Leap Therapeutics, Inc.

After previous rejections, Astellas reached a milestone to celebrate over the weekend when its new stomach cancer treatment, Vyloy (zolbetuximab), received its first approval from the U.S. Food and Drug Administration (FDA). On Friday, the FDA officially approved Vyloy as a first-line treatment for ClDN18.2-positive adult patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2 (HER2) negative gastric or gastroesophageal junction adenocarcinoma. This approval marks Vyloy as the first anti-ClDN18.2 (known as Claudin-18.2) drug approved in the United States, a transmembrane protein that has become a high-profile target in oncology. It has attracted the attention of several companies, including AstraZeneca, Leap Therapeutics, Legend and Moderna. The FDA approval specifically covers Vyloy in combination with fluoropyrimidine and platinum-containing chemotherapy agents. To ensure patient availability, the FDA has approved both Ventana Medical System and Roche's CLDN18.2-positive companion diagnostic test. In clinical studies, Vyloy has demonstrated significant efficacy. In the SPOTLIGHT study, which included 565 patients, the median progression-free survival (PFS) of patients in the Vyloy combined chemotherapy group was 10.6 months, which was significantly better than 8.7 months in the placebo combined chemotherapy group. At the same time, the median overall survival (OS) of patients in the Vyloy group was 18.2 months, which was also better than 15.5 months in the control group. Another GLOW study of 507 patients showed that Vyloy helped patients achieve a median PFS of 8.2 months, compared to 6.8 months in the placebo/chemotherapy group, and a median OS of 14.4 months and 12.2 months, respectively. It's worth noting that Vyloy's path to approval was not smooth. Despite being granted a priority review label by the FDA in July 2023, after receiving a full response letter in January, the FDA rejected the application for the drug due to unresolved deficiencies identified during pre-licensing inspections at third-party manufacturing facilities. However, Astellas responded quickly, announcing in late May that the FDA had accepted its resubmitted application. The approval of Vyloy is significant for Astellas. The company acquired its interest in Vyloy in 2016 when it acquired Ganymed Pharmaceuticals for $1.4 billion. Despite setbacks in the U.S. regulatory process, Vyloy has received several approvals overseas, including a successful listing in Japan. In addition, Vyloy has received regulatory approvals in Europe and the United Kingdom. While Astellas currently has a leading position in the anti-ClDN18.2 field, several other companies are also actively advancing clinical trials of related drug candidates. For example, Astrazeneca has invested tens of millions of dollars to acquire global rights to an antibody-drug conjugate that targets CLDN18.2. At the same time, while Merck has adjusted its business in this area, other companies such as Kellen are still showing positive research results and potential.

此次医博会由同写意策划，以“发展新质生产力，共享健康新未来”为主题，用全新的视角瞄准国内外医药及大健康产业发展前沿。诚邀海内外医药及大健康各界嘉宾齐聚中国医药城，共赴时代之约。展位/报告火热征集中！ 在今年早些时候遭到拒绝之后，安斯泰来终于可以庆祝其新型胃癌药物Vyloy（zolbetuximab）获批进入美国市场了。 10月18日，FDA批准Vyloy作为局部晚期不可切除或转移性、HER2阴性的胃癌或胃食管结合部腺癌（其肿瘤为CLDN18.2阳性）成人患者的一线治疗药物。 这也意味着，Vyloy成为美国首个获批的CLDN18.2抗体药物。该靶点又被称为Claudin 18.2，已成为抗肿瘤领域的热门目标，引起了阿斯利康、Leap Therapeutics、传奇生物、Moderna等公司的兴趣。 CLDN18.2在多种原发恶性肿瘤中异常激活和过度表达，尤其好发于消化系统恶性肿瘤，包括胃癌（70%），胰腺癌（50％），食管癌（30％）等，因此，靶向CLDN18.2的药物研发有望为更多的患者提供有效的治疗手段。但CLDN18.2的靶向药要发挥作用，需要与肿瘤细胞结合，如果患者CLDN18.2靶点表现不突出，药物的效果就会大打折扣。 Vyloy需与含氟嘧啶和铂类化疗联合使用。患者必须通过检测确认其肿瘤的CLDN18.2阳性，为此，FDA同时批准了Ventana Medical Systems和罗氏的一种新伴随诊断产品。 FDA的批准是基于两项III期试验（分别称为SPOTLIGHT和GLOW）的积极结果。 在565名患者的SPOTLIGHT研究中，接受Vyloy联合化疗的患者中位PFS为10.6个月，而接受安慰剂加化疗的患者中位PFS为8.7个月；Vyloy组的患者中位OS为18.2个月，而对照组患者中位OS为15.5个月。 而招募了507名患者的GLOW研究中，Vyloy帮助患者实现了8.2个月的中位PFS，而对照组为6.8个月。中位OS分别为14.4个月和12.2个月。 Vyloy的此次批准提前了几周，FDA审批日期定在11月9日。2023年7月，FDA授予Vyloy优先审查标签，但安斯泰来在今年1月收到CRL，其时间表被打乱。 安斯泰来当时解释称，FDA拒绝的理由是在对第三方生产设施进行许可前检查时发现了未解决的缺陷。FDA并未对Vyloy的临床数据（包括有效性或安全性）提出任何担忧，也未要求进行额外的临床研究。 5月底，安斯泰来表示，FDA已接受该药物的重新提交。 安斯泰来于2016年以14亿美元收购Ganymed Pharmaceuticals，由此获得Vyloy。尽管在美国监管方面遭遇挫折，但Vyloy已在国外拿到多项批准，包括安斯泰来所在的日本。今年3月，Vyloy已通过日本厚生劳动省的审批。 当时，安斯泰来宣称，Vyloy是全球首个获得批准的CLDN18.2靶向疗法。随后，该药还获得了欧洲和英国的监管批准。 虽然安斯泰来独占CLDN18.2药物的商业市场，但其他几家公司也正在研发临床试验候选药物。 去年，阿斯利康向KYM Biosciences预付了6300万美元，获得针对CLDN18.2的ADC全球权利，这是继2022年与Harbour BioMed签订2500万美元的协议进入该领域后的又一次加码。 与此同时，默沙东最近退回了科伦博泰针对CLDN18.2的ADC SKB315全球权利，减少了在该领域的投资。不过，科伦博泰在8月表示，该药物在早期测试中对CLDN18.2表达的胃癌显示出了积极疗效和可接受的安全性。 参考资料： 1.Astellas nabs class-first FDA approval for CLDN18.2 gastric cancer med Vyloy 2.全球首个！CLDN18.2抗体药物在日本获批 同写意媒体矩阵，欢迎关注↓↓↓

The FDA on Friday approved Astellas’ treatment for a type of gastric cancer, marketed as Vyloy (zolbetuximab). The approval came three weeks ahead of its scheduled PDUFA date of Nov. 9. Vyloy targets a protein called Claudin18.2 that is expressed on the surface of some gastric cancer cells. The drug is now approved in combination with chemotherapy for the first-line treatment of locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction adenocarcinoma. According to the company, Claudin18.2 is expressed by 38% of patients with advanced gastric cancer. The treatment previously won approval in Japan in March based on data from two Phase 3 clinical trials, with Astellas saying at the time ​​that it’s the first of its class to receive approval worldwide. The drug was also authorized in Europe in September and approved by the UK in August. Data from the Phase 3 SPOTLIGHT and GLOW trials showed statistically significant improvements in progression-free survival and overall survival compared to standard of care chemotherapy. But Vyloy had faced hurdles in the US, including a CRL in January a week before its original decision date, after the FDA found “unresolved deficiencies” at a third-party manufacturer. The FDA gave the drug priority review back in July 2023. Astellas did not immediately respond to a request for comment on the approval, pricing and launch details. Other companies are also in the Claudin18.2 space, though further behind: Leap Therapeutics bought out Flame Biosciences last year with a focus on an antibody called FL-301 and a preclinical anti-Claudin18.2/CD137 bispecific. Also in 2023 , AstraZeneca licensed the antibody-drug conjugate CMG901, which is in a Phase 1 trial in China for Claudin18.2-positive solid tumors, including gastric cancer.