Etripamil (CARDAMYST™): A Comprehensive Monograph on a Novel, Patient-Administered Therapy for Paroxysmal Supraventricular Tachycardia

I. Executive Summary

Etripamil is an investigational, small molecule drug being developed by Milestone Pharmaceuticals as a novel, short-acting, non-dihydropyridine L-type calcium channel blocker.[1] It is formulated as an intranasal spray intended for patient self-administration, representing a potential paradigm shift in the management of acute cardiovascular conditions.[4]

The core therapeutic proposition of Etripamil is to provide a rapid, on-demand treatment for episodes of paroxysmal supraventricular tachycardia (PSVT), particularly atrioventricular (AV)-nodal dependent forms such as atrioventricular nodal re-entrant tachycardia (AVNRT) and atrioventricular re-entrant tachycardia (AVRT).[2] Its development is aimed at empowering patients to manage their condition in a medically unsupervised, at-home setting, thereby reducing the burden of symptoms and the need for urgent medical care.[4]

The mechanism of action involves the selective inhibition of slow inward calcium channels in the AV node. This action slows AV nodal conduction and prolongs the refractory period, which effectively interrupts the re-entrant electrical circuit responsible for the tachycardia and restores normal sinus rhythm.[2]

The clinical development program has yielded robust evidence supporting its efficacy. The pivotal Phase 3 RAPID trial demonstrated a statistically significant and clinically meaningful benefit, with 64.3% of patients receiving Etripamil converting to sinus rhythm within 30 minutes, compared to 31.2% in the placebo group.[7] Subsequent large-scale safety studies have reported a median time to conversion of approximately 17 minutes.[9]

Etripamil has been generally well-tolerated across its clinical program. The safety profile is characterized predominantly by mild-to-moderate, transient, and localized adverse events related to the intranasal administration, such as nasal discomfort and congestion.[9] Critically, large-scale studies of at-home, unsupervised use have not identified any serious drug-related cardiovascular adverse events, such as severe hypotension or high-degree heart block.[9]

The drug has navigated a complex regulatory pathway with the U.S. Food and Drug Administration (FDA). Following an initial New Drug Application (NDA) submission, Milestone Pharmaceuticals received a Complete Response Letter (CRL) that cited Chemistry, Manufacturing, and Controls (CMC) issues, but raised no concerns regarding the clinical safety or efficacy data.[7] The company has since submitted its response, and the FDA has set a new Prescription Drug User Fee Act (PDUFA) target action date of December 13, 2025.[15]

If approved, Etripamil, under the proposed brand name CARDAMYST™, would be a first-in-class, patient-administered therapy. It is positioned to fill a significant therapeutic gap between often-ineffective vagal maneuvers and the necessity of emergency medical intervention for the acute termination of PSVT episodes.[6]

II. Drug Profile: Identification and Physicochemical Characteristics

Nomenclature and Identifiers

Etripamil is a novel small molecule entity with a well-defined set of chemical identifiers used across global databases and regulatory filings.

• Generic Name: Etripamil [19]
• Proposed Brand Name: CARDAMYST™ (This name has been conditionally approved by the FDA) [15]
• Synonyms and Development Codes: The compound has been referred to by several codes during its development, most notably MSP-2017 and (-)-MSP-2017. Other identifiers include MSP 2017A/B, HY-17611, and DA-53053.[20]
• Standard Identifiers:
• DrugBank ID: DB12605 [19]
• CAS Number: 1593673-23-4 (for the free base form). A related hydrochloride salt is identified by CAS number 2560549-35-9.[19]
• UNII (Unique Ingredient Identifier): S82A18Y42P [19]
• InChI Key: VAZNEHLGJGSQEL-MHZLTWQESA-N [19]
• Other Database IDs: The molecule is cataloged in various chemical and biomedical databases, including ChEMBL (CHEMBL3707312), KEGG (D10932), and the NCI Thesaurus (C169972).[20]

Chemical Structure and Classification

Etripamil is a synthetic organic compound classified as a phenylalkylamine derivative, a class known for its cardiovascular activity.

• Modality: Small Molecule [19]
• Chemical Formula: $C_{27}H_{36}N_{2}O_{4}$ [19]
• IUPAC Name: The formal IUPAC nomenclature for the molecule is methyl 3--methylamino]ethyl]benzoate.[20]
• Structural Representations:
• SMILES: CC(C)[C@](CCCN(C)CCC1=CC(=CC=C1)C(=O)OC)(C#N)C2=CC(=C(C=C2)OC)OC [20]
• InChI: InChI=1S/C27H36N2O4/c1-20(2)27(19-28,23-11-12-24(31-4)25(18-23)32-5)14-8-15-29(3)16-13-21-9-7-10-22(17-21)26(30)33-6/h7,9-12,17-18,20H,8,13-16H2,1-6H3/t27-/m0/s1 [19]
• Chemical Ontology:
• Class: Etripamil is a phenylalkylamine derivative, belonging more specifically to the subclass of phenylbutylamines.[19] This structural classification is significant as it places it in the same chemical family as verapamil, another well-known calcium channel blocker.
• Pharmacological Relationship: It is frequently described as a structural analogue of verapamil, indicating that it was likely designed to retain verapamil's core mechanism of action while modifying its pharmacokinetic properties for rapid onset and short duration.[1]
• ATC Code: Its Anatomical Therapeutic Chemical (ATC) classification code is C08DA03. This code systematically places it within the cardiovascular system (C), as a calcium channel blocker (C08), specifically a selective calcium channel blocker with direct cardiac effects (C08D), and finally within the phenylalkylamine derivatives subclass (C08DA).[19]

Physicochemical Properties

The physical and chemical properties of Etripamil are fundamental to understanding its formulation, pharmacokinetic behavior, and mechanism of action.

• Molecular Weight: The average molecular weight is 452.6 g/mol, with a monoisotopic mass of 452.2675 Da.[19]
• Solubility: The compound exhibits very poor aqueous solubility, measured at 0.00305 mg/mL. In contrast, it is highly soluble in organic solvents such as ethanol, at 120.0 mg/mL.[19] This solubility profile is a critical determinant of its formulation. A drug with such low water solubility would be exceptionally difficult to formulate as a standard oral tablet or aqueous injection, making a specialized delivery system necessary. The development of an intranasal spray is a direct and logical consequence of this intrinsic chemical property.
• Lipophilicity: The partition coefficient (logP) is reported as 4.56 (ALOGPS) and 5.36 (Chemaxon), indicating that the molecule is highly lipophilic.[19] This high lipophilicity facilitates rapid passage across biological membranes, such as the nasal mucosa, which is essential for its rapid absorption and onset of action.
• Ionization: With a strongest basic pKa of 9.52, Etripamil is protonated at physiological pH, carrying a positive charge (+1).[19]
• Drug-Likeness Rules: According to computational models, Etripamil fails several common "drug-likeness" filters, including Lipinski's Rule of Five, the Ghose Filter, and Veber's Rule.[19] These rules are empirical heuristics developed primarily to predict the oral bioavailability of drug candidates. Their failure in this case is not indicative of a flawed molecule but rather highlights the limitations of these rules when applied to drugs designed for non-oral routes of administration. Since Etripamil is delivered intranasally, bypassing the gastrointestinal tract, these oral-centric predictive rules are largely irrelevant to its clinical performance.

Table 1: Key Chemical and Physical Properties of Etripamil

Property	Value	Source(s)
IUPAC Name	methyl 3--methylamino]ethyl]benzoate	20
CAS Number	1593673-23-4 (free base)	19
Molecular Formula	$C_{27}H_{36}N_{2}O_{4}$	19
Average Molecular Weight	452.6 g/mol	20
Monoisotopic Mass	452.267507647 Da	19
Water Solubility	0.00305 mg/mL	19
logP (Lipophilicity)	4.56 (ALOGPS), 5.36 (Chemaxon)	19
pKa (Strongest Basic)	9.52	19
Physiological Charge	+1	19
Polar Surface Area	71.79 Ų	19
Rotatable Bond Count	13	19

III. Pharmacology and Mechanism of Action

Primary Mechanism

Etripamil exerts its antiarrhythmic effect through a well-defined mechanism consistent with its classification as a non-dihydropyridine calcium channel blocker.[1] The primary molecular target is the L-type calcium channel, which is crucial for the electrical conduction system of the heart.[4]

During a typical PSVT episode, an abnormal re-entrant electrical circuit forms within or involving the AV node.[2] This circuit causes electrical signals to propagate aberrantly, leading to a rapid heart rate. Etripamil acts by selectively inhibiting the slow inward calcium current ($I_{Ca,L}$) through L-type calcium channels, particularly within the cardiac tissue of the AV node.[2] By blocking this calcium influx, Etripamil directly interrupts the propagation of electrical signals through the abnormal circuit, thereby terminating the tachycardia and allowing the heart to restore a normal sinus rhythm.[4] Its therapeutic action is specifically directed at the most common subtypes of PSVT that involve the AV node: AVNRT and AVRT, which together account for up to 90% of all PSVT cases.[2]

Pharmacodynamics

The pharmacodynamic effects of Etripamil are a direct consequence of its mechanism of action and are measurable through clinical and electrophysiological assessments.

The principal pharmacodynamic effect is the slowing of conduction velocity through the AV node and the prolongation of the AV nodal effective refractory period.[2] This effect is readily observable on a standard electrocardiogram (ECG) as a dose-dependent prolongation of the PR interval, which serves as a reliable biomarker for the drug's activity.[2] Advanced high-density electroanatomic mapping studies have provided further mechanistic detail, demonstrating that Etripamil causes a loss of voltage in the slow pathway bridge of the AV node, which correlates with the observed electrophysiological changes.[2]

A critical aspect of Etripamil's pharmacodynamic profile is its specificity. Clinical studies have consistently shown that while it produces a marked effect on the PR interval, it has no significant effect on the QRS duration or the QT interval.[2] This indicates a targeted action on the AV node without affecting ventricular depolarization or repolarization, a crucial safety feature that minimizes the risk of proarrhythmic effects, such as Torsades de Pointes, which can be associated with other classes of antiarrhythmic drugs.

The drug's effects on systemic hemodynamics, such as blood pressure, are dose-dependent. While higher doses tested in early clinical trials (e.g., 105 mg and 140 mg) were associated with transient reductions in blood pressure, the selected therapeutic dose of 70 mg has demonstrated a more favorable safety profile with minimal hemodynamic impact in the outpatient setting.[21]

Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of Etripamil has been deliberately optimized to support its intended use as a rapid-acting, on-demand therapy. The entire ADME profile is engineered to provide a fast onset of action followed by a rapid clearance, minimizing the duration of systemic effects and enhancing its safety for unsupervised use.

• Absorption: Etripamil is administered intranasally, a route chosen to bypass the gastrointestinal tract and first-pass hepatic metabolism.[1] It is rapidly absorbed through the highly vascular nasal mucosa, leading to a very short time to maximum plasma concentration (Tmax). Multiple studies have consistently reported a Tmax of approximately 5 to 8.5 minutes following a 70 mg dose.[1] This rapid absorption is the cornerstone of its clinical utility, allowing the drug to reach therapeutic concentrations and exert its effect within minutes of administration.
• Distribution: Pharmacokinetic modeling indicates that Etripamil follows a two-compartment model.[26] After reaching peak concentration, systemic drug levels decline very quickly. The plasma concentration falls by approximately 80% from its peak within 50 minutes, contributing to a short and predictable duration of action.[25]
• Metabolism: Etripamil undergoes rapid and extensive metabolism, primarily mediated by ubiquitous serum esterases.[2] This metabolic pathway is a key design feature. Unlike metabolism via the hepatic cytochrome P450 (CYP) enzyme system, clearance by serum esterases is generally high-capacity and less prone to genetic polymorphisms or the drug-drug interactions that frequently complicate therapies involving CYP substrates, inhibitors, or inducers. This choice of metabolic pathway inherently enhances the drug's safety and predictability, which are paramount for a self-administered therapy. The major metabolite, identified as MSP-2030, is an inactive carboxylic acid, ensuring that the therapeutic effect is terminated as the parent drug is cleared and does not persist due to active metabolites.[2]
• Excretion: The drug demonstrates a biphasic elimination profile. Following the initial rapid decline in concentration, the elimination curve flattens, resulting in a longer terminal half-life ($t_{1/2}$) of approximately 2.5 to 3 hours for the 70 mg dose.[9] While the terminal half-life is a few hours, the pharmacologically relevant concentrations that produce the desired effect on the AV node are present for a much shorter duration, with PR interval prolongation generally sustained for about 45 minutes.[24]

IV. Clinical Development Program in Paroxysmal Supraventricular Tachycardia (PSVT)

Overview of Clinical Program

Milestone Pharmaceuticals has executed a comprehensive and strategically designed clinical development program for Etripamil in PSVT. This program, planned in consultation with U.S. and European regulatory authorities, has systematically progressed from foundational studies in controlled settings to large-scale, pivotal trials validating the drug's use in its intended real-world, at-home environment.[3]

Phase 1 and 2 Studies (Foundation)

The initial phases of clinical development were focused on establishing the fundamental safety, pharmacokinetic (PK), and pharmacodynamic (PD) properties of Etripamil.

• Phase 1 Studies (e.g., MSP-2017-1096, NODE-102): These first-in-human studies were conducted in healthy volunteers. They successfully characterized the drug's PK/PD profile, confirming its rapid intranasal absorption, short Tmax, and dose-dependent effect on PR interval prolongation.[2] The studies established general tolerability and, importantly, the NODE-102 study demonstrated no significant ethnic differences in PK/PD between Japanese and non-Japanese subjects, supporting broader global development.[2]
• Phase 2 Study (NODE-1, NCT02296190): This was a critical dose-ranging study conducted in a controlled electrophysiology laboratory setting where PSVT was induced in patients.[21] The study evaluated doses ranging from 35 mg to 140 mg and demonstrated the clear superiority of Etripamil over placebo in terminating these induced arrhythmias. Conversion rates for the three highest active dose groups (70 mg, 105 mg, and 140 mg) were statistically significant, ranging from 75% to 95%, compared to just 35% for placebo.[21] This study was instrumental in dose selection for the Phase 3 program. The 70 mg dose was identified as providing the optimal balance of robust efficacy (87% conversion rate) and a favorable safety profile, particularly with respect to minimizing transient blood pressure reductions seen at higher doses.[26]

Pivotal Phase 3 Program (Validation for At-Home Use)

The Phase 3 program was designed to rigorously test the efficacy and safety of the 70 mg dose in the intended at-home, patient-administered setting. The evolution of this program demonstrates a sophisticated "learn and adapt" strategy based on emerging data.

• NODE-301 (NCT03464019): This was the first major at-home, randomized, double-blind, placebo-controlled study.[32]
• Design: Patients self-administered a single 70 mg dose of Etripamil or placebo upon experiencing a PSVT episode.[27]
• Outcome: The study did not meet its primary endpoint, which was defined as time to conversion over a five-hour period.[5] This outcome was not a reflection of the drug's inactivity but rather a misalignment between the long duration of the endpoint and the drug's known short-acting pharmacology. A pre-specified analysis revealed a clinically meaningful and statistically significant treatment effect within the first 30-45 minutes, providing the crucial data needed to refine the trial design for subsequent studies.[5]
• RAPID (NODE-301 Part 2): Building directly on the insights from NODE-301 Part 1, the RAPID trial was the pivotal efficacy study for the NDA submission.
• Design: This trial incorporated two key modifications: the primary endpoint was changed to the more clinically relevant time to conversion within 30 minutes, and a symptom-prompted, repeat-dose regimen was introduced, allowing patients to take a second 70 mg dose if symptoms persisted 10 minutes after the first.[7]
• Outcome: The RAPID trial was highly successful, meeting its primary endpoint with strong statistical significance. The Kaplan-Meier estimated conversion rate at 30 minutes was 64.3% for the Etripamil group versus 31.2% for the placebo group, corresponding to a Hazard Ratio of 2.62 (p < 0.0001).[7] These results form the cornerstone of the evidence for Etripamil's efficacy.
• NODE-302 (NCT03635996): This was an open-label extension of the NODE-301 study, designed to collect long-term safety and efficacy data from patients treating multiple PSVT episodes over time.[12] The study confirmed the consistency of Etripamil's effect and reinforced its favorable safety profile with repeated, long-term use.[12]
• NODE-303 (NCT04072835): Described as the largest safety study ever conducted in PSVT, NODE-303 was designed to generate robust, real-world safety data to support the drug's use without medical supervision.[10]
• Design: This global, open-label study enrolled a broad patient population and, importantly, did not require a supervised "test dose" prior to at-home use, thus closely mimicking real-world clinical practice. Patients could treat up to four separate PSVT episodes.[9]
• Outcome: The study successfully reaffirmed the drug's safety and efficacy profile. The overall conversion rate was 69.9% by 60 minutes, with a median time-to-conversion of 17.0 minutes, consistent with the findings from the RAPID trial.[9] The safety profile remained consistent, with no new signals identified. Notably, the frequency of local adverse events appeared to decrease with successive episodes, suggesting patient acclimation to the nasal spray.[9] This study was strategically designed to directly address the primary safety concerns a regulator would have about moving a potent cardiovascular therapy into the patient's hands for unsupervised use, and its positive results are critical to the overall regulatory submission.

Table 2: Summary of Major Clinical Trials for Etripamil in PSVT

Study Name (ID)	Phase	Design	Key Endpoints	Summary of Results
NODE-1 (NCT02296190)	2	Randomized, Placebo-Controlled, Dose-Ranging (in EP Lab)	Conversion of induced PSVT within 15 min	Demonstrated dose-dependent efficacy. 70 mg dose converted 87% of episodes vs. 35% for placebo. Established 70 mg as optimal dose.21
NODE-301 Part 1 (NCT03464019)	3	Randomized, Placebo-Controlled (At-Home, Single Dose)	Time to PSVT conversion over 5 hours	Did not meet the 5-hour primary endpoint. Showed significant effect in the first 30-45 minutes, informing future trial design.5
RAPID (NODE-301 Part 2)	3	Randomized, Placebo-Controlled (At-Home, Repeat Dose)	Time to PSVT conversion within 30 min	Met primary endpoint: 64.3% conversion for Etripamil vs. 31.2% for placebo (p < 0.0001). Pivotal efficacy trial for NDA.7
NODE-303 (NCT04072835)	3	Open-Label, "Real-World" Safety Study (At-Home)	Safety and tolerability over multiple episodes	Confirmed safety and efficacy in a large population without a test dose. Conversion rate of 69.9% by 60 min. No serious drug-related AEs.9

V. Safety and Tolerability Profile

Overall Summary

Across a comprehensive clinical program that has included over 1,600 patients, Etripamil has consistently demonstrated a favorable and predictable safety and tolerability profile.[38] This profile is a cornerstone of its potential for use as a self-administered therapy in an unsupervised, outpatient setting. The nature of the adverse events observed is pivotal to its viability; the fact that they are overwhelmingly local and transient is what makes the at-home use model feasible.

Common Adverse Events

The most frequently reported treatment-emergent adverse events (TEAEs) are consistently characterized as being mild-to-moderate in intensity, transient in duration, and localized to the site of intranasal administration.[7] These events are related to the physical administration of the nasal spray and its formulation rather than systemic drug effects.

The most common TEAEs reported across the Phase 3 program include:

• Nasal discomfort or a burning sensation (reported in up to 30% of patients) [5]
• Nasal congestion (up to 14%) [7]
• Rhinorrhea (runny nose) (up to 13%) [7]
• Epistaxis (nosebleed) (up to 7.4%) [9]

Cardiovascular Safety

The cardiovascular safety profile of Etripamil is a critical finding of the clinical program, particularly in the context of at-home use. Despite being a potent calcium channel blocker, the unsupervised administration of the 70 mg dose has not been associated with serious cardiac adverse events.[9]

Specifically, the large-scale NODE-303 safety study, which did not require a supervised test dose, found no instances of drug-related severe hypotension, syncope, or high-degree (third-degree) atrioventricular block.[9] This robust safety profile was maintained even in the substantial proportion of patients (71%) who were on concomitant AV-nodal acting medications like beta-blockers or other calcium channel blockers for chronic management.[9] This suggests a low risk of dangerous additive effects when Etripamil is used acutely on top of standard background therapies.

Contraindications and Excluded Populations

The design of the clinical trials provides a clear indication of the patient populations for whom Etripamil is not intended, and these exclusion criteria are likely to form the basis of contraindications and warnings in the final product labeling. The criteria demonstrate a proactive risk mitigation strategy, defining a target population with AV-nodal dependent tachycardias and structurally normal hearts who are at low risk of complications from AV nodal blockade.

Key exclusion criteria from the Phase 3 trials included:

• Ventricular pre-excitation syndromes (e.g., Wolff-Parkinson-White), where blocking the AV node could lead to dangerously rapid conduction down an accessory pathway.[5]
• Pre-existing second- or third-degree AV block, sick sinus syndrome, or clinically significant bradycardia.[5]
• History of severe symptomatic hypotension or syncope during PSVT episodes, or a baseline systolic blood pressure below 90 mmHg.[5]
• Current New York Heart Association (NYHA) Class II-IV heart failure or major structural heart disease.[5]

While the drug has been studied in a broad population, data in certain subgroups, such as the very elderly, patients with diagnosed heart failure, and those on extensive polypharmacy, are still limited, and these may be areas for post-marketing surveillance.[6]

Potential Drug Interactions

The clinical trial protocols restricted the use of certain potent antiarrhythmic drugs. Chronic therapy with Class I (e.g., flecainide) or Class III (e.g., amiodarone) antiarrhythmics, as well as digoxin, was an exclusion criterion.[5] This suggests caution will be advised regarding concomitant use with these agents. However, as noted, the widespread and safe use of Etripamil alongside background beta-blockers and non-dihydropyridine calcium channel blockers in the NODE-303 trial is a strong indicator of a manageable interaction profile for the most common maintenance therapies used in this patient population.[9]

VI. Dosage, Formulation, and Patient Administration

Product Formulation

Etripamil is formulated as a sterile solution specifically designed for intranasal administration.[5] The drug is delivered via a pre-filled, single-use, unit-dose nasal spray device, such as the Aptar Pharma Bidose System, which is designed for ease of use by patients in a non-clinical setting.[26] Each actuation delivers a precise volume of the drug solution.

Dosing Regimen

The clinical development program has established a clear, evidence-based dosing regimen for the acute treatment of PSVT.

• Therapeutic Dose: The validated dose is 70 mg of Etripamil.[9]
• Administration Protocol: The recommended protocol, which was validated in the pivotal RAPID trial, is a symptom-prompted approach designed for patient self-management [9]:

1. Upon experiencing symptoms characteristic of a PSVT episode, the patient is instructed to first attempt a standard or modified vagal maneuver.[9]
2. If symptoms persist after the vagal maneuver, the patient self-administers a single 70 mg dose of Etripamil nasal spray.[9]
3. A repeat-dose option is available: if symptoms have not resolved after 10 minutes, the patient may self-administer a second 70 mg dose.[9]

Method of Administration

The central innovation of the Etripamil therapeutic concept is its method of administration. The entire program is built around a patient-centric model of self-administration that occurs outside of a medically supervised environment.[4] This approach is intended to empower patients with an active role in managing their condition, provide a greater sense of control over unpredictable episodes, and ultimately reduce the need for costly and burdensome visits to the emergency department or other urgent care settings.[6]

VII. Therapeutic Context and Comparative Analysis

The Unmet Need in PSVT Management

Paroxysmal supraventricular tachycardia is a common cardiac arrhythmia that affects approximately two million people in the United States.[34] While episodes are typically not life-threatening, they are characterized by the abrupt onset of a rapid heartbeat and can be accompanied by debilitating symptoms such as palpitations, chest pain, dizziness, and shortness of breath.[15] These unpredictable episodes significantly impair quality of life, provoke anxiety, and are a major driver of healthcare utilization, particularly visits to the emergency department.[6]

The current treatment landscape reveals a significant therapeutic gap for a treatment that is rapid-acting, highly effective, and can be safely administered by the patient at the onset of symptoms at home.[6] Existing options force a trade-off between convenience and efficacy, leaving many patients without a satisfactory solution for acute management.

Comparative Positioning

Etripamil is positioned to directly address this unmet need by offering a unique combination of rapid onset, high efficacy, and a patient-friendly, non-invasive administration route.

• Versus Vagal Maneuvers: Vagal maneuvers are recommended as the first-line intervention due to their non-invasive nature, but their success rate is often low.[6] Etripamil is designed not to replace vagal maneuvers but to serve as the immediate, more effective next step when they fail, providing a reliable option before resorting to medical care.[9]
• Versus Oral "Pill-in-the-Pocket" Therapy: The use of oral antiarrhythmics (such as beta-blockers or calcium channel blockers) on an as-needed basis is limited by a slow onset of action, often taking 30 minutes or longer to achieve therapeutic effect due to gastrointestinal absorption and metabolism.[6] Etripamil's intranasal delivery bypasses these delays, with a Tmax of approximately 7 minutes, offering much faster symptom relief.[4]
• Versus Intravenous (IV) Hospital Treatment: IV administration of drugs like adenosine, verapamil, or diltiazem is highly effective for terminating PSVT but necessitates a visit to a hospital or clinic, the establishment of IV access, and continuous medical monitoring.[15] Etripamil's primary value proposition is to obviate the need for this entire cascade of events for a majority of episodes, allowing patients to terminate their arrhythmia at home and avoid the associated time, cost, and distress of an emergency department visit.[8]
• Versus Catheter Ablation: Catheter ablation is a curative, first-line therapy for many patients with recurrent PSVT. However, it is an invasive procedure that carries procedural risks and is not desired by or suitable for all patients.[6] Etripamil offers a highly effective, non-invasive, long-term management strategy for this population, as well as for patients who are on a waiting list for an ablation procedure or experience recurrences post-ablation.[6]

Table 3: Comparative Profile of Etripamil vs. Current PSVT Treatments

Treatment Modality	Onset of Action	Typical Efficacy	Setting of Use	Invasiveness/Convenience	Primary Limitation
Etripamil Nasal Spray	~7-17 minutes	High (~64-70% conversion)	At-home, unsupervised	Non-invasive, convenient	Local nasal irritation; not curative
Vagal Maneuvers	Seconds to minutes	Low to moderate	At-home, unsupervised	Non-invasive, convenient	Often ineffective
Oral "Pill-in-the-Pocket"	>30 minutes	Moderate	At-home, unsupervised	Non-invasive, convenient	Slow onset of action
IV Hospital Therapy	Seconds to minutes	Very High	Hospital / Clinic	Invasive (IV access), inconvenient	Requires medical supervision and facility visit
Catheter Ablation	N/A (Procedure)	Very High (Curative)	Hospital (EP Lab)	Highly invasive, inconvenient	Procedural risks; not desired by all patients

VIII. Regulatory and Commercial Outlook

Developer and Commercialization

Etripamil was conceived, discovered, and developed by Milestone Pharmaceuticals Inc., a clinical-stage biopharmaceutical company with headquarters in Montreal, Canada, and Charlotte, North Carolina, USA.[3] The company is focused on developing and commercializing innovative cardiovascular medicines, with Etripamil as its lead pipeline candidate.[3] Milestone has established a robust intellectual property portfolio for the drug, including a new Method of Use patent granted in the United States that covers the repeat-dose regimen and extends potential patent protection until 2042.[44]

Regulatory Journey with the US FDA

Etripamil's path to potential approval in the United States has been detailed and reflects evolving regulatory standards.

• Initial Submission and Refusal to File: Milestone initially submitted a New Drug Application (NDA) to the FDA on October 24, 2023.[15] On December 26, 2023, the company received a Refusal to File (RTF) letter, indicating the FDA found the application was not sufficiently complete to permit a substantive review.[15]
• Resubmission and Complete Response Letter: Following a Type A meeting with the agency, Milestone resubmitted the NDA with restructured data sets on March 28, 2024.[15] On March 28, 2025, the FDA issued a Complete Response Letter (CRL).[7] This CRL did not raise any concerns regarding the clinical safety or efficacy data from the extensive Phase 3 program. Instead, the agency's feedback was focused on two key Chemistry, Manufacturing, and Controls (CMC) issues:

1. A request for additional information on potential nitrosamine impurities. This request was based on new draft guidance that had been issued by the FDA after the original NDA submission, highlighting a broader industry trend of increased regulatory scrutiny in this area.[7]
2. A requirement for a pre-approval inspection of a facility responsible for release testing of the drug product.[7]

• Response to CRL and New PDUFA Date: Milestone held a productive Type A meeting with the FDA in early June 2025 to clarify the outstanding items.[17] The company submitted its comprehensive response to the CRL on June 13, 2025. In July 2025, the FDA accepted this response for review and assigned a new PDUFA target action date of December 13, 2025.[15]

Global Regulatory Status

The primary regulatory focus for Etripamil has been the United States. As of the latest available information, Etripamil does not have marketing authorization in other major jurisdictions, including the European Union, the United Kingdom, Canada, or Australia.[10] However, Milestone has a partnership with Ji Xing Pharmaceuticals, which holds exclusive rights to develop and commercialize the drug in Greater China and has reported positive results from its own Phase 3 study.[47]

Future Directions and Market Potential

If approved, Etripamil would be the first and only fast-acting, patient-administered therapy for the acute treatment of PSVT episodes, positioning it to create a new standard of care for at-home management.[10]

Beyond PSVT, Milestone is strategically pursuing a second indication for Etripamil: the temporary control of rapid ventricular rate (RVR) in patients with Atrial Fibrillation (AFib-RVR).[3] This is a logical expansion of the drug's use, as the underlying goal of rate control in AFib also relies on slowing conduction through the AV node—the same mechanism of action used in PSVT. The company has completed a Phase 2 proof-of-concept trial (ReVeRA) and is planning a Phase 3 study.[35] As the patient population with AFib is substantially larger than that with PSVT, success in this second indication would represent a significant expansion of Etripamil's commercial potential, transforming it from a specialized arrhythmia drug into a broader cardiovascular therapy.

IX. Conclusion

Etripamil (CARDAMYST™) represents a significant and targeted innovation in the management of paroxysmal supraventricular tachycardia. As a novel, intranasally delivered, short-acting L-type calcium channel blocker, its development has been guided by a clear clinical need for a rapid, effective, and safe treatment that can be self-administered by patients outside of a medical facility.

The comprehensive clinical development program, culminating in the successful pivotal RAPID trial and the large-scale NODE-303 safety study, has produced compelling evidence of its ability to rapidly convert PSVT to sinus rhythm, with a median time to conversion under 20 minutes. The drug's safety profile is a key enabler of its therapeutic proposition, characterized by predominantly mild, transient, and local adverse events, and a notable absence of serious systemic cardiovascular events in the unsupervised setting.

The drug's pharmacokinetic and pharmacodynamic properties are deliberately engineered for its intended on-demand use, featuring rapid absorption, a fast onset of action, and a short duration of effect driven by metabolism via serum esterases to an inactive metabolite. This profile distinguishes it from all current PSVT management strategies, positioning it as a superior alternative to slow-acting oral therapies and a convenient, cost-effective option to prevent emergency department visits required for intravenous treatments.

While its regulatory journey in the U.S. has been delayed by Chemistry, Manufacturing, and Controls issues—reflecting a broader trend of heightened regulatory scrutiny—the absence of clinical safety or efficacy concerns in the FDA's feedback is a positive indicator. With a new PDUFA date set for December 13, 2025, Etripamil is poised for a potential approval that could fundamentally alter the treatment paradigm for millions of patients living with the unpredictable and burdensome nature of PSVT. Furthermore, its potential expansion into the larger market of Atrial Fibrillation with Rapid Ventricular Rate underscores its strategic importance and long-term potential as a valuable cardiovascular therapeutic.

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