Etripamil

近日，Milestone公司宣布收到FDA发出的完整回复函（CRL），拒绝批准Cardamyst用于治疗阵发性室上性心动过速（PSVT）。这是Cardamyst第二次被拒。在新闻稿中，公司表示了对FDA这一决定的深感失望，并仍相信作为PSVT一种新疗法的潜力，针对CRL中提出的问题，公司打算与FDA进行A类会议。受此影响，Milestone股价下跌了60%以上。这次是CMC问题Cardamyst是Milestone开发的L型钙离子通道阻滞剂etripamil的鼻喷雾剂，旨在为发作性心血管疾病患者提供一种快速起效的疗法，主要开发了PSVT和心房颤动伴快速心室率这两个适应症。2023年10月，Milestone首次向FDA提交了Cardamyst的新药申请（NDA），但因数据格式错误收到了拒绝受理信函（RTF）。2024年3月，Milestone重新提交了上市申请，并补充了额外信息，两个月后，FDA重新受理了上市申请。根据CRL ，这次被拒的原因主要是CMC问题，在CRL中，FDA要求Milestone补充关于硝胺杂质的信息，并对其进行放行测试的设施进行检查。时间很紧迫这次被拒对于Milestone而言是一个相当大的打击。Cardamyst的批准时间对于公司而言极为关键，可以看到，公司2025年的里程碑事件基本都是围绕这款药物的。据CEO Joe Oliveto表示，公司一直为这款药物的推出做准备，包括已经聘请了相应的销售团队。如今公司财务处境比较堪忧，亟待Cardamyst获得批准，解决现金流问题。据公司2024年财报，截至2024年12月31日，公司的现金及其等价物，短期投资仅有6700万美元，公司的预计是维持运营到2026年。除了PSVT之外，Cardamyst还被开发用于治疗心房颤动伴快速心室率，目前处于临床II期开发阶段。另外，箕星药业获得了Cardamyst在大中华区的开发和商业化独家权益（2021年达成合作）。2024年9月，箕星药业宣布在中国开展的Ⅲ期JX02002达到主要终点，与安慰剂相比，Etripamil组患者30分钟内的转复率（转复为窦性心律）显著增加（40.5% vs 15.9%）。今年1月，CDE已经受理了Cardamyst治疗PSVT的新药上市申请（NDA）。参考出处https://www.biospace.com/fda/milestone-stock-crashes-after-surprise-tachycardia-drug-rejectionhttps://investors.milestonepharma.com/news-releases/news-release-details/fda-issues-complete-response-letter-etripamil-psvthttps://investors.milestonepharma.com/static-files/bedc9cf4-4abb-4f7d-8715-0a4e94c84448

Established in Montreal 22 years ago, Milestone Pharmaceuticals still has work to do to gain its first FDA approval as the regulator has sent a complete response letter, citing two manufacturing issues for Cardamyst, a nasal spray to treat sudden episodes of the heart racing condition paroxysmal supraventricular tachycardia (PSVT). Clearing clinical and regulatory hurdles in the development of a fast-acting nasal spray for a heart condition has been a challenge for Milestone Pharmaceutical in its 22 years.Now the wait will be longer for its first FDA approval as the regulator has rejected its application for Cardamyst (etripamil) to quell symptomatic episodes from paroxysmal supraventricular tachycardia (PSVT), which is a type of abnormal heart rhythm.In a complete response letter (CRL), the FDA cited two chemistry, manufacturing and control (CMC) issues. Milestone will have to address a problem with nitrosamine impurities. An FDA inspection also will be required at a facility that performs “release testing” for the drug, the company said in a release. During the FDA’s review of Milestone’s application, the manufacturing facility “changed ownership,” the company said.“We are deeply disappointed by the CRL but remain committed to the potential of Cardamyst as a novel treatment option that can help patients with PSVT. Our team is evaluating the feedback provided and intends to request a Type A meeting to discuss the issues raised in the CRL,” Joe Oliveto, Milestone’s CEO for the last eight years, said in a statement. “We are appreciative of the FDA’s efforts and are confident we can collaborate with the agency with the goal of addressing these issues in a resubmission.”Milestone said that the FDA did not raise any concerns with Cardamyst’s clinical safety or efficacy. The company opened the year with cash and cash equivalents of $70 million.With an approval, Cardamyst would become the first self-administered treatment patients can use to manage their PSVT symptoms. The calcium channel blocker is designed to be a more convenient alternative to an emergency room visit, where patients receive an intravenous dose of a drug that “basically reboots your heart,” Oliveto said in an interview two weeks ago.Results from a phase trial have shown that Cardamyst was twice as effective and worked three times as fast as a placebo in restoring normal heart rhythm. Of the patients on etripamil, 64% achieved termination of their PSVT compared to 31% of those on placebo.Getting that result took some time, however, after a phase 3 trial in 2020 came up short as Cardamyst failed to top placebo. After discussions with the FDA, Milestone got improved results when it allowed patients to use a second dose and adjusted to a shorter timeframe (30 minutes) for measuring the success of the treatment.There are roughly 2 million in the U.S. with PSVT. Beyond that, Milestone is hoping to gain approval for Cardamyst in a larger indication—atrial fibrillation with rapid ventricular response (AFib-RVR), which includes approximately 10–12 million U.S. patients.