Cardamyst (etripamil) / Milestone - LARVOL DELTA

Milestone Pharmaceuticals…announced that the U.S. Food and Drug Administration (FDA) approved its first commercial product, CARDAMYST (etripamil) nasal spray, a prescription medication for the conversion of acute symptomatic episodes of paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm in adults (GlobeNewswire) - "CARDAMYST is expected to be available in retail pharmacies in the first quarter of 2026....The FDA approval of CARDAMYST is supported by a robust clinical trial program based on safety data from more than 1,800 participants and more than 2,000 episodes of PSVT. This includes the successful Phase 3 RAPID trial, a global, randomized, double-blind comparison of CARDAMYST vs. placebo..."

FDA approval • Launch US • Ventricular Tachycardia

Phase 3 protocol of etripamil in AFib-RVR (ReVeRA-301) finalized. (The Manila Times) - "Milestone is poised to enter a pivotal Phase 3 program in AFib-RVR, on the strength of the successful ReVeRA Phase 2 trial. The Company intends to follow the supplemental NDA regulatory approval pathway, discussed with the FDA, and expects to leverage data from the PSVT NDA along with the results from the planned single AFib-RVR Phase 3 study for what would potentially be a second indication for etripamil. The ReVeRA-301 study design for etripamil in AFib-RVR was presented at HRX 2025."

Clinical protocol • P3 data • Atrial Fibrillation

A New Drug Application (NDA) for CARDAMYST is currently being reviewed by the U.S. Food and Drug Administration (FDA), with a PDFUA action date of December 13, 2025. (The Manila Times)

PDUFA • Ventricular Tachycardia

Milestone Pharmaceuticals to Present New Analysis from Investigational Etripamil Nasal Spray Clinical Trials for PSVT at the American Heart Association Scientific Sessions 2025 (GlobeNewswire) - "Analysis of data from 622 unique enrolled patients across multiple trials showed consistent efficacy of etripamil across multiple study phases, types of trial design, and geographic regions, with etripamil treatment showing similarly greater conversion rates for symptomatic PSVT episodes compared with placebo arms; Across studies, the median time to conversion in patients self-administering etripamil was 18.5 minutes (95% CI: 15.7 to 21.0 minutes); The Kaplan-Meier estimate, from the pooled data for conversion of PSVT to sinus rhythm (SR) by 30 minutes of drug administration, was 59.6% (range: 53.6% to 64.3%). By 60 minutes post-administration, etripamil conversion rates rose to 63.2% to 75.1% across studies....The low rate of test-dose failures (1.4%) among over 1,100 patients administered etripamil in SR further indicates the consistent tolerability of etripamil."

Retrospective data • Ventricular Tachycardia

Combined Efficacy, Safety, and Test Dose Tolerability of Etripamil for Acute Paroxysmal Supraventricular Tachycardia (PSVT) Across Multiple Clinical Trials (AHA 2025) - "Across multiple clinical studies of acute PSVT management, self-administered etripamil consistently demonstrated robust efficacy and a favorable safety profile for acute PSVT management. Safety data and the low rate of test dose failures indicate favorable tolerability, suggesting no need for a pretreatment test dose. These findings support the potential of etripamil as a patient-administered therapy for PSVT, which may reduce reliance on emergency care."

Clinical • Cardiovascular • Ventricular Tachycardia

Methodological Considerations in the NODE-303 Trial of Etripamil for PSVT. (PubMed, J Cardiovasc Electrophysiol) - No abstract available

Journal

Etripamil Nasal Spray to Keep the Doctor Away. (PubMed, J Cardiovasc Electrophysiol) - No abstract available

Journal

Etripamil Nasal Spray for Recurrent Paroxysmal Supraventricular Tachycardia Conversion: Results From the NODE-303 Open-Label Study. (PubMed, J Cardiovasc Electrophysiol) - P3 | "Etripamil nasal spray self-administered in a real-world setting was well tolerated, effective, and had a consistent safety profile as a single- or repeat-dose regimen across multiple PSVT episodes."

Journal • Cardiovascular • Ventricular Tachycardia

Etripamil for patients with atrial fibrillation with rapid ventricular rate (AFib-RVR) (Milestone Pharma Press Release) - "Phase 3 protocol of etripamil 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 has paused initiation of enrollment in the study to prioritize resources for the preparation of the expected launch of etripamil in PSVT."

Clinical protocol • Trial status • Atrial Fibrillation

Etripamil Nasal Spray in Patients With Paroxysmal Supraventricular Tachycardia (clinicaltrials.gov) - P3 | N=130 | Enrolling by invitation | Sponsor: Milestone Pharmaceuticals Inc. | Trial completion date: Jun 2025 ➔ Mar 2026 | Trial primary completion date: Jun 2025 ➔ Mar 2026

Trial completion date • Trial primary completion date • Cardiovascular • Ventricular Tachycardia

Milestone Pharmaceuticals Announces FDA Acceptance of the Company’s Response to the CRL for CARDAMYST (etripamil) Nasal Spray (The Manila Times) - "Milestone Pharmaceuticals Inc...announced that the U.S. Food and Drug Administration (FDA) has accepted for review Milestone’s response to issues raised in the Complete Response Letter (CRL) for CARDAMYST (etripamil) nasal spray, an investigational, novel therapy for the treatment of patients with paroxysmal supraventricular tachycardia (PSVT). The FDA has assigned a new Prescription Drug User Fee Act (PDUFA) target action date of December 13, 2025."

FDA event • PDUFA • Cardiovascular • Ventricular Tachycardia

Milestone Pharmaceuticals Announces Pricing of $52.5 Million Public Offering of Common Shares, Pre-Funded Warrants, Series A Common Warrants and Series B Common Warrants (GlobeNewswire) - "Milestone...announced the pricing of its previously announced underwritten public offering (the 'Offering') of (i) 31,500,000 of its common shares (the 'Shares'), accompanying Series A common warrants...to purchase an aggregate of 31,500,000 common shares and accompanying Series B common warrants...to purchase an aggregate of 31,500,000 common shares, at a combined public offering price of $1.50 per share....The proceeds to Milestone from the Offering, before deducting underwriting commissions and offering expenses payable by Milestone, are expected to be approximately $52.5 million. The Offering is expected to close on or about July 14, 2025, subject to satisfaction of customary closing conditions....Milestone intends to use the net proceeds from the Offering together with existing cash and cash equivalents, to fund the clinical development and commercial launch of etripamil in its lead indication of paroxysmal supraventricular tachycardia (PSVT)..."

Financing • Ventricular Tachycardia

Landiolol (Rapiblyk), A Newly Approved, Ultra-Short Acting Intravenous β1-Adrenoreceptor Blocker for the Treatment of Supraventricular Arrhythmias. (PubMed, Cardiol Rev) - "Other intravenous β-blockers approved for the same indication include esmolol (Brevibloc) and generics, and propranolol generics...Other rate-reducing treatments include intravenous nondihydropyridine calcium channel blockers such as diltiazem and verapamil. Etripamil is also being evaluated as a parenteral intranasal formulation for arrhythmia management. The clinical effectiveness, pharmacokinetic properties, and side effect profile of landiolol are reviewed in this article. At this juncture, the effectiveness of the drug in reducing the heart rate in patients with supraventricular arrhythmias, including atrial fibrillation and flutter, has been demonstrated to be as effective as generic β-blockers and calcium channel blockers."

Journal • Atrial Fibrillation • Cardiovascular • Ventricular Tachycardia

Milestone Pharmaceuticals Submits Response to the FDA's CRL for CARDAMYST (etripamil) Nasal Spray for PSVT Following Type A Meeting (The Manila Times) - "Milestone Pharmaceuticals Inc...today announced submission of its response to the U.S. Food and Drug Administration (FDA)'s 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 paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm in adults. The response follows a Type A meeting recently held with the FDA. The acceptance of the response and corresponding Prescription Drug User Fee Act (PDUFA) date will be determined within the next thirty days per FDA policy. The review time is expected to be within 2 or 6 months from the resubmission, depending on the classification."

FDA event • Ventricular Tachycardia

Efficacy and Safety of Intranasal Etripamil for Paroxysmal Supraventricular Tachycardia: Meta-Analysis of Randomized Controlled Trials. (PubMed, J Clin Med) - " Etripamil appears to be a promising treatment for cardiac arrhythmias. Larger long-term RCTs are needed to confirm its safety and efficacy in clinical practice."

Journal • Retrospective data • Review • Atrial Fibrillation • Cardiovascular • Ventricular Tachycardia

ReVeRA-301: Etripamil in Atrial Fibrillation Phase 3 (clinicaltrials.gov) - P3 | N=750 | Not yet recruiting | Sponsor: Milestone Pharmaceuticals Inc. | Trial completion date: Mar 2028 ➔ Jan 2029 | Initiation date: Mar 2025 ➔ Jan 2026 | Trial primary completion date: Mar 2027 ➔ Jan 2028

Trial completion date • Trial initiation date • Trial primary completion date • Atrial Fibrillation • Cardiovascular

Milestone CRL affirms integrity of clinical data, says H.C. Wainwright (MSN News) - "H.C. Wainwright keeps a Buy rating on Milestone Pharmaceuticals (MIST) after the company announced receipt of a complete response letter from the FDA regarding its new drug application for its etripamil nasal spray for the treatment of paroxysmal supraventricular tachycardia...H.C. Wainwright expects the launch to be delayed until the first half of 2026. Its $25 price target is under review."

Commercial • Launch • Ventricular Tachycardia

Safety of intranasally administered etripamil: RAPID trial update. (PubMed, Lancet) - No abstract available

Journal

Self-Administered Etripamil and Emergency Department Visits in Supraventricular Tachycardia: A Secondary Analysis of a Randomized Clinical Trial. (PubMed, JAMA Cardiol) - No abstract available

Clinical • Journal • Cardiovascular • Ventricular Tachycardia

THE SAFETY AND EFFICACY OF ETRIPAMIL IN PAROXYSMAL SUPRAVENTRICULAR TACHYCARDIA (PSVT) - Alexander Sacher (ACC 2025) - "This meta-analysis concludes that etripamil can be a safe and effective non-parenteral option for treating cardiac arrhythmias. ."

Clinical • Atrial Fibrillation • Cardiovascular • Ventricular Tachycardia

CONSISTENCY AND PREDICTIVENESS OF CONVERSION AMONG MULTIPLE EPISODES OF PAROXYSMAL SUPRAVENTRICULAR TACHYCARDIA (PSVT) TREATED WITH ETRIPAMIL: OUTCOMES FROM NODE-303 - James E. Ip (ACC 2025) - "Conversion of PSVT to SR with etripamil occurred in the majority of patients over multiple episodes, and conversion in earlier episodes was consistently predictive of conversion in subsequent episodes. These data support potential efficacy of etripamil to treat successive episodes of PSVT."

Cardiovascular • Ventricular Tachycardia

Cardiovascular and Pharmacokinetic Profiles of Intravenous Etripamil in Conscious Telemetered Cynomolgus Monkeys. (PubMed, Int J Toxicol) - "Results were consistent with data from subsequent intranasal preclinical and clinical studies. Intravenous etripamil demonstrated the desired targeted pharmacokinetic and pharmacodynamic profiles in conscious cynomolgus monkeys."

Journal • PK/PD data • Cardiovascular • Ventricular Tachycardia

FDA Issues Complete Response Letter for Etripamil for PSVT (GlobeNewswire) - "Milestone Pharmaceuticals Inc...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."

CRL • Atrial Fibrillation • Cardiovascular • Ventricular Tachycardia

Milestone Pharmaceuticals to Present Clinical Data on Etripamil at the American College of Cardiology (GlobeNewswire) - "Milestone Pharmaceuticals Inc...today announced that it will present a moderated poster presentation at the American College of Cardiology annual meeting (ACC25), to be held March 29th to 31st, 2025 in Chicago, Illinois....This presentation highlights the potential ability of etripamil to successfully convert multiple episodes of Paroxysmal Supraventricular Tachycardia (PSVT) to restore normal sinus rhythm."

P3 data • Ventricular Tachycardia

Milestone Pharmaceuticals Reports Fourth Quarter and Full Year 2024 Financial Results and Provides Regulatory and Corporate Update (GlobeNewswire) - "Poster on Etripamil to be presented at American College of Cardiology Annual Meeting (ACC.25) The poster...is scheduled to be presented on March 30, 2025 by James Ip, M.D., Division of Cardiology, Weill Cornell Medicine, New York Presbyterian Hospital...Milestone is on track to initiate a Phase 3 trial evaluating etripamil in AFib-RVR in 2025."

New P3 trial • P3 data • Atrial Fibrillation • Cardiovascular • Ventricular Tachycardia