多代激酶抑制剂的发展所展示的那样。联合用药方案是另一种方法，例如在黑色素瘤治疗中使用BRAF和MEK抑制剂的组合。此外，随着多种激酶抑制剂的组合用于创建有效的、持久的治疗方法，理性开发单一分子以抑制多个相关激酶可能是另一种雄心勃勃的方法。
还有许多功能性挑战，例如癌症激酶组中遗传变异的表征，以及真正驱动肿瘤发展的基因的识别。对激酶的生物学途径及其与细胞生物学和治疗干预的关系进行仔细分析至关重要，因为一个激酶在非恶性细胞中可能是肿瘤抑制因子，而在恶性细胞中却可能介导肿瘤生存。例如，长期以来人们就知道ATR-ATM途径在DNA损伤后启动凋亡，而其功能障碍会导致肿瘤的发生。然而，后来发现这一途径也被肿瘤细胞利用来抵抗DNA损伤性癌症治疗的影响，这导致了ATR、DNA-PK和CHK1等激酶抑制剂的开发，这些抑制剂目前正处于临床试验阶段。
我们的分析表明，至少70%（约400种激酶）的激酶组在药物开发中仍未被探索，因为这些激酶被视为主要靶标的药物尚未进入临床试验。几个指标可以提供激酶家族成员的相对探索水平的一些指示，包括文献输出、数据库Chembl中抑制每种激酶的化合物数量以及蛋白质数据库中可用解析结构的数量。一项整合此类知识的持续计划是NIH Illuminating the Druggable Genome（IDG）项目，该项目整理来自多个领域的证据，以绘制围绕潜在药物靶点的知识差距，并促进对研究不足但可能可成药的蛋白质的调查。IDG在用户界面Pharos中提供了信息，并突出显示了有趣的未被充分研究的目标。IDG根据不同的靶标发育水平对635种蛋白激酶进行了分类，他们估计3%（21种激酶，Tdark）的特征是“暗”的，其中对这些激酶几乎一无所知，大约30%（188种激酶；Tbio）没有已知的药物或小分子活性超过其特定活性阈值，其中包括来自文本挖掘文献的分数和Gene Reference Into Function注释。有趣的是，研究不足的蛋白质，包括在Tdark和Tbio类别中鉴定的蛋白质，可能在不同类型的癌症中经常发生改变，这表明它们对以前未表征的肿瘤细胞表型具有潜在的功能重要性。此外，在最近一项评估三阴性乳腺癌肿瘤转录改变的临床研究中，发现Tdark和Tbio研究不足的蛋白都存在转录改变，表明它们与其他已被更多研究的激酶（例如，已批准药物靶向的激酶）共同转录调控，这说明了识别和进一步开发这些研究不足的激酶的潜在治疗重要性。
总体而言，激酶研究的现状表明，公开可用的知识很强，结构覆盖面广，并且有大量化学探针可用于研究激酶组。结构基因组学联盟（Structural Genomics Consortium）在很大程度上促进了这些阐明激酶结构、探针和靶标表征以及药物发现的许多其他方面的工作，该联盟是一个由科学家和制药公司组成的开放式合作网络，专注于为科学界提供可用的研究成果。为了继续扩大激酶药物发现，需要进一步开发和改进高效的化合物筛选和分析技术。特别是，需要解决可以识别新化学物质（包括天然化合物）的方法。此外，在获得靶标选择性以减少脱靶毒性方面也存在挑战。具有不同类型结合模式的抑制剂（如变构和共价抑制剂）和靶向降解剂（如PROTAC和分子胶）的开发，可能在未来二十年的激酶药物发现中发挥关键作用。
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临床研究
2024-11-06
FOSTER CITY, Calif.--(
BUSINESS WIRE
)--Gilead Sciences, Inc. (Nasdaq: GILD) announced today its third quarter 2024 results of operations.
“Gilead’s third quarter results are the strongest of the year to date, with 7% year-over-year revenue growth, including 13% year-over-year growth for Biktarvy. Based on this very strong topline growth and disciplined operating expense management, we are increasing our full year revenue, operating income, and earnings per share guidance,” said Daniel O’Day, Gilead’s Chairman and Chief Executive Officer. “We are excited to further increase our impact for patients and communities in the months ahead. This includes building on the momentum from the U.S. launch of Livdelzi for primary biliary cholangitis and preparing for the potential launch of the first twice-yearly option for HIV prevention option, lenacapavir.”
Third Quarter 2024 Financial Results
Total third quarter 2024 revenue increased 7% to $7.5 billion compared to the same period in 2023, primarily due to higher sales in HIV as well as in Veklury
®
(remdesivir), Oncology and Liver Disease.
Diluted earnings per share (“EPS”) was $1.00 in the third quarter 2024 compared to $1.73 in the same period in 2023. The decrease was primarily driven by a pre-tax in-process research and development (“IPR&D”) impairment of $1.75 billion, or $1.04 per share net of tax impact, related to assets acquired by Gilead from Immunomedics, Inc. (“Immunomedics”) in 2020, as well as higher acquired IPR&D expense. This was partially offset by higher product sales and higher net unrealized gains on equity securities.
Non-GAAP diluted EPS was $2.02 in the third quarter 2024 compared to $2.29 in the same period in 2023. The decrease was primarily driven by higher acquired IPR&D and tax expense, partially offset by higher product sales.
As of September 30, 2024, Gilead had $5.0 billion of cash, cash equivalents and marketable debt securities compared to $8.4 billion as of December 31, 2023. The decrease primarily reflects the $3.9 billion acquisition of CymaBay Therapeutics, Inc.
During the third quarter 2024 Gilead generated $4.3 billion in operating cash flow.
During the third quarter 2024 Gilead paid dividends of $983 million and repurchased $300 million of common stock.
Third Quarter 2024 Product Sales
Total third quarter 2024 product sales increased 7% to $7.5 billion compared to the same period in 2023. Total third quarter 2024 product sales, excluding Veklury, increased 7% to $6.8 billion compared to the same period in 2023, primarily due to higher sales in HIV as well as in Oncology and Liver Disease.
HIV
product sales increased 9% to $5.1 billion in the third quarter 2024 compared to the same period in 2023, driven by higher average realized price, primarily due to shifts in channel mix, and higher demand, partially offset by inventory dynamics.
Biktarvy
®
(bictegravir 50mg/emtricitabine 200mg (“FTC”)/tenofovir alafenamide 25mg (“TAF”)) sales increased 13% to $3.5 billion in the third quarter 2024 compared to the same period in 2023, primarily driven by higher demand and average realized price, partially offset by inventory dynamics.
Descovy
®
(FTC 200mg/TAF 25mg) sales increased 15% to $586 million in the third quarter 2024 compared to the same period in 2023, primarily driven by higher demand and average realized price, partially offset by inventory dynamics.
The
Liver Disease
portfolio sales increased 4% to $733 million in the third quarter 2024 compared to the same period in 2023. This was primarily driven by higher demand in viral hepatitis medicines, partially offset by unfavorable pricing dynamics.
Veklury
sales increased 9% to $692 million
in the third quarter 2024 compared to the same period in 2023, primarily driven by increased rates of COVID-19 related hospitalizations, particularly in the United States.
Cell Therapy
product sales of $485 million in the third quarter 2024 were relatively flat compared to the same period in 2023.
Yescarta
®
(axicabtagene ciloleucel) sales decreased 1% to $387 million in the third quarter 2024 compared to the same period in 2023, reflecting increased in- and out-of-class competition in the United States, partially offset by increased demand in relapsed or refractory (“R/R”) large B-cell lymphoma (“LBCL”) in other regions.
Tecartus
®
(brexucabtagene autoleucel) sales increased 2% to $98 million in the third quarter 2024 compared to the same period in 2023, driven by increased demand in adult acute lymphoblastic leukemia (“ALL”).
Trodelvy
®
(sacituzumab govitecan-hziy) sales increased 17% to $332 million in the third quarter 2024 compared to the same period in 2023, primarily driven by higher demand across all regions.
Third Quarter 2024 Product Gross Margin, Operating Expenses and Effective Tax Rate
Product gross margin was 79.1% in the third quarter 2024 compared to 77.6% in the same period in 2023. Non-GAAP product gross margin was 86.8% in the third quarter 2024 compared to 85.9% in the same period in 2023. The increases in GAAP and non-GAAP were primarily driven by product mix.
Research & development (“R&D”) expenses and non-GAAP R&D expenses were $1.4 billion in the third quarter 2024 compared to $1.5 billion in the same period in 2023. The decreases were primarily driven by the timing of clinical activities, including the wind-down of the magrolimab and obeldesivir COVID programs.
Acquired IPR&D expenses were $505 million in the third quarter 2024, primarily driven by a $320 million charge related to the buy-out of global Livdelzi
®
(seladelpar) royalties from Janssen Pharmaceutica NV, as well as payments related to ongoing collaborations.
IPR&D impairment was $1.75 billion related to the assets acquired from Immunomedics in 2020 with no similar charges in 2023.
Selling, general and administrative (“SG&A”) expenses and non-GAAP SG&A expenses were $1.4 billion in the third quarter 2024 compared to $1.3 billion in the same period in 2023. The increases reflect the timing of commercial activities, including the launch of Livdelzi in the United States, and other corporate activities.
The effective tax rate (“ETR”) was (31.1)% in the third quarter 2024 compared to 6.3% in the same period in 2023. The decrease in ETR primarily reflects the impact of a legal entity restructuring and the aforementioned Immunomedics IPR&D impairment expense, partially offset by a prior year decrease in tax reserves that did not repeat. Non-GAAP ETR was 17.5% in the third quarter 2024 compared to 7.0% in the same period in 2023, primarily reflecting the impact of the prior year decrease in tax reserves.
Guidance and Outlook
For the full-year 2024, Gilead expects:
(in millions, except per share amounts)
November 6, 2024 Guidance
Low End
High End
Comparison to August 8, 2024 Guidance
Product sales
$
27,800
$
28,100
Previously $27,100 to $27,500
Product sales, excluding Veklury
$
26,000
$
26,300
Previously $25,800 to $26,200
Veklury
$
1,800
$
1,800
Previously $1,300
Diluted EPS
$
0.05
$
0.25
Previously $0.00 to $0.30
Non-GAAP diluted EPS
$
4.25
$
4.45
Previously $3.60 to $3.90
Additional information and a reconciliation between GAAP and non-GAAP financial information for the 2024 guidance is provided in the accompanying tables. The financial guidance is subject to a number of risks and uncertainties. See the Forward-Looking Statements section below.
Key Updates Since Our Last Quarterly Release
Virology
Announced results of PURPOSE 2, the second Phase 3 study of twice-yearly lenacapavir for HIV prevention, with data presented at the HIV Research for Prevention Conference. In the lenacapavir group, 99.9% of participants did not acquire HIV infection, with 2 incident cases among 2,179 participants. Lenacapavir reduced HIV infections by 96% compared to background HIV incidence in cisgender men and gender-diverse people, and additionally demonstrated superiority to daily Truvada
®
(FTC 200mg and tenofovir disoproxil fumarate 300mg; 89% relative risk reduction). Lenacapavir was generally well-tolerated and no significant or new safety concerns were identified. Gilead expects to file for U.S. Food and Drug Administration (“FDA”) approval before the end of the year, with global filings to follow. The use of lenacapavir for the prevention of HIV is investigational.
Presented HIV treatment data at the Infection Disease Week (“IDWeek”) meeting, including Week 48 data from the Phase 2 study evaluating the investigational oral once-weekly combination regimen of lenacapavir with Merck’s, known as MSD outside of the United States and Canada (“Merck”), islatravir. In addition, Phase 1a data of the investigational once-weekly GS-1720 and 3-year follow up from the Phase 2/3 CAPELLA trial of twice-yearly lenacapavir in people with multi-drug resistant HIV were also highlighted.
Signed royalty-free voluntary licensing agreements with six manufacturers to make and sell generic lenacapavir for HIV prevention and for HIV treatment in heavily treatment-experienced adults with multi-drug resistant HIV in 120 high-incidence, resource-limited countries, subject to regulatory approval of lenacapavir in those markets.
Presented data at IDWeek from the Phase 3 BIRCH and OAKTREE trials of investigational obeldesivir in non-hospitalized participants at high-risk or standard-risk for severe COVID-19, respectively. Previously, Gilead announced the early termination of the BIRCH trial and top-line results from the OAKTREE trial which found that while the study did not meet its primary endpoint, obeldesivir was found to have a generally well tolerated safety profile. The detailed data presented add to the breadth of safety data on obeldesivir.
Donated approximately 5,000 vials of remdesivir to the Rwanda Medical Supply in response to the Marburg Virus Disease (“MVD”) outbreak for emergency use. Remdesivir is not approved for the treatment of MVD anywhere globally, and the safety and efficacy of this use is not known.
Oncology
Announced abstracts for the American Society of Hematology 2024 Annual Meeting (“ASH”), including preliminary data from the registrational Phase 2 iMMagine-1 trial evaluating the Arcellx, Inc. (“Arcellx”) partnered investigational CAR T anito-cel (anitocabtagene autoleucel) in R/R multiple myeloma, as well as updated results from the Phase 1 trial. Additionally, the first patient has been dosed in the Phase 3 iMMagine-3 trial in 2L+ R/R multiple myeloma.
Announced ASH abstracts for long-term follow-up of Yescarta in R/R indolent non-Hodgkin’s lymphoma and Tecartus in R/R mantle cell lymphoma, as well as real world data for Tecartus in B-cell precursor ALL.
Presented Trodelvy data at the International Association for the Study of Lung Cancer World Conference on Lung Cancer across first- and second-line advanced or metastatic non-small cell lung cancer, as well as in extensive-stage small cell lung cancer. The use of Trodelvy for lung cancer is investigational.
Announced plans to voluntarily withdraw the U.S. accelerated approval of Trodelvy for use in pre-treated adult patients with locally advanced or metastatic urothelial cancer, following the results of the Phase 3 TROPiCS-04 trial announced in May 2024.
Received FDA Regenerative Medicine Advanced Therapy Designation for the evaluation of Yescarta as first-line treatment for adult patients with newly diagnosed, high-risk LBCL, an investigational use.
Inflammation
Received FDA accelerated approval for Livdelzi for the treatment of primary biliary cholangitis in combination with ursodeoxycholic acid (“UDCA”) in adults who have an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA. The use of Livdelzi is not recommended for people who have or develop decompensated cirrhosis.
Corporate
Announced a strategic collaboration with Genesis Therapeutics, Inc. (“Genesis”) to discover and develop novel small molecule therapies across multiple targets using Genesis’ GEMS AI platform.
The Board declared a quarterly dividend of $0.77 per share of common stock for the fourth quarter of 2024. The dividend is payable on December 30, 2024, to stockholders of record at the close of business on December 13, 2024. Future dividends will be subject to Board approval.
Certain amounts and percentages in this press release may not sum or recalculate due to rounding.
Conference Call
At 1:30 p.m. Pacific Time today, Gilead will host a conference call to discuss Gilead’s results. A live webcast will be available on
http://investors.gilead.com
and will be archived on
www.gilead.com
for one year.
Non-GAAP Financial Information
The information presented in this document has been prepared in accordance with U.S. generally accepted accounting principles (“GAAP”), unless otherwise noted as non-GAAP. Management believes non-GAAP information is useful for investors, when considered in conjunction with Gilead’s GAAP financial information, because management uses such information internally for its operating, budgeting and financial planning purposes. Non-GAAP information is not prepared under a comprehensive set of accounting rules and should only be used to supplement an understanding of Gilead’s operating results as reported under GAAP. Non-GAAP financial information generally excludes acquisition-related expenses including amortization of acquired intangible assets and other items that are considered unusual or not representative of underlying trends of Gilead’s business, fair value adjustments of equity securities and discrete and related tax charges or benefits associated with such exclusions as well as changes in tax-related laws and guidelines, transfers of intangible assets between certain legal entities, and legal entity restructurings. Although Gilead consistently excludes the amortization of acquired intangible assets from the non-GAAP financial information, management believes that it is important for investors to understand that such intangible assets were recorded as part of acquisitions and contribute to ongoing revenue generation.
Non-GAAP measures may be defined and calculated differently by other companies in the same industry. Reconciliations of the non-GAAP financial measures to the most directly comparable GAAP financial measures are provided in the accompanying tables.
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 and cancer. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California.
Forward-Looking Statements
Statements included in this press release that are not historical in nature are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Gilead cautions readers that forward-looking statements are subject to certain risks and uncertainties that could cause actual results to differ materially. These risks and uncertainties include those relating to: Gilead’s ability to achieve its anticipated full year 2024 financial results, including as a result of the uncertainty of the amount and timing of Veklury revenues; Gilead’s ability to make progress on any of its long-term ambitions or priorities laid out in its corporate strategy; Gilead’s ability to accelerate or sustain revenues for its virology, oncology and other programs; Gilead’s ability to realize the potential benefits of acquisitions, collaborations or licensing arrangements, including the arrangements with Arcellx, Genesis and Merck; patent protection and estimated loss of exclusivity for our products and product candidates; Gilead’s ability to initiate, progress or complete clinical trials within currently anticipated timeframes or at all, the possibility of unfavorable results from ongoing and additional clinical trials, including those involving Trodelvy, anito-cel, GS-1720, lenacapavir, and obeldesivir (such as the BIRCH, CAPELLA, iMMagine-1, iMMagine-3, OAKTREE, and PURPOSE-2 studies), and the risk that safety and efficacy data from clinical trials may not warrant further development of Gilead’s product candidates or the product candidates of Gilead’s strategic partners; Gilead’s ability to submit new drug applications for new product candidates or expanded indications in the currently anticipated timelines, including for lenacapavir for HIV PrEP; Gilead’s ability to receive or maintain regulatory approvals in a timely manner or at all, and the risk that any such approvals, if granted, may be subject to significant limitations on use and may be subject to withdrawal or other adverse actions by the applicable regulatory authority; Gilead’s ability to successfully commercialize its products; the risk of potential disruptions to the manufacturing and supply chain of Gilead’s products; pricing and reimbursement pressures from government agencies and other third parties, including required rebates and other discounts; a larger than anticipated shift in payer mix to more highly discounted payer segments; market share and price erosion caused by the introduction of generic versions of Gilead products; the risk that physicians and patients may not see advantages of Gilead’s products over other therapies and may therefore be reluctant to prescribe the products, including Livdelzi; and other risks identified from time to time in Gilead’s reports filed with the SEC, including annual reports on Form 10-K, quarterly reports on Form 10-Q and current reports on Form 8-K. In addition, Gilead makes estimates and judgments that affect the reported amounts of assets, liabilities, revenues and expenses and related disclosures. Gilead bases its estimates on historical experience and on various other market specific and other relevant assumptions that it believes to be reasonable under the circumstances, the results of which form the basis for making judgments about the carrying values of assets and liabilities that are not readily apparent from other sources. There may be other factors of which Gilead is not currently aware that may affect matters discussed in the forward-looking statements and may also cause actual results to differ significantly from these estimates. Further, results for the quarter ended September 30, 2024 are not necessarily indicative of operating results for any future periods. Gilead directs readers to its press releases, annual reports on Form 10-K, quarterly reports on Form 10-Q and other subsequent disclosure documents filed with the SEC. Gilead claims the protection of the Safe Harbor contained in the Private Securities Litigation Reform Act of 1995 for forward-looking statements.
The reader is cautioned that forward-looking statements are not guarantees of future performance 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 to update or supplement any such forward-looking statements other than as required by law. Any forward-looking statements speak only as of the date hereof or as of the dates indicated in the statements.
Gilead owns or has rights to various trademarks, copyrights and trade names used in its business, including the following: GILEAD
®
, GILEAD SCIENCES
®
, KITE
TM
, AMBISOME
®
, ATRIPLA
®
, BIKTARVY
®
, CAYSTON
®
, COMPLERA
®
, DESCOVY
®
, DESCOVY FOR PREP
®
, EMTRIVA
®
, EPCLUSA
®
, EVIPLERA
®
, GENVOYA
®
, HARVONI
®
, HEPCLUDEX
®
, HEPSERA
®
, JYSELECA
®
, LIVDELZI
®
, LETAIRIS
®
, ODEFSEY
®
, SOVALDI
®
, STRIBILD
®
, SUNLENCA
®
, TECARTUS
®
, TRODELVY
®
, TRUVADA
®
, TRUVADA FOR PREP
®
, TYBOST
®
, VEKLURY
®
, VEMLIDY
®
, VIREAD
®
, VOSEVI
®
, YESCARTA
®
and ZYDELIG
®
.
For more information on Gilead Sciences, Inc., please visit
www.gilead.com
or call the Gilead Public Affairs Department at 1-800-GILEAD-5 (1-800-445-3235).
GILEAD SCIENCES, INC.
CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS
(unaudited)
Three Months Ended
Nine Months Ended
September 30,
September 30,
(in millions, except per share amounts)
2024
2023
2024
2023
Revenues:
Product sales
$
7,515
$
6,994
$
21,074
$
19,864
Royalty, contract and other revenues
30
56
111
138
Total revenues
7,545
7,051
21,185
20,002
Costs and expenses:
Cost of goods sold
1,574
1,565
4,670
4,408
Research and development expenses
1,395
1,457
4,266
4,310
Acquired in-process research and development expenses
505
91
4,674
808
In-process research and development impairment
1,750
—
4,180
—
Selling, general and administrative expenses
1,433
1,315
4,184
4,482
Total costs and expenses
6,657
4,428
21,975
14,009
Operating income (loss)
888
2,623
(790
)
5,993
Interest expense
238
232
728
692
Other (income) expense, net
(306
)
72
(41
)
95
Income (loss) before income taxes
956
2,318
(1,477
)
5,206
Income tax (benefit) expense
(297
)
146
(174
)
1,010
Net income (loss)
1,253
2,172
(1,303
)
4,196
Net loss attributable to noncontrolling interest
—
(8
)
—
(40
)
Net income (loss) attributable to Gilead
$
1,253
$
2,180
$
(1,303
)
$
4,236
Basic earnings (loss) per share attributable to Gilead
$
1.00
$
1.75
$
(1.04
)
$
3.39
Shares used in basic earnings (loss) per share attributable to Gilead calculation
1,247
1,248
1,247
1,249
Diluted earnings (loss) per share attributable to Gilead
$
1.00
$
1.73
$
(1.04
)
$
3.37
Shares used in diluted earnings (loss) per share attributable to Gilead calculation
1,254
1,257
1,247
1,259
Supplemental Information:
Cash dividends declared per share
$
0.77
$
0.75
$
2.31
$
2.25
Product gross margin
79.1
%
77.6
%
77.8
%
77.8
%
Research and development expenses as a % of revenues
18.5
%
20.7
%
20.1
%
21.5
%
Selling, general and administrative expenses as a % of revenues
19.0
%
18.6
%
19.8
%
22.4
%
Operating margin
11.8
%
37.2
%
(3.7
)%
30.0
%
Effective tax rate
(31.1
)%
6.3
%
11.8
%
19.4
%
GILEAD SCIENCES, INC.
TOTAL REVENUE SUMMARY
(unaudited)
Three Months Ended
Nine Months Ended
September 30,
September 30,
(in millions, except percentages)
2024
2023
Change
2024
2023
Change
Product sales:
HIV
$
5,073
$
4,667
9%
$
14,160
$
13,482
5%
Liver Disease
733
706
4%
2,302
2,093
10%
Oncology
816
769
6%
2,446
2,167
13%
Other
201
216
(7)%
705
658
7%
Total product sales excluding Veklury
6,823
6,358
7%
19,613
18,400
7%
Veklury
692
636
9%
1,461
1,465
—%
Total product sales
7,515
6,994
7%
21,074
19,864
6%
Royalty, contract and other revenues
30
56
(46)%
111
138
(19)%
Total revenues
$
7,545
$
7,051
7%
$
21,185
$
20,002
6%
GILEAD SCIENCES, INC.
NON-GAAP FINANCIAL INFORMATION
(1)
(unaudited)
Three Months Ended
Nine Months Ended
September 30,
September 30,
(in millions, except percentages)
2024
2023
Change
2024
2023
Change
Non-GAAP:
Cost of goods sold
$
995
$
985
1%
$
2,933
$
2,717
8%
Research and development expenses
$
1,382
$
1,453
(5)%
$
4,120
$
4,268
(3)%
Acquired IPR&D expenses
(2)
$
505
$
91
NM
$
4,674
$
808
NM
Selling, general and administrative expenses
$
1,405
$
1,298
8%
$
4,051
$
4,464
(9)%
Other (income) expense, net
$
(48
)
$
(96
)
(50)%
$
(189
)
$
(261
)
(28)%
Diluted earnings per share attributable to Gilead
$
2.02
$
2.29
(12)%
$
2.72
$
5.00
(46)%
Shares used in non-GAAP diluted earnings per share attributable to Gilead calculation
1,254
1,257
—%
1,254
1,259
—%
Product gross margin
86.8
%
85.9
%
84 bps
86.1
%
86.3
%
-24 bps
Research and development expenses as a % of revenues
18.3
%
20.6
%
-229 bps
19.4
%
21.3
%
-189 bps
Selling, general and administrative expenses as a % of revenues
18.6
%
18.4
%
21 bps
19.1
%
22.3
%
-320 bps
Operating margin
43.2
%
45.7
%
-255 bps
25.5
%
38.7
%
-1320 bps
Effective tax rate
17.5
%
7.0
%
1052 bps
30.0
%
14.5
%
1552 bps
________________________________
NM - Not Meaningful
(1)
Refer to Non-GAAP Financial Information section above for further disclosures on non-GAAP financial measures. A reconciliation between GAAP and non-GAAP financial information is provided in the tables below.
(2)
Equal to GAAP financial information.
GILEAD SCIENCES, INC.
RECONCILIATION OF GAAP TO NON-GAAP FINANCIAL INFORMATION
(unaudited)
Three Months Ended
Nine Months Ended
September 30,
September 30,
(in millions, except percentages and per share amounts)
2024
2023
2024
2023
Cost of goods sold reconciliation:
GAAP cost of goods sold
$
1,574
$
1,565
$
4,670
$
4,408
Acquisition-related – amortization
(1)
(579
)
(581
)
(1,737
)
(1,691
)
Restructuring
—
—
1
—
Non-GAAP cost of goods sold
$
995
$
985
$
2,933
$
2,717
Product gross margin reconciliation:
GAAP product gross margin
79.1
%
77.6
%
77.8
%
77.8
%
Acquisition-related – amortization
(1)
7.7
%
8.3
%
8.2
%
8.5
%
Restructuring
—
%
—
%
(—
)%
—
%
Non-GAAP product gross margin
86.8
%
85.9
%
86.1
%
86.3
%
Research and development expenses reconciliation:
GAAP research and development expenses
$
1,395
$
1,457
$
4,266
$
4,310
Acquisition-related – other costs
(2)
(9
)
1
(78
)
(37
)
Restructuring
(5
)
(5
)
(68
)
(5
)
Non-GAAP research and development expenses
$
1,382
$
1,453
$
4,120
$
4,268
IPR&D impairment reconciliation:
GAAP IPR&D impairment
$
1,750
$
—
$
4,180
$
—
IPR&D impairment
(1,750
)
—
(4,180
)
—
Non-GAAP IPR&D impairment
$
—
$
—
$
—
$
—
Selling, general and administrative expenses reconciliation:
GAAP selling, general and administrative expenses
$
1,433
$
1,315
$
4,184
$
4,482
Acquisition-related – other costs
(2)
(5
)
—
(88
)
(2
)
Restructuring
(23
)
(17
)
(45
)
(17
)
Non-GAAP selling, general and administrative expenses
$
1,405
$
1,298
$
4,051
$
4,464
Operating income (loss) reconciliation:
GAAP operating income (loss)
$
888
$
2,623
$
(790
)
$
5,993
Acquisition-related – amortization
(1)
579
581
1,737
1,691
Acquisition-related – other costs
(2)
13
(1
)
167
39
Restructuring
28
22
112
22
IPR&D impairment
1,750
—
4,180
—
Non-GAAP operating income
$
3,258
$
3,224
$
5,406
$
7,745
Operating margin reconciliation:
GAAP operating margin
11.8
%
37.2
%
(3.7
)%
30.0
%
Acquisition-related – amortization
(1)
7.7
%
8.2
%
8.2
%
8.5
%
Acquisition-related – other costs
(2)
0.2
%
—
%
0.8
%
0.2
%
Restructuring
0.4
%
0.3
%
0.5
%
0.1
%
IPR&D impairment
23.2
%
—
%
19.7
%
—
%
Non-GAAP operating margin
43.2
%
45.7
%
25.5
%
38.7
%
Other (income) expense, net reconciliation:
GAAP other (income) expense, net
$
(306
)
$
72
$
(41
)
$
95
Gain (loss) from equity securities, net
258
(168
)
(148
)
(356
)
Non-GAAP other (income) expense, net
$
(48
)
$
(96
)
$
(189
)
$
(261
)
Income (loss) before income taxes reconciliation:
GAAP income (loss) before income taxes
$
956
$
2,318
$
(1,477
)
$
5,206
Acquisition-related – amortization
(1)
579
581
1,737
1,691
Acquisition-related – other costs
(2)
13
(1
)
167
39
Restructuring
28
22
112
22
IPR&D impairment
1,750
—
4,180
—
(Gain) loss from equity securities, net
(258
)
168
148
356
Non-GAAP income before income taxes
$
3,068
$
3,088
$
4,866
$
7,314
GILEAD SCIENCES, INC.
RECONCILIATION OF GAAP TO NON-GAAP FINANCIAL INFORMATION - (Continued)
(unaudited)
Three Months Ended
Nine Months Ended
September 30,
September 30,
(in millions, except percentages and per share amounts)
2024
2023
2024
2023
Income tax (benefit) expense reconciliation:
GAAP income tax (benefit) expense
$
(297
)
$
146
$
(174
)
$
1,010
Income tax effect of non-GAAP adjustments:
Acquisition-related – amortization
(1)
121
120
363
347
Acquisition-related – other costs
(2)
2
—
39
8
Restructuring
4
5
21
5
IPR&D impairment
440
—
1,051
—
(Gain) loss from equity securities, net
(46
)
4
(52
)
5
Discrete and related tax charges
(3)
314
(58
)
214
(314
)
Non-GAAP income tax expense
$
538
$
216
$
1,461
$
1,061
Effective tax rate reconciliation:
GAAP effective tax rate
(31.1
)%
6.3
%
11.8
%
19.4
%
Income tax effect of above non-GAAP adjustments and discrete and related tax adjustments
(3)
48.6
%
0.7
%
18.2
%
(4.9
)%
Non-GAAP effective tax rate
17.5
%
7.0
%
30.0
%
14.5
%
Net income (loss) attributable to Gilead reconciliation:
GAAP net income (loss) attributable to Gilead
$
1,253
$
2,180
$
(1,303
)
$
4,236
Acquisition-related – amortization
(1)
458
461
1,374
1,345
Acquisition-related – other costs
(2)
11
(1
)
128
31
Restructuring
24
17
92
17
IPR&D impairment
1,310
—
3,129
—
(Gain) loss from equity securities, net
(212
)
164
200
351
Discrete and related tax charges
(3)
(314
)
58
(214
)
314
Non-GAAP net income attributable to Gilead
$
2,531
$
2,879
$
3,405
$
6,293
Diluted earnings (loss) per share reconciliation:
GAAP diluted earnings (loss) per share
$
1.00
$
1.73
$
(1.04
)
$
3.37
Acquisition-related – amortization
(1)
0.37
0.37
1.10
1.07
Acquisition-related – other costs
(2)
0.01
—
0.10
0.02
Restructuring
0.02
0.01
0.07
0.01
IPR&D impairment
1.04
—
2.51
—
(Gain) loss from equity securities, net
(0.17
)
0.13
0.16
0.28
Discrete and related tax charges
(3)
(0.25
)
0.05
(0.17
)
0.25
Difference in shares used for GAAP vs. Non-GAAP
—
—
(0.01
)
—
Non-GAAP diluted earnings per share
$
2.02
$
2.29
$
2.72
$
5.00
Non-GAAP adjustment summary:
Cost of goods sold adjustments
$
579
$
581
$
1,736
$
1,691
Research and development expenses adjustments
13
4
146
42
IPR&D impairment adjustments
1,750
—
4,180
—
Selling, general and administrative expenses adjustments
28
17
133
19
Total non-GAAP adjustments to costs and expenses
2,370
602
6,196
1,752
Other (income) expense, net adjustments
(258
)
168
148
356
Total non-GAAP adjustments before income taxes
2,113
770
6,343
2,108
Income tax effect of non-GAAP adjustments above
(521
)
(129
)
(1,421
)
(364
)
Discrete and related tax charges
(3)
(314
)
58
(214
)
314
Total non-GAAP adjustments to net income attributable to Gilead
$
1,278
$
699
$
4,708
$
2,057
________________________________
(1)
Relates to amortization of acquired intangibles.
(2)
Adjustments include integration expenses, contingent consideration fair value adjustments and other expenses associated with Gilead’s acquisitions of MYR GmbH, MiroBio, Ltd., Tmunity Therapeutics, Inc., XinThera, Inc. and CymaBay Therapeutics, Inc.
(3)
Represents discrete and related deferred tax charges or benefits primarily associated with acquired intangible assets and in-process research and development, transfers of intangible assets from a foreign subsidiary to Ireland and the United States, and legal entity restructurings.
GILEAD SCIENCES, INC.
RECONCILIATION OF GAAP TO NON-GAAP 2024 FULL-YEAR GUIDANCE
(1)
(unaudited)
(in millions, except percentages and per share amounts)
Provided
February 6, 2024
Updated
April 25, 2024
Updated
August 8, 2024
Updated
November 6, 2024
Projected product gross margin GAAP to non-GAAP reconciliation:
GAAP projected product gross margin
76.0% - 77.0%
76.0% - 77.0%
76.0% - 77.0%
78.0%
Acquisition-related expenses and restructuring expenses
~ 9.0%
~ 9.0%
~ 9.0%
~ 8.0%
Non-GAAP projected product gross margin
85.0% - 86.0%
85.0% - 86.0%
85.0% - 86.0%
86.0%
Projected operating income GAAP to non-GAAP reconciliation:
GAAP projected operating income
$8,700 - $9,200
$1,900 - $2,400
$2,100 - $2,500
$1,100 - $1,400
IPR&D impairment, acquisition-related and restructuring expenses
~ 2,500
~ 5,100
~ 5,100
~ 6,900
Non-GAAP projected operating income
$11,200 - $11,700
$7,000 - $7,500
$7,200 - $7,600
$8,000 - $8,300
Projected effective tax rate GAAP to non-GAAP reconciliation:
GAAP projected effective tax rate
~ 21%
~ 65%
~ 87%
~ 56%
Income tax effect of above non-GAAP adjustments and fair value adjustments of equity securities, and discrete and related tax adjustments
(~ 2%)
(~ 35%)
(~ 57%)
(~ 29%)
Non-GAAP projected effective tax rate
~ 19%
~ 30%
~ 30%
~ 27%
Projected diluted EPS GAAP to non-GAAP reconciliation:
GAAP projected diluted EPS
$5.15 - $5.55
$0.10 - $0.50
$0.00 - $0.30
$0.05 - $0.25
IPR&D impairment, acquisition-related and restructuring expenses, fair value adjustments of equity securities and discrete and related tax adjustments
~ 1.70
~ 3.35
~ 3.60
~ 4.20
Non-GAAP projected diluted EPS
$6.85 - $7.25
$3.45 - $3.85
$3.60 - $3.90
$4.25 - $4.45
________________________________
(1)
Our full-year guidance excludes the potential impact of any (i) acquisitions or business development transactions that have not been executed, (ii) future fair value adjustments of equity securities and (iii) discrete tax charges or benefits associated with changes in tax related laws and guidelines that have not been enacted, as Gilead is unable to project such amounts. The non-GAAP full-year guidance includes non-GAAP adjustments to actual current period results as well as adjustments for the known future impact associated with events that have already occurred, such as future amortization of our intangible assets and the future impact of discrete and related deferred tax charges or benefits primarily associated with acquired intangible assets and in-process research and development, transfers of intangible assets from a foreign subsidiary to Ireland and the United States, and legal entity restructurings.
GILEAD SCIENCES, INC.
CONDENSED CONSOLIDATED BALANCE SHEETS
(unaudited)
September 30,
December 31,
(in millions)
2024
2023
Assets
Cash, cash equivalents and marketable debt securities
$
5,037
$
8,428
Accounts receivable, net
4,587
4,660
Inventories
3,435
3,366
Property, plant and equipment, net
5,391
5,317
Intangible assets, net
20,546
26,454
Goodwill
8,314
8,314
Other assets
7,215
5,586
Total assets
$
54,525
$
62,125
Liabilities and Stockholders’ Equity
Current liabilities
$
11,725
$
11,280
Long-term liabilities
24,409
28,096
Stockholders’ equity
(1)
18,390
22,749
Total liabilities and stockholders’ equity
$
54,525
$
62,125
________________________________
(1)
As of September 30, 2024 and December 31, 2023, there were 1,246 shares of common stock issued and outstanding.
GILEAD SCIENCES, INC.
SELECTED CASH FLOW INFORMATION
(unaudited)
Three Months Ended
Nine Months Ended
September 30,
September 30,
(in millions)
2024
2023
2024
2023
Net cash provided by operating activities
$
4,309
$
1,756
$
7,853
$
5,837
Net cash used in investing activities
(710
)
(229
)
(3,224
)
(1,538
)
Net cash used in financing activities
(1,379
)
(1,518
)
(5,693
)
(4,026
)
Effect of exchange rate changes on cash and cash equivalents
44
(7
)
15
20
Net change in cash and cash equivalents
2,265
1
(1,049
)
293
Cash and cash equivalents at beginning of period
2,772
5,704
6,085
5,412
Cash and cash equivalents at end of period
$
5,037
$
5,705
$
5,037
$
5,705
Three Months Ended
Nine Months Ended
September 30,
September 30,
(in millions)
2024
2023
2024
2023
Net cash provided by operating activities
$
4,309
$
1,756
$
7,853
$
5,837
Capital expenditures
(140
)
(122
)
(376
)
(370
)
Free cash flow
(1)
$
4,169
$
1,633
$
7,478
$
5,467
________________________________
(1)
Free cash flow is a non-GAAP liquidity measure. Please refer to our disclosures in the Non-GAAP Financial Information section above.
GILEAD SCIENCES, INC.
PRODUCT SALES SUMMARY
(unaudited)
Three Months Ended
Nine Months Ended
September 30,
September 30,
(in millions)
2024
2023
2024
2023
HIV
Biktarvy – U.S.
$
2,826
$
2,504
$
7,726
$
7,104
Biktarvy – Europe
375
313
1,110
920
Biktarvy – Rest of World
272
268
814
717
3,472
3,085
9,649
8,741
Descovy – U.S.
534
460
1,339
1,314
Descovy – Europe
24
25
75
75
Descovy – Rest of World
28
26
82
86
586
511
1,496
1,475
Genvoya – U.S.
384
433
1,088
1,305
Genvoya – Europe
44
47
138
157
Genvoya – Rest of World
21
23
66
81
449
503
1,292
1,544
Odefsey – U.S.
248
257
705
754
Odefsey – Europe
69
74
217
223
Odefsey – Rest of World
9
11
30
33
326
343
952
1,011
Symtuza - Revenue share
(1)
– U.S.
103
96
338
278
Symtuza - Revenue share
(1)
– Europe
33
32
101
101
Symtuza - Revenue share
(1)
– Rest of World
3
3
9
10
139
131
448
390
Other HIV
(2)
– U.S.
65
56
190
192
Other HIV
(2)
– Europe
26
28
96
91
Other HIV
(2)
– Rest of World
9
9
36
38
100
94
322
321
Total HIV – U.S.
4,161
3,807
11,386
10,949
Total HIV – Europe
570
519
1,737
1,568
Total HIV – Rest of World
342
341
1,038
965
5,073
4,667
14,160
13,482
Liver Disease
Sofosbuvir / Velpatasvir
(3)
– U.S.
222
215
737
643
Sofosbuvir / Velpatasvir
(3)
– Europe
67
76
230
250
Sofosbuvir / Velpatasvir
(3)
– Rest of World
96
85
299
266
385
377
1,266
1,159
Vemlidy – U.S.
126
112
338
295
Vemlidy – Europe
11
9
33
28
Vemlidy – Rest of World
95
106
328
322
232
228
699
645
Other Liver Disease
(4)
– U.S.
45
49
134
113
Other Liver Disease
(4)
– Europe
54
33
148
112
Other Liver Disease
(4)
– Rest of World
17
20
55
64
116
102
337
289
Total Liver Disease – U.S.
393
376
1,210
1,051
Total Liver Disease – Europe
132
119
411
390
Total Liver Disease – Rest of World
207
211
682
652
733
706
2,302
2,093
Veklury
Veklury – U.S.
393
258
784
607
Veklury – Europe
81
65
204
227
Veklury – Rest of World
219
313
473
630
692
636
1,461
1,465
GILEAD SCIENCES, INC.
PRODUCT SALES SUMMARY - (Continued)
(unaudited)
Three Months Ended
Nine Months Ended
September 30,
September 30,
(in millions)
2024
2023
2024
2023
Oncology
Cell Therapy
Tecartus – U.S.
63
64
181
179
Tecartus – Europe
29
27
102
83
Tecartus – Rest of World
6
4
22
11
98
96
305
272
Yescarta – U.S.
145
197
502
624
Yescarta – Europe
182
154
509
408
Yescarta – Rest of World
60
40
170
99
387
391
1,181
1,130
Total Cell Therapy – U.S.
208
261
683
802
Total Cell Therapy – Europe
211
181
611
491
Total Cell Therapy – Rest of World
66
45
192
109
485
486
1,485
1,402
Trodelvy
Trodelvy – U.S.
226
201
655
551
Trodelvy – Europe
80
62
217
169
Trodelvy – Rest of World
26
21
88
44
332
283
960
764
Total Oncology – U.S.
433
462
1,338
1,354
Total Oncology – Europe
291
243
828
660
Total Oncology – Rest of World
92
65
280
153
816
769
2,446
2,167
Other
AmBisome – U.S.
6
12
37
39
AmBisome – Europe
71
63
210
192
AmBisome – Rest of World
52
39
176
150
130
115
424
381
Other
(5)
– U.S.
47
69
203
197
Other
(5)
– Europe
8
9
26
31
Other
(5)
– Rest of World
16
23
52
49
71
101
281
277
Total Other – U.S.
53
82
241
236
Total Other – Europe
80
72
236
224
Total Other – Rest of World
68
62
228
199
201
216
705
658
Total product sales – U.S.
5,433
4,985
14,958
14,196
Total product sales – Europe
1,154
1,017
3,416
3,069
Total product sales – Rest of World
928
992
2,700
2,599
$
7,515
$
6,994
$
21,074
$
19,864
________________________________
(1)
Represents Gilead’s revenue from cobicistat (“C”), FTC and TAF in Symtuza (darunavir/C/FTC/TAF), a fixed dose combination product commercialized by Janssen Sciences Ireland Unlimited Company.
(2)
Includes Atripla, Complera/Eviplera, Emtriva, Sunlenca, Stribild, Truvada and Tybost.
(3)
Includes Epclusa and the authorized generic version of Epclusa sold by Gilead’s separate subsidiary, Asegua Therapeutics LLC (“Asegua”).
(4)
Includes ledipasvir/sofosbuvir (Harvoni and the authorized generic version of Harvoni sold by Asegua), Hepcludex, Hepsera, Livdelzi, Sovaldi, Viread and Vosevi.
(5)
Includes Cayston, Jyseleca, Letairis, Ranexa and Zydelig.
临床结果临床2期临床3期突破性疗法上市批准
2024-11-06
FOSTER CITY, Calif.--(
BUSINESS WIRE
)--Gilead Sciences, Inc. (Nasdaq: GILD) announced today its third quarter 2024 results of operations.
“Gilead’s third quarter results are the strongest of the year to date, with 7% year-over-year revenue growth, including 13% year-over-year growth for Biktarvy. Based on this very strong topline growth and disciplined operating expense management, we are increasing our full year revenue, operating income, and earnings per share guidance,” said Daniel O’Day, Gilead’s Chairman and Chief Executive Officer. “We are excited to further increase our impact for patients and communities in the months ahead. This includes building on the momentum from the U.S. launch of Livdelzi for primary biliary cholangitis and preparing for the potential launch of the first twice-yearly option for HIV prevention option, lenacapavir.”
Third Quarter 2024 Financial Results
Total third quarter 2024 revenue increased 7% to $7.5 billion compared to the same period in 2023, primarily due to higher sales in HIV as well as in Veklury
®
(remdesivir), Oncology and Liver Disease.
Diluted earnings per share (“EPS”) was $1.00 in the third quarter 2024 compared to $1.73 in the same period in 2023. The decrease was primarily driven by a pre-tax in-process research and development (“IPR&D”) impairment of $1.75 billion, or $1.04 per share net of tax impact, related to assets acquired by Gilead from Immunomedics, Inc. (“Immunomedics”) in 2020, as well as higher acquired IPR&D expense. This was partially offset by higher product sales and higher net unrealized gains on equity securities.
Non-GAAP diluted EPS was $2.02 in the third quarter 2024 compared to $2.29 in the same period in 2023. The decrease was primarily driven by higher acquired IPR&D and tax expense, partially offset by higher product sales.
As of September 30, 2024, Gilead had $5.0 billion of cash, cash equivalents and marketable debt securities compared to $8.4 billion as of December 31, 2023. The decrease primarily reflects the $3.9 billion acquisition of CymaBay Therapeutics, Inc.
During the third quarter 2024 Gilead generated $4.3 billion in operating cash flow.
During the third quarter 2024 Gilead paid dividends of $983 million and repurchased $300 million of common stock.
Third Quarter 2024 Product Sales
Total third quarter 2024 product sales increased 7% to $7.5 billion compared to the same period in 2023. Total third quarter 2024 product sales, excluding Veklury, increased 7% to $6.8 billion compared to the same period in 2023, primarily due to higher sales in HIV as well as in Oncology and Liver Disease.
HIV
product sales increased 9% to $5.1 billion in the third quarter 2024 compared to the same period in 2023, driven by higher average realized price, primarily due to shifts in channel mix, and higher demand, partially offset by inventory dynamics.
Biktarvy
®
(bictegravir 50mg/emtricitabine 200mg (“FTC”)/tenofovir alafenamide 25mg (“TAF”)) sales increased 13% to $3.5 billion in the third quarter 2024 compared to the same period in 2023, primarily driven by higher demand and average realized price, partially offset by inventory dynamics.
Descovy
®
(FTC 200mg/TAF 25mg) sales increased 15% to $586 million in the third quarter 2024 compared to the same period in 2023, primarily driven by higher demand and average realized price, partially offset by inventory dynamics.
The
Liver Disease
portfolio sales increased 4% to $733 million in the third quarter 2024 compared to the same period in 2023. This was primarily driven by higher demand in viral hepatitis medicines, partially offset by unfavorable pricing dynamics.
Veklury
sales increased 9% to $692 million
in the third quarter 2024 compared to the same period in 2023, primarily driven by increased rates of COVID-19 related hospitalizations, particularly in the United States.
Cell Therapy
product sales of $485 million in the third quarter 2024 were relatively flat compared to the same period in 2023.
Yescarta
®
(axicabtagene ciloleucel) sales decreased 1% to $387 million in the third quarter 2024 compared to the same period in 2023, reflecting increased in- and out-of-class competition in the United States, partially offset by increased demand in relapsed or refractory (“R/R”) large B-cell lymphoma (“LBCL”) in other regions.
Tecartus
®
(brexucabtagene autoleucel) sales increased 2% to $98 million in the third quarter 2024 compared to the same period in 2023, driven by increased demand in adult acute lymphoblastic leukemia (“ALL”).
Trodelvy
®
(sacituzumab govitecan-hziy) sales increased 17% to $332 million in the third quarter 2024 compared to the same period in 2023, primarily driven by higher demand across all regions.
Third Quarter 2024 Product Gross Margin, Operating Expenses and Effective Tax Rate
Product gross margin was 79.1% in the third quarter 2024 compared to 77.6% in the same period in 2023. Non-GAAP product gross margin was 86.8% in the third quarter 2024 compared to 85.9% in the same period in 2023. The increases in GAAP and non-GAAP were primarily driven by product mix.
Research & development (“R&D”) expenses and non-GAAP R&D expenses were $1.4 billion in the third quarter 2024 compared to $1.5 billion in the same period in 2023. The decreases were primarily driven by the timing of clinical activities, including the wind-down of the magrolimab and obeldesivir COVID programs.
Acquired IPR&D expenses were $505 million in the third quarter 2024, primarily driven by a $320 million charge related to the buy-out of global Livdelzi
®
(seladelpar) royalties from Janssen Pharmaceutica NV, as well as payments related to ongoing collaborations.
IPR&D impairment was $1.75 billion related to the assets acquired from Immunomedics in 2020 with no similar charges in 2023.
Selling, general and administrative (“SG&A”) expenses and non-GAAP SG&A expenses were $1.4 billion in the third quarter 2024 compared to $1.3 billion in the same period in 2023. The increases reflect the timing of commercial activities, including the launch of Livdelzi in the United States, and other corporate activities.
The effective tax rate (“ETR”) was (31.1)% in the third quarter 2024 compared to 6.3% in the same period in 2023. The decrease in ETR primarily reflects the impact of a legal entity restructuring and the aforementioned Immunomedics IPR&D impairment expense, partially offset by a prior year decrease in tax reserves that did not repeat. Non-GAAP ETR was 17.5% in the third quarter 2024 compared to 7.0% in the same period in 2023, primarily reflecting the impact of the prior year decrease in tax reserves.
Guidance and Outlook
For the full-year 2024, Gilead expects:
(in millions, except per share amounts)
November 6, 2024 Guidance
Low End
High End
Comparison to August 8, 2024 Guidance
Product sales
$
27,800
$
28,100
Previously $27,100 to $27,500
Product sales, excluding Veklury
$
26,000
$
26,300
Previously $25,800 to $26,200
Veklury
$
1,800
$
1,800
Previously $1,300
Diluted EPS
$
0.05
$
0.25
Previously $0.00 to $0.30
Non-GAAP diluted EPS
$
4.25
$
4.45
Previously $3.60 to $3.90
Additional information and a reconciliation between GAAP and non-GAAP financial information for the 2024 guidance is provided in the accompanying tables. The financial guidance is subject to a number of risks and uncertainties. See the Forward-Looking Statements section below.
Key Updates Since Our Last Quarterly Release
Virology
Announced results of PURPOSE 2, the second Phase 3 study of twice-yearly lenacapavir for HIV prevention, with data presented at the HIV Research for Prevention Conference. In the lenacapavir group, 99.9% of participants did not acquire HIV infection, with 2 incident cases among 2,179 participants. Lenacapavir reduced HIV infections by 96% compared to background HIV incidence in cisgender men and gender-diverse people, and additionally demonstrated superiority to daily Truvada
®
(FTC 200mg and tenofovir disoproxil fumarate 300mg; 89% relative risk reduction). Lenacapavir was generally well-tolerated and no significant or new safety concerns were identified. Gilead expects to file for U.S. Food and Drug Administration (“FDA”) approval before the end of the year, with global filings to follow. The use of lenacapavir for the prevention of HIV is investigational.
Presented HIV treatment data at the Infection Disease Week (“IDWeek”) meeting, including Week 48 data from the Phase 2 study evaluating the investigational oral once-weekly combination regimen of lenacapavir with Merck’s, known as MSD outside of the United States and Canada (“Merck”), islatravir. In addition, Phase 1a data of the investigational once-weekly GS-1720 and 3-year follow up from the Phase 2/3 CAPELLA trial of twice-yearly lenacapavir in people with multi-drug resistant HIV were also highlighted.
Signed royalty-free voluntary licensing agreements with six manufacturers to make and sell generic lenacapavir for HIV prevention and for HIV treatment in heavily treatment-experienced adults with multi-drug resistant HIV in 120 high-incidence, resource-limited countries, subject to regulatory approval of lenacapavir in those markets.
Presented data at IDWeek from the Phase 3 BIRCH and OAKTREE trials of investigational obeldesivir in non-hospitalized participants at high-risk or standard-risk for severe COVID-19, respectively. Previously, Gilead announced the early termination of the BIRCH trial and top-line results from the OAKTREE trial which found that while the study did not meet its primary endpoint, obeldesivir was found to have a generally well tolerated safety profile. The detailed data presented add to the breadth of safety data on obeldesivir.
Donated approximately 5,000 vials of remdesivir to the Rwanda Medical Supply in response to the Marburg Virus Disease (“MVD”) outbreak for emergency use. Remdesivir is not approved for the treatment of MVD anywhere globally, and the safety and efficacy of this use is not known.
Oncology
Announced abstracts for the American Society of Hematology 2024 Annual Meeting (“ASH”), including preliminary data from the registrational Phase 2 iMMagine-1 trial evaluating the Arcellx, Inc. (“Arcellx”) partnered investigational CAR T anito-cel (anitocabtagene autoleucel) in R/R multiple myeloma, as well as updated results from the Phase 1 trial. Additionally, the first patient has been dosed in the Phase 3 iMMagine-3 trial in 2L+ R/R multiple myeloma.
Announced ASH abstracts for long-term follow-up of Yescarta in R/R indolent non-Hodgkin’s lymphoma and Tecartus in R/R mantle cell lymphoma, as well as real world data for Tecartus in B-cell precursor ALL.
Presented Trodelvy data at the International Association for the Study of Lung Cancer World Conference on Lung Cancer across first- and second-line advanced or metastatic non-small cell lung cancer, as well as in extensive-stage small cell lung cancer. The use of Trodelvy for lung cancer is investigational.
Announced plans to voluntarily withdraw the U.S. accelerated approval of Trodelvy for use in pre-treated adult patients with locally advanced or metastatic urothelial cancer, following the results of the Phase 3 TROPiCS-04 trial announced in May 2024.
Received FDA Regenerative Medicine Advanced Therapy Designation for the evaluation of Yescarta as first-line treatment for adult patients with newly diagnosed, high-risk LBCL, an investigational use.
Inflammation
Received FDA accelerated approval for Livdelzi for the treatment of primary biliary cholangitis in combination with ursodeoxycholic acid (“UDCA”) in adults who have an inadequate response to UDCA, or as monotherapy in patients unable to tolerate UDCA. The use of Livdelzi is not recommended for people who have or develop decompensated cirrhosis.
Corporate
Announced a strategic collaboration with Genesis Therapeutics, Inc. (“Genesis”) to discover and develop novel small molecule therapies across multiple targets using Genesis’ GEMS AI platform.
The Board declared a quarterly dividend of $0.77 per share of common stock for the fourth quarter of 2024. The dividend is payable on December 30, 2024, to stockholders of record at the close of business on December 13, 2024. Future dividends will be subject to Board approval.
Certain amounts and percentages in this press release may not sum or recalculate due to rounding.
Conference Call
At 1:30 p.m. Pacific Time today, Gilead will host a conference call to discuss Gilead’s results. A live webcast will be available on
http://investors.gilead.com
and will be archived on
www.gilead.com
for one year.
Non-GAAP Financial Information
The information presented in this document has been prepared in accordance with U.S. generally accepted accounting principles (“GAAP”), unless otherwise noted as non-GAAP. Management believes non-GAAP information is useful for investors, when considered in conjunction with Gilead’s GAAP financial information, because management uses such information internally for its operating, budgeting and financial planning purposes. Non-GAAP information is not prepared under a comprehensive set of accounting rules and should only be used to supplement an understanding of Gilead’s operating results as reported under GAAP. Non-GAAP financial information generally excludes acquisition-related expenses including amortization of acquired intangible assets and other items that are considered unusual or not representative of underlying trends of Gilead’s business, fair value adjustments of equity securities and discrete and related tax charges or benefits associated with such exclusions as well as changes in tax-related laws and guidelines, transfers of intangible assets between certain legal entities, and legal entity restructurings. Although Gilead consistently excludes the amortization of acquired intangible assets from the non-GAAP financial information, management believes that it is important for investors to understand that such intangible assets were recorded as part of acquisitions and contribute to ongoing revenue generation.
Non-GAAP measures may be defined and calculated differently by other companies in the same industry. Reconciliations of the non-GAAP financial measures to the most directly comparable GAAP financial measures are provided in the accompanying tables.
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 and cancer. Gilead operates in more than 35 countries worldwide, with headquarters in Foster City, California.
Forward-Looking Statements
Statements included in this press release that are not historical in nature are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Gilead cautions readers that forward-looking statements are subject to certain risks and uncertainties that could cause actual results to differ materially. These risks and uncertainties include those relating to: Gilead’s ability to achieve its anticipated full year 2024 financial results, including as a result of the uncertainty of the amount and timing of Veklury revenues; Gilead’s ability to make progress on any of its long-term ambitions or priorities laid out in its corporate strategy; Gilead’s ability to accelerate or sustain revenues for its virology, oncology and other programs; Gilead’s ability to realize the potential benefits of acquisitions, collaborations or licensing arrangements, including the arrangements with Arcellx, Genesis and Merck; patent protection and estimated loss of exclusivity for our products and product candidates; Gilead’s ability to initiate, progress or complete clinical trials within currently anticipated timeframes or at all, the possibility of unfavorable results from ongoing and additional clinical trials, including those involving Trodelvy, anito-cel, GS-1720, lenacapavir, and obeldesivir (such as the BIRCH, CAPELLA, iMMagine-1, iMMagine-3, OAKTREE, and PURPOSE-2 studies), and the risk that safety and efficacy data from clinical trials may not warrant further development of Gilead’s product candidates or the product candidates of Gilead’s strategic partners; Gilead’s ability to submit new drug applications for new product candidates or expanded indications in the currently anticipated timelines, including for lenacapavir for HIV PrEP; Gilead’s ability to receive or maintain regulatory approvals in a timely manner or at all, and the risk that any such approvals, if granted, may be subject to significant limitations on use and may be subject to withdrawal or other adverse actions by the applicable regulatory authority; Gilead’s ability to successfully commercialize its products; the risk of potential disruptions to the manufacturing and supply chain of Gilead’s products; pricing and reimbursement pressures from government agencies and other third parties, including required rebates and other discounts; a larger than anticipated shift in payer mix to more highly discounted payer segments; market share and price erosion caused by the introduction of generic versions of Gilead products; the risk that physicians and patients may not see advantages of Gilead’s products over other therapies and may therefore be reluctant to prescribe the products, including Livdelzi; and other risks identified from time to time in Gilead’s reports filed with the SEC, including annual reports on Form 10-K, quarterly reports on Form 10-Q and current reports on Form 8-K. In addition, Gilead makes estimates and judgments that affect the reported amounts of assets, liabilities, revenues and expenses and related disclosures. Gilead bases its estimates on historical experience and on various other market specific and other relevant assumptions that it believes to be reasonable under the circumstances, the results of which form the basis for making judgments about the carrying values of assets and liabilities that are not readily apparent from other sources. There may be other factors of which Gilead is not currently aware that may affect matters discussed in the forward-looking statements and may also cause actual results to differ significantly from these estimates. Further, results for the quarter ended September 30, 2024 are not necessarily indicative of operating results for any future periods. Gilead directs readers to its press releases, annual reports on Form 10-K, quarterly reports on Form 10-Q and other subsequent disclosure documents filed with the SEC. Gilead claims the protection of the Safe Harbor contained in the Private Securities Litigation Reform Act of 1995 for forward-looking statements.
The reader is cautioned that forward-looking statements are not guarantees of future performance 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 to update or supplement any such forward-looking statements other than as required by law. Any forward-looking statements speak only as of the date hereof or as of the dates indicated in the statements.
Gilead owns or has rights to various trademarks, copyrights and trade names used in its business, including the following: GILEAD
®
, GILEAD SCIENCES
®
, KITE
TM
, AMBISOME
®
, ATRIPLA
®
, BIKTARVY
®
, CAYSTON
®
, COMPLERA
®
, DESCOVY
®
, DESCOVY FOR PREP
®
, EMTRIVA
®
, EPCLUSA
®
, EVIPLERA
®
, GENVOYA
®
, HARVONI
®
, HEPCLUDEX
®
, HEPSERA
®
, JYSELECA
®
, LIVDELZI
®
, LETAIRIS
®
, ODEFSEY
®
, SOVALDI
®
, STRIBILD
®
, SUNLENCA
®
, TECARTUS
®
, TRODELVY
®
, TRUVADA
®
, TRUVADA FOR PREP
®
, TYBOST
®
, VEKLURY
®
, VEMLIDY
®
, VIREAD
®
, VOSEVI
®
, YESCARTA
®
and ZYDELIG
®
.
For more information on Gilead Sciences, Inc., please visit
www.gilead.com
or call the Gilead Public Affairs Department at 1-800-GILEAD-5 (1-800-445-3235).
GILEAD SCIENCES, INC.
CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS
(unaudited)
Three Months Ended
Nine Months Ended
September 30,
September 30,
(in millions, except per share amounts)
2024
2023
2024
2023
Revenues:
Product sales
$
7,515
$
6,994
$
21,074
$
19,864
Royalty, contract and other revenues
30
56
111
138
Total revenues
7,545
7,051
21,185
20,002
Costs and expenses:
Cost of goods sold
1,574
1,565
4,670
4,408
Research and development expenses
1,395
1,457
4,266
4,310
Acquired in-process research and development expenses
505
91
4,674
808
In-process research and development impairment
1,750
—
4,180
—
Selling, general and administrative expenses
1,433
1,315
4,184
4,482
Total costs and expenses
6,657
4,428
21,975
14,009
Operating income (loss)
888
2,623
(790
)
5,993
Interest expense
238
232
728
692
Other (income) expense, net
(306
)
72
(41
)
95
Income (loss) before income taxes
956
2,318
(1,477
)
5,206
Income tax (benefit) expense
(297
)
146
(174
)
1,010
Net income (loss)
1,253
2,172
(1,303
)
4,196
Net loss attributable to noncontrolling interest
—
(8
)
—
(40
)
Net income (loss) attributable to Gilead
$
1,253
$
2,180
$
(1,303
)
$
4,236
Basic earnings (loss) per share attributable to Gilead
$
1.00
$
1.75
$
(1.04
)
$
3.39
Shares used in basic earnings (loss) per share attributable to Gilead calculation
1,247
1,248
1,247
1,249
Diluted earnings (loss) per share attributable to Gilead
$
1.00
$
1.73
$
(1.04
)
$
3.37
Shares used in diluted earnings (loss) per share attributable to Gilead calculation
1,254
1,257
1,247
1,259
Supplemental Information:
Cash dividends declared per share
$
0.77
$
0.75
$
2.31
$
2.25
Product gross margin
79.1
%
77.6
%
77.8
%
77.8
%
Research and development expenses as a % of revenues
18.5
%
20.7
%
20.1
%
21.5
%
Selling, general and administrative expenses as a % of revenues
19.0
%
18.6
%
19.8
%
22.4
%
Operating margin
11.8
%
37.2
%
(3.7
)%
30.0
%
Effective tax rate
(31.1
)%
6.3
%
11.8
%
19.4
%
GILEAD SCIENCES, INC.
TOTAL REVENUE SUMMARY
(unaudited)
Three Months Ended
Nine Months Ended
September 30,
September 30,
(in millions, except percentages)
2024
2023
Change
2024
2023
Change
Product sales:
HIV
$
5,073
$
4,667
9%
$
14,160
$
13,482
5%
Liver Disease
733
706
4%
2,302
2,093
10%
Oncology
816
769
6%
2,446
2,167
13%
Other
201
216
(7)%
705
658
7%
Total product sales excluding Veklury
6,823
6,358
7%
19,613
18,400
7%
Veklury
692
636
9%
1,461
1,465
—%
Total product sales
7,515
6,994
7%
21,074
19,864
6%
Royalty, contract and other revenues
30
56
(46)%
111
138
(19)%
Total revenues
$
7,545
$
7,051
7%
$
21,185
$
20,002
6%
GILEAD SCIENCES, INC.
NON-GAAP FINANCIAL INFORMATION
(1)
(unaudited)
Three Months Ended
Nine Months Ended
September 30,
September 30,
(in millions, except percentages)
2024
2023
Change
2024
2023
Change
Non-GAAP:
Cost of goods sold
$
995
$
985
1%
$
2,933
$
2,717
8%
Research and development expenses
$
1,382
$
1,453
(5)%
$
4,120
$
4,268
(3)%
Acquired IPR&D expenses
(2)
$
505
$
91
NM
$
4,674
$
808
NM
Selling, general and administrative expenses
$
1,405
$
1,298
8%
$
4,051
$
4,464
(9)%
Other (income) expense, net
$
(48
)
$
(96
)
(50)%
$
(189
)
$
(261
)
(28)%
Diluted earnings per share attributable to Gilead
$
2.02
$
2.29
(12)%
$
2.72
$
5.00
(46)%
Shares used in non-GAAP diluted earnings per share attributable to Gilead calculation
1,254
1,257
—%
1,254
1,259
—%
Product gross margin
86.8
%
85.9
%
84 bps
86.1
%
86.3
%
-24 bps
Research and development expenses as a % of revenues
18.3
%
20.6
%
-229 bps
19.4
%
21.3
%
-189 bps
Selling, general and administrative expenses as a % of revenues
18.6
%
18.4
%
21 bps
19.1
%
22.3
%
-320 bps
Operating margin
43.2
%
45.7
%
-255 bps
25.5
%
38.7
%
-1320 bps
Effective tax rate
17.5
%
7.0
%
1052 bps
30.0
%
14.5
%
1552 bps
________________________________
NM - Not Meaningful
(1)
Refer to Non-GAAP Financial Information section above for further disclosures on non-GAAP financial measures. A reconciliation between GAAP and non-GAAP financial information is provided in the tables below.
(2)
Equal to GAAP financial information.
GILEAD SCIENCES, INC.
RECONCILIATION OF GAAP TO NON-GAAP FINANCIAL INFORMATION
(unaudited)
Three Months Ended
Nine Months Ended
September 30,
September 30,
(in millions, except percentages and per share amounts)
2024
2023
2024
2023
Cost of goods sold reconciliation:
GAAP cost of goods sold
$
1,574
$
1,565
$
4,670
$
4,408
Acquisition-related – amortization
(1)
(579
)
(581
)
(1,737
)
(1,691
)
Restructuring
—
—
1
—
Non-GAAP cost of goods sold
$
995
$
985
$
2,933
$
2,717
Product gross margin reconciliation:
GAAP product gross margin
79.1
%
77.6
%
77.8
%
77.8
%
Acquisition-related – amortization
(1)
7.7
%
8.3
%
8.2
%
8.5
%
Restructuring
—
%
—
%
(—
)%
—
%
Non-GAAP product gross margin
86.8
%
85.9
%
86.1
%
86.3
%
Research and development expenses reconciliation:
GAAP research and development expenses
$
1,395
$
1,457
$
4,266
$
4,310
Acquisition-related – other costs
(2)
(9
)
1
(78
)
(37
)
Restructuring
(5
)
(5
)
(68
)
(5
)
Non-GAAP research and development expenses
$
1,382
$
1,453
$
4,120
$
4,268
IPR&D impairment reconciliation:
GAAP IPR&D impairment
$
1,750
$
—
$
4,180
$
—
IPR&D impairment
(1,750
)
—
(4,180
)
—
Non-GAAP IPR&D impairment
$
—
$
—
$
—
$
—
Selling, general and administrative expenses reconciliation:
GAAP selling, general and administrative expenses
$
1,433
$
1,315
$
4,184
$
4,482
Acquisition-related – other costs
(2)
(5
)
—
(88
)
(2
)
Restructuring
(23
)
(17
)
(45
)
(17
)
Non-GAAP selling, general and administrative expenses
$
1,405
$
1,298
$
4,051
$
4,464
Operating income (loss) reconciliation:
GAAP operating income (loss)
$
888
$
2,623
$
(790
)
$
5,993
Acquisition-related – amortization
(1)
579
581
1,737
1,691
Acquisition-related – other costs
(2)
13
(1
)
167
39
Restructuring
28
22
112
22
IPR&D impairment
1,750
—
4,180
—
Non-GAAP operating income
$
3,258
$
3,224
$
5,406
$
7,745
Operating margin reconciliation:
GAAP operating margin
11.8
%
37.2
%
(3.7
)%
30.0
%
Acquisition-related – amortization
(1)
7.7
%
8.2
%
8.2
%
8.5
%
Acquisition-related – other costs
(2)
0.2
%
—
%
0.8
%
0.2
%
Restructuring
0.4
%
0.3
%
0.5
%
0.1
%
IPR&D impairment
23.2
%
—
%
19.7
%
—
%
Non-GAAP operating margin
43.2
%
45.7
%
25.5
%
38.7
%
Other (income) expense, net reconciliation:
GAAP other (income) expense, net
$
(306
)
$
72
$
(41
)
$
95
Gain (loss) from equity securities, net
258
(168
)
(148
)
(356
)
Non-GAAP other (income) expense, net
$
(48
)
$
(96
)
$
(189
)
$
(261
)
Income (loss) before income taxes reconciliation:
GAAP income (loss) before income taxes
$
956
$
2,318
$
(1,477
)
$
5,206
Acquisition-related – amortization
(1)
579
581
1,737
1,691
Acquisition-related – other costs
(2)
13
(1
)
167
39
Restructuring
28
22
112
22
IPR&D impairment
1,750
—
4,180
—
(Gain) loss from equity securities, net
(258
)
168
148
356
Non-GAAP income before income taxes
$
3,068
$
3,088
$
4,866
$
7,314
GILEAD SCIENCES, INC.
RECONCILIATION OF GAAP TO NON-GAAP FINANCIAL INFORMATION - (Continued)
(unaudited)
Three Months Ended
Nine Months Ended
September 30,
September 30,
(in millions, except percentages and per share amounts)
2024
2023
2024
2023
Income tax (benefit) expense reconciliation:
GAAP income tax (benefit) expense
$
(297
)
$
146
$
(174
)
$
1,010
Income tax effect of non-GAAP adjustments:
Acquisition-related – amortization
(1)
121
120
363
347
Acquisition-related – other costs
(2)
2
—
39
8
Restructuring
4
5
21
5
IPR&D impairment
440
—
1,051
—
(Gain) loss from equity securities, net
(46
)
4
(52
)
5
Discrete and related tax charges
(3)
314
(58
)
214
(314
)
Non-GAAP income tax expense
$
538
$
216
$
1,461
$
1,061
Effective tax rate reconciliation:
GAAP effective tax rate
(31.1
)%
6.3
%
11.8
%
19.4
%
Income tax effect of above non-GAAP adjustments and discrete and related tax adjustments
(3)
48.6
%
0.7
%
18.2
%
(4.9
)%
Non-GAAP effective tax rate
17.5
%
7.0
%
30.0
%
14.5
%
Net income (loss) attributable to Gilead reconciliation:
GAAP net income (loss) attributable to Gilead
$
1,253
$
2,180
$
(1,303
)
$
4,236
Acquisition-related – amortization
(1)
458
461
1,374
1,345
Acquisition-related – other costs
(2)
11
(1
)
128
31
Restructuring
24
17
92
17
IPR&D impairment
1,310
—
3,129
—
(Gain) loss from equity securities, net
(212
)
164
200
351
Discrete and related tax charges
(3)
(314
)
58
(214
)
314
Non-GAAP net income attributable to Gilead
$
2,531
$
2,879
$
3,405
$
6,293
Diluted earnings (loss) per share reconciliation:
GAAP diluted earnings (loss) per share
$
1.00
$
1.73
$
(1.04
)
$
3.37
Acquisition-related – amortization
(1)
0.37
0.37
1.10
1.07
Acquisition-related – other costs
(2)
0.01
—
0.10
0.02
Restructuring
0.02
0.01
0.07
0.01
IPR&D impairment
1.04
—
2.51
—
(Gain) loss from equity securities, net
(0.17
)
0.13
0.16
0.28
Discrete and related tax charges
(3)
(0.25
)
0.05
(0.17
)
0.25
Difference in shares used for GAAP vs. Non-GAAP
—
—
(0.01
)
—
Non-GAAP diluted earnings per share
$
2.02
$
2.29
$
2.72
$
5.00
Non-GAAP adjustment summary:
Cost of goods sold adjustments
$
579
$
581
$
1,736
$
1,691
Research and development expenses adjustments
13
4
146
42
IPR&D impairment adjustments
1,750
—
4,180
—
Selling, general and administrative expenses adjustments
28
17
133
19
Total non-GAAP adjustments to costs and expenses
2,370
602
6,196
1,752
Other (income) expense, net adjustments
(258
)
168
148
356
Total non-GAAP adjustments before income taxes
2,113
770
6,343
2,108
Income tax effect of non-GAAP adjustments above
(521
)
(129
)
(1,421
)
(364
)
Discrete and related tax charges
(3)
(314
)
58
(214
)
314
Total non-GAAP adjustments to net income attributable to Gilead
$
1,278
$
699
$
4,708
$
2,057
________________________________
(1)
Relates to amortization of acquired intangibles.
(2)
Adjustments include integration expenses, contingent consideration fair value adjustments and other expenses associated with Gilead’s acquisitions of MYR GmbH, MiroBio, Ltd., Tmunity Therapeutics, Inc., XinThera, Inc. and CymaBay Therapeutics, Inc.
(3)
Represents discrete and related deferred tax charges or benefits primarily associated with acquired intangible assets and in-process research and development, transfers of intangible assets from a foreign subsidiary to Ireland and the United States, and legal entity restructurings.
GILEAD SCIENCES, INC.
RECONCILIATION OF GAAP TO NON-GAAP 2024 FULL-YEAR GUIDANCE
(1)
(unaudited)
(in millions, except percentages and per share amounts)
Provided
February 6, 2024
Updated
April 25, 2024
Updated
August 8, 2024
Updated
November 6, 2024
Projected product gross margin GAAP to non-GAAP reconciliation:
GAAP projected product gross margin
76.0% - 77.0%
76.0% - 77.0%
76.0% - 77.0%
78.0%
Acquisition-related expenses and restructuring expenses
~ 9.0%
~ 9.0%
~ 9.0%
~ 8.0%
Non-GAAP projected product gross margin
85.0% - 86.0%
85.0% - 86.0%
85.0% - 86.0%
86.0%
Projected operating income GAAP to non-GAAP reconciliation:
GAAP projected operating income
$8,700 - $9,200
$1,900 - $2,400
$2,100 - $2,500
$1,100 - $1,400
IPR&D impairment, acquisition-related and restructuring expenses
~ 2,500
~ 5,100
~ 5,100
~ 6,900
Non-GAAP projected operating income
$11,200 - $11,700
$7,000 - $7,500
$7,200 - $7,600
$8,000 - $8,300
Projected effective tax rate GAAP to non-GAAP reconciliation:
GAAP projected effective tax rate
~ 21%
~ 65%
~ 87%
~ 56%
Income tax effect of above non-GAAP adjustments and fair value adjustments of equity securities, and discrete and related tax adjustments
(~ 2%)
(~ 35%)
(~ 57%)
(~ 29%)
Non-GAAP projected effective tax rate
~ 19%
~ 30%
~ 30%
~ 27%
Projected diluted EPS GAAP to non-GAAP reconciliation:
GAAP projected diluted EPS
$5.15 - $5.55
$0.10 - $0.50
$0.00 - $0.30
$0.05 - $0.25
IPR&D impairment, acquisition-related and restructuring expenses, fair value adjustments of equity securities and discrete and related tax adjustments
~ 1.70
~ 3.35
~ 3.60
~ 4.20
Non-GAAP projected diluted EPS
$6.85 - $7.25
$3.45 - $3.85
$3.60 - $3.90
$4.25 - $4.45
________________________________
(1)
Our full-year guidance excludes the potential impact of any (i) acquisitions or business development transactions that have not been executed, (ii) future fair value adjustments of equity securities and (iii) discrete tax charges or benefits associated with changes in tax related laws and guidelines that have not been enacted, as Gilead is unable to project such amounts. The non-GAAP full-year guidance includes non-GAAP adjustments to actual current period results as well as adjustments for the known future impact associated with events that have already occurred, such as future amortization of our intangible assets and the future impact of discrete and related deferred tax charges or benefits primarily associated with acquired intangible assets and in-process research and development, transfers of intangible assets from a foreign subsidiary to Ireland and the United States, and legal entity restructurings.
GILEAD SCIENCES, INC.
CONDENSED CONSOLIDATED BALANCE SHEETS
(unaudited)
September 30,
December 31,
(in millions)
2024
2023
Assets
Cash, cash equivalents and marketable debt securities
$
5,037
$
8,428
Accounts receivable, net
4,587
4,660
Inventories
3,435
3,366
Property, plant and equipment, net
5,391
5,317
Intangible assets, net
20,546
26,454
Goodwill
8,314
8,314
Other assets
7,215
5,586
Total assets
$
54,525
$
62,125
Liabilities and Stockholders’ Equity
Current liabilities
$
11,725
$
11,280
Long-term liabilities
24,409
28,096
Stockholders’ equity
(1)
18,390
22,749
Total liabilities and stockholders’ equity
$
54,525
$
62,125
________________________________
(1)
As of September 30, 2024 and December 31, 2023, there were 1,246 shares of common stock issued and outstanding.
GILEAD SCIENCES, INC.
SELECTED CASH FLOW INFORMATION
(unaudited)
Three Months Ended
Nine Months Ended
September 30,
September 30,
(in millions)
2024
2023
2024
2023
Net cash provided by operating activities
$
4,309
$
1,756
$
7,853
$
5,837
Net cash used in investing activities
(710
)
(229
)
(3,224
)
(1,538
)
Net cash used in financing activities
(1,379
)
(1,518
)
(5,693
)
(4,026
)
Effect of exchange rate changes on cash and cash equivalents
44
(7
)
15
20
Net change in cash and cash equivalents
2,265
1
(1,049
)
293
Cash and cash equivalents at beginning of period
2,772
5,704
6,085
5,412
Cash and cash equivalents at end of period
$
5,037
$
5,705
$
5,037
$
5,705
Three Months Ended
Nine Months Ended
September 30,
September 30,
(in millions)
2024
2023
2024
2023
Net cash provided by operating activities
$
4,309
$
1,756
$
7,853
$
5,837
Capital expenditures
(140
)
(122
)
(376
)
(370
)
Free cash flow
(1)
$
4,169
$
1,633
$
7,478
$
5,467
________________________________
(1)
Free cash flow is a non-GAAP liquidity measure. Please refer to our disclosures in the Non-GAAP Financial Information section above.
GILEAD SCIENCES, INC.
PRODUCT SALES SUMMARY
(unaudited)
Three Months Ended
Nine Months Ended
September 30,
September 30,
(in millions)
2024
2023
2024
2023
HIV
Biktarvy – U.S.
$
2,826
$
2,504
$
7,726
$
7,104
Biktarvy – Europe
375
313
1,110
920
Biktarvy – Rest of World
272
268
814
717
3,472
3,085
9,649
8,741
Descovy – U.S.
534
460
1,339
1,314
Descovy – Europe
24
25
75
75
Descovy – Rest of World
28
26
82
86
586
511
1,496
1,475
Genvoya – U.S.
384
433
1,088
1,305
Genvoya – Europe
44
47
138
157
Genvoya – Rest of World
21
23
66
81
449
503
1,292
1,544
Odefsey – U.S.
248
257
705
754
Odefsey – Europe
69
74
217
223
Odefsey – Rest of World
9
11
30
33
326
343
952
1,011
Symtuza - Revenue share
(1)
– U.S.
103
96
338
278
Symtuza - Revenue share
(1)
– Europe
33
32
101
101
Symtuza - Revenue share
(1)
– Rest of World
3
3
9
10
139
131
448
390
Other HIV
(2)
– U.S.
65
56
190
192
Other HIV
(2)
– Europe
26
28
96
91
Other HIV
(2)
– Rest of World
9
9
36
38
100
94
322
321
Total HIV – U.S.
4,161
3,807
11,386
10,949
Total HIV – Europe
570
519
1,737
1,568
Total HIV – Rest of World
342
341
1,038
965
5,073
4,667
14,160
13,482
Liver Disease
Sofosbuvir / Velpatasvir
(3)
– U.S.
222
215
737
643
Sofosbuvir / Velpatasvir
(3)
– Europe
67
76
230
250
Sofosbuvir / Velpatasvir
(3)
– Rest of World
96
85
299
266
385
377
1,266
1,159
Vemlidy – U.S.
126
112
338
295
Vemlidy – Europe
11
9
33
28
Vemlidy – Rest of World
95
106
328
322
232
228
699
645
Other Liver Disease
(4)
– U.S.
45
49
134
113
Other Liver Disease
(4)
– Europe
54
33
148
112
Other Liver Disease
(4)
– Rest of World
17
20
55
64
116
102
337
289
Total Liver Disease – U.S.
393
376
1,210
1,051
Total Liver Disease – Europe
132
119
411
390
Total Liver Disease – Rest of World
207
211
682
652
733
706
2,302
2,093
Veklury
Veklury – U.S.
393
258
784
607
Veklury – Europe
81
65
204
227
Veklury – Rest of World
219
313
473
630
692
636
1,461
1,465
GILEAD SCIENCES, INC.
PRODUCT SALES SUMMARY - (Continued)
(unaudited)
Three Months Ended
Nine Months Ended
September 30,
September 30,
(in millions)
2024
2023
2024
2023
Oncology
Cell Therapy
Tecartus – U.S.
63
64
181
179
Tecartus – Europe
29
27
102
83
Tecartus – Rest of World
6
4
22
11
98
96
305
272
Yescarta – U.S.
145
197
502
624
Yescarta – Europe
182
154
509
408
Yescarta – Rest of World
60
40
170
99
387
391
1,181
1,130
Total Cell Therapy – U.S.
208
261
683
802
Total Cell Therapy – Europe
211
181
611
491
Total Cell Therapy – Rest of World
66
45
192
109
485
486
1,485
1,402
Trodelvy
Trodelvy – U.S.
226
201
655
551
Trodelvy – Europe
80
62
217
169
Trodelvy – Rest of World
26
21
88
44
332
283
960
764
Total Oncology – U.S.
433
462
1,338
1,354
Total Oncology – Europe
291
243
828
660
Total Oncology – Rest of World
92
65
280
153
816
769
2,446
2,167
Other
AmBisome – U.S.
6
12
37
39
AmBisome – Europe
71
63
210
192
AmBisome – Rest of World
52
39
176
150
130
115
424
381
Other
(5)
– U.S.
47
69
203
197
Other
(5)
– Europe
8
9
26
31
Other
(5)
– Rest of World
16
23
52
49
71
101
281
277
Total Other – U.S.
53
82
241
236
Total Other – Europe
80
72
236
224
Total Other – Rest of World
68
62
228
199
201
216
705
658
Total product sales – U.S.
5,433
4,985
14,958
14,196
Total product sales – Europe
1,154
1,017
3,416
3,069
Total product sales – Rest of World
928
992
2,700
2,599
$
7,515
$
6,994
$
21,074
$
19,864
________________________________
(1)
Represents Gilead’s revenue from cobicistat (“C”), FTC and TAF in Symtuza (darunavir/C/FTC/TAF), a fixed dose combination product commercialized by Janssen Sciences Ireland Unlimited Company.
(2)
Includes Atripla, Complera/Eviplera, Emtriva, Sunlenca, Stribild, Truvada and Tybost.
(3)
Includes Epclusa and the authorized generic version of Epclusa sold by Gilead’s separate subsidiary, Asegua Therapeutics LLC (“Asegua”).
(4)
Includes ledipasvir/sofosbuvir (Harvoni and the authorized generic version of Harvoni sold by Asegua), Hepcludex, Hepsera, Livdelzi, Sovaldi, Viread and Vosevi.
(5)
Includes Cayston, Jyseleca, Letairis, Ranexa and Zydelig.
临床结果临床2期临床3期突破性疗法上市批准
100 项与 非戈替尼 相关的药物交易
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研发状态
批准上市
10 条最早获批的记录, 后查看更多信息
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| 适应症 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|
| 溃疡性结肠炎 | 欧盟 | 2020-09-24 | |
| 溃疡性结肠炎 | 冰岛 | 2020-09-24 | |
| 溃疡性结肠炎 | 列支敦士登 | 2020-09-24 | |
| 溃疡性结肠炎 | 挪威 | 2020-09-24 | |
| 类风湿关节炎 | 欧盟 | 2020-09-24 | |
| 类风湿关节炎 | 冰岛 | 2020-09-24 | |
| 类风湿关节炎 | 列支敦士登 | 2020-09-24 | |
| 类风湿关节炎 | 挪威 | 2020-09-24 | |
| 活动性中度溃疡性结肠炎 | 欧盟 | 2020-09-24 | |
| 活动性中度溃疡性结肠炎 | 冰岛 | 2020-09-24 | |
| 活动性中度溃疡性结肠炎 | 列支敦士登 | 2020-09-24 | |
| 活动性中度溃疡性结肠炎 | 挪威 | 2020-09-24 | |
| 活动性重度溃疡性结肠炎 | 欧盟 | 2020-09-24 | |
| 活动性重度溃疡性结肠炎 | 冰岛 | 2020-09-24 | |
| 活动性重度溃疡性结肠炎 | 列支敦士登 | 2020-09-24 | |
| 活动性重度溃疡性结肠炎 | 挪威 | 2020-09-24 |
未上市
10 条进展最快的记录, 后查看更多信息
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| 中轴性脊柱关节炎 | 临床3期 | 比利时 | 2023-04-05 | |
| 中轴性脊柱关节炎 | 临床3期 | 保加利亚 | 2023-04-05 | |
| 中轴性脊柱关节炎 | 临床3期 | 克罗地亚 | 2023-04-05 | |
| 中轴性脊柱关节炎 | 临床3期 | 捷克 | 2023-04-05 | |
| 中轴性脊柱关节炎 | 临床3期 | 爱沙尼亚 | 2023-04-05 | |
| 中轴性脊柱关节炎 | 临床3期 | 法国 | 2023-04-05 | |
| 中轴性脊柱关节炎 | 临床3期 | 德国 | 2023-04-05 | |
| 中轴性脊柱关节炎 | 临床3期 | 希腊 | 2023-04-05 | |
| 中轴性脊柱关节炎 | 临床3期 | 匈牙利 | 2023-04-05 | |
| 中轴性脊柱关节炎 | 临床3期 | 意大利 | 2023-04-05 |
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临床结果
临床结果
适应症
分期
评价
查看全部结果
| 研究 | 分期 | 人群特征 | 评价人数 | 分组 | 结果 | 评价 | 发布日期 |
|---|
临床2/3期 | - | 選網鏇築遞築夢廠廠艱(糧獵簾鹹齋顧鹽獵獵蓋) = 鹽夢齋鹹構襯憲遞觸範 壓繭簾壓簾構鹹構衊夢 (餘獵簾夢鹽範齋壓憲廠 ) | 积极 | 2024-10-25 | |||
選網鏇築遞築夢廠廠艱(糧獵簾鹹齋顧鹽獵獵蓋) = 繭鹹願廠壓襯鑰醖醖網 壓繭簾壓簾構鹹構衊夢 (餘獵簾夢鹽範齋壓憲廠 ) | |||||||
N/A | 20 | 壓壓繭餘積積遞簾鬱製(鏇遞鹽衊衊鑰構簾構顧) = 鏇鏇鬱憲衊鏇醖鬱糧鑰 憲蓋醖齋築糧淵顧遞壓 (鬱選鏇繭衊遞範顧鹹鹹, 3.2 ~ 6.2) | 积极 | 2024-10-13 | |||
N/A | - | Filgotinib therapy | 範製築衊遞鹹顧餘鹹願(遞襯蓋衊網蓋艱網觸糧) = 構醖築鏇夢簾衊蓋糧衊 壓艱觸選獵築簾選鬱憲 (簾選鑰簾襯齋廠獵齋餘 ) 更多 | - | 2024-10-13 | ||
Placebo | 襯壓選簾窪憲餘選齋壓(顧範鏇廠鹹餘餘構鏇鑰) = 鹹襯遞淵鑰遞襯醖積範 憲鑰齋夢膚夢衊築願顧 (觸獵顧鹽夢窪膚遞窪鑰 ) | ||||||
临床3期 | - | 壓衊獵糧網壓築範範範(範遞衊淵簾餘窪遞廠築) = AEs and AESIs in patients treated with open-label FIL200 (2464.7 PYE) showed no new safety signals, and safety events were comparable to those seen in previous analyses 齋繭夢艱淵鹹獵製構鹽 (顧糧繭遞憲窪餘範廠齋 ) | 积极 | 2024-10-13 | |||
Placebo | |||||||
N/A | - | - | 鹽鏇網觸鏇選簾襯願選(鏇鑰築膚膚範艱夢窪醖) = 夢憲願觸窪壓鑰構壓遞 衊衊夢窪範膚製鹽獵廠 (遞壓製選衊蓋顧築鬱網 ) 更多 | - | 2024-10-13 | ||
临床3期 | 22 | Placebo+Filgotinib (Filgotinib 200 mg) | 鑰遞選顧壓衊積淵構願(遞餘觸蓋齋蓋襯遞齋蓋) = 築觸製膚獵廠構繭淵築 積憲繭獵鹹膚淵觸鑰醖 (網遞艱鏇鹹襯淵鹹糧鹽, 鹽鏇鬱窪鬱顧鏇憲齋憲 ~ 餘構糧餘顧壓襯製齋顧) 更多 | - | 2024-10-04 | ||
Placebo+Filgotinib (Filgotinib 100 mg) | 鑰遞選顧壓衊積淵構願(遞餘觸蓋齋蓋襯遞齋蓋) = 齋顧鹹鑰糧膚製壓構齋 積憲繭獵鹹膚淵觸鑰醖 (網遞艱鏇鹹襯淵鹹糧鹽, 願襯衊繭簾壓獵範顧網 ~ 積蓋襯淵觸顧觸觸範餘) 更多 | ||||||
临床3期 | - | Filgotinib 200 mg | 積鬱願鬱獵鏇廠積願簾(構壓鹹壓築鹹築鹽願襯) = 鹹鑰膚願鹽艱簾遞網膚 繭淵鑰糧顧遞糧觸壓構 (繭製膚繭鹹選鹹夢艱鏇 ) | 积极 | 2024-09-27 | ||
Filgotinib 100 mg | 積鬱願鬱獵鏇廠積願簾(構壓鹹壓築鹹築鹽願襯) = 壓構鏇願選鏇鑰鹽鏇餘 繭淵鑰糧顧遞糧觸壓構 (繭製膚繭鹹選鹹夢艱鏇 ) | ||||||
临床2/3期 | 溃疡性结肠炎 inflammatory biomarkers | 622 | Filgotinib 200 mg | 選鏇襯艱築顧範獵鹹廠(選遞構淵構醖廠鹹範鏇) = 襯憲艱範鬱憲鏇繭壓衊 築製襯簾憲蓋衊繭廠鹽 (蓋製鑰獵範構鑰膚膚鬱 ) 更多 | 积极 | 2024-07-31 | |
(non-responders) | 選鏇襯艱築顧範獵鹹廠(選遞構淵構醖廠鹹範鏇) = 窪遞夢壓壓簾襯糧窪獵 築製襯簾憲蓋衊繭廠鹽 (蓋製鑰獵範構鑰膚膚鬱 ) 更多 | ||||||
临床3期 | 1,188 | (Filgotinib 200 mg) | 繭淵膚襯願糧鏇願壓遞(衊襯簾襯鑰憲遞廠餘構) = 觸觸鬱鬱蓋壓餘憲顧醖 餘繭衊範醖積選鏇艱製 (衊獵簾憲齋鏇壓廠獵選, 淵遞簾構顧鹹衊製範蓋 ~ 淵築遞鬱繭願夢糧製蓋) 更多 | - | 2024-07-10 | ||
(Filgotinib 100 mg) | 繭淵膚襯願糧鏇願壓遞(衊襯簾襯鑰憲遞廠餘構) = 鏇遞糧積鏇製鬱鏇製壓 餘繭衊範醖積選鏇艱製 (衊獵簾憲齋鏇壓廠獵選, 蓋醖觸糧製繭醖範淵繭 ~ 夢繭遞餘構齋窪襯顧鹽) 更多 | ||||||
N/A | - | 鹹簾願簾構獵糧鹹範鏇(憲願壓鏇襯顧鹽淵餘願) = 製廠構衊範夢窪積構鬱 積廠壓製選網鹹築餘膚 (顧選鏇壓齋醖窪憲範簾 ) 更多 | - | 2024-06-05 | |||
bDMARDs | 鹹簾願簾構獵糧鹹範鏇(憲願壓鏇襯顧鹽淵餘願) = 選願窪衊鹽範鏇築夢鑰 積廠壓製選網鹹築餘膚 (顧選鏇壓齋醖窪憲範簾 ) 更多 |
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