Niraparib Tosylate

The PARP inhibitor class, featuring drugs from GSK, AstraZeneca/Merck and pharma&, has faced serious regulatory setbacks before this pair of clinical disappointments. In a rough day for PARP inhibitors in ovarian cancer, GSK’s Zejula didn’t deliver a life extension benefit in the final analysis of a phase 3 trial. Another study showed that pharma&’s attempt to enhance its Rubraca with Bristol Myers Squibb’s Opdivo seriously backfired.GSK’s Zejula boasts a broad U.S. approval as a first-line maintenance treatment for ovarian cancer patients who have responded to initial platinum-based chemotherapy. But the phase 3 study that earned the drug that approval, PRIMA, has now shown at its final analysis that Zejula didn’t extend patients’ lives compared with placebo.After a median follow-up of about 74 months, patients in the PRIMA trial who took Zejula as a first-line maintenance treatment were essentially as likely to die as those who received placebo. In fact, Zejula was linked to a 1% higher risk of death, as Zejula takers lived a median 46.6 months, versus 48.8 months for control, according to results presented at the European Society for Medical Oncology (ESMO) 2024 annual meeting.The negative overall survival showing, however marginal, raises the possibility of an FDA crackdown like the one the agency waged on the PARP inhibitor class about two years ago. At that time, several later-line ovarian cancer indications for Zejula, AstraZeneca and Merck’s Lynparza, and the then-Clovis Oncology-owned Rubraca were withdrawn or restricted after the FDA noted a potential long-term detriment to patient survival. Zejula’s OS readoutThe risk of death in PRIMA only turned against Zejula after a small group of patients with undetermined status on the homologous-recombination biomarker were counted, GSK’s global head of oncology R&D, Hesham Abdullah, M.D., noted in an interview with Fierce Pharma. Zejula was associated with a positive 5% reduction in the risk of death in patients with homologous recombination-deficient (HRd) tumors and a 7% improvement in the homologous recombination-proficient (HRp) population. None of the above numbers carry statistical significance.Zejula secured its FDA approval for the first-line maintenance treatment of ovarian cancer—regardless of biomarker status—in 2020 after the PRIMA trial demonstrated that the drug could reduce the risk of disease progression or death by 38% versus placebo. At the time, the biggest benefit was seen in those with BRCA mutations, followed by other HRd types, then HRp tumors, with those with undetermined biomarker status experiencing the least benefit.More therapies have emerged for ovarian cancer since the PRIMA trial, and the overall survival analysis was likely confounded by the use of subsequent therapies, Abdullah said. About 38% of patients in the placebo arm received subsequent PARP inhibitor treatment in PRIMA, versus 12% for the Zejula arm. In the HRd subgroup, the difference was even bigger, with the rates at 48% and 16%, respectively. Still, at first glance, Zejula’s overall survival performance in PRIMA appears weaker than the result from its rival Lynparza in the PAOLA-1 trial, with cross-trial caveats considered. In a descriptive analysis of overall survival in HRd-positive patients, Lynparza plus bevacizumab reduced the risk of death by 38% versus bevacizumab alone in the PAOLA-1 trial.Lynparza’s FDA approval in first-line maintenance ovarian cancer is limited to HRd patients, and the AZ/Merck drug remains the PARP class leader within its approved HRd population. As doctors are more reluctant to use PARP inhibitors in HRp patients, Zejula’s sales have been lagging far behind Lynparza’s quarterly figures.PRIMA enrolled a higher-risk patient population compared with other studies, Abdullah said, pointing to such factors as stage of disease, visible residual disease and prior use of neoadjuvant chemotherapy as evidence.GSK will communicate the latest PRIMA data with the FDA, but Abdullah declined to comment further about potential regulatory actions.Zejula continued to show a benefit in slowing disease progression or death. At five years, about 22% of patients in the Zejula arm were estimated to be alive, versus 12% for placebo. The rates in the HRd population were 35% and 16%, respectively.“We’re comforted by the long-term safety profile and data that we see through survival despite the impact of subsequent therapies,” Abdullah said. Rubraca’s combo setbackAmong the three PARP inhibitors that have an ovarian cancer indication, pharma&’s Rubraca is the smallest player by market share. The Austrian company took over the struggling drug from the bankrupt Clovis Oncology last year. Before that, Clovis had tried to plump up Rubraca’s profile by combining the drug with BMS’ PD-1 inhibitor Opdivo. That now appears to have been a bad idea.Pharma& unveiled the failure of the Rubraca-Opdivo combo as a first-line maintenance treatment for ovarian cancer in May. Now, data from the phase 3 ATHENA-COMBO trial presented at ESMO 2024 show that patients who got the cocktail performed even worse than those who received Rubraca alone.The ATHENA-COMBO trial was a complete failure no matter which patient group was examined. In the overall trial group, the combo showed a 30% increased risk of disease progression or death versus solo Rubraca, as the median PFS was 15 months for the combo and 20.2 months for Rubraca monotherapy.In patients with or without BRCA mutations, with various levels of heterozygosity, or those with PD-L1-positive tumors, the results were the same: The Rubrca-Opdivo regimen was worse.In terms of treatment-related adverse events at grade 3 or higher, the combo arm saw a higher rate of elevated liver enzymes, which suggest liver dysfunction, at 21.2%, compared with 10% for the monotherapy arm. Patients in the combo arm stayed notably shorter on their treatment, as the median exposure to Rubraca was 8.4 months among them, compared with 14.7 months in the control group.How thoroughly the ATHENA-COMBO trial failed was somewhat of a surprise. The phase 3 DUO-O trial previously showed positive tumor progression results for adding AZ’s PD-L1 inhibitor Imfinzi to first-line chemo and bevacizumab and then adding Imfinzi and Lynparza to bevacizumab in the maintenance phase. However, that study didn’t establish a clear contribution from Imfinzi, and AZ doesn't seem to have made any regulatory filing for that use.“While the negative primary results were disappointing, the findings provide further support of Rubraca monotherapy” in the first-line maintenance setting, a pharma& spokesperson said about ATHENA-COMBO in a statement to Fierce Pharma.The problem is, Rubraca as a monotherapy has yet to win an FDA approval as a first-line maintenance treatment in ovarian cancer. Amid the FDA’s previous crackdown on the PARP inhibitor class, the agency last year rejected Rubraca’s application in that first-line setting, requesting long-term overall survival analysis from the phase 3 ATHENA-MONO trial. Likely as a punishment for Clovis’ rogue decision to file the application despite the agency’s prior warning, the FDA actually elevated its request in the rejection, asking for the final overall survival analysis in any potential future refiling. The final analysis from ATHENA-MONO will happen when 70% of patients in the trial have passed away, whereas the agency had previously told Clovis that a 50% maturity threshold would have been enough.Pharma& spoke with the FDA again in May this year, and the agency maintained its stance stated in the complete response letter, the pharma& spokesperson told Fierce. As such, the company will continue the ATHENA-MONO trial and explore a future FDA regulatory path, the spokesperson added.Even as the FDA wards off Rubraca’s first-line bid, the European Commission in November approved that indication. This month, the drug just won reimbursement in France for that first-line maintenance use, the company spokesperson said.

▲10月26-27日成都中国临床试验产业发展大会点击免费报名 注：本文不构成任何投资意见和建议，以官方/公司公告为准；本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及），不代表平台立场。任何文章转载需得到授权。 2024年8月22日，Zenas BioPharma（泽纳仕生物）纳斯达克IPO申请正式获得受理，招股书公开，该公司计划以“ZBIO”为代码在纳斯达克全球市场上市。这距离Zenas上一轮融资仅仅过去了三个多月，距离该公司正式开始运营也不过三年多时间。 Zenas是一家拥有中美“双基因”的全球性生物制药公司。 药融云数据www.pharnexcloud.com显示，2021年3月23日，Zenas BioPharma作为一家跨国（美国-中国）生物制药公司正式成立，致力于成为中国和世界各地患者免疫疗法开发和交付的全球领先企业。 在创立之时，Zenas由Tellus BioVentures和Fairmount Funds Management提供初期投资，还得到包括泉创资本、WuXi Biologics HealthCare Venture和Wellington Management在内的全球生命科学领先投资基金的联合投资支持。泉创资本董事巫荟博士担任Zenas当时的董事总经理。 Zenas创始人Lonnie Moulder是生命科学投资基金Tellus BioVentures的创始人和高级管理人员，在加入Zenas之前，他曾联合创立Tesaro公司并担任首席执行官兼董事，直到该公司在2019年1月被GSK以51亿美元收购，Tesaro的主要上市产品是其开发的Zejula（尼拉帕利，中文商品名：则乐®）。（Zenas目前的领导团队中有多位成员曾在Tesaro担任过重要职位。）从2019年开始，Lonnie Moulder还是再鼎医药的董事会成员。 Zenas还曾在2021年5月任命牟骅博士担任公司的总裁兼首席执行官及代理首席医疗官。在加入Zenas之前，牟博士作为联合创办人建立了瓴路药业，同时还担任高瓴资本的风险合伙人。此外，牟博士还曾供职于先声药业、药明康德、和黄医药、Biogen和基因泰克。 2022年11月8日，Zenas宣布完成1.18亿美元的B轮股权融资，由Patient Square Capital的投资组合公司Enavate Sciences领投，新投资者包括Longitude Capital和维梧资本等。（维梧资本合伙人卢红波博士加入Zenas董事会。） 2024年5月7日，Zenas宣布完成2亿美元的C轮优先股融资。（相关阅读：海外融资已恢复，这家引进模式biotech募资2亿美金） 截图自药融云数据库 “零首付”引进新药，获BMS豪掷半个亿 Zenas当前的核心在研产品Obexelimab是一种具有first-in-class潜力的双功能单克隆抗体，通过结合CD19和FcγRIIb以抑制B谱系细胞活性，有望治疗多种自身免疫性疾病。在已完成的5项临床试验中，Obexelimab治疗了198名受试者，显示出良好得耐受性和临床活性。 该候选药物出自Xencor的XmAb抗体工程技术平台。2021年11月21日，Zenas宣布从Xencor获得Obexelimab的全球独家权利。根据合作协议，Xencor获得Zenas的额外股权作为预付款，并有资格获得高达4.8亿美元的潜在里程碑付款和商业化产品净销售额的特许权使用费。 Obexelimab作用机制 这并不是Xencor第一次将Obexelimab对外授权。 早在2011年，Xencor宣布与安进就Obexelimab（前称Xmab5871/AMG-729）达成合作。根据当时的协议条款，安进可以选择在Xmab5871完成预定义的2期临床研究之后获得该药的全球独家许可，若安进行使其选择权，Xencor将获得期权行权费，加上前期和早期开发里程碑，总计7500万美元，另外，Xencor将有资格获得高达4.25亿美元的临床、监管和商业化里程碑付款，以及未来销售额的分级特许权使用费。然而在2014年，Xmab5871遭安进“退货”，Xencor重获该药的全球权益。 2018年，Xencor宣布Xmab5871治疗系统性红斑狼疮（SLE）的2期临床研究未达主要终点，但显示出积极趋势，在治疗的第225天，XmAb5871组患者有42%保持病情改善，而接受安慰剂的患者为28.6%，p=0.18，缺乏统计学意义。此前Xencor曾计划开展Xmab5871治疗IgG4相关性疾病的3期临床试验，但是这一2期研究失败的消息迫使该公司暂停这一计划，而是决定在推进3期临床之前为该药寻找合作伙伴，此后该药物开发在很长一段时间内陷入停滞。 终于在2021年，Xencor为Obexelimab（Xmab5871）寻到了买家，这在短期内并不会给Xencor带来多少财务回报，因为买家Zenas仅以股权作为首付款，在此之前Xencor就已持有Zenas公司15%的股权，价值1600万美元，而这笔交易使Xencor在Zenas完成下一轮融资时对其持股比例依然保持在15%。 不过从长期来看，这笔交易还是非常有意义的。 从Xencor取得Obexelimab全球许可后，Zenas在2022年底启动了Obexelimab治疗IgG4相关性疾病（IgG4-RD）的关键全球3期临床试验（INDIGO），并于2023年1月完成首例患者给药。药融云数据www.pharnexcloud.com显示，一项在IgG4相关性疾病患者中评价Obexelimab疗效和安全性的3期、多中心、随机、双盲、安慰剂对照研究（INDIGO）正在国内开展，国内计划招募30人，国际200人。该公司预计在2025年底之前报告INDIGO试验的顶线数据，并根据数据在2026年递交BLA申请。 截图自药融云数据库 IgG4-RD是一种慢性和严重的纤维炎症性疾病，通常影响多个器官（例如胰腺、肝脏、肾脏、胆管、唾液腺和泪腺）。仅在美国，大约有2万人被诊断出患有IgG4-RD。该病目前尚无获批的治疗方案，使用糖皮质激素是IgG4-RD的标准治疗方案，但大多数患者在停止治疗后几个月内会复发，很少能实现无需再接受治疗的长期缓解效果，并且会增加这些患者的高毒性风险，以及损害疫苗反应。 2023年8月，Zenas宣布Obexelimab治疗IgG4-RD的2期临床研究结果已刊登于《柳叶刀风湿病学》。该研究显示，治疗第169天，有12名患者（80%）的IgG4-RD RI（应答指数）评分比基线至少降低了2分，其中8名患者（67%）的RI评分为零（完全缓解）。所有在最初产生应答的患者都在试验结束时实现了持续应答。 2023年9月5日，Zenas宣布与百时美施贵宝（BMS）达成战略许可和合作协议，授予后者在日本、韩国、台湾地区、新加坡、香港和澳大利亚开发和商业化Obexelimab用于治疗自身免疫性疾病的独家权利。根据协议条款，Zenas将获得5000万美元的预付款现金，并有资格获得与实现某些开发、监管和商业里程碑有关的额外付款，以及Obexelimab在许可地区的净销售特许权使用费。（据招股书披露，开发和监管里程碑付款最高可达7950万美元，销售里程碑付款最高可达7000万美元。）此外，百时美施贵宝对Zenas进行了股权投资。 除了IgG4-RD，Obexelimab正在被开发用于多种自身免疫性疾病。 温抗体型自身免疫性溶血性贫血（wAIHA）由IgG型自身抗体与红细胞结合驱动，导致健康红细胞过早破坏（溶血）。wAIHA是自身免疫性溶血性贫血（AIHA）最常见的亚型（占成人病例的70-80%）。据统计，美国有超过4万人受到这种疾病的影响。2023年末，Zenas启动了一项全球多中心、随机、双盲、安慰剂对照的2/3期临床试验（SApHiAre），以评估Obexelimab在wAIHA患者中的疗效和安全性。 另据招股书披露，Zenas计划在2024年第三季度启动一项评估Obexelimab治疗多发性硬化症（MS）患者的有效性和安全性的2期临床试验（MoonStone），以及一项评估Obexelimab治疗系统性红斑狼疮（SLE）患者的有效性和安全性的2期临床试验（SunStone）。 多款引进产品寻求再合作 Zenas管线中还有一系列临床项目，以期为其他免疫与炎症疾病提供潜在治疗药物，Zenas可能会与合作伙伴继续开发这些项目并最终进行商业化。 ZB002是一种抗TNFα单克隆抗体，由Zenas引进自Xencor，Zenas拥有全球权利。2024年第二季度，Zenas启动了ZB002针对类风湿性关节炎患者的1b期MAD研究。在小鼠中进行的头对头临床前研究表明，ZB002的半衰期比阿达木单抗更长（≥2倍）。若1b期MAD研究获得积极结果，Zenas可能会寻求对外合作，以在后续的试验中推进ZB002。 ZB004是一种CTLA-4-Ig融合蛋白，旨在提供比现有CTLA-4-Ig融合蛋白疗法更长的半衰期，该候选药物也是由Zenas引进自Xencor，Zenas拥有全球权利。基于正在进行的1期研究结果，该公司计划评估ZB004治疗免疫与炎症适应症的未来开发方向。 ZB001（又称VRDN-001）是一种IGF-1R（胰岛素样生长因子-1受体）单克隆抗体，由Zenas引进自Viridian Therapeutics，Zenas拥有ZB001和相关项目在大中华区的研发和商业化权利，拟在国内开发用于治疗甲状腺眼病（TED）患者。2024年4月，ZB001治疗中国TED患者的1期MAD临床研究完成了最后的患者随访。初步数据显示，接受ZB001注射治疗后，患者体征和症状均有显著和快速的改善。在ZB001完成初步临床开发后，Zenas计划与第三方达成协议，以进一步推进ZB001和相关项目在大中华区的临床开发和商业化工作。 ZB005（又称DNTH103）是一种高选择性、靶向补体C1s活性形式的单克隆抗体，由Zenas引进自Dianthus Therapeutics，Zenas拥有ZB005在大中华区的独家研发、制造和商业化权利。2023年8月，Dianthus报告了1期研究的数据，证实了ZB005延长半衰期和强大的经典途径抑制作用。Dianthus目前正在开展ZB005治疗全身性重症肌无力的2期临床研究。Zenas计划与第三方达成协议，以进一步推进ZB005在大中华区的临床开发和商业化工作。 财务状况 据招股书披露，截至2024年6月底，Zenas累计筹集3.583亿美元资金，投资者包括Enavate Sciences、SR One、Longitude Capital、Tellus BioVentures、Fairmount、New Enterprise Associates、Norwest Venture Partners，以及百时美施贵宝（BMS）等，并通过与BMS的合作获得了5000万美元预付款。截至2024年6月底，Zenas持有1.839亿美元的现金。 持股5%及以上的股东 2023全年Zenas经营业绩如下： 全年各项目研发开支如下： 2024年上半年经营开支如下： 上半年各项目研发开支如下： 此文仅用于向医疗卫生专业人士提供科学信息，不代表平台立场，不作任何用药推荐 参考： NMPA/CDE； 药融云数据www.pharnexcloud.com； FDA/EMA/PMDA； 相关公司公开披露（正文图片均来自企业官方，除非另有说明）； https://zenasbio.com/news/zenas-biopharma-launches/； https://zenasbio.com/news/zenas-biopharma-secures-118-million-to-advance-its-broad-pipeline-of-autoimmune-disease-therapeutics/； https://www.fiercebiotech.com/biotech/xencor-finally-finds-buyer-for-one-time-lead-drug-offloading-autoimmune-asset-to-tesaro； https://xueqiu.com/1335311504/260395589； https://www.pharnexcloud.com/data/lcsy_a439d92ab6bed223216f037e41892922.html；等等 【关于药融圈】 药融圈PRHub旨在帮助生物医药科技型企业进行品牌推广及商务拓展服务，针对客户的真实需求制定系统化解决方案，通过“翻译-降维-场景化”将客户的品牌信息以直白易懂的方式被公众知悉，同时在流量渠道覆盖100万+垂直用户基础上实现合作目的，帮助合作伙伴完成从品牌开始到商务为终的闭环营销服务。我们已经完成了数十场线下1000人规模的生物医药研发类会议，涵盖小分子新药，大分子新药，改良型新药，BD跨境交易等多个领域，服务了百余家上市/独角兽/生物技术/制药企业。