PARP3

8月26日，上海君派英实药业有限公司1类新药「IMP4297胶囊」的上市申请获CDE受理。IMP4297（senaparib，JS109）是英派药业研发的一款聚腺苷二磷酸核糖聚合酶（PARP）抑制剂。2020年8月，英派药业与君实生物宣布成立合资公司君派英实，主要从事包括IMP4297在内的小分子抗肿瘤药物的研发和商业化。 2023年4月，英派药业与君实生物宣布IMP4297在针对晚期卵巢癌全人群一线维持治疗的3期临床研究FLAMES中达到主要研究终点。该研究是一项随机、双盲、安慰剂对照、多中心临床研究，旨在评价一线含铂化疗达到完全缓解（CR）或部分缓解（PR）后IMP4297单药维持治疗FIGO Ⅲ-Ⅳ期卵巢癌患者的有效性和安全性。期中分析结果显示：IMP4297可显著延长晚期卵巢癌患者的无进展生存期（PFS），不论患者的乳腺癌易感基因（BRCA）表达如何。 卵巢癌是最常见的致死性女性生殖道恶性肿瘤之一，据统计全球患卵巢癌年新发病例数达31万，死亡病例数达21万。卵巢癌早期症状隐匿且非特异，约80%的患者确诊时已为晚期，5年生存率仅有40%。尽管卵巢癌经初始含铂化疗后可以得到缓解，但大多数患者都不可避免面临复发。近年来，PARP抑制剂正在改变卵巢癌的治疗格局，其维持治疗可延长一线含铂化疗后的缓解时间，延缓复发。IMP4297的申报上市距离其惠及卵巢癌患者又近一步，期待其可以早日获批上市。 此外，除了IMP4297，英派药业还有一款PARP抑制剂，即IMP1734。该药对PARP1抑制活性很高，对PARP2抑制活性较低，临床前体内模型显示其具有很高的抗肿瘤活性和很宽的治疗窗口。相比已上市的非选择性PARP1/2抑制剂，IMP1734可以改善治疗指数，成为单药治疗以及与其他药物联合应用的理想药物。 关于PARP抑制剂及其研究进展 ARP，即聚腺苷二磷酸核糖聚合酶，是一种单链DNA修复酶，在DNA损伤修复、维持基因组稳定性方面起着重要作用。PARP家族包括多个成员，其中仅PARP1、PARP2和PARP3参与DNA的修复。PARP1是PARP家族中最主要的成员，占PARP家族酶活性的80%—90%，是DNA损伤修复中的关键作用因子。 BCRA1/2是早期被发现的两种抑癌基因，在同源重组修复（HR）过程发挥重要作用。当DNA发生断裂时，BRCA1与BRCA2表达的蛋白与DNA重组酶RAD51结合，完成DNA修复过程。研究发现，BRCA基因突变会使DNA修复功能受到限制，导致癌症的发生，尤其是乳腺癌和卵巢癌。 2005年首次证实PARP抑制剂与乳腺癌易感基因（BRCA）1/2突变之间存在“合成致死”效应。当PARP功能受抑制时，往往导致单链断裂发展成为双链断裂。在同源重组修复途径正常的细胞中，上述DNA双链断裂立即被修复，但在缺乏同源重组修复的肿瘤细胞中，如携带 BRCA1/2突变的乳腺癌细胞中，PARP1功能的丧失缺乏代偿机制，肿瘤细胞无法及时修复DNA损伤，最终导致细胞死亡，该机制即为合成致死。 根据合成致死原理，PARP抑制剂可以诱导携带BRCA 胚系突变的肿瘤细胞死亡。目前全球监管机构已批准6款PARP抑制剂，四款进口，两款国产，详见下表。已获批的PARP抑制剂大多被批准用于治疗卵巢癌，仅Talzenna利被批准用于治疗乳腺癌。 市场表现上，Lynparza获批最早，适应症最广泛，销售额也最高，2022年高达37.54亿美元。Zejula是第三款获批的PARP抑制剂，市场表现次之，2021年、2022年销售额在5-6亿美元之间。Rubraca是第二款获批的PARP抑制剂，但其市场表现一般，2021年销售额开始下滑。值得一提的是，Rubraca的持有者Clovis已于去年12月申请破产。Talzenna销售额未公布，其联合Xtandi（恩扎卢胺）治疗转移性去势抵抗性前列腺癌（mCRPC）的适应症上市申请正在美国接受优先审查，而且该药还于今年4月在国内申请上市。 已上市的两款国产PARP抑制剂中，氟唑帕利销售额未公布，目前该药已在国内获批两项适应症，且已于今年8月在国内申报第三项适应症，用于晚期上皮性卵巢癌、输卵管癌或原发性腹膜癌患者在一线含铂化疗达到完全缓解或部分缓解后的维持治疗。帕米帕利在国内仅获批一项适应症，用于既往经过二线及以上化疗的伴有胚系BRCA（gBRCA）突变的复发性晚期卵巢癌、 输卵管癌或原发性腹膜癌患者的治疗，2021年、2022年其销售额分别为0.04亿美元和0.05亿美元。 此外，目前全球还有多款在研PARP抑制剂，详见下表。值得一提的是，在研PARP抑制剂的选择性越高，已出现PARP1抑制剂（如AZD-5305、AZD-9574）、PARP7抑制剂（如JAB-26766）、PRAP14抑制剂（如RBN-3143）。适应症上，除了治疗肿瘤，部分PARP抑制剂还被开发用于治疗炎性疾病，如RBN-3143。 然而，这两年PARP抑制剂的发展并不顺利。随着临床试验随访时间的延长，临床数据显示卵巢癌患者使用Rubraca 、Lynparza和Zejula的死亡风险有所增加。2022年FDA先后撤回上述3个PARP抑制剂在卵巢癌的4个适应症：2022 年 6 月，FDA撤回Rubraca后线治疗BRCA突变卵巢癌；2022 年 8 月，FDA撤回Lynparza后线治疗BRCA突变晚期卵巢癌患者的适应症；2022年9月，FDA撤回Zejula后线治疗BRCA突变、HRD阳性且铂敏感复发性上皮性卵巢癌、输卵管癌或原发性腹膜癌成人患者的适应症；2022年11月，FDA撤回Zejula用于有害或疑似有害生殖系BRCA突变（gBRCAm）铂敏感复发卵巢癌维持治疗的适应症。 总结 自2014年首款PARP抑制剂获批以来，目前全球已批准6款PARP抑制剂，2022年全球PARP抑制剂的市场规模也已突破50亿美元。然而，近两年PARP抑制剂似乎进入平台期，2022年多款PARP抑制剂适应症被撤回，且未再有新产品获批上市。我国药企也积极布局PARP抑制剂市场，目前已有两款药物获批上市，此外还有多款进入临床试验阶段。期待未来PARP抑制剂早日添丁进口，企业巨额研发投入见到回报。 内容来源于网络，如有侵权，请联系删除。

Conditional approval based on data from Phase 3 PROpel trial MISSISSAUGA, ON, July 13, 2023 /CNW/ - Health Canada has granted a Notice of Compliance with Conditions (NOC/c) for Lynparza® (olaparib) in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with deleterious or suspected deleterious germline and/or somatic BRCA mutated metastatic castration-resistant prostate cancer (mCRPC) in whom chemotherapy is not clinically indicated. BRCA mutation must be confirmed before Lynparza treatment is initiated.1 The conditional approval of Lynparza was granted based on the results from the PROpel Phase III clinical trial, which was published in the New England Journal of Medicine Evidence in June 2022. PROpel met its pre-specified primary endpoint. Subgroup analysis showed radiographic progression free survival (rPFS) improvement for Lynparza/abiraterone compared to placebo/abiraterone in mCRPC patients with a BRCA mutated mCRPC. For the BRCA subgroup, median rPFS was not calculable for the study arm at the time of the analysis because the median was not reached, compared to abiraterone/prednisone alone with rPFS 8.4 months (95% confidence interval [CI] 5.5 months-14.8 months). There was a reduced risk of radiological progression or death by 77% versus abiraterone/prednisone alone (based on a hazard ratio [HR] of 0.23 (95% confidence interval [CI] (0.12-0.43). At the time of the first interim analysis, overall survival showed a trend towards an improvement for Lynparza/abiraterone compared to placebo/abiraterone in mCRPC patients with a BRCA mutation. The safety and tolerability of Lynparza plus abiraterone in PROpel was in line with that observed in prior clinical trials and the known profiles of the individual medicines. The most common adverse reactions of any grade (>10%) were anemia (46.0%), fatigue (37.2%) and nausea (28.1%).1,2 "Metastatic castration-resistant prostate cancer is a complex disease with a poor prognosis, making informed treatment decisions after a man's initial diagnosis critical," said Dr. Fred Saad, MD, FRCSC, Professor and Chairman of the Department of Surgery and Director of G-U Oncology at the University of Montreal. "Lynparza has demonstrated its clinical benefit in combination with a new generation hormonal agent in this setting, offering patients an effective and well tolerated new treatment option that can potentially reduce the risk of disease progression or death." Prostate cancer is the most common cancer among Canadian men (excluding non-melanoma skin cancers) and is the third leading cause of death from cancer. On average, 67 Canadian men will be diagnosed with prostate cancer every day, while 13 will die from it.3 Approximately 10–20% of patients with prostate cancer develop mCRPC within 5 years of follow-up after initial therapy. More than 80% of patients have bone metastases at castration-resistant prostate cancer (CRPC) diagnosis.4 "The high mortality rates associated with metastatic castration-resistant prostate cancer can invoke an added layer of fear and anxiety for men who have been diagnosed," said Jackie Manthorne, President & CEO, Canadian Cancer Survivor Network. "We welcome the approval of new treatments like Lynparza that can help bring a renewed sense of hope to patients and their families." About the PROpel Phase III Clinical Trial PROpel is a randomized, double-blind, placebo-controlled, multi-centre Phase III clinical trial testing the efficacy, safety, and tolerability of Lynparza in combination with abiraterone compared with placebo plus abiraterone in men with mCRPC. Men in both treatment groups also received either prednisone or prednisolone twice daily.1 The primary endpoint was rPFS and key secondary outcome measures included overall survival (OS), time to secondary progression or death, and time to first subsequent therapy.1,2 The safety and tolerability of Lynparza in combination with abiraterone was in line with that observed in prior clinical trials and the known profiles of the individual medicines. 1,2 About Lynparza Lynparza was the first oral (PARP) inhibitor approved in Canada. Lynparza exploits tumour DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination repair (HRR), such as mutations in BRCA1 and/or BRCA2, to selectively kill cancer cells.1 Lynparza is the only PARP inhibitor currently approved in multiple tumour types in Canada including breast, ovarian, pancreatic and prostate cancers. Lynparza has been issued conditional marketing authorization for use in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with deleterious or suspected deleterious germline and/or somatic BRCA mutated metastatic castration-resistant prostate cancer (mCRPC) in whom chemotherapy is not clinically indicated, pending the results of studies to verify its clinical benefit. Patients should be advised of this conditional marketing authorization. Lynparza is jointly developed and commercialized by AstraZeneca and Merck. Lynparza is the foundation of AstraZeneca's industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells. For more information about Lynparza, access the Canadian Product Monograph here. The AstraZeneca and Merck strategic oncology collaboration In July 2017, AstraZeneca and Merck & Co., Inc., Rahway, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world's first PARP inhibitor, for multiple cancer types. About AstraZeneca AstraZeneca is a global, science-led biopharmaceutical business whose innovative medicines are used by millions of patients worldwide. The company's core areas of scientific focus are Oncology; Cardiovascular, Renal and Metabolic (CVRM); Rare Disease; Respiratory & Immunology; and Vaccine & Immune Therapies. AstraZeneca employs more than 1,300 people across Canada and recently announced a major expansion of its research footprint in Canada – including the expansion of its existing AstraZeneca R&D Hub and the creation of a new Alexion Development Hub for Rare Diseases. For more information, please visit the company's website at . About Merck At Merck, known as MSD outside of the United States and Canada, we are unified around our purpose: We use the power of leading-edge science to save and improve lives around the world. For more than 130 years, we have brought hope to humanity through the development of important medicines and vaccines. We aspire to be the premier research-intensive biopharmaceutical company in the world – and today, we are at the forefront of research to deliver innovative health solutions that advance the prevention and treatment of diseases in people and animals. We foster a diverse and inclusive global workforce and operate responsibly every day to enable a safe, sustainable, and healthy future for all people and communities. For more information about our operations in Canada, visit and connect with us on LinkedIn and Twitter @MerckCanada. References LYNPARZA® and the AstraZeneca logo are registered trademarks of AstraZeneca AB, used under license by AstraZeneca Canada Inc. © 2023 AstraZeneca Canada Inc. and Merck & Co., Inc., Rahway, NJ, USA and its affiliates. All rights reserved. MERCK® is a registered trademark of Merck Sharp & Dohme LLC. Used under license. _____________________ SOURCE AstraZeneca

2022年，全球PARP抑制剂市场超过55.1亿美元。对治疗癌症以及其他慢性疾病的先进靶向疗法的需求激增，正在促进市场的增长。根据未来市场洞察(FMI)，PARP抑制剂市场的需求预计将超过84.3亿美元，在2022-2026年预测期内以11.2%的惊人复合年增长率增长。奥拉帕尼仍将是全球市场上最受欢迎的药物，到2022年占PARP抑制剂销售额的62.9%以上。FMI指出，PARP抑制剂估计占全球细胞毒性药物市场收入份额的28.5%以上。 PARP7继续内卷 阿斯利康作为PARP赛道的老大哥，自然不会错过这一巨大市场，根据智慧芽新药情报库，奥拉帕利的化合物专利在2024年3月到期，用途专利在2024年11月到期。阿斯利康为构筑护城河，开发了高选择性的PARP1抑制剂AZD5305和AZD9574（入脑）。PARP酶家族亚型众多，下一代抑制剂主要针对其家族的各个亚型，同时开发新适应症（脑转移癌症、自免疾病等）。 PARP7是一种聚腺苷二磷酸核糖聚合酶，它催化adp-核糖的单个单位转移到底物上以改变其功能。PARP7是肿瘤细胞核酸感知的负调控因子。抑制PARP7在肿瘤模型中可恢复I型干扰素(IFN)信号通路对核酸的响应。恢复信号可以直接抑制细胞增殖和激活免疫系统，这两者都有助于肿瘤的消退。 临床前成功的POC，以及通路已经验证过了成药性，让PARP7成为一个颇具吸引力的靶点。AZ最早关注到PARP7抑制剂的成药潜力。在智慧芽专利数据库搜索到的最早一篇PARP7抑制剂的专利来自AZ的WO2016116602 (A1)，优先权日为2015年1月，但PCT并未进入具体国家。 RBN2397结构公布加剧国内公司内卷 如图2，Ribon Therapeutics以AZ的化合物为先导，设计的分子基于吡啶嗪酮核，之前通过片段筛选被确定为主要抑制monoARTs的优势结构，并用于获得PARP酶的NAD+竞争性探针，保留了哌啶酰胺的linker，继续结构优化得到RBN2397。来看一下时间线，2019.9.4，Ribon Therapeutics启动RBN-2397的一期临床研究；2019.11.7，Ribon Therapeutics的PARP7抑制剂专利公开（WO2019212937）；2020.4.28，Ribon Therapeutics在AACR会议上披露RBN-2397临床前数据，并在poster中公布其结构；国内公司也同时开启了fast follow。在智慧芽新药情报数据库搜索PARP7，可以看到众多国内公司已经纷纷参与到PARP7抑制剂的开发中。如成都百裕、南京明德、诺沃斯达、加科思、海思科、杭州英创、齐鲁、英硒智能、轩竹、誉祥、上海优理惠生、武汉人福、重庆财富生物等十几家公司，成都百裕follow的最快，其PARP7专利的最早优先权日为2020.11.27。令人奇怪的是，并未看到国外公司follow的专利公开。至于AZ为何没有推进PARP7项目，可能和市场前景关系较大，奥拉帕尼仍是全球市场上最受欢迎的PARP抑制剂药物，到2022年占PARP抑制剂销售额的62.9%以上，AZ也有奥拉帕利的迭代产品在开发中。 RBN2397的临床前景如何？ RBN-2397先进行了单药临床研究，爬坡阶段中，纳入50例患者；通过剂量方案和相对生物利用度评估测试了25毫克至500毫克的BID给药，最常见的肿瘤类型为乳腺(n=8)、肺部(n=7)和结肠(n=5)。二期推荐（RP2D）的剂量为200 mg BID，与微粉片剂一起连续给药。剂量扩大阶段中，入组患者53例；SCCL(22例)、HNSCC(17例)、HR+乳腺(14例)；RBN-2397在RP2D具有良好的耐受性，在观察到的暴露下具有生物和抗肿瘤活性。 单药RBN-2397具有良好的安全性和耐受性，具体表现在以下几点。只有5例(4.9%)发生了与治疗相关的急性肺泡损伤；28例(27.2%)发生了不良事件导致的治疗中断；12例(11.7%)患者因不良事件中断治疗。与已批准的PARP1/2抑制剂相比，血液学毒性发生率较低。 总体看来，RBN-2397耐受性良好，大多数AE为轻度至中度，并且在剂量递增和扩大队列研究中，初步观察到抗肿瘤活性，剂量递增:HR+乳腺癌患者1例PR，13例SD且临床获益> 4个月；扩大剂量:1例HNSCC病人缓解, 4例SD，且临床获益> 4个月。在所有评估的基线活检中均可见PARP7表达，与基质细胞相比，肿瘤细胞中PARP7表达更高。 在大多数肿瘤类型的扩展队列患者中，CD8+T细胞和/或颗粒酶B表达增加，表明RBN-2397治疗后存在适应性免疫诱导，RBN-2397诱导肿瘤特异性IFN通路激活并增加免疫细胞浸润到患者肿瘤，为诱导适应性免疫反应提供了证据。这些数据证实了PARP7作为一种新的抗癌治疗靶点，并证实了RBN-2397的机制。支持了正在进行的RBN-2397联合派姆单抗(NCT05127590)和纳武利尤单抗(jRCT2031210373)的临床试验。 PARP其他亚型仍具有巨大的潜力 已有17个PARP成员被报道，其中16个具有PARP催化活性。如图4所示，根据催化功能的不同，PARPs又分为多聚PARPs (PARP1、PARP2、PARP5a、PARP5b)、单ADP-核糖转移酶(PARP3、PARP4、PARP6−PARP12、PARP14−PARP16)和无催化活性的PARPs (PARP13)。其中，ADP-核糖转移酶在细胞增殖、代谢与凋亡、细胞周期调控、免疫应答等方面发挥重要作用。 除了PARP1的作用外，TNKS1−2目前正在作为癌症的潜在治疗靶点进行研究，这主要是因为它们在控制Wnt/β- catenin信号通路方面的作用。TNKS1−2通过PARylation和靶向蛋白进行蛋白酶体降解来控制蛋白质复合物和蛋白质稳定性。在Wnt/β-catenin信号通路中，它们控制所谓的“β-catenin破坏复合体”，由轴蛋白、酪蛋白激酶1、腺瘤性大肠息肉病(APC)、糖原合成酶激酶3 GSK3和蛋白磷酸酶2A组成。TNKS抑制剂可用于治疗一系列癌症，包括结肠癌、肺癌、肝癌、卵巢癌、脑癌。 如图5，已经开发了几种TNKS抑制剂，如化合物E744969和STP100270(结构未公开)，这些化合物已在临床研究中取得进展，即使化合物E7449表现为TNKS1−2和PARP1−2的双重抑制剂。其他TNKS抑制剂，如RK287107和OM-153正在临床前研究中进行评估。此外，PARP10抑制剂、PARP14抑制剂、PARP11抑制剂、PARP15抑制剂、PARP6抑制剂、PARP12抑制剂都在进行广泛的研究。 总结 PARP抑制剂市场前景广阔，上市的第一代PARP抑制剂都是针对PARP1和PARP2的双重抑制剂，因为对PARP2的抑制会带来血液学相关毒性。AZ等公司率先开发了高选择性的PARP1抑制剂如AZD5305、AZD9574等。 PARP蛋白家族亚型众多，其他亚型的成药性也在逐步验证中。Ribon Therapeutics走在最前列，开发的PARP7和PARP14选择性抑制剂都已进入临床。其中PARP7选择性抑制剂RBN-2397目前处于临床一期，从公布的部分临床数据看，与已批准的PARP1/2抑制剂相比，血液学毒性发生率较低，且机制上支持与免疫检查点抑制剂PD1抗体的联用。 然而，PARP7赛道却极其拥挤，国内多达十几家药企follow这个靶点，不乏第一梯队的biotech如加科思，传统药企齐鲁药业、CRO龙头药明康德，以及AI公司英硒智能。足以可见国内药企对这个靶点的重视，但是，根据专利所披露的结构来看，同质化极其严重，未来哪家公司能够脱颖而出仍不明朗。 参考资料： 1.https://www.futuremarketinsights.com/reports/parp-inhibitors-market. 2.Gru.研发前沿|枯燥数据背后的秘密. Minions的新药研发随笔. 3.Heike Keilhack, et al. PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity. https://doi.org/10.1016/j.ccell.2021.06.018. 4.Melissa Johnson, et al. First-in-Class First-in-Human Phase 1 Trial of RBN-2397 in Patients with Advanced Solid Tumors Validates PARP7 as a Novel Anticancer Therapeutic Target.2023,ESMO,TAT. 5.Yun genxu, et al. Discovery of the Potent and Highly Selective PARP7 Inhibitor as a Novel Immunotherapeutic Agent for Tumors.J. Med. Chem. 2023, 66, 473−490. 6.Oriana Tabarrini, et al. Medicinal Chemistry Perspective on Targeting Mono-ADPRibosylating PARPs with Small Molecules.J. Med. Chem. 2022, 65, 7532−7560. 7.谁能接班奥拉帕利？智慧芽新药科讯. 8.智慧芽新药情报库.