Seikagaku Corp.

▎药明康德内容团队编辑 根据PDUFA的预期目标日期，预计2025年3月，美国FDA将对8款创新药物的批准做出监管决定，本文将对这些疗法进行相关介绍。 ▲2025年3月有望在美国获批的新药（药明康德内容团队制图，点击可见大图） 活性成分：SI-6603（condoliase） 适应症：因腰椎间盘突出（LDH）引起的根性腿痛 公司名称：Ferring Pharmaceuticals，生化工业株式会社（Seikagaku） SI-6603是一种用于治疗与腰椎间盘突出相关的坐骨神经痛的在研药物，其活性成分为condoliase，能够特异性地降解糖胺聚糖（GAG），而GAG是髓核的主要成分。该药物通过单次、直接椎间盘内注射给药，通过减轻神经根压迫从而减轻疼痛。SI-6603已在日本获批上市，商品名为Hernicore。 2024年5月，美国FDA接受了SI-6603的生物制品许可申请（BLA），用于治疗因LDH引起的根性腿痛。3期临床研究结果显示，接受一剂SI-6603注射的LDH患者最严重腿痛获得显著改善。在试验中，LDH患者被随机分配接受单次椎间盘内注射SI-6603或模拟注射，随后进行52周的观察。修正意向治疗（mITT）人群包括341名参与者（SI-6603组169人；模拟注射组172人）。研究达到了其主要终点，显示第13周最严重腿痛的改善显著优于模拟注射组（最小二乘均值[LSM]差异：-7.5；p=0.0263），并在第4周（-6.0；p=0.0418）和第6周（-7.4；p=0.0146）就已显示出显著差异。 2025年1月10日，美国FDA咨询委员会以8票赞成、4票反对的结果，支持SI-6603用于治疗成人LDH引起的根性腿痛。 活性成分：Revakinagene taroretcel 适应症：2型黄斑毛细管扩张症（MacTel） 公司名称：Neurotech Pharmaceuticals Revakinagene taroretcel（NT-501）是一款细胞疗法，基于Neurotech Pharmaceuticals独特的封装细胞疗法（encapsulated cell therapy，ECT）平台构建而成。它将表达睫状神经营养因子（CNTF）的同种异体视网膜色素上皮（RPE）细胞封装在微小的移植物中，这些移植物在植入到眼睛中后可以持续释放CNTF，从而延缓视网膜退化，潜在改善患者的长期视力。移植物具有通透性的外膜在允许营养物质进入和CNTF释放的同时，保护移植细胞不受到宿主免疫系统的攻击，确保它们的长期存活和功能。 2024年6月，Neurotech Pharmaceuticals宣布，其为revakinagene taroretcel递交的BLA已获得美国FDA授予的优先审评资格，用于治疗2型黄斑毛细血管扩张症。Revakinagene taroretcel在两项3期临床试验中已经获得积极结果，显著降低了2型MacTel患者的疾病进展速度。 活性成分：Rivoceranib、Camrelizumab 适应症：肝细胞癌 公司名称：Elevar Therapeutics，恒瑞医药 Rivoceranib是一种小分子酪氨酸激酶抑制剂（TKI），是血管内皮生长因子受体2（VEGFR-2）的强效抑制剂，VEGFR-2是肿瘤血管生成的主要途径。VEGFR-2抑制是一种经过临床验证限制肿瘤生长和疾病进展的方法。Rivoceranib正开发作为单药疗法以及与化疗和免疫治疗联合以治疗各种实体瘤适应症。Camrelizumab是一种靶向PD-1的人源化单克隆抗体，由恒瑞医药所开发。2023年10月，Elevar从恒瑞医药获得了camrelizumab的全球（大中华地区和韩国除外）商业化许可。 2024年10月，Elevar Therapeutics宣布美国FDA已接受其重新提交的新药申请（NDA），寻求批准该公司与恒瑞医药联合开发的在研药物rivoceranib与camrelizumab（SHR-1210）联用，一线治疗不可切除或转移性肝细胞癌。FDA预计在2025年3月20日之前完成审评。同时，恒瑞医药也重新向美国FDA提交了camrelizumab联合rivoceranib用于不可切除或转移性肝细胞癌患者一线治疗的BLA，并得到正式受理。 根据3期临床研究（CARES-310研究）的结果，rivoceranib与camrelizumab组合一线治疗晚期不可切除或转移性肝细胞癌具有显著的生存获益和可耐受的安全性。中位无进展生存期（mPFS）为5.6个月，将疾病进展及死亡风险降低48.0%，中位总生存期（mOS）为22.1个月，死亡风险显著降低38%。此外，联合治疗组客观缓解率（ORR）为25.4%（RECIST v1.1标准），中位至缓解时间（mTTR）为1.9个月，中位缓解持续时间（mDoR）14.8个月，可为更多肝癌患者带来肿瘤缓解和手术切除的可能性。安全性方面，该组合疗法整体未出现新的不良事件信号，安全性可控，耐受性良好。2023年7月，CARES-310研究期中数据发表于《柳叶刀》主刊。 活性成分：Gepotidacin 适应症：尿路感染 公司名称：GSK Gepotidacin是一款具有全新作用机制的抗生素，它可以口服，并具有双重作用机制，能同时选择性地结合并抑制DNA促旋酶和DNA拓扑异构酶IV，从而诱发在复制进程的DNA发生单链断裂，进而达到杀死病原体的目的。 2024年10月，美国FDA接受了gepotidacin的NDA，用于治疗患有单纯性尿路感染（uUTI，也称为急性膀胱炎）成年或青少年（≥12岁）女性患者，患者体重须≥40公斤。FDA同时授予该申请优先审评资格，并预计在2025年3月26日前完成审评。根据新闻稿，若获批，gepotidacin将成为20多年来首个用于治疗uUTI的新型口服抗生素药物。 该新药申请得到了关键性3期EAGLE-2和EAGLE-3试验积极结果的支持。在这些研究中，与目前uUTI标准疗法nitrofurantoin抗生素相比，gepotidacin在治疗确诊的uUTI成年与青少年女性患者中展现非劣效性，这些患者已知对nitrofurantoin应答。 活性成分：Etripamil 适应症：阵发性室上性心动过速 公司名称：Milestone Pharmaceuticals Etripamil是一种速效非二氢吡啶类L型钙通道阻滞剂（CCB），由Milestone Pharmaceuticals公司开发用于治疗阵发性室上性心动过速（PSVT）和其他心律失常。作为一款鼻喷雾剂，etripamil鼻喷雾剂可由患者随时随地自行给药，有望将目前在急诊才能获得的治疗方式转移至家中，为患者提供更加快速的治疗方法。2021年5月，箕星药业与Milestone公司达成独家许可及合作协议，获得在大中华区开发和商业化etripamil的独家权益。 2024年5月，美国FDA接受了etripamil鼻喷雾剂的NDA，用于PSVT的管理，PDUFA目标行动日期定为2025年3月27日。2025年1月17日，中国国家药品监督管理局药品审评中心（CDE）也正式受理了etripamil鼻喷雾剂治疗PSVT的NDA。 3期JX02002临床研究结果显示，JX02002研究达到了方案预设的主要终点，与安慰剂相比，使用etripamil的患者在给药后的30分钟内，PSVT转复为窦性心律的时间方面具有显著优效性（风险比3.002；p=0.0005）。总体而言，治疗期出现的不良事件在etripamil治疗组和安慰剂组之间无显著差异。尤为值得注意的是，在etripamil给药后24小时内未观察到任何严重不良事件。 活性成分：Diazoxide choline（DCCR） 适应症：Prader-Willi综合征（PWS） 公司名称：Soleno Therapeutics DCCR是一种含有二氮嗪胆碱（diazoxide choline）的创新专有缓释剂型，每日口服一次。DCCR开发项目的数据支持来自五项在健康志愿者中完成的1期临床研究和3项完成的2期临床研究，其中一项是在PWS患者中进行的。在PWS的3期临床开发项目中，DCCR在解决PWS的标志性症状暴食症以及其他几种症状（如攻击性/破坏性行为、脂肪质量和其他代谢参数）方面显示出可喜的效果。 2024年8月，美国FDA接受了DCCR的NDA并授予其优先审评资格，用于治疗4岁及以上伴有暴食行为的PWS患者。2024年11月，FDA将DCCR的NDA的审查期延长，新的PDUFA日期调整为2025年3月27日。 目前，DCCR已在美国和欧盟获得治疗PWS的孤儿药资格，并且在美国获得快速通道资格认定。2024年4月，美国FDA授予DCCR突破性疗法认定，用于治疗4岁及以上经基因检测确认的PWS患者的高食欲症。这一认定是基于对3期临床试验初步数据的评估，FDA认为DCCR可能在具有临床意义的终点上与现有疗法相比，显示出显著改善。 活性成分：Fitusiran 适应症：血友病A与血友病B 公司名称：Alnylam Pharmaceuticals，赛诺菲（Sanofi） Fitusiran是一款小干扰RNA（siRNA）疗法，旨在作为体内产生/未产生凝血因子抑制物的血友病A或血友病B患者的预防性治疗。Fitusiran可降低抗凝血酶水平，从而促进凝血酶生成，重新平衡止血功能并预防出血。Fitusiran注射液的上市申请已于2024年5月获得中国国家药品监督管理局受理，并于6月获得美国FDA受理，用于治疗血友病A和血友病B患者。 2023年4月，《柳叶刀》和《柳叶刀-血液病学》发表了2项3期临床研究结果，这些研究旨在评估fitusiran用于血友病A与血友病B成人和青少年患者的预防性治疗的有效性和安全性。在两项3期试验中，与对照组相比，fitusiran预防治疗组患者的年化出血率降低了90%。这表明，与按需治疗相比，fitusiran预防治疗显著减少了患者的出血事件，研究结果不但具有统计学意义，同时具有重要临床意义，患者生活质量得到改善。 值得一提的是，业内知名机构科睿唯安（Clarivate）在其发布的Drugs to Watch报告中将这款疗法列为有望在五年内成为重磅的创新疗法。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放 参考资料： [1] Ferring Announces U.S. FDA Acceptance of Biologics License Application Submission for SI-6603, an Investigational Therapy in Lumbar Disc Herniation，Retrieved Feb 17, 2025 from https://ferringusa.com/?press=ferring-announces-u-s-fda-acceptance-of-biologics-license-application-submission-for-si-6603-an-investigational-therapy-in-lumbar-disc-herniation [2] FDA adcomm votes to support Seikagaku's herniated disc injection，Retrieved Feb 17, 2025 from https://endpts.com/fda-adcomm-votes-to-support-seikagakus-herniated-disc-injection/#:~:text=Despite%20some%20safety%20concerns%2C%20an,lumbar%20disc%20herniation%20in%20adults [3] Neurotech Pharmaceuticals, Inc. Receives Priority Review of Biologics License Application (BLA) for NT-501 (revakinagene taroretcel) as a Treatment for Macular Telangiectasia Type 2 (MacTel)，Retrieved Feb 17, 2025 from https://www.businesswire.com/news/home/20240620620734/en/Neurotech-Pharmaceuticals-Inc.-Receives-Priority-Review-of-Biologics-License-Application-BLA-for-NT-501-revakinagene-taroretcel-as-a-Treatment-for-Macular-Telangiectasia-Type-2-MacTel [4] Neurotech Provides Update on BLA for NT-501 as a Treatment for Macular Telangiectasia Type 2 (MacTel)，Retrieved Feb 17, 2025 from https://www.businesswire.com/news/home/20241106194221/en/Neurotech-Provides-Update-on-BLA-for-NT-501-as-a-Treatment-for-Macular-Telangiectasia-Type-2-MacTel [5] Elevar Therapeutics Announces FDA Acceptance of New Drug Application Resubmission for Rivoceranib in Combination with Camrelizumab as a First-line Systemic Treatment for Unresectable Hepatocellular Carcinoma，Retrieved Feb 17, 2025 from https://elevartherapeutics.com/2024/10/21/elevar-therapeutics-fda-acceptance-of-new-drug-resubmission-2/ [6] 恒瑞医药重新向FDA提交“双艾”组合肝癌一线治疗适应症上市申请并获受理，Retrieved Feb 17, 2025 from https://mp.weixin.qq.com/s/lrCGcTjRHE6tN2hj6t4vQA [7] Gepotidacin accepted for priority review by US FDA for treatment of uncomplicated urinary tract infections in female adults and adolescents. Retrieved Feb 17, 2025 from https://www.gsk.com/en-gb/media/press-releases/gepotidacin-accepted-for-priority-review-by-us-fda-for-treatment-of-uncomplicated-urinary-tract-infections-in-female-adults-and-adolescents/ [8] Milestone Pharmaceuticals Announces FDA Acceptance of New Drug Application for CARDAMYST，Retrieved Feb 17, 2025 from https://investors.milestonepharma.com/news-releases/news-release-details/milestone-pharmaceuticals-announces-fda-acceptance-new-drug [9] 箕星宣布国家药品监督管理局受理Etripamil的新药上市申请，Retrieved Feb 17, 2025 from https://www.corxelbio.com/zh/%E6%96%B0%E9%97%BB%E8%B5%84%E8%AE%AF/%E7%AE%95%E6%98%9F%E5%AE%A3%E5%B8%83%E5%9B%BD%E5%AE%B6%E8%8D%AF%E5%93%81%E7%9B%91%E7%9D%A3%E7%AE%A1%E7%90%86%E5%B1%80%E5%8F%97%E7%90%86etripamil%E7%9A%84%E6%96%B0%E8%8D%AF%E4%B8%8A%E5%B8%82%E7%94%B3%E8%AF%B7/ [10] SOLENO THERAPEUTICS ANNOUNCES U.S. FDA ACCEPTANCE FOR FILING AND PRIORITY REVIEW OF NDA FOR DCCR (DIAZOXIDE CHOLINE) EXTENDED-RELEASE TABLETS IN PRADER-WILLI SYNDROME，Retrieved Feb 17, 2025 from https://investors.soleno.life/news-releases/news-release-details/soleno-therapeutics-announces-us-fda-acceptance-filing-and [11] SOLENO THERAPEUTICS ANNOUNCES FDA EXTENSION OF REVIEW PERIOD FOR DCCR (DIAZOXIDE CHOLINE) EXTENDED-RELEASE TABLETS IN PRADER-WILLI SYNDROME，Retrieved Feb 17, 2025 from https://investors.soleno.life/news-releases/news-release-details/soleno-therapeutics-announces-fda-extension-review-period-dccr [12] Press Release: Two fitusiran Phase 3 studies published in The Lancet and The Lancet Haematology highlight potential to address unmet needs across all types of hemophilia，Retrieved Feb 17, 2025 from https://www.sanofi.com/en/media-room/press-releases/2023/2023-04-04-05-00-00-2640246 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。 版权说明：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。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新

Despite some safety concerns, an FDA advisory committee on Friday voted 8 to 4 in favor of Japan-based Seikagaku’s condoliase injection for the treatment of radicular leg pain associated with lumbar disc herniation in adults. Much of the discussion centered on one of Seikagaku’s three clinical trials presented before the committee that failed on its primary endpoint and several secondary endpoints. Overall, the members of the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee said the negative study should be weighed appropriately by the agency, and they raised short and long-term safety questions about the injection. Committee chair Brian Bateman of Stanford University School of Medicine, who voted against the injection, cautioned that the population in the negative, US-based study “might reflect the population that would ultimately use it.” He also noted several safety concerns, including that the drug has to be used in a setting that can treat anaphylaxis, and that those receiving the drug can be at risk of severe cutaneous adverse reactions (SCARs). Committee panelist Steven Schiff, professor of neurosurgery at Yale University, who voted in favor of condoliase, also raised concerns about larger numbers of people accessing it. “I could envision in the next years, a million people might get this therapy,” Schiff said, and if the prevalence of SCARs is about one in 1,000, as Seikagaku estimates, a few hundred cases of these life-threatening reactions in the US “might cause the FDA to think twice” about the approval. Michael Sprintz of Ethos Behavioral Health Group in Houston voted in favor of the injection but said he hopes the label will be appropriately narrow and ensure that those who receive it fail on the more commonly used therapies. Lumbar disc herniation can cause lower back or leg pain, but is typically resolved with existing medicines. About 20% to 50% of those in pain progress to surgery, Seikagaku said Friday. The company has presented condoliase as a less invasive alternative to surgery. About 29,000 patients have been treated with condoliase, first approved in Japan in 2018, the company said. Two of the studies were based in the US, but only one of those was positive. One key way that the two trials differed was that in the positive trial, the company used MRIs to find evidence of nerve impingement before administering the drug. But some of the panelists questioned if the MRI scans were the primary reason for the differences between the failed and positive studies. Schiff noted that the two US-based studies had very different populations and indications. And while he’s not surprised by the one failed study, he did ask: “How do you translate the success of the second study given the very rigorous inclusion and exclusion criteria? How does that get translated into approval?” DJ Kennedy of the Vanderbilt University Medical Center, who voted in favor of the drug, also said that the application of condoliase in the real world will likely be more similar to what occurred in the negative study, “unless there’s significant efforts to make that not the case.” But the experience of using the drug in Japan could be informative to the FDA in making its approval decision. ‘The longer term studies out of Japan are reassuring, maybe not completely sufficient, but they are reassuring,” Kennedy said.

Japan-based Seikagaku will face an FDA advisory committee on Friday, with the agency raising concerns ahead of the meeting regarding the efficacy of its condoliase injection for the treatment of radicular leg pain associated with lumbar disc herniation in adults. Ahead of the meeting of the Anesthetic and Analgesic Drug Products Advisory Committee, the FDA notes that one of the clinical trials failed on its primary endpoint. Overall, the agency sounded positive on an approval, noting in briefing documents released Wednesday that “the negative study may inform the benefit-risk assessment for specific populations who may be considered for treatment with condoliase if the product is approved.” One of the three clinical trials evaluated by the FDA did not meet its primary efficacy endpoint (change in worst leg pain from baseline to week 13), nor did it meet either of its two key secondary endpoints, including a pain outcome assessment after a year. The change from worst leg pain from baseline to week 52 slightly favored the control in the failed study, FDA said, but the difference was not statistically significant. The agency also noted that the study that failed likely did so because herniation resulting in symptomatic nerve impingement was not present in most of the patients enrolled, and that’s what the injection targets. The agency said that Seikagaku “performed a detailed analysis to explain the negative U.S. findings despite the positive findings in Study 1031 in Japan.” The company highlighted two key issues: 1) A majority of patients in the failed trial did not have definitive impingement of the nerve root by the disc herniation on an MRI. 2) Baseline back pain was significantly higher in the US study compared to the study in Japan. Two other Phase 3 clinical trials were positive, although one was conducted exclusively in Japan. And in both trials, nerve impingement conducive to condoliase treatment was confirmed by imaging, FDA said. Friday’s committee will have an up-or-down vote on the injection, with the question presented as, “Do the benefits of condoliase injection for treatment of radicular leg pain associated with confirmed nerve root impingement caused by lumbar disc herniation in adults with radicular leg pain outweigh the risks?” Seikagaku, which also markets an intra-articular injection for the treatment of knee osteoarthritis in the US, calls its condoliase injection an improvement on the current treatment landscape, because it does not require general anesthesia and is “less invasive to the patient than surgical treatment.”