Etripamil

Resolution of CRL Manufacturing issues in progress - Type A meeting requested No clinical safety or efficacy concerns raised by FDA MONTREAL and CHARLOTTE, N.C., May 14, 2025 (GLOBE NEWSWIRE) -- Milestone Pharmaceuticals Inc. (Nasdaq: MIST) today reported financial results for the first quarter ended March 31, 2025. The Company also announced the submission of a meeting request to the U.S. Food and Drug Administration (FDA) as the next step in the resolution of CRL issues. “Our immediate priority is to engage with the U.S. FDA in order to address the CMC-related issues raised in the CRL received for CARDAMYST as a treatment for PSVT,” said Joe Oliveto, President and Chief Executive Officer of Milestone Pharmaceuticals. “We are confident we can work with the FDA to fully respond to the CRL and remain committed to the potential of CARDAMYST. If approved, it will be the first and only self-administered therapy for the rapid termination of episodes of PSVT.” First Quarter and Recent Program Updates Etripamil for Patients with PSVT CRL for CARDAMYST™ for PSVT received from FDA. In March 2025, Milestone received a CRL regarding its NDA for CARDAMYST, its lead investigational product for the management of paroxysmal supraventricular tachycardia (PSVT). In the letter, the Agency highlighted two key Chemistry, Manufacturing and Controls (CMC) issues to be addressed: 1) additional information on nitrosamine impurities was requested, based on new draft guidance that was issued during the review of the NDA , and 2) a new inspection of a facility listed in the NDA is required, to ensure it is in compliance with current Good Manufacturing Practices (GMP). The facility, which previously performed a portion of the testing required to release etripamil final product, changed ownership during the review of the NDA. Milestone is prepared to discuss the issues raised in the CRL during the Type A meeting with the FDA. Patent Issued by the U.S. Patent and Trademark Office (USPTO) on a new Method of Use patent for etripamil nasal spray. The new patent (U.S. Patent No. 12,257,224) covers the repeat dose regimen that was used in the RAPID Phase 3 study that evaluated etripamil in PSVT and is included in the proposed package insert for CARDAMYST. The issued patent potentially extends the intellectual property protection for CARDAMYST in the United States until July 2042, which would be an additional six years of protection for the company’s intellectual property portfolio. CARDAMYST highlighted in independent Survey of Managed Care professionals. Results from an independent survey conducted by Managed Healthcare Executive and The American Journal of Managed Care were published on May 6, 2025. CARDAMYST was selected by 40% of respondents (which included payers, providers and academics) when asked which new drug is expected to make the biggest difference in patient health. A copy of the article can be accessed here. Commercial Launch Plan investor event held in February. The event, held on February 25, 2025 in New York City, provided an in-depth overview of the Company’s commercial strategy for CARDAMYST nasal spray, if approved. A replay of the event, as well as a copy of the slides, can be found on the corporate website here. Poster on etripamil presented at American College of Cardiology Annual Meeting (ACC.25). The poster titled, “Consistency and Predictiveness of Conversion Among Multiple Episodes of Paroxysmal Supraventricular Tachycardia (PSVT) treated with Etripamil: Outcomes from the NODE-303 trial,” was presented at the meeting on March 30, 2025 by James Ip, M.D., Professor, Division of Cardiology, Weill Cornell Medicine, New York Presbyterian Hospital. A copy of the poster can be accessed here. Etripamil for patients with atrial fibrillation with rapid ventricular rate (AFib-RVR) Phase 3 protocol in AFib-RVR finalized Milestone has finalized the Phase 3 study protocol following FDA’s review and obtained concurrence with the Agency to proceed. The Company is pausing initiation of enrollment of the study due to prioritizing resources to resolve the CRL received on the NDA for etripamil in PSVT. First Quarter 2025 Financial Results As of March 31, 2025, Milestone had cash, cash equivalents, and short-term investments of $56.0 million, compared to $69.7 million as of December 31, 2024. There was no revenue for the first quarter ended March 31, 2025 or for the first quarter of 2024. Research and development expense for the first quarter of 2025 was $5.0 million, compared with $3.6 million for the prior year period. The increase was primarily due to higher consulting costs in drug manufacturing and regulatory costs. General and administrative expense for the first quarter of 2025 was $5.2 million, compared with $4.0 million for the prior year period. This increase was driven primarily by an increase in outside service costs, partially offset by a decrease in personnel costs. Commercial expense for the first quarter of 2025 was $10.4 million, compared with $2.9 million for the prior year period. This increase is a result of additional personnel costs, professional costs and other operational expenses related to preparation for the launch of CARDAMYST. As a result of the CRL, Milestone has temporarily paused the ramping of operational expenditures related to launch, but will maintain the capability to launch quickly, pending approval of CARDAMYST by the FDA. For the first quarter of 2025, net loss was $20.8 million, compared to $10.4 million for the prior year period. For further details on the Company’s financials, refer to the Quarterly Report on Form 10-Q for the quarter ended March 31, 2025, filed with the SEC. About Etripamil Etripamil is Milestone's lead investigational product. It is a novel calcium channel blocker nasal spray under clinical development for frequent and often highly symptomatic episodes of PSVT and AFib-RVR. It is designed as a self-administered rapid response therapy for patients thereby bypassing the need for immediate medical oversight. If approved, etripamil is intended to provide health care providers with a new treatment option to enable on-demand care and patient self-management. This portable, self-administered treatment may provide patients with active management and a greater sense of control over their condition. CARDAMYST™, the conditionally approved brand name for etripamil nasal spray, is well studied with a robust clinical trial program that includes a completed Phase 3 clinical-stage program for the treatment of PSVT and Phase 2 trial for the treatment of patients with AFib-RVR. About Milestone Pharmaceuticals Milestone Pharmaceuticals Inc. (Nasdaq: MIST) is a biopharmaceutical company developing and commercializing innovative cardiovascular solutions to improve the lives of people living with complex and life-altering heart conditions. The Company’s focus on understanding unmet patient needs and improving the patient experience has led us to develop new treatment approaches that provide patients with an active role in self-managing their care. Milestone's lead investigational product is etripamil, a novel calcium channel blocker nasal spray that is being studied for patients to self-administer without medical supervision to treat symptomatic episodic attacks associated with PSVT and AFib-RVR. Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Words such as “believe,” “continue,” “could,” “demonstrate,” “designed,” “develop,” “estimate,” “expect,” “may,” “pending,” “plan,” “potential,” “progress,” “will”, “intend” and similar expressions (as well as other words or expressions referencing future events, conditions, or circumstances) are intended to identify forward-looking statements. These forward-looking statements are based on Milestone’s expectations and assumptions as of the date of this press release. Each of these forward-looking statements involves risks and uncertainties. Actual results may differ materially from these forward-looking statements. Forward-looking statements contained in this press release include statements regarding: the outcomes of future interactions with the FDA, including the potential Type A meeting; Milestone’s ability to address the issues raised in the CRL on a timely basis, if at all; the outcome of the potential NDA resubmission; CARDAMYST’s potential as a novel treatment option to help patients with PSVT; potential protections afforded by U.S. patents; CARDAMYST’s ability to make the biggest difference in patient health, as compared to other available treatment options; the timing of patient enrollment in the Phase 3 study of etripamil for AFib-RVR; and other statements not related to historical facts. Important factors that could cause actual results to differ materially from those in the forward-looking statements include, but are not limited to, whether our future interactions with the FDA will have satisfactory outcomes; whether and when, if at all, our NDA for etripamil will be approved by the FDA; uncertainties related to the timing of initiation, enrollment, completion, evaluation and results of our clinical trials; risks and uncertainty related to the complexity inherent in cleaning, verifying and analyzing trial data; and whether the clinical trials will validate the safety and efficacy of etripamil for PSVT or other indications, among others, general economic, political, and market conditions, including deteriorating market conditions due to investor concerns regarding inflation, international tariffs, Russian hostilities in Ukraine and ongoing disputes in Israel and Gaza and overall fluctuations in the financial markets in the United States and abroad, risks related to pandemics and public health emergencies, and risks related the sufficiency of Milestone’s capital resources and its ability to raise additional capital in the current economic climate. These and other risks are set forth in Milestone’s filings with the U.S. Securities and Exchange Commission (SEC), including in its annual report on Form 10-K for the year ended December 31, 2025 and its quarterly report on Form 10-Q for the quarter ended March 31, 2025, in each case under the caption “Risk Factors,” as such discussions may be updated from time to time by subsequent filings Milestone may make with the SEC. Except as required by law, Milestone assumes no obligation to update any forward-looking statements contained herein to reflect any change in expectations, even as new information becomes available. Contact: Kim Fox, Vice President, Communications, kfox@milestonepharma.com Investor Relations Kevin Gardner, kgardner@lifesciadvisors.com Source: Milestone Pharmaceuticals Inc.

声明：因水平有限，错误不可避免，或有些信息非最及时，欢迎留言指出。本文仅作医疗健康相关药物介绍，非治疗方案推荐（若涉及）;本文不构成任何投资建议。据不完全统计，2025年1-4月FDA共拒批了6款药物，“双艾疗法”和干眼症药物Reproxalap已不是首次在FDA碰壁。究其原因，其中有两款药物因CMC问题被拒批，两款药物因临床数据问题被拒批，一款药物因第三方问题被拒批。小编总结如下：Atara：Ebvallo2025年1月16日，Atara Biotherapeutics宣布美国FDA拒绝批准其细胞疗法Ebvallo（Tabelecleucel）的生物制品许可申请 (BLA)。该申请作为单一疗法治疗2岁及以上患有Epstein-Barr病毒阳性（EBV+）移植后淋巴细胞增殖性疾病（PTLD) 的成人和儿童患者，这些患者之前至少接受过一种疗法，包括含抗CD20的方案。根据新闻稿，本次未获得FDA批准仅与第三方生产商的检查结果有关。CRL中没有提及BLA中的生产工艺、临床疗效或临床安全性数据相关的缺陷，FDA也没有要求进行任何新的临床研究来支持Ebvallo的获批。Tab-cel是一种同种异体、“现货型” EBV特异性T细胞免疫疗法，可靶向并消除EBV 感染的细胞，除了用于治疗EBV阳性的移植后淋巴增殖性疾病，目前处在针对其他 EBV 相关的血液恶性肿瘤和实体瘤的早期开发阶段 。受此影响，Atara 股价暴跌40%。尽管如此，Atara还是寻求与FDA、Pierre Fabre实验室和第三方制造商合作，以实现Ebvallo在美国的获批。Atara的首席执行官Cokey Nguyen博士表示，对Ebvallo最终获批充满信心，重新申请后可能在六个月内获批。欧盟已于2022年12月授予EBVALLO上市许可。恒瑞医药：“双艾”疗法2025年3月21日，恒瑞医药公告称：收到FDA关于卡瑞利珠单抗联合甲磺酸阿帕替尼用于不可切除或转移性肝细胞癌患者一线治疗的生物制品许可申请的完整回复信。回复信中，FDA表示相关生产场地检查需进一步提交答复，但FDA并未在回复信中说明具体原因。韩国HLB公司方面说法指出，此次FDA拒批的原因仍与卡瑞利珠单抗的生产和质量控制(CMC)问题有关。而“双艾”组合第一次遭拒的原因也涉及CMC问题。2024年5月，恒瑞医药第一次收到该上市申请的完整回复信，FDA在回复信中表示，由于生产场地检查缺陷和部分国家的旅行限制，导致无法全部完成该项目必需的生物学研究监测计划（BIMO）临床检查，该申请无法在规定审查时间内得到批准。同年10月，恒瑞医药表示已重新向FDA提交注射用卡瑞利珠单抗联合甲磺酸阿帕替尼片肝癌一线治疗适应证上市申请并获受理。恒瑞医药表示，相关生产场地在2025年1月再次接受FDA检查，FDA核实去年发出CRL的检查中发现的问题都已经整改完毕，仅提出了3个新的改进要求，公司在规定时间内已对相关问题进行了积极回复，并一直与FDA保持密切沟通。公司将在确认具体原因后尽快采取措施并重新提交申请，以期能够获得批准。Milestone：Etripamil鼻喷雾剂3月28日，FDA 拒绝批准Milestone Pharmaceuticals的Cardamyst (etripamil) 鼻喷雾剂用于治疗阵发性室上性心动过速 (PSVT)，导致该公司股价在消息发布后下跌逾 60%。Milestone 指出，CRL主要集中在CMC问题，不涉及临床研究。在CRL中FDA要求：NDA递交后根据新指南递交亚硝胺杂质补充信息；针对NDA审评期间更换的设备开展现场检查以确保其遵循cGMP。Milestone制药称对CRL表示失望，其团队将评估反馈并计划与FDA召开A类会议以讨论CRL事项。Etripamil Nasal Spray（商品名CARDAMYST™）是Milestone Pharmaceuticals开发的一种新型钙通道阻滞剂鼻喷雾剂，用于治疗阵发性室上性心动过速（PSVT）。Aldeyra：Reproxalap4月3日，美国FDA再次驳回了Aldeyra Therapeutics在研干眼症药物Reproxalap的新药上市申请 (NDA)。Aldeyra计划在未来几周内与FDA 会面，讨论本次CRL的具体内容和后续要求。FDA明确指出，需要更多临床数据来支持该药物的有效性，要求Aldeyra至少再完成一项充分且良好对照的临床试验 ，以确保reproxalap在改善干眼症相关眼部症状方面的疗效。FDA明确的关注有包括治疗臂间基线评分差异在内的方法学相关问题对结果解释等。Reproxalap为一款活性醛化物质（RASP）抑制剂，活性醛化物质含量会在眼部或系统性发炎时上升，造成眼睛发炎、泪水分泌降低、眼睛发红以及改变泪水内脂质组成，许多干眼症患者具有较高的活性醛化物质含量。2023年11月，FDA曾对Reproxalap干眼症NDA发出的CRL，指出Reproxalap未能证明治疗干眼症的有效性，同样要求至少需要额外开展一个控制良好和充分的试验证明有效性。再生元：EYLEA HD2025年4月18日，FDA已向再生元发出了完全回复信函（CRL），拒绝了其将EYLEA HD®（阿柏西普8mg注射液）的给药间隔从最长16周延长至24周的sBLA。FDA不同意再生元关于增加额外延长给药间隔的提议，但并未提供进一步的解释。再生元表示，监管机构并未指出任何安全性或有效性问题。Regeneron正在评估FDA的决定，并将在适当的时候确定未来的行动方案。EYLEA HD被批准用于湿性年龄相关性黄斑变性（wAMD）和糖尿病性黄斑水肿（DME）患者的给药间隔为每8至16周，以及糖尿病视网膜病变（DR）患者的给药间隔为每8至12周，此前需连续3个月每月给药一次。在FDA拒绝延长给药间隔的前一天，FDA已接受了再生元关于批准Eylea HD用于治疗视网膜静脉阻塞（RVO）后黄斑水肿以及将Eylea HD在所有已批准适应症中的给药频率扩大至每四周一次的补充生物制品许可申请（sBLA）并授予优先审评资格。目前的最低给药间隔在加载期后为每八周一次， FDA的目标审批日期是2025年8月19日。Telix：Pixclara4月28日，美国FDA向Telix Pharmaceuticals发出了一封完整回应函，针对其神经胶质瘤成像剂TLX-101-CDx（18F-floretyrosine或18F-FET，Pixclara）的 NDA，指出需要额外的确认性临床证据。Telix表示有几种方法可以解决 CRL 问题，包括重新分析现有（未公开）数据，或开展额外的临床试验。Pixclara是一种PET试剂，用于表征成人和儿童患者治疗相关变化引起的进展性或复发性神经胶质瘤。FET PET已被纳入神经胶质瘤成像的国际临床实践指南中，但目前美国还没有FDA批准的用于成人和儿童脑癌成像的靶向氨基酸PET试剂，鉴于Pixclara有可能解决严重未满足的医疗需求，它已被FDA指定为孤儿药并授予快速通道指定。参考资料：各公司公告