奥拉帕尼胶囊，Lynparza, 50mg hard capsules(olaparib)，第一个LDT协同诊断测试也被批准鉴定适宜的患者
LYNPARZA(olaparib)Approved for the Treatment of Advanced Relapsed Ovarian Cancer in Patients with Germline BRCA Mutations, Available Exclusively at Biologics, Inc.
Synthesis of Olaparib (Lynparza), AstraZeneca’s First-In-Class PARP Inhibitor for Ovarian Cancer 阿斯利康卵巢癌药物奥拉帕尼的化学合成
AstraZeneca’s  Lynparza (olaparib, Chinese Name: 奥拉帕尼, Japanese Name:オラパリブ) received accelerated approval from the U.S. Food and Drug Administration (FDA) on December 19, 2014 as the first monotherapy to treat women with advanced ovarian cancer associated with defective BRCA genes, known as BRCA1 and BRCA2, in conjunction with a genetic test called BRACAnalysis CDx from Myriad Genetics to test for BRCA mutations before doctors prescribe the treatment.
Olaparib (Lynparza) was also approved in the EU on December 18, 2014 as a monotherapy for the maintenance treatment of adults suffering from platinum sensitive relapsed BRCA-mutated high grade serous epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.

Olaparib (Lynparza, AZD-2281, KU-0059436, オラパリブ), discovered by KuDOS Pharmaceuticals, has experienced several twists and turns during its clinical development. Promising results for the drug were reported at the 2011 ASCO Annual Meeting, based on impressive early phase II results, only to have clinical development discontinued later that year after disappointing phase II trial results in a more generalized group of ovarian cancer patients. However, a re-analysis of the data in BRCA-positive patients – coupled with a reformulation of the drug – convinced the British drugmaker to think again and keep it going. AstraZeneca initiates Phase III clinical studies (SOLO 1 and SOLO 2) for olaparib in the U.S. in September 2013. AstraZeneca has filed Marketing Authorisation Application (MAA) for olaparib in EU in September 2013 based on Phase II study 19 data. The U.S. Food and Drug Administration has already granted olaparib orphan drug status for ovarian cancer and will hold an advisory panel hearing on the company’s application on June 25, 2014.
Chemical Structures of PARP inhibitors currently in clinical development for cancer treatment

Olaparib is currently the leader in the field of PARP inhibitor, a drug class which is starting to live up to its early promise as a means of treating cancer by blocking the repair of DNA in tumour cells despite some early clinical setbacks including the failed phase III studies for Sanofi’s rival candidate Iniparib (BSI 201). Following most closely is Tesaro’s niraparib (MK4827), a Merck & Co-developed compound which has reached phase III testing for ovarian and breast cancer, while other PARP inhibitors in in early- to mid-stage trials include AbbVie’s veliparib (ABT-888), Clovis Oncology’s rucaparib (AG-014699, PF-0136738, originated by Pfizer), BioMarin’s BMN-673, and Eisai Inc’s  E7016 .

According to media reports, U.S. pharmaceutical giant Pfizer has recently approached AstraZeneca to propose a $101 billion takeover, but AstraZeneca rejected the buyout pitch. AstraZeneca’s promising cancer pipeline is seen as the main draw for Pfizer.

AstraZeneca has several marketed cancer drugs products, including Faslodex (fulvestrant) for breast cancer and Caprelsa (vandetanib) for differentiated thyroid cancer, as well as Iressa (gefitinib) for lung cancer which alone achieved $647 million sales in 2013. AstraZeneca has five cancer drug candidates in Phase III studies, including olaparib for ovarian cancer and breast cancer, moxetumomab, an antibody for late stage hairy cell leukemia, selumetinib for non-small-cell lung cancer (NSCLC). Also showing potential are AZD9291, a ‘third generation’ irreversible inhibitor of  epidermal growth factor receptor (EGFR) for non-small-cell lung cancer (NSCLC) and just awarded “breakthrough therapy designation“status by the FDA, and from AstraZeneca’s biologics R&D arm MedImmune, the closely watched immunotherapy cancer treatment with blockbuster potential MEDI4736, a PD-L1 monoclonal antibody that is advancing to phase III testing for advanced solid tumors after positive Phase I data that will be presented at the May 30-June 3  American Society of Clinical Oncology (ASCO) 2014 Annual Meeting in Chicago (Abstract #3001 and 3002).

AstraZeneca also made a $4.3 billion acquisition of its own late last year, buying Bristol-Myers Squibb’s diabetes business in a move which gives AstraZeneca control over several big-name brands including Onglyza, Farxiga and Byetta in a core therapy area.
Synthesis of PAPP Inhibitor Olaparib (Lynparza), AstraZeneca’s Ovarian Cancer Drug 阿斯利康卵巢癌试验药物奥拉帕尼(Olaparib, オラパリブ)的化学合成
 

Trade Name:Lynparza
Generic Name: Olaparib, オラパリブ
Synonym: AZD2281; KU-0059436
Chinese Name: 奥拉帕尼
Chemical Name:4-[(3-[(4-cyclopropylcarbonyl)piperazin-4-yl]carbonyl)-4-fluorophenyl]methyl(2H) phthalazin-1-one
CAS Number:763113-22-0
Mechanism of Action:Poly(ADP-ribose) polymerase inhibitors
Indication: Ovarian cancer
Date of Approval:December 19, 2014 (US), December 18, 2014 (EU)
Originator:KuDOS Pharmaceuticals
Developer: AstraZeneca
新規卵巣がん治療薬オラパリブ
米食品医薬品局（FDA）は12月19日、英アストラゼネカ（AZ）のPARP（ポリADP-リボース合成酵素）阻害剤Lynparza（オラパリブ）をBRCA遺伝子変異陽性の進行卵巣がんの適応で承認した。また、併せて、同剤のコンパニオン・ダイアグノスティクスであるBRACAnalysisCDxも承認した。オラパリブの適応は、BRCA遺伝子欠損のある前治療歴を持つ進行卵巣がんである。BRCA遺伝子は、損傷されたDNAの修復に関与し、通常、腫瘍の成長を抑制する。BRCA遺伝子欠損をもたらす同遺伝子変異の女性は卵巣がんになりやすく、卵巣がん患者の全体の10%－15%は遺伝性のBRCA変異に関与しているとみられる。
Sources:
Jonathan Ledermann,Philipp Harter,Charlie Gourley,Michael Friedlander et al. Lancet Oncol. 2014;15:852-861
Bella Kaufman,Ronnie Shapira-Frommer,Rita K. Schmutzler,M. William Audeh,Susan M. Domchek et al.,Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation ，J Clin Oncol. Published online November 3, 2014 （JCO.2014.56.2728 ）.
Martin, Niall Morrison Barr et al,Preparation of phthalazinones as PARP inhibitors,PCT Int. Appl., WO2004080976
Menear, Keith Allan et al,Preparation of 4-[3-(4-cyclopropanecarbonyl-piperazine-1-carbonyl)-4-fluoro-benzyl]-2H-phthalazin-1-one and its crystal forms as PARP-1 inhibitors,PCT Int. Appl., WO2008047082
Menear, Keith A. et al.4-[3-(4-Cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: A Novel Bioavailable Inhibitor of Poly(ADP-ribose) Polymerase-1,Journal of Medicinal Chemistry, 51(20), 6581-6591; 2008
Lou, Xi-yu; Yang, Xuan; Ding, Yi-li; Wang, Jian-jun; Yan, Qing-yan; Huang, Xian-gui; Guo, Yang-hui; Wang, Xiang-jing; Xiang, Wen-sheng, Synthesis of Olaparib derivatives and their antitumor activities, Chemical Research in Chinese Universities (2013), 29(2), 231-235.
The Phase II study for Olaparib was published in N Engl J Med 2012; 366:1382-1392 .by Jonathan Ledermann et al, titled “Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer”
Jose Lutzky, A phase 1 study of MEDI4736, an anti–PD-L1 antibody, in patients with advanced solid tumors. American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, June 3, 2014, Abstract 3001
Neil Howard Segal, Preliminary data from a multi-arm expansion study of MEDI4736, an anti-PD-L1 antibody, American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, June 3, 2014, Abstract 3002
阿斯利康卵巢癌试验药物奥拉帕尼(Olaparib, Lynparza)
2014年6月底，阿斯利康（AZN）“死而复生”的抗癌药Lynparza(奥拉帕尼,olaparib)被FDA专家委员会否决。但近日，该药在美国和欧盟监管方面却收获了大好消息，欧盟委员会于2014年12月18日批准Lynparza(奥拉帕尼,olaparib) 作为一种单药疗法，用于铂敏感复发性BRCA突变卵巢癌成人患者的维持治疗，该药也成为用于BRCA突变铂敏感复发性卵巢癌的首个PARP抑制剂。美国食品药品监督管理局（FDA)也于2014年12月19日通过加速批准通道批准了阿斯利康的PARP抑制剂Lynparza(奥拉帕尼,olaparib) 用于既往经至少3次化疗治疗失败的BRCA胚系突变晚期卵巢癌患者的治疗。该药的获批，也标志着阿斯利康管线中新增了一枚重磅产品。阿斯利康对 olaparib寄予厚望，认为该药的年销售额将突破20亿美元。
Lynparza（olaparib）是一种首创口服多聚ADP核糖聚合酶（PARP）抑制剂，利用DNA修复途径的缺陷，优先杀死癌细胞。目前，阿斯利康正开展多个III期研究，调查olaparib用于BRCA突变卵巢癌、胃癌、乳腺癌的治疗。
关于BRCA基因：
BRCA1和BRCA2基因属于肿瘤抑制因子编码基因，这些基因的突变，与遗传性乳腺癌和卵巢癌相关。若一个女性继承了BRCA1或BRCA2突 变，患乳腺癌和/或卵巢癌的风险将大大增加。在癌细胞扩增至卵巢以外之前，仅有15%的卵巢癌被发现。尽管当前治疗和诊断已经取得了很大进步，但癌细胞已 扩散至卵巢外的患者，5年生存率低于50%。
从安吉丽娜·茱莉切除乳腺看BRCA基因
去年5月14日，好莱坞知名女星、联合国难民事务高级办事处亲善大使安吉丽娜•朱莉（Angelina Jolie）披露因为携带有突变的BRCA1基因，患乳腺癌和卵巢癌的几率分别高达87%和50%，为了将风险降到最低，她做出了进行预防性切除双乳腺手 术的决定。她已经于2013年4月27日接受了预防性的双侧乳腺手术，以降低自己发生乳腺癌的风险。这一消息经报道后，迅速占据了各大新闻网站的醒目位 置，在中文网络中亦不例外。
关于Lynparza（olaparib）：
Olaparib是 一种创新的、潜在首创口服多聚ADP核糖聚合酶（PARP）抑制剂，在临床前模型中已被证明，能够利用DNA修复途径的缺陷，优先杀死癌细胞。这种作用模 式，赋予olaparib治疗具有DNA修复缺陷的广泛肿瘤类型的潜力。PARP与广泛的肿瘤类型相关，尤其是乳腺癌和卵巢癌。
FDA批准Lynparza用于晚期卵巢癌
12月19日，美国FDA授予Lynparza （olaparib） 加速批准，这款新药用于治疗与BRCA基因缺陷相关的晚期卵巢癌妇女，该基因缺陷可通过一种 FDA 批准的诊断试剂进行检测。
卵巢癌形成于卵巢中，卵巢是女性生殖腺，共有一对，也是卵细胞（卵子）形成的地方。美国国家癌症研究所预测，2014年美国将有2.198万名妇女被确诊患有卵巢癌，有1.427万人会死于这种疾病。
Lynparza 是一种多聚二磷酸腺苷核糖聚合酶（PARP）抑制剂，它可阻断参与修复受损 DNA 的酶。这款药物适用于高度预处理的与BRCA基因缺陷相关的卵巢癌。
“今天的批准是一种用于治疗卵巢癌的新类型药物的首次批准，”FDA药物评价与研究中心血液及肿瘤产品办公室主任、医学博士Pazdur 称。“Lynparza被批准用于有特 BRCA基因缺陷的患者，这是对疾病潜在机理的一个更好理解，也是开发靶向、更具个体化治疗药物的一个例证。
FDA 批准Lynparza时伴随批准一款叫BRACAnalysis CDx的基因检测试剂，它将用来检测卵巢癌患者的血样中是否存在BRCA基因突变（gBRCAm）。BRCA基因参与修复受损 DNA,正常工作可抑制肿瘤增长。因突变而导致 BRCA基因缺陷的妇女更可能发生卵巢癌，据预测，所有卵巢癌中10-15%的人与这些遗传性BRCA 突变相关。
FDA 通过该机构用于高风险医疗器械的上市前批准通道评价了BRACAnalysis CDx的安全性及有效性。目前为止，该生产商（一家临床实验室）一直在销售这种检测试剂，但不具体用作一种伴随诊断试剂，未获 FDA 批准作为一种实验室开发检测试剂（LDT），即一种被设计、生产及用于单一实验室的试剂。这款新的检测试剂被批准作为一种伴随诊断试剂，特别是用来识别可能成为 Lynparza 治疗候选人的晚期卵巢癌患者。
”安全有效伴随诊断试剂及药物的批准依然是肿瘤领域重要的发展，“FDA器械及放射卫生体外诊断及放射卫生办公室主任、哲学博士Gutierrez称。”我们很高兴 BRACAnalysis CDx成为FDA首款以及市前批准申请的方式而批准的一种LDT,也是一款首次获批的LDT伴随诊断试剂。伴随诊断试剂的使用有助于销售安全有效的特定满足患者需求的治疗药物。
FDA 对 BRACAnalysis CDx的批准基于支持Lynparza批准的临床研究数据。来自临床试验受试者的血样通过检测证实该试剂可用于检测这类人群的 BRCA 突变。
Lynparza 的疗效在一项由137名接受该药物治疗的gBRCAm相关卵巢癌受试者参与的研究中得到检测。这项研究旨在检测客观缓解率 （ORR），亦即经历肿瘤部分缩小或完全消失的受试者的比例。结果显示，34%的受试者经历了平均7.9个月的ORR.
Lynparza 的常见副作用有恶心、疲劳、呕吐、腹泻、扭曲的味道 （味觉障碍）、消化不良、头痛、食欲下降、常见的类似感冒症状（鼻咽炎）、咳嗽、关节疼痛（关节痛）、肌肉骨骼疼痛、肌肉疼痛（肌痛）、背部疼痛、皮疹（皮炎） 和腹痛。严重副作用包括发生骨髓增生异常综合征，这是一种骨髓不能产生足够功能性血细胞的病症，还包括急性骨髓性白血病（一种骨骨髓癌）及肺炎。
最常见的实验室异常情况有肌酐升高、平均红细胞容积增加、白细胞计数降低（淋巴细胞和中性粒细胞）及血小板水平降低。
6 月份，Lynparza 作为维持治疗药物（阻止癌症回转的药物）的潜在立用途受到FDA肿瘤药物顾问委员会的审查。该委员会以11比2的投票结果向FDA建议，数据不支持 Lynparza用于这一适应症的加速批准。在此会议之后，该公司提交了其它支持Lynparza用于不同用途的信息，即用于已接受三种或更多种化疗治疗的 gBRCAm 相关卵巢癌患者。
FDA 是以加速批准计划批准Lynparza的，这一批准计划可允许基于显示一款药物对合理可能预测患者临床收益的代理终点有效的数据来批准这款药物用于治疗一种严重或危及生命的疾病。该计划可以使患者更早地获取新药，同时申请该药物的公司要进行验证性临床试验。
Lynparza的申请审评是在优先审评计划下完成的，这一计划为旨在治疗一种严重疾病或病症的药物提供一个加快的审评，如果获得批准，该药物与已上市产品相比将对疾病提供明显的改善。
BRACAnalysis CDx 的上市申请是以FDA用于器械的优先审评计划而完成审评的，这一计划可为满足某种标准的器械提供优先审评，这包括旨在治疗或诊断一种危及生命或不可逆转的使人衰弱的疾病或病症，如果获得批准，该器械与已上市产品相比，将为疾病提供明显的、具有临床意义的优势。
Lynparza由位于特拉华州威尔明顿的阿斯利康上市销售。BRACAnalysis CDx位于盐湖城的 Myriad Genetic Laboratories 公司生产。