Zelenectide pevedotin

▎医药观澜/报道 编者按：近年来，GLP-1药物如司美格鲁肽等重磅药物的问世，引领了多肽类药物的研发热潮。与此同时，多肽类药物的研发和生产仍然面临极大挑战，可谓机遇与挑战并存。药明康德多年来持续布局多肽药物领域相关前沿技术和能力，通过一体化CRDMO平台深度赋能全球合作伙伴的多肽类药物创新研发，助力创新疗法加速造福病患。今天这篇文章，将带领读者了解2024年多肽药物的发展风向，并复盘过去一年在中国首次迈入临床阶段的在研分子管线。我们期待，随着前沿技术的不断创新和更多管线推进，多肽药物能够发挥更多治疗潜力，为患者带来更多福音。 刚刚过去的2024年，多肽药物仍然是产业重点投资方向之一，保持迅猛发展势头。 一方面，投融资市场持续保持活跃。即刻药数显示，2024年以来，全球多肽药物领域的融资事件超过83次，其中包括中国公司的26起融资。在这些融资事件中，多家公司融资额超1亿美元。例如，专注于代谢药物研发的Metsera公司去年4月宣布2.9亿美元种子轮和A轮融资，并于11月宣布完成了2.15亿美元B轮融资，以推进其超长效GLP-1受体激动剂以及营养刺激激素肽类似物产品的研发。再例如，Kailera Therapeutics于去年10月宣布成立并完成4亿美元A轮融资，以开发多款肽类减肥疗法。 另一方面，2024年多肽疗法领域发生了超50起交易事件，多起交易金额超10亿美元。其中也有不少中国公司的参与，例如，5月份，恒瑞医药将其GLP-1产品组合许可给Kailera公司，潜在总额有望达60亿美元。就在近日，这一领域再迎重磅消息，先为达生物宣布与英国Verdiva Bio达成授权合作，将包括口服伊诺格鲁肽、胰淀素受体激动剂等产品组合在大中华区和韩国以外的全球权益授予后者，首付款近7000万美元，潜在总金额超24亿美元。Verdiva Bio专注于开发代谢性疾病疗法，其于今年1月刚宣布成立并获得超4亿美元A轮融资。 持续的资金流入，为多肽药物的不断创新和突破提供了强大支持。据Insight数据库，除了已上市药物，截止2024年底全球范围内超500条多肽类新药管线处于临床开发阶段。展望2025年，预计将有6款多肽类疗法有望首次获得FDA批准，覆盖代谢疾病、肿瘤、罕见病等领域。 管线持续推进，17款多肽1类新药在中国迈入临床开发阶段 作为全球生物医药创新生态的重要组成部分，在中国当前也有超150条分子管线在研发，且正在加速临床推进。2024年全年，至少17款多肽1类新药在中国首次获批IND，迈入临床开发阶段。其中，既有来自恒瑞医药、诺和诺德等大药企的在研管线，也有来自星联肽、质肽生物等小型biotech公司的创新分子。这些在研新药多为多肽，也包括多肽偶联药物（PDC）、双环肽偶联药物、环状多肽等创新类型，其中GLP-1类药物至少7款（占比超40%），治疗领域涉及代谢性疾病、癌症、感染性疾病等。 注射用SC-101：星联肽在研的一款靶向Nectin-4的PDC药物，于2024年1月获CDE临床默示许可，拟开发治疗表达Nectin-4的晚期恶性实体瘤。 注射用LN005：惠永制药在研的一款靶向GRP78的PDC药物，于2024年1月获CDE临床默示许可，拟开发治疗恶性肿瘤。 TY751注射液：天津药物研究院在研的一款多肽类GLP-1R/GCGR双重激动剂，于2024年2月获CDE临床默示许可，拟开发治疗2型糖尿病。 HDM1005注射液：华东医药在研的一款多肽类GLP-1受体和GIP受体的双靶点激动剂，于2024年3月获CDE临床默示许可，拟开发用于治疗2型糖尿病和超重或肥胖人群体重管理。 注射用JR8603：JiaRay Pharmaceuticals在研的一款PDC药物，于2024年5月获CDE临床默示许可，拟开发治疗晚期实体瘤。 PJ020（注射用重组酰化胰高血糖素样肽2类似物）：派金生物在研的一款GLP-2类似物长效重组多肽，于2024年5月获CDE临床默示许可，拟开发治疗化疗相关性腹泻。 Amycretin片：诺和诺德（Novo Nordisk）在研的一款多肽类GLP-1R和胰淀素受体的长效协同激动剂，于2024年6月获CDE临床默示许可，拟开发用于降低超重或肥胖成人患者的体重。 注射用SC-102：星联肽在研的一款靶向EphA2蛋白的PDC，于2024年8月获CDE临床默示许可，拟开发治疗表达EphA2的晚期恶性实体瘤。 BT8009：BicycleTx在研的一款靶向Nectin-4的双环肽偶联药物，于2024年10月获CDE临床默示许可，拟开发治疗尿路上皮癌。 注射用BRII-693：一款新型合成脂肽抗菌药，于2024年10月获CDE临床默示许可, 拟开发用于治疗难治性多重耐药/广泛耐药（MDR/XDR）革兰氏阴性菌感染，特别是耐碳青霉烯类鲍曼不动杆菌和耐碳青霉烯类铜绿假单胞菌感染。根据与Qpex Biopharma签订的授权许可协议，腾盛博药拥有在全球开发和商业化BRII-693 的权益。 注射用SM-V-61：一款糖肽抗生素，由中国科学院上海药物研究所研发，并由糖霁生物进行后续开发。该产品于2024年10月获CDE临床默示许可，拟开发用于治疗对本品敏感的革兰阳性菌引起的：复杂性皮肤和皮肤结构感染；医院获得性和呼吸机相关性肺炎；导管及其它人工植入物相关性感染；血流感染；在治疗方案选择有限的成人患者中治疗对本品敏感的耐药革兰阳性菌引起的感染等。 ZT006片：质肽生物在研的一款GLP-1类多肽药物，于2024年11月获CDE临床默示许可，拟开发用于成人2型糖尿病患者的血糖控制，以及成人超重或肥胖患者减重治疗。 MWN109注射液：民为生物在研的一款GIP/GLP-1/GCG三靶点脂肪酸链修饰多肽药物，于2024年11月获CDE临床默示许可，拟开发用于治疗2型糖尿病、超重或者肥胖。 HRS-4729注射液：恒瑞医药在研的一款多肽类GLP-1R/GIPR/GCGR三激动剂，于2024年12月获CDE临床默示许可, 拟开发用于超重或肥胖适应症。 图表：2024年在中国首次获批临床的“GLP-1类”多肽1类新药管线 数据来源：CDE、企业公开信息（2024.01.01~2024.12.31） DD01注射液：一种与PEG偶联的环肽分子，可以选择性激活GLP-1受体和GCG受体。该产品于2024年12月获CDE临床默示许可，拟用于成人肥胖患者或伴发一种及以上与体重相关危险因素（如高血压、2型糖尿病或血脂异常等）的超重患者的体重管理。DD01由D&D Pharmatech研发，信立泰通过一项超1.75亿元的合作获得了其在中国大陆地区的权益。 AZD6234注射液：阿斯利康（AstraZeneca）在研的一款肽类长效胰淀素类似物，于2024年12月获CDE临床默示许可，拟开发用于在至少有一种肥胖相关合并症的超重或肥胖成年人中长期体重管理。 PD-DP-008凝胶：佩德生物在研的一款创新多肽药物，活性成分来源于青蛙的皮肤分泌物中的天然多肽，经设计与改良后，通过特有作用机制与致病菌的细胞膜发生作用，导致细菌破裂死亡从而达到杀菌目的。该产品于2024年12月获CDE临床默示许可，拟治疗寻常痤疮。 CRDMO模式，为多肽疗法研发和生产赋能 尽管多肽药物前景广阔，推动了研发和生产的强趋势，但这类药物的研发和生产技术门槛高，尤其是生产工艺路线复杂，质量控制与纯化分离要求极高，大规模合成更是面临重重壁垒，也因此导致了产能短缺的行业挑战。 共同推动多肽药物创新研发，合同研发和生产机构（CXO）在其中发挥着重要作用。例如，在前述提到的2024年在中国首次获批IND的多肽类1类新药中，就有一些在研产品得到药明康德专注于寡核苷酸和多肽一体化服务的WuXi TIDES平台的赋能和支持。根据近日药明康德在摩根大通医疗健康大会上的公开信息，2024年全球GLP-1临床阶段候选药物从62个增加到85个，增长37%；药明康德的项目管线从13个增加到20个，增长54%，超过行业增速。这些分子中包括小分子药物和肽类药物，在47个肽类药物中，药明康德支持了9个。 作为全球支持多肽类药物研发的重要CRDMO赋能平台，药明康德的合成服务涵盖所有类型的多肽以及非天然氨基酸、连接子、毒素和多肽偶联物，支持从序列设计到临床前候选药物（PCC）筛选，并提供相应测试支持。药明康德还提供各种剂型和灌装形式的制剂开发和生产服务等，助力加速推进多肽药物开发进程。早期研究可无缝衔接后续工艺开发，并快速扩大到任何生产规模，提供从临床前、临床到商业化的一体化解决方案。 早在2011年，药明康德就布局了多肽研究和测试能力，更于2018年整合并推出新分子业务板块WuXi TIDES，专注于提供寡核苷酸、多肽及相关化学偶联物的一体化、端到端的CRDMO服务。在这一领域，药明康德近年来不仅引入了多项创新技术，如反应釜串联技术、连续流动色谱法、切向流过滤（TFF）/沉淀等，还多次扩建产能。2023年4月，常州基地就投产了两个2000升多肽固相合成釜（SPPS），2024年也多次投产常州和泰兴两个生产基地的多肽车间，SPPS总体积快速提升至41000升。根据近期药明康德在摩根大通医疗健康大会上的公开信息，预计2025年底该产能将超过100000升。 2024年11月，药明康德宣布其位于常州的全新研发中心正式启用，首栋研发大楼已投入运营，专注于寡核苷酸、多肽及复杂化学偶联药物的工艺开发和分析研究。该研发中心占地13.4万平方米，全部投入运营后，将配备超过170个专业实验室，将进一步提升公司原料药工艺开发能力，更加高效地支持合作伙伴合成分子的开发需求。 总的来说，2024年多肽药物以其独特的治疗策略和创新潜力，展现出巨大治疗潜力和广阔发展前景。展望2025年，随着前沿技术的不断创新，以及CXO机构的坚定支持，期待这一领域为医药健康产业注入更多发展动力，更为患者带来更多福音。 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。转载授权或其他合作需求，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。

CAMBRIDGE, England & BOSTON--( BUSINESS WIRE )--Bicycle Therapeutics plc (NASDAQ: BCYC), a pharmaceutical company pioneering a new and differentiated class of therapeutics based on its proprietary bicyclic peptide (Bicycle ® ) technology, today announced updated topline Phase 1 combination data for zelenectide pevedotin plus pembrolizumab in previously untreated (first-line) cisplatin-ineligible patients with metastatic urothelial cancer (mUC). The company also announced recent accomplishments and outlined strategic priorities and anticipated milestones for 2025. “Bicycle Therapeutics made significant advances across all aspects of our business in 2024. Notably, we drove important clinical progress of our targeted therapeutics in solid tumors, including greatly expanding the number of patients who could potentially benefit from our lead therapy zelenectide pevedotin, advanced our emerging pipeline of novel radiopharmaceuticals and strengthened our financial position and operational capabilities to advance our strategic priorities,” said CEO Kevin Lee, Ph.D. “We are encouraged by our updated topline Phase 1 combination data for zelenectide pevedotin plus pembrolizumab in first-line cisplatin-ineligible patients, which we believe continue to demonstrate a differentiated safety profile and encouraging response rates in patients with poor prognosis and limited treatment options. We believe we are well-positioned to continue our strong momentum of execution over the course of 2025, which will be another year of important data milestones across our pipeline as we work to develop potentially transformative treatments that will help patients live longer and live well.” Updated Topline Zelenectide Pevedotin Plus Pembrolizumab Combination Data in First-Line mUC Highlights Zelenectide pevedotin, a Bicycle ® Toxin Conjugate (BTC ® ), has significant potential to treat Nectin-4 cancers. As of Jan. 3, 2025, updated topline results from the ongoing Phase 1 Duravelo-1 trial evaluating zelenectide pevedotin 5 mg/m 2 weekly plus pembrolizumab 200 mg once every three weeks in 22 first-line cisplatin-ineligible patients with mUC showed: 65% overall response rate (ORR) (13/20) among all efficacy-evaluable patients, and a 50% ORR (10/20) among patients with confirmed responses. Of the 3 unconfirmed responses, 1 patient remained on treatment at the time of the data cut. Median duration of response (mDOR) is not yet mature, with 12 patients still on treatment at the time of the data cut. Safety and tolerability profile continues to be broadly consistent with other Phase 1 zelenectide pevedotin monotherapy and combination cohorts. Adverse events of clinical interest such as peripheral neuropathy, skin reactions and eye disorders were primarily low grade. All cases of Grade 3 treatment-related adverse events (TRAEs) of clinical interest were reversible, and there were no Grade 4 or Grade 5 TRAEs of clinical interest. Notably, no patients withdrew from the study due to zelenectide TRAEs. Altogether, these updated data continue to position zelenectide pevedotin as a potentially promising best-in-class therapy for mUC. Bicycle Therapeutics is currently conducting the Phase 2/3 Duravelo-2 registrational trial evaluating zelenectide pevedotin plus pembrolizumab versus chemotherapy in first-line mUC (Cohort 1), and zelenectide pevedotin monotherapy and in combination with pembrolizumab in late-line mUC (Cohort 2). In each cohort, two doses of zelenectide pevedotin – 5 mg/m 2 weekly and 6 mg/m 2 two weeks on, one week off – are initially being assessed before a final dose is selected. 2024 Key Accomplishments Initiated the global Phase 2/3 Duravelo-2 trial for zelenectide pevedotin in mUC, providing multiple opportunities for potential accelerated approval. Presented updated monotherapy data for zelenectide pevedotin showing a promising 45% ORR in patients with late-line mUC who had not previously been treated with enfortumab vedotin. The data continue to support zelenectide pevedotin’s emerging differentiated profile as a potential treatment for mUC. Presented updated monotherapy data for BT5528, a BTC ® targeting EphA2, and BT7480, a Bicycle Tumor-Targeted Immune Cell Agonist ® (Bicycle TICA ® ), in advanced solid tumors. The data support each molecule’s emerging differentiated safety and tolerability profile and provide important information for continued dose selection exploration. Presented first human imaging data validating the potential of MT1-MMP as a novel target in the treatment of cancer and highlighting the potential of Bicycle ® molecules for targeted radionuclide therapy. The company also selected EphA2 as its second radiopharmaceutical target. Reported monotherapy data for zelenectide pevedotin showing an enhanced response in late-line breast cancer and non-small cell lung cancer (NSCLC) patients with NECTIN4 gene amplification and/or polysomy. Based on these data, the U.S. Food and Drug Administration granted Fast Track designation to zelenectide pevedotin for the treatment of adult patients with previously treated, NECTIN4-amplified, advanced or metastatic triple-negative breast cancer and NSCLC. Raised $555 million to help advance research and development and strategic priorities. As of Sept. 30, 2024, the company had $890.9 million in cash and cash equivalents, with expected financial runway into 2H 2027. 2025 Strategic Priorities and Anticipated Milestones Seek to transform treatment across multiple Nectin-4 associated cancers with zelenectide pevedotin Report additional Phase 1 Duravelo-1 combination data with pembrolizumab in first-line cisplatin-ineligible mUC in 2H 2025. Report longer-term follow-up Phase 1 Duravelo-1 monotherapy data in late-line mUC in 2H 2025. Report Phase 2/3 Duravelo-2 Cohort 1 and Cohort 2 dose selection data in 2H 2025. Initiate Phase 1 trials in NECTIN4 gene-amplified breast cancer (Duravelo-3) in 1H 2025 and NECTIN4 gene-amplified lung cancer (Duravelo-4) and multi-tumor (Duravelo-5) in 2H 2025. Advance emerging Bicycle ® Radionuclide Conjugates (BRC ® ) pipeline and progress strategy for leadership in next-generation radiopharmaceuticals Report additional MT1-MMP human imaging data in mid-2025. Report initial EphA2 human imaging data in 2H 2025. Advance targeted therapeutics pipeline addressing novel targets that have historically been challenging to treat Report Phase 1 combination data for BT5528 plus nivolumab in 4Q 2025. Report Phase 1 combination data for BT7480 plus nivolumab in 4Q 2025. J.P. Morgan Healthcare Conference Presentation and Webcast Bicycle Therapeutics will highlight these updates and strategic priorities in a corporate presentation at the 43rd Annual J.P. Morgan Healthcare Conference on Tuesday, Jan. 14, 2025, at 5:15 p.m. PT, followed by a question-and-answer breakout session at 5:35 p.m. PT. A live webcast of the presentation will be accessible from the Investor section of the company’s website at www.bicycletherapeutics.com . A replay of the webcast will be archived and available following the event. About Bicycle Therapeutics Bicycle Therapeutics is a clinical-stage pharmaceutical company developing a novel class of medicines, referred to as Bicycle ® molecules, for diseases that are underserved by existing therapeutics. Bicycle molecules are fully synthetic short peptides constrained with small molecule scaffolds to form two loops that stabilize their structural geometry. This constraint facilitates target binding with high affinity and selectivity, making Bicycle molecules attractive candidates for drug development. The company is evaluating zelenectide pevedotin (formerly BT8009), a Bicycle ® Toxin Conjugate (BTC ® ) targeting Nectin-4, a well-validated tumor antigen; BT5528, a BTC molecule targeting EphA2, a historically undruggable target; and BT7480, a Bicycle Tumor-Targeted Immune Cell Agonist ® (Bicycle TICA ® ) targeting Nectin-4 and agonizing CD137, in company-sponsored clinical trials. Additionally, the company is developing Bicycle ® Radionuclide Conjugates (BRC ® ) for radiopharmaceutical use and, through various partnerships, is exploring the use of Bicycle ® technology to develop therapies for diseases beyond oncology. Bicycle Therapeutics is headquartered in Cambridge, UK, with many key functions and members of its leadership team located in Cambridge, Mass. For more information, visit www.bicycletherapeutics.com . Forward Looking Statements This press release may contain forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements may be identified by words such as “aims,” “anticipates,” “believes,” “could,” “estimates,” “expects,” “forecasts,” “goal,” “intends,” “may,” “plans,” “possible,” “potential,” “seeks,” “will” and variations of these words or similar expressions that are intended to identify forward-looking statements, although not all forward-looking statements contain these words. Forward-looking statements in this press release include, but are not limited to, statements regarding Bicycle’s ability to continue its momentum, including with respect to the development of zelenectide pevedotin, BT5528 and BT7480 as well as potential radiopharmaceutical product candidates; the company’s plans to utilize a NECTIN4 gene amplification strategy in the clinical development of zelenectide pevedotin; Bicycle’s strategic goals to transform treatment across multiple Nectin-4 associated cancers, to become a leader in next-generation radiopharmaceuticals, and to advance a targeted therapeutics pipeline addressing novel targets that have historically been challenging to treat; the planned initiation of clinical trials of zelenectide pevedotin in breast cancer, lung cancer, and other cancers; achievement of multiple data milestones during the course of 2025, and the timing of announcement of data from clinical trials for zelenectide pevedotin, BT5528, BT7480, and human imaging data for MT1-MMP and EphA2 targeting Bicycle ® Radionuclide Conjugates; expectations with respect to Bicycle’s financial runway; and the use of Bicycle’s technology through various partnerships to develop potential therapies in diseases beyond oncology. Bicycle may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various factors, including: uncertainties inherent in research and development and in the initiation, progress and completion of clinical trials and clinical development of Bicycle’s product candidates; the risk that Bicycle may not realize the intended benefits of its technology, partnerships or NECTIN4 gene amplification strategy; the risk that Bicycle may not achieve any of its clinical development strategies; timing of results from clinical trials; whether the outcomes of preclinical studies and prior clinical trials will be predictive of future clinical trial results; the risk that trials may have unsatisfactory outcomes; potential adverse effects arising from the testing or use of Bicycle’s product candidates; the risk that Bicycle’s projections regarding its expected cash runway are inaccurate or that its conduct of its business requires more cash than anticipated; and other important factors, any of which could cause Bicycle’s actual results to differ from those contained in the forward-looking statements, are described in greater detail in the section entitled “Risk Factors” in Bicycle’s Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on October 31, 2024, as well as in other filings Bicycle may make with the SEC in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and Bicycle expressly disclaims any obligation to update any forward-looking statements contained herein, whether because of any new information, future events, changed circumstances or otherwise, except as otherwise required by law.