Etripamil

iStock, Tymofii Riabets Milestone Pharmaceuticals hit another bump in the road in its quest to get Cardamyst approved for paroxysmal supraventricular tachycardia when the FDA issued a Complete Response Letter on Friday. Milestone Pharmaceuticals revealed on Friday that the FDA has rejected its cardiovascular drug Cardamyst, sending the company’s shares down by more than 60%. The complete response letter, which focused on two key chemistry, manufacturing and controls (CMC) issues, is the latest knock in the Montreal and Charlotte, N.C.–based company’s quest to get Cardamyst approved for paroxysmal supraventricular tachycardia (PSVT), a type of abnormal heart rhythm affecting around 2 million people in the U.S. In December 2023, the FDA hit Milestone with a Refusal to File letter for the nasal spray, saying the company’s application was not sufficient to warrant a full review. Milestone refiled its application in March 2024 with additional information, including restructured data sets that captured the timing of reported adverse events. The FDA accepted the application in May of that year. The rejection may have come as a surprise to Milestone, which had been actively preparing for the drug’s launch. In an interview earlier this week, CEO Joe Oliveto told BioSpace the company was “transitioning to a commercial organization” and had already hired the sales management team for Cardamyst’s rollout but was waiting for formal approval before issuing offers to sales representatives. In its CRL, the FDA requested that Milestone submit additional information on nitrosamine impurities based on a new draft guidance issued after the new drug application was submitted and complete an inspection at the facility that performs release testing for Cardamyst. The facility had changed ownership during the review process, according to Milestone. There is high unmet need for patients with PSVT, which is characterized by episodes of rapid heart rate often exceeding 150 to 200 beats per minute. The condition instills a lot of fear in patients because “you don’t know when [events are] going to come and how bad it’s going to be and how long it’s going to last,” Oliveto said. Cardamyst offers patients “a little bit of peace of mind.” A novel calcium channel blocker, Cardamyst is formulated to deliver IV-like potency in the convenience of a nasal spray, Oliveto explained, so patients can manage PSVT events wherever they occur without needing to go to the hospital. PSVT is somewhat of an orphan indication, as “there’s no one else working in the space,” Oliveto said. There have been advances in an ablation procedure where doctors use small radio waves to destroy a small amount of heart tissue that might trigger PSVT, he noted. However, Cardamyst would be the first new drug for the condition since adenosine , an intravenous drug used in emergency rooms, was approved by the FDA in 1989. In its NDA submission, Milestone touted a “comprehensive data package” from the pivotal Phase III RAPID trial that suggested the drug was “twice as effective and three times as fast as placebo” in normalizing heart rhythm. Cardamyst is also in Phase II development for another cardiovascular disease, atrial fibrillation. In this indication, “there are interventions in development, but they’re really more for anticoagulants,” Oliveto said. There are “none to actually treat the episode in the moment like [Cardamyst] will be.” Responding to the rejection, Oliveto said in a statement: “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.” The company intends to request a Type A meeting with the FDA to discuss the issues raised in the CRL, he added.

CRL focused on CMC; no clinical issues relating to etripamil raised $69.7M in cash, cash equivalents and short-term investments as of December 31, 2024 MONTREAL and CHARLOTTE, N.C., March 28, 2025 (GLOBE NEWSWIRE) -- Milestone® Pharmaceuticals Inc. (Nasdaq: MIST) today announced the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) regarding its New Drug Application (NDA) for CARDAMYST™ (etripamil) nasal spray, a prescription medication in development for the conversion of acute episodes of PSVT to sinus rhythm in adults. The FDA did not raise any concerns regarding etripamil clinical safety or efficacy data and highlighted two key Chemistry, Manufacturing and Controls (CMC) issues to be addressed: Company to submit additional information on nitrosamine impurities based on new draft guidance issued after the NDA submission; and An inspection is required at a facility that performs release testing for etripamil, to ensure it is in compliance with Current Good Manufacturing Practices. The facility changed ownership during the review of the NDA. “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,” said Joe Oliveto, President and Chief Executive Officer of Milestone Pharmaceuticals. “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 Pharmaceuticals had $69.7M in cash, cash equivalents and short-term investments as of December 31, 2024. 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; the outcome of the potential NDA resubmission; CARDAMYST’s potential as a novel treatment option to help patients with PSVT; 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, 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, 2024, under the caption “Risk Factors,” as such discussion 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.