Endometriosis, a chronic gynecological disorder associated with pain and infertility, is a common condition affecting approximately one in ten women. Up to 50% of patients with endometriosis have ovarian endometriomas (or "chocolate cysts"). These cysts directly impact fertility and ovarian reserve (ie. ability to have children) and can cause additional symptoms in women such as added pain, discomfort, and surgical emergencies (cyst rupture, or more rarely twisting). While endometriomas tend to require surgical excision as a solution, medical management with a variety of medications has been shown to be effective in reducing their size.
Medical management (ie. medications and treatments that don't involve surgery) to reduce cyst size can help relieve symptoms either as a long term solution, before fertility treatments, or temporarily until surgery can be offered. Because the COVID-19 pandemic caused significantly reduced access to surgery and resources, medical management has become important for relief of the overburdened healthcare network.
The purpose of this study is to see how effective Estetrol/drospirenone, a combined oral contraceptive (COC), is in the reduction of ovarian endometriomas after a 3- and 6-month period of treatment.
This single arm interventional study will recruit women 18 years or older with an ovarian endometrioma of at least 3cm, who are seeking a hormonal treatment for their endometrioma(s). Consenting participants of the study will take Estetrol/drospirenone once daily, orally, for a 6 month duration. An ultrasound assessment of ovarian endometrioma(s) will be performed before starting the drug (0 months), and will be repeated at 3-months and 6-months time. At each of these hospital visits (0, 3 & 6 months), participants will have their weight and blood pressure measured, and they will complete questionnaires regarding their endometriosis symptoms, incidence of amenorrhea, compliance and incidence of any adverse effects.

开始日期2024-10-01

申办/合作机构-

NCT06611514 / Not yet recruiting临床3期IIT

Effect of Intravaginal Prasterone on Genitourinary Syndrome in Women in Menopause with Previous Breast Cancer or Currently Under Treatment with Endocrine Therapy for Breast Cancer with Aromatase Inhibitor +/- LHRHa

The goal of this interventional study is to evaluate the effect of Intravaginal Prasterone for the treatment of moderate to severe symptoms of genitourinary syndrome (GSM) due to natural, surgical or treatment-induced menopause and the effect on the quality of life, including sexual function and mood well-being, in women with Breast Cancer. A sample size of 95 patients will be needed to show that the proportion of women showing symptom improvement is greater than 50%. Subjects will be followed up at four weeks and twelve weeks of treatment. One and three-month outcomes will be provided after the end of treatment. Comparison between menopausal women with previous breast cancer that have finished hormonal therapy or with ER negative breast cancer and women currently under endocrine therapy with AIs will be performed.

开始日期2024-10-01

申办/合作机构

Istituto Europeo di Oncologia SRL

NCT06577974 / RecruitingN/AIIT

Does the Medical Tretament Prior to Stimulation Affect the Fertility Outcome in Cases of Endometriosis Associated Infertiltiy

The aim of this study to assess the effect of medical treatment prior to stimulation on fertility (ICSI) outcome in cases with endometriosis associated infertility.

开始日期2024-07-01

申办/合作机构

Cairo University

100 项与 ER x AR 相关的临床结果

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100 项与 ER x AR 相关的转化医学

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0 项与 ER x AR 相关的专利（医药）

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3,541

项与 ER x AR 相关的文献（医药）

2025-01-01·Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology

Embryonal exposure to 4-methylbenzylidene camphor induces reproduction impairment in adult zebrafish (Danio rerio)

Article

作者: Prakash, Ved ; Ansari, Mohammad Imran ; Anbumani, Sadasivam ; Parthasarathi, Ramakrishnan ; Chauhan, Shwetha Singh

This study investigated how early exposure to xenobiotics can lead to disease in adulthood, which is challenging for toxicologists. We employed a 'cradle to grave' approach using zebrafish (Danio rerio) embryos exposed to 4-methylbenzylidene camphor (4-MBC), a commonly used organic UV filter. Molecular docking and simulation studies confirmed the predictive toxicity and stable interaction of 4-MBC with androgen and estrogen receptors, with binding energies of -9.28 and -9.01 kcal/mol, respectively. Exposure to 4-MBC at 5, 50, and 500 μg/L concentrations resulted in significantly altered transcriptional and translational responses of ar, esr1, and vtg1 genes in embryos at 120 h post-fertilization (hpf). The exposure induced a non-monotonic dose-response pattern (NMDR), a characteristic feature of endocrine-disrupting chemicals. Additionally, a significant decrease in fertilization was observed in adults. Although fecundity was not affected in inter- and intra-breeding performances, developmental deformities were observed in F1 progenies with impaired survival at 10 days post-fertilization. The findings of this study show that embryonic exposure to 4-MBC is likely to induce reproductive and transgenerational toxicity in D. rerio and exhibit endocrine disruption in aquatic non-target organisms. This work is the first to elucidate the low-level long-term effects of 4-MBC from the embryonic stage to adulthood.

2024-12-31·The Aging Male

Prostate-specific antigen, androgen, progesterone and oestrogen receptors in Benign prostatic hyperplasia: human tissues and animal model study

Article

作者: Wang, Haohan ; Zhang, Ping ; Dong, Ziqiang ; Liu, Chengcheng ; Chen, Xiaobo

BACKGROUNDDirect evidence for the relationship between a large prostate (≥80 ml) and androgen receptor/PSA signal remains lacking in benign prostatic hyperplasia (BPH). Our aim is to identify whether the cause of a large prostate is related to progesterone receptor (PGR) androgen receptor (AR), oestrogen receptor α, β (ERα,β) and prostate-specific antigen (PSA).MATERIALS AND METHODSSurgical specimens of BPH in plasmakinetic resection of the prostate (PKRP) with three groups of different prostate-sizes with mean volumes of 25.97 ml, 63.80 ml, and 122.37 ml were collected for immunohistochemical analysis of the tissue microarray with PGR, AR, PSA and ERs. Rats were castrated and treated with testosterone replacement to explore androgen and PGR, AR and ERs expression levels in the prostate. Quantitative real-time reverse transcription polymerase chain reaction (Rt-PCR) for mRNA detection of above genes was conducted.RESULTSImmunoblotting, Rt-PCR and immunohistochemistry assays showed that PGR, PSA, AR, ERα expression levels were positively correlated with prostate size and that ERβ expression levels were negatively correlated with prostate volume. Animal experiments have shown that prostate volume is decreased in castrated rats with decreased PGR, AR, ERα and increased ERβ expression levels.CONCLUSIONPGR, AR, ERs signals can be regarded as important factors for large-sized prostates in BPH patients (≥100 ml).

2024-12-01·Molecular Biology Reports

Morin hydrate ameliorates heat-induced testicular impairment in a mouse model

Article

作者: Kumar, Vikash ; Gurusubramanian, Guruswami ; Roy, Vikas Kumar ; Rathore, Saurabh Singh ; Kumar, Rahul

BACKGROUNDHeat stress is known to adversely affect testicular activity and manifest the pathogenesis of spermatogenesis. Morin hydrate is a plant-derived compound, which contains a wide range of biological activities. Thus, it is hypothesized that morin hydrate might have an ameliorative effect on heat-induced testicular impairment. There has not been any research on the impact of morin hydrate on heat-induced testicular damage.METHODSThe experimental mice were divided into four groups, groups1 as the normal control group (CN), and the second which underwent heat stress (HS) by immersing the lower body for 15 min in a thermostatically controlled water bath kept at 43 °C (HS), and third and fourth heat-stressed followed by two different dosages of morin hydrate 10 mg/kg (HSM10) and 100 mg/kg (HSM100) for 14 days.RESULTSMorin hydrate treatment at 10 mg/kg improved, circulating testosterone levels (increases 3βHSD), and oxidative stress along with improvement in the testis and caput and corpus epididymis histoarchitecture, however, both doses of morin hydrate improved sperm parameters. Morin hydrate treatment significantly increases germ cell proliferation, (GCNA, BrdU staining), expression of Bcl2 and decreases expression of active caspase 3. Heat stress also decreased the expression of AR, ER- α, and ER-β, and Morin hydrate treatment increased the expression of these markers in the 10 mg/kg treatment group.CONCLUSIONMorin hydrate ameliorates heat-induced testicular impairment modulating testosterone synthesis, germ cell proliferation, and oxidative stress. These effects could be manifested by regulating androgen and estrogen receptors. However, the two doses showed differential effects of some parameters, which requires further investigations.

162

项与 ER x AR 相关的新闻（医药）

2024-10-24

·BioSpace

Havah Therapeutics Announces Formation of Clinical Advisory Board to Advance Its New Breast Cancer Treatment Approach

Chaired by founder Stephen Birrell, MD PhD, group includes experts in breast cancer biology, endocrine signaling and biomarker-driven risk reduction strategies BOULDER, Colo.--(BUSINESS WIRE)--Havah Therapeutics, a clinical stage biopharmaceutical company developing innovative, proprietary hormonal implant therapies for prevention and treatment of breast cancers, announced the formation of their Clinical Advisory Board Chaired by Havah Therapeutics founder Stephen Birrell, MD, PhD. “The scientific and clinical guidance of this esteemed group will be invaluable as we advance our androgen targeted therapy into late-stage clinical studies for Ductal Carcinoma In-Situ (DCIS) and investigator-sponsored combination studies in more advanced disease,” said, Matthew Brewer, CEO of Havah Therapeutics. Shelley Hwang, MD, MPH, Breast Cancer Research Foundation (BCRF) Investigator and internationally recognized expert in pre-invasive disease and DCIS, added: “I am thrilled to be involved with Havah Therapeutics at this critical stage of their development. Insights gained from their ongoing Phase 2 study ( RECAST DCIS ), coupled with my experience as the principal investigator of the COMET Study , will potentially enable the company’s androgen receptor targeting therapy to provide a much needed treatment alternative to invasive surgery and radiation treatment.” The members of Havah Therapeutics’ Clinical Advisory Board include: Stephen Birrell, MD, PhD (Chair), is founder of Havah Therapeutics and Chief Medical Officer of Wellend Health, an Australia-wide clinic that specializes in breast hormone-health, women at high-risk breast cancer and clinical trials. He is a Clinical Affiliate academic at the University of Adelaide Dame Roma Mitchell Cancer Research Laboratories. Shelley Hwang, MD, MPH is the Mary and Deryl Hart Distinguished Professor of Surgical Oncology and Radiology, Vice Chair of Research and Disease Group Leader for the Breast Cancer Program at Duke University Comprehensive Cancer Center. Her research focus includes breast cancer prevention, identifying less invasive treatments for early-stage breast cancers including DCIS and addressing and mitigating health care disparities in breast cancer. Seema A. Khan, MD is Professor of Surgery in the Feinberg School of Medicine at Northwestern University, and the Bluhm Family Professor of Cancer Research. She is the Co-Leader of the Cancer Prevention Research Program at the Robert H. Lurie Comprehensive Cancer Center. Her research focuses on applying biomarker knowledge to improve breast cancer risk stratification and develop preventive interventions for high-risk women. Her research is funded by the National Institutes of Health, The Breast Cancer Research Foundation, the Avon Foundation, and the Susan G. Komen Foundation Professor Wayne Tilley, PhD is the Inaugural Director of the Dame Roma Mitchell Cancer Research Laboratories, University of Adelaide. He completed a Fellowship at UT Southwestern in Dallas Texas in the late 1980s where he was one of the first to clone the human androgen receptor (AR) with Professor Jean Wilson, MD. A current major research focus of Professor Tilley’s lab is the development of new treatments for breast cancer that stimulate the tumor suppressive activity of the AR in the breast (Nature Medicine 2021; Lancet Oncology 2024) to counter the proliferative effects of estrogen. Additional background information on the CAB members can be found on the company’s website: About RECAST DCIS Havah Therapeutics is currently participating in the Re-Evaluating Conditions for Active Surveillance Suitability as Treatment: Ductal Carcinoma In Situ (RECAST DCIS), a Phase 2 platform study aimed at preventing the progression of DCIS to breast cancer. Havah Therapeutics’ HAVAH T+Ai™, a proprietary combination of testosterone (T) and anastrozole (Ai) that targets the androgen and estrogen receptor pathways, is being evaluated alongside two other endocrine therapy arms. About Havah Therapeutics Havah Therapeutics is developing a novel therapeutic implant for treating hormonally sensitive cancers and other breast conditions. This groundbreaking method relies on stimulating (agonizing) the androgen receptor in breast tissue, utilizing natural hormonal mechanisms to treat patients safely and with greatly reduced side effects. The product is a combination of two registered agents (testosterone and anastrozole, a low dose aromatase inhibitor) that when dosed, provides three months of continuous medication enabling a superior product pro compliance, safety and efficacy. For more information, visit . Contacts Media Contacts: Matthew Brewer mb@havahtx.com Danielle Clark-Brown dcb@havahtx.com

临床2期放射疗法

2024-10-19

·医药观澜

恒瑞医药4款癌症新药获批临床，3款为蛋白降解剂

▎药明康德内容团队报道 10月18日，中国国家药监局（NMPA）药品审评中心（CDE）官网最新公示，恒瑞医药有4款癌症新药获批多项新的临床试验默示许可。其中一款为抗CTLA-4单克隆抗体新药，其余3款均为蛋白降解疗法1类新药。这些新药均获批以双药或三药联合疗法开展治疗恶性肿瘤的临床研究，意味着恒瑞医药在癌症治疗方面重要的探索方向。本文将根据恒瑞医药公开资料，对这些产品进行介绍。 SHR-8068注射液作用机制：抗CTLA-4单克隆抗体 SHR-8068注射液是恒瑞医药自基石药业引进的一款全人源抗CTLA-4单克隆抗体，它可增强抗肿瘤免疫效应。该产品联合阿得贝利单抗及含铂双药化疗一线治疗STK11/KEAP1/KRAS突变晚期或转移性非鳞状非小细胞肺癌已经进入3期临床阶段；联合阿得贝利单抗及贝伐珠单抗一线治疗晚期肝细胞癌的3期临床研究也已经于近日启动。截图来源：CDE官网该产品本次获批一项新的临床试验默示许可，拟联合HRS-2189+阿得贝利单抗±化疗用于恶性肿瘤的治疗，意味着该产品将探索新的三药联合方案。其中，HRS-2189是一款化药新药，具体靶点尚未披露，它可通过调控多种癌基因表达进而发挥抗肿瘤作用。该产品单药治疗晚期恶性肿瘤目前正处于1期临床研究阶段。阿得贝利单抗是恒瑞医药研发的人源化抗PD-L1单克隆抗体，此前已在中国获批上市，治疗广泛期小细胞肺癌等癌症。 HRS-5041片作用机制：靶向AR的靶向蛋白降解剂截图来源：CDE官网 HRS-5041片是一款靶向雄激素受体（AR）的蛋白降解靶向嵌合体（简称PROTAC）分子。根据恒瑞医药公开资料介绍，HRS-5041对野生型及各类突变体的AR蛋白有显著的降解作用，与二代AR抑制剂相比，有克服耐药的潜力。 HRS-5041片单药用于转移性去势抵抗性前列腺癌正处于1期临床研究阶段；联合PARP1小分子抑制剂HRS-1167、口服EZH2抑制剂SHR2554以及醋酸阿比特龙片（II）、多西他赛用于晚期前列腺癌的临床研究也已经于近日获批临床。该产品本次获批新的临床试验默示许可，拟联合HRS-2189用于恶性肿瘤的治疗。 HRS-1358片作用机制：靶向ER的靶向蛋白降解剂 HRS-1358是一款新型靶向雌激素受体（ER）降解的PROTAC分子，它能够强效且高选择性地降解ER，抑制ER转录活性及下游信号，进而抑制肿瘤细胞增殖，发挥抗肿瘤作用。截图来源：CDE官网该产品本次获批新的临床试验默示许可，拟联合HRS-2189和HRS-6209用于恶性肿瘤的治疗。其中，HRS-6209为一款选择性CDK4抑制剂，它能够强效抑制CDK4/cyclinD复合物及下游信号，诱导肿瘤细胞阻滞在G1期，进而发挥抗肿瘤作用。该产品还提高了对CDK6/cyclinD3信号通路的选择性，有望改善CDK4/6抑制剂相关血液毒性。根据恒瑞医药年报资料，HRS-1358联合HRS-6209的双药联合疗法治疗乳腺癌的临床研究此前已经开展。本次三药联合疗法获批临床，意味着新的临床探索即将开展。 HRS-8080片作用机制：口服雌激素受体降解剂（SERD）作为一种新型选择性口服ER降解剂，HRS-8080片可强效且高选择性地降解ER，抑制ER活性及下游信号，进而抑制肿瘤细胞增殖，拟用于ER阳性及ER突变的乳腺癌治疗。根据恒瑞医药年报资料，该产品的多项联合疗法治疗乳腺癌的2期临床研究正在开展，包括联合SHR-A1811（靶向HER2的ADC）和SHR-A2009（靶向HER3的ADC）、联合达尔西利（CDK4/6抑制剂）、联合HRS7415（AKT抑制剂）、联合HRS-6209（CDK4抑制剂）。截图来源：CDE官网本次该药获批新的临床试验默示许可，拟联合HRS-2189和HRS-6209用于恶性肿瘤的治疗。这意味着该产品即将开展三药联合疗法的临床研究。参考资料： [1]中国国家药监局药品审评中心官网. Retrieved Oct 18， 2024, from https://www.cde.org.cn/main/xxgk/listpage/da6efd086c099b7fc949121166f0130c [2] 恒瑞医药2024年半年度报告. Retrieved Aug 22, 2024. from http://www.cninfo.com.cn/new/disclosure/detail?plate=sse&orgId=gssh0600276&stockCode=600276&announcementId=1220938296&announcementTime=2024-08-22 [3]恒瑞医药2023年年度报告. Retrieved Apr 18, 2024 from http://www.cninfo.com.cn/new/disclosure/detail?plate=sse&orgId=gssh0600276&stockCode=600276&announcementId=1219650115&announcementTime=2024-04-18 [4]恒瑞医药新闻稿. 本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权及其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

临床3期临床1期蛋白降解靶向嵌合体上市批准临床结果

2024-09-04

·药智网

下一个大BD密码

当大家还在看ADC时这类大分子的主流偶联方式时，有一小分子偶联方式即将改写小分子药物的底层逻辑。在国外，该疗法的最快管线已经被推进至III期临床，做的也是癌症中最大的市场之一——乳腺癌市场。而在国内，创新药一哥也表现出了对该疗法的青睐，其相关管线BGB-16673已经在近日获得了FDA快速通道认证。 PROTAC疗法正在对传统的小分子药物呈现降维打击之势，未来拥有巨大的颠覆传统小分子药物市场逻辑的潜力。 PROTAC，降维打击的小分子疗法 PROTAC疗法的生物学底层逻辑是用细胞内的泛素-蛋白酶体蛋白降解机制来实现对目标蛋白的降解。泛素（简称Ub）是体内的一种用于标记蛋白质的小号蛋白（仅76个氨基酸），经由它标记的蛋白质将经过E1，E2，E3三种泛素酶，完成泛素的激活，转运，最后连接到E3酶上（该酶是特异性识别靶蛋白的酶），通过E3酶，泛素完成和靶蛋白的结合，形成泛素-蛋白复合物。在蛋白完成泛素化后，26S蛋白酶体可以特异性地识别这个带有泛素标签的底物蛋白，进而将其降解。该过程可以完成细胞内大部分短寿命蛋白质的降解。于是，能够降解特异性蛋白质的PROTAC疗法应运而生。 PROTAC全称为蛋白水解‒靶向嵌合体，其结构由三部分组成：蛋白结合配体、E3泛素连接酶结合配体和linker，其底层逻辑是把目标蛋白通过PROTAC分子和E3泛素酶连接，使得该目标蛋白被打上泛素的标记，然后便会按上问的泛素降解过程形成泛素-蛋白复合物，继而进入26S蛋白酶体完成降解。在该过程中，PROTAC分子可以被循环使用，在完成一个靶蛋白的催化降解后迅速进入另一个靶蛋白的降解过程，因此，PROTAC分子仅仅是作为催化剂的作用而存在。对于传统小分子药物来说，小分子药物首先必须要找准靶蛋白上的活性位点，亲和力要高，且为了维持活性浓度，必须频率较高去给药。而作为催化剂的PROTAC分子没有这个顾虑，它偶联的靶蛋白靶点不需要考虑活性的问题，只要能够连接便可。而从这样的逻辑来说，PROTAC分子将对于传统的小分子药物来说，可以看作是一次非常成功的迭代，其相对传统小分子药物的优势如下： 1.小分子药物需要不断用较高的浓度去刺激靶蛋白的活性靶点，但时间一长便会产生耐药性的问题。而作为催化剂的PROTAC而言，不需要传统小分子那样的大剂量不停刺激活性靶点，这样使其耐药性更加难以产生。 2.PROTAC由于不是必须去偶联靶蛋白中的活性位点，因此理论上它将大大拓宽未来对于蛋白质靶点的选择，众多不可成药的靶点未来都有可能被用于PROTAC分子上。此外，值得一提的是，运用泛素-蛋白酶体蛋白降解机制来开发的疗法并不只有PROTAC，另一项进展较快的疗法是分子胶。虽然都是通过E3酶进行作用，但二者有相当大的差异性。从优势上说，分子胶的分子量相较于PROTAC而言要更小一些，改结构和优化理化性质更加方便。而PROTAC由于分子量相对较大，可能从传统的成药角度来看，药代动力学特性相对而言可能没有分子胶好。此外，分子胶可以很好地避免PROTAC的一个重要问题：钩状效应(hook effect)。对于PROTAC而言，当作为中介的PROTAC浓度过高时，它更倾向于和E3或者靶蛋白中的一种形成二元复合物，而不是预期的三元复合物，而三元复合物不形成，预期内的降解就无法发生。该效应对PROTAC的治疗浓度产生了一定的限制。分子胶很好，它避免了PROTAC的诸多问题，但它目前而言由于太过前沿，对于它的很多机制研究还不是很明确，而导致对分子胶相应分子的筛选机制还不是特别明确，目前筛出来并商业化的分子胶基本都是通过偶然的方式发现的。从这个角度而言，目前在泛素-蛋白酶体降解途径疗法中，离可以大规模商业化最近的，仍然是PROTAC。即将打开商业化大门的PROTAC先驱在深耕PROTAC疗法的biotech中，目前距离商业化最近的则是深耕该疗法十余年的Arvinas。其实从Arvinas的管线布局中也可以看出，开拓者们在肿瘤领域多会选择在乳腺癌和前列腺癌两个瘤种上去进行突破，因为这两种癌症都与性激素密切相关，因此可以通过PROTAC疗法去降解性激素的受体，来达到治疗癌症的目的。 Arvinas在癌症领域进展最快的管线是针对乳腺癌适应症的ARV-471，在乳腺癌中，它主要针对的是ER＋/HER2-的分型。乳腺癌的市场规模有目共睹，根据最新的映恩生物招股书的数据，全球乳腺癌人数在2023年达到了240.8万人，预计将于2032年达到319.6万人，这其中，HER2-/ER+分型占所有乳腺癌的45-50%，根据Arvinas自身的说法，该分型的乳腺癌市场达到了170亿美元。 ER就是雌激素受体，对于雌激素受体阳性的乳腺癌患者而言，雌激素拮抗治疗是小分子药物中最为常见的治疗手段。在这其中，一线疗法可以用AI（芳香酶抑制剂）以及前线的CDK4/6抑制剂，例如哌柏西利这种早期获批的CDK4/6i，而二线治疗则可以使用氟维司群和新型的CDK4/6抑制剂例如瑞博西尼（Ribociclib）联用治疗；但对于小分子药物（例如CDK4/6抑制剂），耐药仍然是目前的大问题，这与前文所述的小分子药物底层逻辑相关。而ARV-471这条管线来说，其早期的临床试验设计则主要也是在针对小分子药物耐药的后线治疗来设计的。今年ESMO乳腺癌年度大会，它的临床Ib期结果较为全面地展现了出来。患者基线上，其患者中87%接受过CDK4/6抑制剂的治疗，45.7%的患者接受过化疗，80%的患者接受过雌激素抑制剂氟维司群的治疗，在31名患者中展现出了非常惊艳的疗效。其联用K药时，评估后的ORR达到了41.9%，这个数字超过了目前众多CDK4/6抑制剂耐药后的后线疗法。目前公布的临床数据中，Ribociclib联合ET化疗方案的ORR是20%（n=35，临床样本量接近），而患者基线二者也较为相似，都是为了处理CDK4/6抑制剂耐药后的情况，该次试验中患者全部接受了CDK4/6抑制剂的治疗，不过接受化疗和氟维司群的患者比例远远比AV-471的早期临床少：接受化疗的比例为6.7%，接受氟维司群的比例为16.8%。在患者基线相差较大的情况下，ARV-471仍然达到了两倍多的ORR，真正实现了对传统小分子疗法的降维打击。在另外的重要指标例如mPFS上，同样达到了两倍多的差距，ARV-471的这mPFS达到了11.2个月，而Ribociclib的此前研究的数字是5.3个月。其它疗法，例如帕博西尼联用ET化疗等，更是没有疗效上的可比性。从目前Arvinas的预期来看，虽然早期该药是专门针对后线治疗去开展临床的，但其也已经在一线治疗上早早开始布局：目前，该药联用帕博西尼的一线治疗ER+/HER2-局部晚期乳腺癌的III期临床试验已经在进行中，而后线治疗则是重头戏，既包括单药治疗，也包括联用小分子靶向药物依维莫司，联用新一代CDK4/6抑制剂PF-07220060(Atirmociclib)等。作为一个和CDK4/6抑制剂机制完全不同的乳腺癌药物，其在CDK4/6抑制剂的同质化内卷中脱颖而出，从远期看，它有着非常高的天花板；从近期看，它在年底到明年初有关键数据读出，是一个股价的关键催化机会。而另一款关于肿瘤的重磅管线则是针对前列腺癌的ARV-766。该药是从PROTAC疗法的元老级药物ARV-110基础上迭代而来，ARV-110可以看作是一个试错品，由于局限性较大，目前已经暂停管线进度推进。 ARV-766在其基础上加以改进。结构上，比较关键的改进是将氟取代的沙利度胺替换为氟取代的苯甲酰胺，这一结构上的改进增强了分子的选择性以及在血浆中的稳定性。而结构上的改进拓宽了该药物的适应症范围：ARV-110不能应对AR L702H突变的情况，而ARV-766成功突破了该困境，增加了可用药人群的数量。根据2023年8月公布的1/2期临床试验数据，3名雄激素受体（AR）H875/T878/L702H突变患者中，前列腺特异性抗原（PSA）水平降幅均大于50%，实现了突变患者疗效上质的突破。当然，ARV-766目前还需要样本量更大的临床去验证。但值得一提的是，MNC诺华对该管线相当看好，今年4月，诺华直接付了预付款1.5亿美元，后续里程碑付款更是达到10.1亿美元，就为拿下ARV-766与另一款处于临床前的前列腺癌药物在全球开发和商业化的权益。除了先驱Arvinas之外，Nurix以及Kymara等早期biotech也值得关注。 Nurix做的PROTAC主要靶向BTK，针对的是各式各样的B细胞血液瘤，并且其管线目前处于非常早期的阶段，进展最快的NX-5948和NX-2127目前处于临床1b期。NX-5948今年得到了较大的进展，6月份发布了其针对CLL（慢性淋巴细胞白血病）较为积极的早期临床数据。在Ia期试验中，患者接受过的中位治疗为4线，包括共价BTK抑制剂（96.8%）、BCL-2抑制剂（90.3%）和非共价BTK抑制剂（25.8%）等。在可评估疗效的CLL患者（n=26）中，接受所有剂量水平NX-5948治疗患者的ORR达到了69.2%，也是非常值得期待的CLL后线治疗的新星。 Kymera目前进展最快的管线KT-474已经进展到了临床II期，其主要针对自免适应症。目前两条个适应症为化脓性汗腺炎(HS)和特应性皮炎(AD)。其针对KT-474与赛诺菲早在2020年就展开了全面的合作，赛诺菲潜在的支付金额高达20亿美元。今年7月8日，Kymera宣布在IDRC审查数据之后，其partner赛诺菲决定扩大KT-474治疗化脓性汗腺炎、特应性皮炎两项二期临床试验，以求更快推进到关键临床。在之后的一个礼拜，股价迎来了非常迅猛的大涨，从7月8号的30美元上涨至7月16号的45美元。 PROTAC的想象力空间，在美股股价上体现的非常充分。国内的突破性进展国内方面，目前药企们也正在紧锣密鼓地追赶。不久前百济神州官宣的BGB-16673无疑是国内PROTAC领域一个巨大的突破。百济本身就是BTK小分子抑制剂深耕十余年的老玩家，以其现有的技术平台为根基去发展靶向BTK的PROTAC，基础上是打得较为牢固的。在2021年的研发日上，百济公布了其PROTAC平台——CDAC平台。根据百济神州的阐述，该平台相较于其它PROTAC平台的差异性优势在于其能够利用更加广泛的E3连接酶，从而达到减轻DLT（剂量依赖性毒性）的效果，其对耐药性的解决方面也有进一步的提升，此外，也进一步拓展了潜在靶点范围。而BGB-16673就是百济利用该平台开发出的第一条PROTAC管线，主要目的是针对BTK小分子抑制剂耐药的后线治疗问题。由于其靶点和适应症与Nurix的NX-5948相类似，因此二者可以进行一定的非头对头比较。从BGB-16673的临床I期剂量递增试验的初步数据来看，其在CLL/SLL适应症中的表现非常不错，患者（n=10）基线BTK抑制剂耐药的情况下，它的ORR达到了70%，该数据与上文的NX-5948疗效相当。后续的大样本临床中，两条管线将进行更为激烈的角逐。另一家Biotech则是深耕PROTAC技术多年的海创药业，其在2016年就建立了自己的PROTAC技术平台，目前主要深耕的适应症为前列腺癌。海创药业PROTAC方面核心的管线是HP518，也是国内首个进入临床阶段的针对AR的PROTAC药物。其于2023年11月获NMPA批准进入临床，目前该管线获得了中国，美国和澳大利亚三地的临床试验批准。除了口服的AR PROTAC药物外，还有药企开发出了外用的AR PROTAC疗法。开拓药业的GT20029用于治疗雄激素性脱发和痤疮，通过降解雄激素受体蛋白来达到治疗雄性激素过盛导致脱发的问题。GT20029也是首款进入临床的外用PROTAC化合物。今年4月，该管线在脱发适应症上达到了II期临床试验终点，从最佳剂量的1.0%浓度且一周两次给药剂量组的效果来看，TAHC（区域内头发计数的指标）较基线增加了11.94根毛发/cm²，比安慰剂多了7.36根毛发/cm²。但非口服的局部给药制剂究竟能不能走通，目前而言是个有待商榷的话题。从临床II期试验设计来看，其临床设计主要终点为12周目标区域内非毳毛数量，这个时间太过短暂，目前需要的是III期临床中更长周期随访的验证，观察期达到平台期的时间。不得不说，这是PROTAC技术在一个意想不到领域上的出色应用，真正做到了在AR降解剂上的差异化竞争。结语：PROTAC疗法的意义主要在于面对目前小分子同质化内卷的困局上打开了一扇新的大门，带来了后线治疗的全新想象力。此外，该疗法目前来看并不只是局限于肿瘤，其想象力空间非常巨大，甚至连外用用于脱发都可以到达III期临床。现在适应症的挖掘上仅仅是冰山一角，未来随着AIDD靶点筛选速度的大大提升，PROTAC疗法的适应症领域也将会得到相当大程度的继续拓展。来源 | 瞪羚社（药智网获取授权转载）撰稿 | Jerry.Z 责任编辑 | 八角声明：本文系药智网转载内容，图片、文字版权归原作者所有，转载目的在于传递更多信息，并不代表本平台观点。如涉及作品内容、版权和其它问题，请在本平台留言，我们将在第一时间删除。商务合作 | 王存星 19922864877（同微信）阅读原文，是受欢迎的文章哦

蛋白降解靶向嵌合体抗体药物偶联物临床3期