Etripamil AFib-RVR Bet: Platform Credibility Meets Unproven Indication in Small Pivotal Trial

Milestone Enrolls First Canadian Patient in AFib-RVR Phase 3 Trial

Milestone Pharmaceuticals Inc. announced the enrollment of the first Canadian patient in its ReVeRA-301 Phase 3 pivotal trial. This multinational study is evaluating etripamil nasal spray for the treatment of atrial fibrillation with rapid ventricular rate (AFib-RVR) and aims to enroll approximately 150 patients. The trial uses the same 70 mg repeat-dose regimen of etripamil that is FDA-approved for paroxysmal supraventricular tachycardia (PSVT) as CARDAMYST®. The Montreal Heart Institute is the first Canadian clinical trial site, marking a significant step in advancing global enrollment efforts for this self-administered therapy.

• The ReVeRA-301 trial is designed as a Phase 3 multinational, multi-center, randomized, double-blind, placebo-controlled study. It aims to evaluate the effects of etripamil nasal spray in approximately 150 patient events with AFib-RVR. Patients will self-administer the 70 mg dose in a medically unsupervised setting, with the primary endpoint being the reduction in ventricular rate within 30 minutes, and a key secondary endpoint of symptom improvement via patient-reported outcomes.
• Milestone Pharmaceuticals is pursuing a single-study supplemental new drug application (sNDA) registration pathway for the treatment of AFib-RVR, based on safety data demonstrated to date. This pivotal trial builds upon promising Phase 2 data from ReVeRA-201, which showed that a single 70 mg dose of etripamil nasal spray effectively reduced ventricular rate and improved both symptom relief and treatment satisfaction in an emergency room setting.
• Atrial fibrillation with rapid ventricular rate (AFib-RVR) is a common and serious condition affecting millions, with 30-40% of AFib patients experiencing RVR episodes annually that often require urgent medical attention. Current acute management options are limited, typically involving emergency department visits for intravenous beta blockers, calcium channel blockers, or electrical cardioversion, underscoring the significant unmet need for a prompt, self-administered therapy outside of a clinical setting.

The Challenges of Managing Acute AFib-RVR Episodes

Managing acute AFib-RVR presents clinicians with a complex set of pharmacological trade-offs, where no single agent offers an optimal combination of efficacy, speed of action, and safety across all patient populations. The heterogeneity of underlying comorbidities — particularly heart failure, thyrotoxicosis, and ventricular pre-excitation syndromes — significantly constrains agent selection and demands individualized risk assessment before initiating rate control.

• Beta-1 selectivity determines efficacy and safety of intravenous beta-blockers. Across all intravenous beta-blockers, there was no overall difference versus other medications for acute heart rate control in AF and atrial flutter. However, conventional selective beta-1 blockers were inferior for target heart rate reduction versus control (RR 0.33, 95% CI 0.17–0.64; p < 0.001), whereas super-selective beta-1 blockers were superior (RR 1.98, 95% CI 1.54–2.54; p < 0.001). Non-selective beta-blockers carried a significantly greater incidence of hypotension (p = 0.031) and bradycardia (p < 0.001).

• Diltiazem achieves faster early rate reduction but at the cost of higher hypotension rates. In an emergency department cohort, diltiazem produced a significantly greater heart rate decrease at 0.5 hours compared to metoprolol (29.3 ± 23.1 bpm vs. 21.8 ± 18.9 bpm; p = 0.012), yet more patients in the diltiazem group experienced hypotension (39.3% vs. 23.5%; p = 0.002), driven primarily by diastolic hypotension events (37.7% vs. 22.3%; p = 0.002). Rate control at two hours was similar between groups (45.8% vs. 42.6%; p = 0.590).

• Heart failure with systolic dysfunction severely limits agent selection. Non-dihydropyridine calcium channel blockers are often contraindicated when AF is associated with HF with systolic dysfunction. The benefit of beta-blockers on survival may be lower in patients with HF with reduced ejection fraction when AF is present. Digoxin does not improve survival but may help obtain satisfactory rate control in combination with a beta-blocker, and may be useful in the presence of hypotension or an absolute contraindication to beta-blocker treatment.

• Thyrotoxicosis-associated AFib-RVR carries risk of rapid decompensation with beta-blockers. The administration of a non-cardioselective beta-blocker in decompensated heart failure has been implicated in the development of severe decompensation and even cardiogenic shock, underscoring the importance of assessing cardiac function — preferably by echocardiography — before initiating beta-blocker therapy in this setting.

• Wolff-Parkinson-White syndrome renders standard AV nodal blockade potentially lethal. In patients with pre-excited AF, blocking the AV node may increase the ventricular rate and potentially result in hemodynamic instability. Administration of AV nodal blockers in unrecognized WPW has been documented to precipitate ventricular fibrillation, making prompt and accurate arrhythmia diagnosis a critical prerequisite to pharmacological rate control.

• Thromboembolic risk management adds a parallel layer of complexity. Post-cardioversion thromboembolic complications are high in certain subgroups when no anticoagulation is used; age, female sex, heart failure (OR: 2.9; 95% CI: 1.1–7.2), and diabetes (OR: 2.3; 95% CI: 1.1–4.9) are independent predictors of definite embolic events. Additionally, periprocedural anticoagulation intensity is associated with thromboembolic risk, with patients at INR 2.0–2.4 experiencing more events than those at INR ≥ 2.5 (0.9% vs. 0.1%; p = 0.03).

ReVeRA-301: Key Design and Endpoints for AFib-RVR

The retrospective cohort study by Fromm et al. examined intravenous pharmacotherapy for AF with rapid ventricular response (RVR) in a clinically challenging population — patients with heart failure with reduced ejection fraction (HFrEF) — comparing metoprolol and diltiazem on rate control efficacy and safety outcomes.

Etripamil's Expanding Role Beyond PSVT

Etripamil is being investigated for the acute termination of paroxysmal supraventricular tachycardia (PSVT), specifically atrioventricular nodal-dependent PSVT, across multiple clinical development stages. The phase 2 NODE-1 study evaluated etripamil nasal spray during electrophysiologically induced SVT, demonstrating conversion rates of 65% to 95% across the three highest active dose groups versus 35% in the placebo group, with a median time to conversion of less than 3 minutes in patients who converted. This established the dose-selection rationale for subsequent self-administration studies in real-world settings.

The phase 3 programme has advanced through several distinct trial designs. NODE-301 was a multicenter, double-blind, placebo-controlled study in which patients were randomised 2:1 to etripamil 70 mg or placebo, self-administering treatment in an unsupervised setting following a medically supervised test dose. Although the primary 5-hour efficacy endpoint was not met (hazard ratio 1.086; 95% CI, 0.726–1.623; P=0.12), predefined sensitivity analyses demonstrated a statistically significant etripamil treatment effect at 3, 5, 10, 20, and 30 minutes (P<0.05), with 53.7% SVT conversion in the treatment arm versus 34.7% in the placebo arm at 30 minutes. The RAPID trial, also a phase 3 multicenter, randomised, double-blind, placebo-controlled study, employed a repeat-dosing regimen — an initial 70 mg dose with an optional second dose after 10 minutes — and randomised patients 1:1 following a mandatory observed test dose. RAPID met its primary endpoint, with 64.3% of etripamil-treated subjects achieving conversion within 30 minutes versus 31.2% of placebo-treated subjects, and a median time to conversion of 17.2 minutes versus 53.5 minutes.

The open-label NODE-302 extension study further characterised long-term safety and efficacy across repeated self-treated PSVT episodes, reporting a 60.2% probability of conversion within 30 minutes (median time to conversion, 15.5 minutes) across 188 positively adjudicated episodes. Building on this, the ongoing NODE-303 study is a real-world safety evaluation of symptom-prompted, self-administered etripamil 70 mg — with an optional repeat dose if symptoms persist beyond 10 minutes — for up to four PSVT episodes per patient, and notably eliminates the mandatory test-dose requirement prior to first use. Secondary endpoints in NODE-303 include efficacy and disease burden, with patient-reported outcomes captured across multiple validated instruments.

Etripamil's Bid to Reshape Acute AFib-RVR Management

The initiation of the ReVeRA-301 Phase 3 trial for etripamil nasal spray in atrial fibrillation with rapid ventricular rate (AFib-RVR) signals a pivotal moment for Milestone Pharmaceuticals and the broader cardiology landscape. Etripamil, already approved as CARDAMYST® for paroxysmal supraventricular tachycardia (PSVT), has demonstrated the power of a rapid-acting, self-administered, non-parenteral therapy in acute arrhythmia management. Its expansion into AFib-RVR aims to address a significant unmet need: the lack of an accessible, patient-controlled option for acute ventricular rate control outside of a clinical setting.

Early insights from a post-hoc analysis of the NODE-303 study are encouraging, indicating that etripamil can achieve a clinically significant and sustained reduction in ventricular rate for patients experiencing AF. This suggests a potential paradigm shift, empowering patients to manage symptomatic AFib-RVR episodes at home, thereby potentially reducing the reliance on emergency department visits and hospitalizations. Such a development would not only enhance patient autonomy and quality of life but also offer a substantial competitive advantage in the arrhythmia market, establishing a novel therapeutic class.

However, the path forward is not without its considerations. The promising data from the NODE-303 post-hoc analysis, while compelling, was derived from a small subgroup of patients. The ReVeRA-301 trial must now rigorously confirm these efficacy findings in a larger, dedicated AFib-RVR population. Furthermore, while etripamil has a well-established safety profile for PSVT, its tolerability and the absence of serious cardiac adverse events, such as bradyarrhythmias or AV block, must be meticulously validated in the AFib-RVR cohort, which may present with different comorbidities. Regulatory bodies will undoubtedly scrutinize these data closely, given the new indication and potentially higher-risk patient demographic. If these hurdles are successfully navigated, etripamil could redefine acute AFib-RVR management, offering a transformative solution for millions of patients worldwide.